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Medicine
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Medicine
SIXTH
EDITION
VOLUME
2
SECTIONS 10-15

Firth SIXTH EDITION edited by

Conlon VOLUME 2 John D. Firth
Cox Christopher P. Conlon
ISBN 978-0-19-885345-9 Timothy M. Cox
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Medicine
Oxford Textbook of

Medicine
SIXTH EDITION
Volume 2: Sections 10–15

EDITED BY

John D. Firth

Christopher P. Conlon

Timothy M. Cox

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Foreword
Professor Sir John Bell, Regius Professor of Medicine, University of Oxford

In 1983, David Weatherall, John Ledingham, and David Warrell nomenclature of disease, all crucial roles for a textbook of medicine.
launched the first edition of the Oxford Textbook of Medicine. That We now are aware that many of the classic definitions of diseases
era of medicine looked entirely different from today but the need for such as diabetes or cancer were descriptions of phenotypic charac-
a scholarly repository of medical knowledge remains as important as teristics. Interrogation of these disorders at a molecular level has
ever. Medicine is now firmly in a digital age; sources of information demonstrated that these terms mask disease subtypes defined by
abound and are readily available and the field is moving so quickly molecular pathology where natural history and response to therapy
that it is harder than ever to provide up to date relevant informa- may differ. Combine this with the explosion of new diseases coming
tion for the profession. Despite this, the sixth edition of the Oxford from studies of rare disease and there is a challenge to conventional
Textbook of Medicine still provides the foundation of knowledge disease nomenclature. This molecular precision creates real oppor-
upon which good clinical practice is based. tunities for targeted highly effective therapies, but it also creates
Never before has there been such a rapid advance of medical know- challenges for the model of drug discovery when novel treatments
ledge and practice. Since the first edition of the Oxford Textbook of can only be used in increasingly small patient populations. These are
Medicine, medical practice has reduced cardiovascular mortality by major issues for medicine, health systems, but also textbooks such as
up to 70% in Western countries, there are now multiple new ther- this one where, historically, the stewardship of disease nomenclature
apies for diseases such as rheumatoid arthritis and multiple scler- has been maintained.
osis, disorders where the descriptions of therapeutic options in the The therapeutic options available to practising clinicians have also
first edition were necessarily brief. Cancer is now increasingly man- advanced beyond all recognition since the first edition of the Oxford
aged with immune and targeted therapies. Whole new diseases have Textbook of Medicine. We have seen an era of biologic therapy which
appeared (Hepatitis C and HIV) and have been either controlled or has provided important new therapeutic alternatives for many hard-​
conquered with drug therapy. The sequencing of the human genome to-​treat diseases including cancer. We are now entering a new era
seemed an impossible dream in 1983 while today we have sequenced where modalities such as gene therapy and interfering RNA thera-
more than a million genomes and have had insights into rare disease peutics have demonstrated their utility in the clinic. Similarly, an
and cancer that were unimaginable then. Life expectancy has risen era of cell therapy has also begun which will provide important
by nine years for men and ten for women in the United Kingdom, new alternatives to some diseases. These new therapeutic alterna-
creating a demographic shift that will fundamentally change society tives and other opportunities for improving healthcare using med-
and medicine forever. The pace of change has been dramatic. ical technology or novel diagnostics such as sequencing also bring
The Oxford Textbook of Medicine gained a reputation by moving with them the challenge of how healthcare systems can continue to
medical practice forward from the Oslerian view of medicine ori- be affordable, either for individuals in private healthcare settings, or
ginally expounded in his text book the Principles and Practice of in state-​funded, single-​payer systems. In this context, it is remark-
Medicine into an era of more molecular and scientifically based able that the authors and editors of the Oxford Textbook of Medicine
understanding of disease. Constrained by the lack of tools for ex- have managed to sustain both its relevance and the accuracy of its
ploring the molecular basis of pathogenesis, Osler was limited in content.
how he could describe the world of disease, largely based on bed- The pace at which our understanding of disease, our therapeutic
side observations or those from the post-​mortem room. The Oxford options, and our healthcare systems are likely to change makes it
Textbook of Medicine shifted this focus and aligned it with the nearly impossible for a textbook of medicine to be truly comprehen-
emerging field of molecular medicine which has begun to create a sive given the speed of change, the impact of new innovations and
new taxonomy of disease but also an approach to therapy which is the multiple additional sources of information available to practi-
based on pathogenesis. There has been a wave of new information, tioners. The Oxford Textbook of Medicine has provided remarkable
with new insights appearing weekly into the underlying molecular levels of detail in this rapidly changing world but, more importantly,
events associated with disease. Diseases characterized by phenotype the textbook continues to provide a source for readers to access
are now broken down into multiple subtypes and disease is being information on the fundamental features of disease. This founda-
individualized. This is rapidly leading to a very significant change tional knowledge remains crucial to our ability to understand, diag-
in our perception of pathogenesis as well as the classification and nose, and treat patients whether they are in the developing world or
vi Foreword

Western healthcare systems. Having a source of such information understanding of disease and has enabled progress in clinical medi-
across all major diseases accessible in a single source remains the cine to occur at a remarkable pace. By providing a textbook that
bedrock of both teaching and practising medicine. The foundations describes the foundations of our understanding of disease and its
provided by the Oxford Textbook of Medicine form a core of know- management, the editors have successfully given us an authoritative
ledge which practising clinicians will continue to need. text which practising clinicians will find invaluable to support their
The editors of this edition have been faithful to the vision of the day-​to-​day decisions. David Weatherall, one of the three original
original three editors. Science, in all its forms, is at the heart of our editors and who died in 2018, would be gratified by this new edition.
Preface

Changes in medicine responsibility, it is rare for doctors be able to stand back and perceive
genuine improvements. However, it is certainly true that today we
The Oxford Textbook of Medicine is published online and has been have greater potential to prevent and treat disease and to maintain
regularly updated for many years, but the production of a new and health than ever before. It is our hope that the Oxford Textbook of
very substantially updated edition provides a moment when it is nat- Medicine will inform doctors about these changes and provide good
ural and proper to reflect on what has changed in medicine—​and guidance as to how they can be translated into clinical practice.
what has not—​in recent years. In the context of burgeoning social
changes and inequality across the world, we have cause to weigh and Advances in biomedical sciences
consider exactly what modern medicine has to offer patients and We seek to embody advances in understanding and practice that
their doctors. Here we reflect on aspects of Medicine that are chan- have arisen through scientific research. In the ten years since
ging rapidly and set out a vision for this in the sixth edition of the publication of the last edition of this book there has been spec-
Oxford Textbook of Medicine. tacular progress in the application of science in medicine, espe-
cially the understanding of genomics and molecular cell biology.
Demand, capacity, magic solutions, and These include: in diagnostics, non-​invasive prenatal diagnosis of
the need for perspective chromosome abnormalities and monogenic disease by sampling
Within all healthcare systems, in rich and poor nations alike, maternal plasma for cell-​free fetal DNA, a technique which also
most physicians feel the inexorable rise in demand and are strug- holds promise for screening and monitoring of cancers; in meta-
gling to provide adequate ‘capacity’—​the term commonly applied bolic disease, the introduction of molecular therapies that address
by healthcare managers charged with the impossible task of con- the defective chloride transport in cystic fibrosis; in oncology, in-
straining expenditure while serving political masters who, almost creased understanding of cancer immunity leading to the develop-
without exception, promise more and more and blame inefficiency ment of immunotherapies for cancers.
and ‘unwarranted variation’ for the failure to deliver. In response Our authors include the very best in their fields. The founding
to the difficulties, claims are made that some new technological editor and author in this edition, the late David Weatherall, was
advance, be it sequencing of patients’ genomes, healthcare apps, a recipient of the Lasker-​Koshland Special Achievement Award
the application of artificial intelligence or ‘Quality Improvement’ in Medical Science. Two new authors have received the Nobel
methodology, will provide the solutions. In the Oxford Textbook of Prize recently—​Professor Tu Youyou the 2015 prize for Medicine
Medicine, we do not shy away from these aspects and have several or Physiology, and Sir Greg Winter the 2018 prize for Chemistry.
new chapters that consider how rich and ‘resource-​poor’ countries Another new author, Professor Y.M. Dennis Lo, was one of two
might best invest their revenues on health. winners of China’s inaugural Future Science Prize in 2016.
It is often very hard for practising physicians, who care for patients Beyond scientific development, the introduction of new technolo-
as individuals, to maintain their bearings within the unfamiliar and gies into practice typically leads to a sequence of events including
depersonalized world of modern healthcare management. Many are initial ‘hype’ from many in the field, with extravagant claims of po-
left wondering whether those who organize health services ‘live on tential benefit. After an interval, these claims are followed by a more
this planet’, or ‘did any working doctor check out that latest directive realistic assessment of what the technology can—​and cannot—​
from above?’. When clinical outcomes that really matter are diffi- provide. Frequently, this familiar pattern is driven by powerful com-
cult to quantify, doctors find themselves and their services judged by mercial influences which can corrupt thinking in a manner that
spurious measures of ‘productivity’ in the process of healthcare ‘de- generates a climate in which those with views contrary to the big
livery’. Unrealistic and often clinically irrelevant targets might drive battalions are inevitably marginalized. In this edition of the Oxford
the thinking of the insurers, managers, and politicians, but who Textbook of Medicine we have strived to bring an authentic perspec-
can determine the human and clinical value of the care provided? tive and realism to recommendations for treatment. We sense, for in-
Timeliness of care is important and sometimes crucial for salutary stance, that the excitement generated by the sequencing of patients’
outcomes, but disaster strikes when clock-​driven targets are blindly genomes continues to increase, but that this trajectory is flattening
pursued for all patients irrespective of clinical urgency and to the ex- and expectations becoming more realistic. For patients very likely
clusion of all else, including patients with greater clinical need. to have genetic disorders, diagnoses can be made for a proportion
In the morass created by financial constraints and zealous pol- that was unimaginable until recently, but for most patients with the
itical control of health services exercised by those without clinical degenerative and/​or polygenic diseases that are the greatest burden
viii Preface

to health, evidence of clinical benefit from genome sequencing re- One hundred and fifty years ago, Darwin’s 1859 masterpiece on
mains elusive. evolution was entitled ‘On the Origin of Species by Means of Natural
Beyond the progress in genomics and cell biology there has been Selection, or the Preservation of Favoured Races in the Struggle for
immense interest in bioinformatics and, especially with the enthu- Life’. The ‘less favoured’ undoubtedly have poorer health outcomes,
siasm of major biomedical charities such as The Wellcome Trust, due largely to the persistent social ill of inequality, in poor as well as
for ‘big data’, and the opportunities that these bring to the practice ostensibly rich countries. Continuing the tradition of previous edi-
of medicine. However, while there are plentiful examples of gen- tions, we have contributions that discuss the impact of social deter-
omics and cell biology having been translated productively from the minants of health, also thoughtful chapters on human disasters (by
bench to the bedside, with enormous benefit to patients, examples another Nobel laureate, Prof Amartya Sen), and the practical and
of transforming clinical impact from big data and bioinformatics critically important aspects of humanitarian medicine. In addition,
are sparse. But examples there are, such as in the analysis of out- the modern problems of pollution and climate change are exam-
breaks of the scourges Clostridium difficile and methicillin-​resistant ined. We contend that all doctors would benefit from reading these
Staphylococcus aureus (MRSA). These discoveries give hope for the chapters.
future as we learn which problems are tractable with this type of
approach and which are not. Patients and their expectations
Clinical skill There are continuing changes in patients’ expectations, particularly
Until recently, it would have been, to paraphrase Thomas Jefferson, those of articulate patients suffering from long-​term conditions and
regarded as self-​evident that the key requirements of a good phys- residing in countries with a rich provision of healthcare. A paternal-
ician are the ability and will to obtain an informative history, carry istic medical approach is no longer acceptable, and several patients
out a thorough physical examination, formulate a relevant differ- have contributed greatly to the book by taking the opportunity to tell
ential diagnosis, instigate appropriate investigations, advise and us how they think doctors should behave towards them and care for
administer correct treatment, including best efforts to relieve symp- them. However, we are very aware that one size does not fit all, and
toms in all cases. These skills, and the commitment to use them, that many patients want a doctor who will give them clear recom-
are often forgotten when healthcare is described in the commercial mendations and not keep repeating a bewildering (to the patient)
terms of demand and capacity. variety of options and ask them to choose. The mature and able
While advances in biomedical sciences have dramatically im- physician will be alert and sensitive to those patients who want this
proved the outcome for some diseases, and Paul Erhlich’s century-​ and will provide them with clear advice, and we have endeavoured to
old magische Kugel (magic bullet) has whetted our appetite for ensure that the Oxford Textbook of Medicine will assist.
wonder, it is prudent to recall Thomas Szasz: ‘Formerly, when reli-
gion was strong and science weak, men mistook magic for medicine; Access to medical knowledge
now, when science is strong and religion weak, men mistake medi-
The ever-​expanding world of the smartphone and tablet device gives
cine for magic’. The term ‘personalized’ medicine imputes remark-
patients, families, doctors, and other healthcare professionals ready
able and as yet unproven powers, excepting in a very few cases, to
access to more information about medicine than all but a very few
gene sequencing and molecular therapies, while the patient wants
would have thought possible a decade ago. This has many benefits
to be treated as a person. It is also alarming to us that some medical
but often leaves users of the internet thoroughly perplexed, and some
curricula increasingly focus on process, ‘behaviours’, and ‘communi-
desperate people vulnerable to online quackery. Those wanting de-
cation skills’, to the detriment of medical content or mature guidance
tails of particular studies will naturally refer to the original literature.
and attitudes to lifelong learning. There is a tendency to forget the
Those wanting in-​depth reviews of particular subjects can refer to
very essence of being, and how to become, a physician in the time-​
diverse resources: these are typically good at apprising the reader of
honoured understanding of the role.
plentiful options for investigation, diagnosis, or management, but
In the Oxford Textbook of Medicine we unashamedly emphasize
often leave them uncertain of what a clinically experienced expert
the primacy of history, examination, differential diagnosis, investi-
in the field would actually recommend. In the sections that form the
gation, and treatment. Without a firm grasp of these essentials the
bulk of the Oxford Textbook of Medicine, we have selected experts
doctor cannot provide good care for patients, and nor can anyone
with specific clinical experience and given them this task, and we
else. Furthermore, having a firm understanding of clinical context
contend that they have met the challenge.
and a well-​informed clinical perspective is an essential prerequisite
for driving biomedical research into avenues that really matter.
Acknowledgements
The broader context of health and disease
The Oxford Textbook of Medicine is a large undertaking: this edition,
The world has become a smaller place. We are now in an era when the most substantial so far, comprises 647 chapters and covers 6654
many regard not having a smartphone as an index of deprivation. printed pages, and its production has required an extraordinary co-
An event that has happened on a different continent can, as a re- ordination of effort from many quarters. In darker moments the edi-
sult of social media, become known to millions of people within tors feared that the process would never end, but as we have read
hours—​the term ‘viral’ has been rightfully translated from commu- and edited the chapters along the way, we have experienced the joy
nicable illness to global phenomenon. Narratives transmitted in this of learning a huge amount of medicine, often in fields far removed
way often concern disasters, wars, and disease, and they are typically from our own. For this we are very grateful to our contributors,
handled by the media in a sensationalized and superficial manner. including those whose submissions were delayed!
 Preface ix

We wish to make particular acknowledgement of our friend and publishing process that at times seemed to be Byzantine in its com-
senior colleague, David Warrell, an editor from the first edition of plexity, as might perhaps be expected in an ancient university. We
this textbook, senior editor of the fourth and fifth editions, and au- also thank Anna Kirton, Jamie Oates, and Jess White at Oxford
thor in this edition. We and our readers, notably those seeking in- University Press for their considerable efforts on behalf of the book.
formation on tropical diseases and especially any who have been Finally, we record that the editors’ personal lives have remained
bitten by snakes, about which his knowledge is truly prodigious, calm, and we are very grateful to Helen, Jenny, and Sue for their in-
owe him a great debt. dulgence of our bizarre editorial pursuit.
We thank Helen Liepman, with whom we remain good friends: she
John D. Firth
has overseen and directed matters at Oxford University Press and
Christopher P. Conlon
coped in a steadfastly pleasant and professional way with expres-
Timothy M. Cox
sions of editorial frustration caused by our failure to understand a
Section editors

Jon G. Ayres Emeritus Professor of Environmental Chris Hatton Cancer and Haematology Centre, Churchill
and Respiratory Medicine, University of Birmingham, Hospital, Oxford, UK
Birmingham, UK Section 22: Haematological disorders
Section 10: Environmental medicine, occupational medicine, and
Deborah Hay Honorary Consultant Haematologist, Nuffield
poisoning
Department of Medicine, University of Oxford, Oxford, UK
Christopher P. Conlon Professor of Infectious Diseases, Nuffield Section 22: Haematological disorders
Department of Medicine, University of Oxford, Oxford, UK Roderick J. Hay King’s College London, London, UK
Section 1: Patients and their treatment; Section 2: Background Section 23: Disorders of the skin
to medicine; Section 3: Cell biology; Section 4: Immunological
mechanisms; Section 5: Principles of clinical oncology; Section Christopher Kennard Nuffield Department of Clinical
8: Infectious diseases; Section 25: Disorders of the eye; Section Neurosciences, University of Oxford, Oxford, UK
29: Biochemistry in medicine Section 24: Neurological disorders

Cyrus Cooper MRC Lifecourse Epidemiology Unit, University Finbarr C. Martin Population Health Sciences, King’s College
of Southampton, Southampton, UK; NIHR Oxford Biomedical London, London, UK
Research Centre, University of Oxford, Oxford, UK Section 6: Old age medicine
Section 20: Disorders of the skeleton Catherine Nelson-Piercy Obstetric Medicine, Women’s
Timothy M. Cox Professor of Medicine Emeritus, Director Health Academic Centre, King’s Health Partners, King’s College
of Research, University of Cambridge; Honorary Consultant London, London, UK
Physician, Addenbrooke’s Hospital, Cambridge, UK Section 14: Medical disorders in pregnancy
Section 1: Patients and their treatment; Section 2: Background Jack Satsangi Oxford Translational Gastroenterology Unit, Nuffield
to medicine; Section 3: Cell biology; Section 4: Immunological Department of Medicine, University of Oxford, Oxford, UK
mechanisms; Section 5: Principles of clinical oncology; Section Section 15: Gastroenterological disorders
12: Metabolic disorders
Pallav L. Shah Imperial College London, London, UK
Jeremy Dwight Previously John Radcliffe Hospital, Oxford, UK Section 18: Respiratory disorders
Section 16: Cardiovascular disorders
Michael Sharpe Psychological Medicine Research, University of
Simon Finfer Malcolm Fisher Department of Intensive Care Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK
Medicine, Royal North Shore Hospital, and The George Section 26: Psychiatric and drug-related disorders
Institute for Global Health, University of New South Wales,
Jackie Sherrard Wycombe General Hospital, High Wycombe,
Sydney, Australia
Section 17: Critical care medicine Bucks, UK
Section 9: Sexually transmitted diseases
John D. Firth Consultant Physician and Nephrologist,
Richard A. Watts Department of Rheumatology, Ipswich
Cambridge University Hospitals, Cambridge, UK
Section 1: Patients and their treatment; Section 2: Background Hospital, Ipswich, UK; Norwich Medical School, University of
to medicine; Section 3: Cell biology; Section 4: Immunological East Anglia, Norwich, UK
mechanisms; Section 5: Principles of clinical oncology; Section Section 19: Rheumatological disorders
21: Disorders of the kidney and urinary tract; Section 27: Forensic Bee Wee Associate Professor of Palliative Care, University of
medicine; Section 28: Sport and exercise medicine; Section Oxford, Oxford, UK
30: Acute medicine Section 7: Pain and palliative care
Mark Gurnell University of Cambridge Medical School, Katherine Younger School of Biological and Health Sciences,
Cambridge, UK Technological University Dublin, Ireland
Section 13: Endocrine disorders Section 11: Nutrition
Contents

Volume 1

List of abbreviations xxxv 2.2 Evolution: Medicine’s most basic science 39

List of contributors xlv Randolph M. Nesse and Richard Dawkins

2.3 The Global Burden of Disease: Measuring the

health of populations 43
SECTION 1 Theo Vos, Alan Lopez, and Christopher Murray

Patients and their treatment 2.4 Large-​scale randomized evidence: Trials and
Section editors: John D. Firth, Christopher P. Conlon, meta-​analyses of trials 51
and Timothy M. Cox Colin Baigent, Richard Peto, Richard Gray, Natalie Staplin,
Sarah Parish, and Rory Collins
1.1 On being a patient 3
Christopher Booth† 2.5 Bioinformatics 67
Afzal Chaudhry
1.2 A young person’s experience of chronic
disease 6 2.6 Principles of clinical pharmacology and drug
therapy 71
1.3 What patients wish you understood 8 Kevin O’Shaughnessy
Rosamund Snow†
2.7 Biological therapies for immune, inflammatory,
1.4 Why do patients attend and what do they want and allergic diseases 100
from the consultation? 14 John D. Isaacs and Nishanthi Thalayasingam
Des Spence
2.8 Traditional medicine exemplified by traditional
1.5 Medical ethics 20 Chinese medicine 108
Mike Parker, Mehrunisha Suleman, and Tony Hope Fulong Liao, Tingliang Jiang, and Youyou Tu

1.6 Clinical decision-​making 26 2.9 Engaging patients in therapeutic

Timothy E.A. Peto and Philippa Peto development 118
Emil Kakkis and Max Bronstein

2.10 Medicine quality, physicians, and patients 124

SECTION 2 Paul N. Newton
Background to medicine 2.11 Preventive medicine 127
Section editors: John D. Firth, Christopher P. Conlon, and David Mant
Timothy M. Cox
2.12 Medical screening 137
2.1 Science in medicine: When, how, and what 33 Nicholas Wald and Malcolm Law
William F. Bynum
2.13 Health promotion 152
Evelyne de Leeuw
†
It is with great regret that we report that Christopher Booth died on 13 July, 2012
and Rosamund Snow died on 2 February, 2017.
xiv Contents

2.14 Deprivation and health 157 3.9 Circulating DNA for molecular diagnostics 299
Harry Burns Y.M. Dennis Lo and Rossa W.K. Chiu

2.15 How much should rich countries’ governments

spend on healthcare? 161
Allyson M. Pollock and David Price SECTION 4
2.16 Financing healthcare in low-​income developing
Immunological mechanisms
countries: A challenge for equity in health 168 Section editors: John D. Firth, Christopher P. Conlon, and
Luis G. Sambo, Jorge Simões, and Maria do Rosario O. Martins Timothy M. Cox

2.17 Research in the developed world 177 4.1 The innate immune system 307
Jeremy Farrar Paul Bowness

2.18 Fostering medical and health research in 4.2 The complement system 315
resource-​constrained countries 181 Marina Botto and Matthew C. Pickering
Malegapuru W. Makgoba and Stephen M. Tollman
4.3 Adaptive immunity 325
2.19 Regulation versus innovation in medicine 185 Paul Klenerman and Constantino López-​Macias
Michael Rawlins
4.4 Immunodeficiency 337
2.20 Human disasters 188 Sophie Hambleton, Sara Marshall, and Dinakantha
Amartya Sen S. Kumararatne

2.21 Humanitarian medicine 193 4.5 Allergy 368

Amy S. Kravitz Pamela Ewan

2.22 Complementary and alternative medicine 201 4.6 Autoimmunity 379

Edzard Ernst Antony Rosen

4.7 Principles of transplantation immunology 392

Elizabeth Wallin and Kathryn J. Wood
SECTION 3
Cell biology
SECTION 5
Section editors: John D. Firth, Christopher P. Conlon, and
Timothy M. Cox Principles of clinical oncology
Section editors: John D. Firth, Christopher P. Conlon, and
3.1 The cell 209
Timothy M. Cox
George Banting and Jean Paul Luzio
5.1 Epidemiology of cancer 411
3.2 The genomic basis of medicine 218
Anthony Swerdlow and Richard Peto
Paweł Stankiewicz and James R. Lupski
5.2 The nature and development of cancer: Cancer
3.3 Cytokines 236
Iain B. McInnes
mutations and their implications 445
James D. Brenton and Tim Eisen
3.4 Ion channels and disease 246
Frances Ashcroft and Paolo Tammaro
5.3 The genetics of inherited cancers 456
Rosalind A. Eeles
3.5 Intracellular signalling 256
R. Andres Floto
5.4 Cancer immunity and immunotherapy 471
Charles G. Drake
3.6 Apoptosis in health and disease 266
Mark J. Arends and Christopher D. Gregory
5.5 Clinical features and management 487
Tim Eisen and Martin Gore†
3.7 Stem cells and regenerative medicine 281
Alexis J. Joannides, Bhuvaneish T. Selvaraj, and
5.6 Systemic treatment and radiotherapy 497
Rajesh Jena and Peter Harper
Siddharthan Chandran

3.8 The evolution of therapeutic antibodies 296

Herman Waldmann and Greg Winter †
It is with great regret that we report that Martin Gore died on 10 January, 2019.
 Contents xv

5.7 Medical management of breast cancer 505 7.4 Care of the dying person 639
Tim Crook, Su Li, and Peter Harper Suzanne Kite and Adam Hurlow

SECTION 6 SECTION 8
Old age medicine Infectious diseases
Section editor: Finbarr C. Martin Section editor: Christopher P. Conlon
6.1 Ageing and clinical medicine 511 8.1 Pathogenic microorganisms and the host 651
Claire Steves and Neil Pendleton 8.1.1 Biology of pathogenic microorganisms 651
6.2 Frailty and sarcopenia 521 Duncan J. Maskell and James L.N. Wood
Andrew Clegg and Harnish Patel 8.1.2 Clinical features and general management of patients
with severe infections 656
6.3 Optimizing well-​being into old age 532 Peter Watkinson and Duncan Young
Steve Iliffe
8.2 The patient with suspected infection 662
6.4 Older people and urgent care 539
Simon Conroy and Jay Banerjee 8.2.1 Clinical approach 662
Christopher J. Ellis
6.5 Older people in hospital 548 8.2.2 Fever of unknown origin 664
Graham Ellis, Alasdair MacLullich, and Rowan Harwood Steven Vanderschueren
6.6 Supporting older peoples’ care in surgical and 8.2.3 Nosocomial infections 669
oncological services 563 Ian C.J.W. Bowler and Matthew Scarborough
Jugdeep Dhesi and Judith Partridge 8.2.4 Infection in the immunocompromised host 673
6.7 Drugs and prescribing in the older patient 571 Jon Cohen and Elham Khatamzas
Miles Witham, Jacob George, and Denis O’Mahony 8.2.5 Antimicrobial chemotherapy 684
Maha Albur, Alasdair MacGowan, and Roger G. Finch
6.8 Falls, faints, and fragility fractures 579
Fiona Kearney and Tahir Masud 8.3 Immunization 706
David Goldblatt and Mary Ramsay
6.9 Bladder and bowels 589
Susie Orme and Danielle Harari 8.4 Travel and expedition medicine 713
Susanna Dunachie and Christopher P. Conlon
6.10 Neurodegenerative disorders in older
people 601 8.5 Viruses 723
John Hindle 8.5.1 Respiratory tract viruses 723
Malik Peiris
6.11 Promotion of dignity in the life and death of
older patients 612 8.5.2 Herpesviruses (excluding Epstein–​Barr virus) 734
Eileen Burns and Claire Scampion J.G.P. Sissons†
8.5.3 Epstein–​Barr virus 754
Alan B. Rickinson and M.A. Epstein

SECTION 7 8.5.4 Poxviruses 764

Geoffrey L. Smith
Pain and palliative care
8.5.5 Mumps: Epidemic parotitis 769
Section editor: Bee Wee B.K. Rima
7.1 Introduction to palliative care 623 8.5.6 Measles 772
Susan Salt Hilton C. Whittle and Peter Aaby
8.5.7 Nipah and Hendra virus encephalitides 784
7.2 Pain management 629
C.T. Tan
Marie Fallon

7.3 Symptoms other than pain 634 †

It is with great regret that we report that J.G.P. Sissons died on 25 September,
Regina McQuillan 2016.
xvi Contents

8.5.8 Enterovirus infections 787 8.5.28 Molluscum contagiosum 949

Philip Minor and Ulrich Desselberger David A. Warrell and Christopher P. Conlon
8.5.9 Virus infections causing diarrhoea and 8.5.29 Newly discovered viruses 951
vomiting 797 Susannah J.A. Froude and Harriet C. Hughes
Philip R. Dormitzer and Ulrich Desselberger
8.6 Bacteria 958
8.5.10 Rhabdoviruses: Rabies and rabies-​related
lyssaviruses 805 8.6.1 Diphtheria 959
Mary J. Warrell and David A. Warrell Delia B. Bethell and Tran Tinh Hien

8.5.11 Colorado tick fever and other arthropod-​borne 8.6.2 Streptococci and enterococci 965
reoviruses 819 Dennis L. Stevens and Sarah Hobdey
Mary J. Warrell and David A. Warrell 8.6.3 Pneumococcal infections 975
8.5.12 Alphaviruses 821 Anthony Scott
Ann M. Powers, E.E. Ooi, L.R. Petersen, and D.J. Gubler 8.6.4 Staphylococci 991
8.5.13 Rubella 827 Kyle J. Popovich, Robert A. Weinstein, and Bala Hota
Pat Tookey and J.M. Best 8.6.5 Meningococcal infections 1010
8.5.14 Flaviviruses excluding dengue 830 Petter Brandtzaeg
Shannan Lee Rossi and Nikos Vasilakis 8.6.6 Neisseria gonorrhoeae 1025
8.5.15 Dengue 845 Jackie Sherrard and Magnus Unemo
Bridget Wills and Yee-​Sin Leo 8.6.7 Enterobacteria and bacterial food poisoning 1032
8.5.16 Bunyaviridae 852 Hugh Pennington
James W. Le Duc and D.A. Bente 8.6.8 Pseudomonas aeruginosa 1041
8.5.17 Arenaviruses 862 G.C.K.W. Koh and Sharon J. Peacock
Jan H. ter Meulen 8.6.9 Typhoid and paratyphoid fevers 1044
8.5.18 Filoviruses 870 Christopher M. Parry and Buddha Basnyat
Jan H. ter Meulen 8.6.10 Intracellular klebsiella infections (donovanosis and

8.5.19 Papillomaviruses and polyomaviruses 877 rhinoscleroma) 1051

Raphael P. Viscidi, Chen Sabrina Tan, and John Richens and Nicole Stoesser
Carole Fakhry 8.6.11 Anaerobic bacteria 1055
8.5.20 Parvovirus B19 886 Anilrudh A. Venugopal and David W. Hecht
Kevin E. Brown 8.6.12 Cholera 1060
8.5.21 Hepatitis viruses (excluding hepatitis C virus) 889 Aldo A.M. Lima and Richard L. Guerrant
Matthew Cramp, Ashwin Dhanda, and 8.6.13 Haemophilus influenzae 1066
Nikolai V. Naoumov Esther Robinson
8.5.22 Hepatitis C virus 896 8.6.14 Haemophilus ducreyi and chancroid 1071
Paul Klenerman, Katie J.M. Jeffery, Ellie J. Barnes, and Nigel O’Farrell
Jane Collier 8.6.15 Bordetella infection 1073
8.5.23 HIV/​AIDS 901 Cameron C. Grant
Sarah Fidler, Timothy E.A. Peto, Philip Goulder, and 8.6.16 Melioidosis and glanders 1076
Christopher P. Conlon Sharon J. Peacock
8.5.24 HIV in low-​and middle-​income countries 933 8.6.17 Plague: Yersinia pestis 1081
Alison D. Grant and Kevin M. De Cock Michael Prentice
8.5.25 HTLV-​1, HTLV-​2, and associated diseases 941 8.6.18 Other Yersinia infections: Yersiniosis 1086
Kristien Verdonck and Eduardo Gotuzzo Michael Prentice
8.5.26 Viruses and cancer 945 8.6.19 Pasteurella 1088
Robin A. Weiss Marina S. Morgan
8.5.27 Orf and Milker’s nodule 947 8.6.20 Francisella tularensis infection 1091
Emma Aarons and David A. Warrell Petra C.F. Oyston
 Contents xvii

8.6.21 Anthrax 1094 8.6.42 Coxiella burnetii infections (Q fever) 1257

Arthur E. Brown Thomas J. Marrie
8.6.22 Brucellosis 1102 8.6.43 Bartonellas excluding B. bacilliformis 1262
Juan D. Colmenero and Pilar Morata Bruno B. Chomel, Henri-​Jean Boulouis, Matthew
8.6.23 Tetanus 1109 J. Stuckey, and Jean-​Marc Rolain
C. Louise Thwaites and Lam Minh Yen 8.6.44 Bartonella bacilliformis infection 1272
8.6.24 Clostridium difficile 1115 A. Llanos-​Cuentas and C. Maguiña-​Vargas
David W. Eyre and Mark H. Wilcox 8.6.45 Chlamydial infections 1278
8.6.25 Botulism, gas gangrene, and clostridial Patrick Horner, David Mabey, David Taylor-​Robinson,
gastrointestinal infections 1120 and Magnus Unemo
Dennis L. Stevens, Michael J. Aldape, and Amy E. Bryant 8.6.46 Mycoplasmas 1295
8.6.26 Tuberculosis 1126 Jørgen Skov Jensen and David Taylor-​Robinson
Richard E. Chaisson and Jean B. Nachega 8.6.47 A checklist of bacteria associated with infection
8.6.27 Disease caused by environmental in humans 1307
mycobacteria 1150 John Paul
Jakko van Ingen 8.7 Fungi (mycoses) 1338
8.6.28 Leprosy (Hansen’s disease) 1154 8.7.1 Fungal infections 1338
Diana N.J. Lockwood Roderick J. Hay
8.6.29 Buruli ulcer: Mycobacterium ulcerans infection 1167 8.7.2 Cryptococcosis 1359
Bouke de Jong, Françoise Portaels, and Wayne M. Meyers William G. Powderly, J. William Campbell, and
8.6.30 Actinomycoses 1170 Larry J. Shapiro
Klaus P. Schaal 8.7.3 Coccidioidomycosis 1361
8.6.31 Nocardiosis 1176 Gregory M. Anstead
Roderick J. Hay 8.7.4 Paracoccidioidomycosis 1364
8.6.32 Rat bite fevers (Streptobacillus moniliformis and M.A. Shikanai-​Yasuda
Spirillum minus infection) 1179 8.7.5 Pneumocystis jirovecii 1371
Andrew F. Woodhouse Robert F. Miller and Christopher P. Eades
8.6.33 Lyme borreliosis 1181 8.7.6 Talaromyces (Penicillium) marneffei infection 1375
Gary P. Wormser, John Nowakowski, and Romanee Chaiwarith, Khuanchai Supparatpinyo, and
Robert B. Nadelman Thira Sirisanthana
8.6.34 Relapsing fevers 1188 8.7.7 Microsporidiosis 1378
David A. Warrell Louis M. Weiss
8.6.35 Leptospirosis 1198
Nicholas P.J. Day 8.8 Protozoa 1384
8.6.36 Nonvenereal endemic treponematoses: Yaws, 8.8.1 Amoebic infections 1384
endemic syphilis (bejel), and pinta 1204 Richard Knight
Michael Marks, Oriol Mitjà, and David Mabey 8.8.2 Malaria 1395
8.6.37 Syphilis 1210 Nicholas J. White and Arjen M. Dondorp
Phillip Read and Basil Donovan 8.8.3 Babesiosis 1414
8.6.38 Listeriosis 1223 Philippe Brasseur
Herbert Hof 8.8.4 Toxoplasmosis 1416
8.6.39 Legionellosis and Legionnaires’ disease 1226 Oliver Liesenfeld and Eskild Petersen
Diego Viasus and Jordi Carratalà 8.8.5 Cryptosporidium and cryptosporidiosis 1424
8.6.40 Rickettsioses 1230 Simone M. Cacciò
Karolina Griffiths, Carole Eldin, Didier Raoult, and 8.8.6 Cyclospora and cyclosporiasis 1432
Philippe Parola Paul Kelly and Ralph Lainson†
8.6.41 Scrub typhus 1252
Daniel H. Paris and Nicholas P.J. Day †
It is with great regret that we report that Ralph Lainson died on 5 May, 2015.
xviii Contents

8.8.7 Cystoisosporiasis 1436 8.11.2 Liver fluke infections 1551

Louis M. Weiss Ross H. Andrews, Narong Khuntikeo,
8.8.8 Sarcocystosis (sarcosporidiosis) 1438 Paiboon Sithithaworn, and Trevor N. Petney
John E. Cooper 8.11.3 Lung flukes (paragonimiasis) 1558
8.8.9 Giardiasis and balantidiasis 1440 Udomsak Silachamroon and Sirivan Vanijanonta
Lars Eckmann and Martin F. Heyworth 8.11.4 Intestinal trematode infections 1562
8.8.10 Blastocystis infection 1449 Alastair McGregor
Richard Knight 8.12 Nonvenomous arthropods 1568
8.8.11 Human African trypanosomiasis 1451 John Paul
Reto Brun and Johannes Blum
8.13 Pentastomiasis (porocephalosis,
8.8.12 Chagas disease 1459
linguatulosis/​linguatuliasis, or tongue
Michael A. Miles
worm infection) 1582
8.8.13 Leishmaniasis 1467 David A. Warrell
Antony D.M. Bryceson and Diana N.J. Lockwood
8.8.14 Trichomoniasis 1475
Jane Schwebke
SECTION 9
8.9 Nematodes (roundworms) 1478 Sexually transmitted diseases
8.9.1 Cutaneous filariasis 1478
Section editor: Jackie Sherrard
Gilbert Burnham
8.9.2 Lymphatic filariasis 1487 9.1 Epidemiology of sexually transmitted
Richard Knight infections 1589
David Mabey and Anita Vas-​Falcao
8.9.3 Guinea worm disease (dracunculiasis) 1495
Richard Knight 9.2 Sexual behaviour 1597
8.9.4 Strongyloidiasis, hookworm, and other gut Catherine H. Mercer and Anne M. Johnson
strongyloid nematodes 1500
9.3 Sexual history and examination 1600
Michael Brown
Gary Brook, Jackie Sherrard, and Graz A. Luzzi
8.9.5 Gut and tissue nematode infections acquired
by ingestion 1506 9.4 Vaginal discharge 1603
Peter L. Chiodini Paul Nyirjesy
8.9.6 Angiostrongyliasis 1516 9.5 Urethritis 1606
Richard Knight Patrick Horner
8.10 Cestodes (tapeworms) 1520 9.6 Genital ulceration 1610
8.10.1 Cestodes (tapeworms) 1520 Patrick French and Raj Patel
Richard Knight
9.7 Anogenital lumps and bumps 1613
8.10.2 Cystic hydatid disease (Echinococcus Henry J.C. de Vries and Charles J.N. Lacey
granulosus) 1529
Pedro L. Moro, Hector H. Garcia, and 9.8 Pelvic inflammatory disease 1622
Armando E. Gonzalez Jonathan D.C. Ross

8.10.3 Cysticercosis 1533 9.9 Principles of contraception 1626

Hector H. Garcia and Robert H. Gilman Zara Haider

8.11 Trematodes (flukes) 1540 Index

8.11.1 Schistosomiasis 1540
David Dunne and Birgitte Vennervald
 Contents xix

Volume 2

List of abbreviations xxxv 10.3.8 Disasters: Earthquakes, hurricanes, floods, and

List of contributors xlv volcanic eruptions 1713
Peter J. Baxter
10.3.9 Bioterrorism 1718
Manfred S. Green
SECTION 10
Environmental medicine, occupational 10.4 Poisoning 1725
medicine, and poisoning 10.4.1 Poisoning by drugs and chemicals 1725
John A. Vale, Sally M. Bradberry, and D. Nicholas
Section editor: Jon G. Ayres Bateman
10.1 Environmental medicine, occupational 10.4.2 Injuries, envenoming, poisoning, and allergic
medicine, and poisoning—​Introduction 1637 reactions caused by animals 1778
Jon G. Ayres David A. Warrell

10.2 Occupational health 1638 10.4.3 Poisonous fungi 1817

Hans Persson and David A. Warrell
10.2.1 Occupational and environmental health 1638
Raymond Agius and Debasish Sen 10.4.4 Poisonous plants 1828
Michael Eddleston and Hans Persson
10.2.2 Occupational safety 1652
Lawrence Waterman 10.5 Podoconiosis (nonfilarial elephantiasis) 1833
10.2.3 Aviation medicine 1656 Gail Davey
Michael Bagshaw
10.2.4 Diving medicine 1664
David M. Denison and Mark A. Glover SECTION 11
10.2.5 Noise 1671 Nutrition
David Koh and Tar-​Ching Aw†
Section editor: Katherine Younger
10.2.6 Vibration 1673
Tar-​Ching Aw† 11.1 Nutrition: Macronutrient metabolism 1839
Keith N. Frayn and Rhys D. Evans
10.3 Environment and health 1677
10.3.1 Air pollution and health 1677
11.2 Vitamins 1855
Om P. Kurmi, Kin Bong Hubert Lam, and Jon G. Ayres Tom R. Hill and David A. Bender

10.3.2 Heat 1687 11.3 Minerals and trace elements 1871

Michael A. Stroud Katherine Younger
10.3.3 Cold 1689 11.4 Severe malnutrition 1880
Michael A. Stroud Alan A. Jackson
10.3.4 Drowning 1691
Peter J. Fenner
11.5 Diseases of affluent societies and the need for
dietary change 1891
10.3.5 Lightning and electrical injuries 1696 J.I. Mann and A.S. Truswell
Chris Andrews
10.3.6 Diseases of high terrestrial altitudes 1701 11.6 Obesity 1903
Tyler Albert, Erik R. Swenson, Andrew J. Pollard, Buddha I. Sadaf Farooqi
Basnyat, and David R. Murdoch 11.7 Artificial nutrition support 1914
10.3.7 Radiation 1709 Jeremy Woodward
Jill Meara
†
It is with great regret that we report that Tar-Ching Aw died on 18 July, 2017.
xx Contents

12.12 The acute phase response, hereditary periodic

SECTION 12 fever syndromes, and amyloidosis 2199
Metabolic disorders 12.12.1 The acute phase response and C-​reactive
protein 2199
Section editor: Timothy M. Cox
Mark B. Pepys
12.1 The inborn errors of metabolism: General 12.12.2 Hereditary periodic fever syndromes 2207
aspects 1929 Helen J. Lachmann, Stefan Berg, and Philip N. Hawkins
Timothy M. Cox and Richard W.E. Watts†
12.12.3 Amyloidosis 2218
12.2 Protein-​dependent inborn errors of Mark B. Pepys and Philip N. Hawkins
metabolism 1942 12.13 α1-​Antitrypsin deficiency and the
Georg F. Hoffmann and Stefan Kölker
serpinopathies 2235
12.3 Disorders of carbohydrate metabolism 1985 David A. Lomas
12.3.1 Glycogen storage diseases 1985
Robin H. Lachmann and Timothy M. Cox
12.3.2 Inborn errors of fructose metabolism 1993 SECTION 13
Timothy M. Cox
Endocrine disorders
12.3.3 Disorders of galactose, pentose, and pyruvate
Section editor: Mark Gurnell
metabolism 2003
Timothy M. Cox 13.1 Principles of hormone action 2245
Rob Fowkes, V. Krishna Chatterjee, and Mark Gurnell
12.4 Disorders of purine and pyrimidine
metabolism 2015 13.2 Pituitary disorders 2258
Anthony M. Marinaki, Lynette D. Fairbanks, and Richard 13.2.1 Disorders of the anterior pituitary gland 2258
W.E. Watts† Niki Karavitaki and John A.H. Wass
12.5 The porphyrias 2032 13.2.2 Disorders of the posterior pituitary gland 2277
Timothy M. Cox Niki Karavitaki, Shahzada K. Ahmed, and John A.H. Wass

12.6 Lipid disorders 2055 13.3 Thyroid disorders 2284

Jaimini Cegla and James Scott 13.3.1 The thyroid gland and disorders of thyroid
12.7 Trace metal disorders 2098 function 2284
Anthony P. Weetman and Kristien Boelaert
12.7.1 Hereditary haemochromatosis 2098
William J.H. Griffiths and Timothy M. Cox 13.3.2 Thyroid cancer 2302
Kristien Boelaert and Anthony P. Weetman
12.7.2 Inherited diseases of copper metabolism:
Wilson’s disease and Menkes’ disease 2115 13.4 Parathyroid disorders and diseases altering
Michael L. Schilsky and Pramod K. Mistry calcium metabolism 2313
R.V. Thakker
12.8 Lysosomal disease 2121
Patrick B. Deegan and Timothy M. Cox 13.5 Adrenal disorders 2331
12.9 Disorders of peroxisomal metabolism in 13.5.1 Disorders of the adrenal cortex 2331
adults 2157 Mark Sherlock and Mark Gurnell
Anthony S. Wierzbicki 13.5.2 Congenital adrenal hyperplasia 2360
Nils P. Krone and Ieuan A. Hughes
12.10 Hereditary disorders of oxalate metabolism:
The primary hyperoxalurias 2174 13.6 Reproductive disorders 2374
Sonia Fargue, Dawn S. Milliner, and Christopher J. Danpure 13.6.1 Ovarian disorders 2374
12.11 A physiological approach to acid–​base Stephen Franks, Kate Hardy, and Lisa J. Webber
disorders: The roles of ion transport and body 13.6.2 Disorders of male reproduction and male
fluid compartments 2182 hypogonadism 2386
Julian Seifter P.-​M.G. Bouloux
†
It is with great regret that we report that Richard W.E. Watts died on 11 February,
13.6.3 Benign breast disease 2406
2018. Gael M. MacLean
 Contents xxi

13.6.4 Sexual dysfunction 2408 14.9 Liver and gastrointestinal diseases of

Ian Eardley pregnancy 2619
Michael Heneghan and Catherine Williamson
13.7 Disorders of growth and development 2416
13.7.1 Normal growth and its disorders 2416 14.10 Diabetes in pregnancy 2627
Gary Butler Bryony Jones and Anne Dornhorst
13.7.2 Normal puberty and its disorders 2428 14.11 Endocrine disease in pregnancy 2638
Fiona Ryan and Sejal Patel David Carty
13.7.3 Normal and abnormal sexual differentiation 2435
14.12 Neurological conditions in pregnancy 2642
S. Faisal Ahmed and Angela K. Lucas-​Herald
Pooja Dassan
13.8 Pancreatic endocrine disorders and multiple
14.13 The skin in pregnancy 2648
endocrine neoplasia 2449 Gudula Kirtschig and Fenella Wojnarowska
B. Khoo, T.M. Tan, and S.R. Bloom
14.14 Autoimmune rheumatic disorders and
13.9 Diabetes and hypoglycaemia 2464
vasculitis in pregnancy 2655
13.9.1 Diabetes 2464 May Ching Soh and Catherine Nelson-​Piercy
Colin Dayan and Julia Platts
14.15 Maternal infection in pregnancy 2671
13.9.2 Hypoglycaemia 2531
Rosie Burton
Mark Evans and Ben Challis
14.16 Fetal effects of maternal infection 2678
13.10 Hormonal manifestations of nonendocrine
Lawrence Impey
disease 2541
Thomas M. Barber and John A.H. Wass 14.17 Blood disorders in pregnancy 2687
David J. Perry and Katharine Lowndes
13.11 The pineal gland and melatonin 2553
J. Arendt and Timothy M. Cox 14.18 Malignant disease in pregnancy 2696
Robin A.F. Crawford

14.19 Maternal critical care 2701

SECTION 14 Rupert Gauntlett
Medical disorders in pregnancy 14.20 Prescribing in pregnancy 2706
Section editor: Catherine Nelson-​Piercy Lucy MacKillop and Charlotte Frise

14.1 Physiological changes of normal pregnancy 2563 14.21 Contraception for women with medical
David J. Williams diseases 2711
Aarthi R. Mohan
14.2 Nutrition in pregnancy 2568
David J. Williams

14.3 Medical management of normal pregnancy 2575 SECTION 15

David J. Williams
Gastroenterological disorders
14.4 Hypertension in pregnancy 2583
Section editor: Jack Satsangi
Fergus McCarthy
15.1 Structure and function of the gastrointestinal
14.5 Renal disease in pregnancy 2589
Kate Wiles
tract 2721
Michael E.B. FitzPatrick and Satish Keshav†
14.6 Heart disease in pregnancy 2597
Catherine E.G. Head
15.2 Symptoms of gastrointestinal disease 2727
Jeremy Woodward
14.7 Thrombosis in pregnancy 2606
Peter K. MacCallum and Louise Bowles
15.3 Methods for investigation of
gastroenterological disease 2734
14.8 Chest diseases in pregnancy 2613 15.3.1 Colonoscopy and flexible sigmoidoscopy 2734
Meredith Pugh and Tina Hartert James E. East and Brian P. Saunders
†
It is with great regret that we report that Satish Keshav died on 23 January, 2019.
xxii Contents

15.3.2 Upper gastrointestinal endoscopy 2740 15.11 Crohn’s disease 2925

James E. East and George J. Webster Miles Parkes and Tim Raine
15.3.3 Radiology of the gastrointestinal tract 2748
15.12 Ulcerative colitis 2937
Fiachra Moloney and Michael Maher
Jeremy Sanderson and Peter Irving
15.3.4 Investigation of gastrointestinal function 2757
Jervoise Andreyev 15.13 Irritable bowel syndrome 2951
Adam D. Farmer and Qasim Aziz
15.4 Common acute abdominal presentations 2765
15.14 Colonic diverticular disease 2960
15.4.1 The acute abdomen 2765
Nicolas C. Buchs, Roel Hompes, Shazad Q. Ashraf, and
Simon J.A. Buczacki and R. Justin Davies
Neil J.McC. Mortensen
15.4.2 Gastrointestinal bleeding 2771
Vanessa Brown and T.A. Rockall 15.15 Congenital abnormalities of the
gastrointestinal tract 2967
15.5 Immune disorders of the gastrointestinal Holm H. Uhlig
tract 2783
Joya Bhattacharyya and Arthur Kaser 15.16 Cancers of the gastrointestinal tract 2977
Peter L. Labib, J.A. Bridgewater, and Stephen P. Pereira
15.6 The mouth and salivary glands 2797
John Gibson and Douglas Robertson 15.17 Vascular disorders of the gastrointestinal
tract 2997
15.7 Diseases of the oesophagus 2828 Ray Boyapati
Rebecca C. Fitzgerald and Massimiliano di Pietro
15.18 Gastrointestinal infections 3008
15.8 Peptic ulcer disease 2849 Sarah O’Brien
Joseph Sung
15.19 Miscellaneous disorders of the bowel 3025
15.9 Hormones and the gastrointestinal tract 2862 Alexander Gimson
15.9.1 Hormones and the gastrointestinal tract 2862
15.20 Structure and function of the liver, biliary tract,
Rebecca Scott, T.M. Tan, and S.R. Bloom
and pancreas 3032
15.9.2 Carcinoid syndrome 2870 William Gelson and Alexander Gimson
B. Khoo, T.M. Tan, and S.R. Bloom
15.21 Pathobiology of chronic liver disease 3043
15.10 Malabsorption 2875 Wajahat Z. Mehal
15.10.1 Differential diagnosis and investigation of
15.22 Presentations and management of liver
malabsorption 2875
Alastair Forbes and Victoria Mulcahy disease 3049
15.10.2 Bacterial overgrowth of the small 15.22.1 Investigation and management of
intestine 2879 jaundice 3049
Stephen J. Middleton and Raymond J. Playford Jane Collier

15.10.3 Coeliac disease 2884 15.22.2 Cirrhosis and ascites 3058

Peter D. Mooney and David S. Sanders Javier Fernández and Vicente Arroyo

15.10.4 Gastrointestinal lymphomas 2892 15.22.3 Portal hypertension and variceal bleeding 3068
Kikkeri N. Naresh Marcus Robertson and Peter Hayes

15.10.5 Disaccharidase deficiency 2902 15.22.4 Hepatic encephalopathy 3080

Timothy M. Cox Paul K. Middleton and Debbie L. Shawcross

15.10.6 Whipple’s disease 2909 15.22.5 Liver failure 3089

Florence Fenollar and Didier Raoult Jane Macnaughtan and Rajiv Jalan

15.10.7 Effects of massive bowel resection 2911 15.22.6 Liver transplantation 3100
Stephen J. Middleton, Simon M. Gabe, and John G. O’Grady
Raymond J. Playford 15.23 Hepatitis and autoimmune liver disease 3108
15.10.8 Malabsorption syndromes in the tropics 2916 15.23.1 Hepatitis A to E 3108
Vineet Ahuja and Govind K. Makharia Graeme J.M. Alexander and Kate Nash
 Contents xxiii

15.23.2 Autoimmune hepatitis 3119 15.24.6 Primary and secondary liver tumours 3178
G.J. Webb and Gideon M. Hirschfield Graeme J.M. Alexander, David J. Lomas,
15.23.3 Primary biliary cholangitis 3127 William J.H. Griffiths, Simon M. Rushbrook, and
Jessica K. Dyson and David E.J. Jones Michael E.D. Allison
15.24.7 Liver and biliary diseases in infancy and
15.23.4 Primary sclerosing cholangitis 3135
Kate D. Lynch and Roger W. Chapman childhood 3191
Richard J. Thompson
15.24 Other liver diseases 3142
15.25 Diseases of the gallbladder and biliary tree 3196
15.24.1 Alcoholic liver disease 3142 Colin Johnson and Mark Wright
Ewan Forrest
15.24.2 Nonalcoholic fatty liver disease 3147 15.26 Diseases of the pancreas 3209
Quentin M. Anstee and Christopher P. Day 15.26.1 Acute pancreatitis 3209
15.24.3 Drug-​induced liver disease 3155 R. Carter, Euan J. Dickson, and C.J. McKay
Guruprasad P. Aithal 15.26.2 Chronic pancreatitis 3218
15.24.4 Vascular disorders of the liver 3166 Marco J. Bruno and Djuna L. Cahen
Alexander Gimson 15.26.3 Tumours of the pancreas 3227
15.24.5 The liver in systemic disease 3169 James R.A. Skipworth and Stephen P. Pereira
James Neuberger Index

Volume 3

List of abbreviations xxxv 16.3 Clinical investigation of cardiac disorders 3294

List of contributors xlv 16.3.1 Electrocardiography 3294
Andrew R. Houghton and David Gray
16.3.2 Echocardiography 3314
SECTION 16 James D. Newton, Adrian P. Banning, and
Andrew R.J. Mitchell
Cardiovascular disorders
16.3.3 Cardiac investigations: Nuclear, MRI, and CT 3326
Section editor: Jeremy Dwight Nikant Sabharwal, Andrew Kelion, Theodoros
16.1 Structure and function 3241 Karamitos, and Stefan Neubauer
16.3.4 Cardiac catheterization and angiography 3339
16.1.1 Blood vessels and the endothelium 3241
Keith Channon and Patrick Vallance Edward D. Folland

16.1.2 Cardiac physiology 3253 16.4 Cardiac arrhythmias 3350

Rhys D. Evans, Kenneth T. MacLeod, Matthew R. Ginks, D.A. Lane, A.D. McGavigan, and
Steven B. Marston, Nicholas J. Severs, and Peter Gregory Y.H. Lip
H. Sugden
16.5 Cardiac failure 3390
16.2 Clinical presentation of heart disease 3276 16.5.1 Epidemiology and general pathophysiological
16.2.1 Chest pain, breathlessness, and fatigue 3276 classification of heart failure 3390
Jeremy Dwight Theresa A. McDonagh and Kaushik Guha
16.2.2 Syncope and palpitation 3284 16.5.2 Acute cardiac failure: Definitions, investigation, and
K. Rajappan, A.C. Rankin, A.D. McGavigan, and management 3397
S.M. Cobbe Andrew L. Clark and John G.F. Cleland
16.5.3 Chronic heart failure: Definitions, investigation,
and management 3407
John G.F. Cleland and Andrew L. Clark
xxiv Contents

16.5.4 Cardiorenal syndrome 3421 16.13.5 Percutaneous interventional cardiac

Darren Green and Philip A. Kalra procedures 3655
16.5.5 Cardiac transplantation and mechanical Edward D. Folland
circulatory support 3428 16.13.6 Coronary artery bypass and valve surgery 3666
Jayan Parameshwar and Steven Tsui Rana Sayeed and David Taggart

16.6 Valvular heart disease 3436 16.14 Diseases of the arteries 3674
Michael Henein
16.14.1 Acute aortic syndromes 3674
16.7 Diseases of heart muscle 3459 James D. Newton, Andrew R.J. Mitchell, and
Adrian P. Banning
16.7.1 Myocarditis 3459
Jay W. Mason and Heinz-​Peter Schultheiss 16.14.2 Peripheral arterial disease 3680
Janet Powell and Alun Davies
16.7.2 The cardiomyopathies: Hypertrophic, dilated,
restrictive, and right ventricular 3468 16.14.3 Cholesterol embolism 3688
Oliver P. Guttmann and Perry Elliott Christopher Dudley

16.7.3 Specific heart muscle disorders 3489 16.15 The pulmonary circulation 3691
Oliver P. Guttmann and Perry Elliott 16.15.1 Structure and function of the pulmonary
16.8 Pericardial disease 3501 circulation 3691
Michael Henein Nicholas W. Morrell
16.15.2 Pulmonary hypertension 3695
16.9 Cardiac involvement in infectious Nicholas W. Morrell
disease 3509
16.9.1 Acute rheumatic fever 3509 16.16 Venous thromboembolism 3711
Jonathan R. Carapetis 16.16.1 Deep venous thrombosis and pulmonary
16.9.2 Endocarditis 3519 embolism 3711
James L. Harrison, John L. Klein, William A. Littler, Paul D. Stein, Fadi Matta, and John D. Firth
and Bernard D. Prendergast 16.16.2 Therapeutic anticoagulation 3729
16.9.3 Cardiac disease in HIV infection 3534 David Keeling
Peter F. Currie 16.17 Hypertension 3735
16.9.4 Cardiovascular syphilis 3539 16.17.1 Essential hypertension: Definition, epidemiology,
Krishna Somers and pathophysiology 3735
16.10 Tumours of the heart 3544 Bryan Williams and John D. Firth
Thomas A. Traill 16.17.2 Essential hypertension: Diagnosis, assessment,
and treatment 3753
16.11 Cardiac involvement in genetic disease 3551 Bryan Williams and John D. Firth
Thomas A. Traill
16.17.3 Secondary hypertension 3778
16.12 Congenital heart disease in the adult 3559 Morris J. Brown and Fraz A. Mir
S.A. Thorne 16.17.4 Mendelian disorders causing
16.13 Coronary heart disease 3596 hypertension 3796
Nilesh J. Samani and Maciej Tomaszewski
16.13.1 Biology and pathology of atherosclerosis 3596
Robin P. Choudhury, Joshua T. Chai, and 16.17.5 Hypertensive urgencies and emergencies 3800
Edward A. Fisher Gregory Y.H. Lip and Alena Shantsila

16.13.2 Coronary heart disease: Epidemiology and 16.18 Chronic peripheral oedema and
prevention 3603 lymphoedema 3811
Goodarz Danaei and Kazem Rahimi Peter S. Mortimer
16.13.3 Management of stable angina 3616
16.19 Idiopathic oedema of women 3823
Adam D. Timmis
John D. Firth
16.13.4 Management of acute coronary syndrome 3626
Rajesh K. Kharbanda and Keith A.A. Fox
 Contents xxv

18.1.2 Airways and alveoli 3937

SECTION 17 Peter D. Wagner and Pallav L. Shah

Critical care medicine 18.2 The clinical presentation of respiratory

Section editor: Simon Finfer disease 3947
Samuel Kemp and Julian Hopkin
17.1 The seriously ill or deteriorating patient 3829
Carole Foot and Liz Hickson 18.3 Clinical investigation of respiratory
disorders 3956
17.2 Cardiac arrest 3839
18.3.1 Respiratory function tests 3956
Gavin D. Perkins, Jasmeet Soar, Jerry P. Nolan, and
G.J. Gibson
David A. Gabbott
18.3.2 Thoracic imaging 3970
17.3 Anaphylaxis 3849 Susan J. Copley and David M. Hansell
Anthony F.T. Brown
18.3.3 Bronchoscopy, thoracoscopy, and tissue
17.4 Assessing and preparing patients with medical biopsy 3992
conditions for major surgery 3860 Pallav L. Shah
Tom Abbott and Rupert Pearse
18.4 Respiratory infection 4004
17.5 Acute respiratory failure 3867 18.4.1 Upper respiratory tract
Susannah Leaver, Jeremy Cordingley, Simon Finney, and Mark infections 4004
Griffiths P. Little
17.6 Circulation and circulatory support in the 18.4.2 Pneumonia in the normal host 4008
critically ill 3881 Wei Shen Lim
Michael R. Pinsky 18.4.3 Nosocomial pneumonia 4022
Wei Shen Lim
17.7 Management of raised intracranial
pressure 3892 18.4.4 Mycobacteria 4026
David K. Menon Hannah Jarvis and Onn Min Kon
18.4.5 Pulmonary complications of HIV
17.8 Sedation and analgesia in the ICU 3898 infection 4031
Michael C. Reade Julia Choy and Anton Pozniak
17.9 Metabolic and endocrine changes in acute and 18.5 The upper respiratory tract 4040
chronic critical illness 3906
18.5.1 Upper airway obstruction 4040
Eva Boonen and Greet Van den Berghe
James H. Hull and Matthew Hind
17.10 Palliative and end-​of-​life care in the ICU 3914 18.5.2 Sleep-​related breathing disorders 4048
Phillip D. Levin and Charles L. Sprung Mary J. Morrell, Julia Kelly, Alison McMillan, and
17.11 Diagnosis of death and organ donation 3918 Matthew Hind
Paul Murphy 18.6 Allergic rhinitis 4059
17.12 Persistent problems and recovery after critical Stephen R. Durham and Hesham A. Saleh
illness 3925 18.7 Asthma 4067
Mark E. Mikkelsen and Theodore J. Iwashyna Alexandra Nanzer-​Kelly, Paul Cullinan, and Andrew
Menzies-​Gow

18.8 Chronic obstructive pulmonary

SECTION 18 disease 4098
Respiratory disorders Nicholas S. Hopkinson

Section editor: Pallav L. Shah 18.9 Bronchiectasis 4142

R. Wilson and D. Bilton
18.1 Structure and function 3933
18.1.1 The upper respiratory tract 3933 18.10 Cystic fibrosis 4151
Pallav L. Shah, J.R. Stradling, and S.E. Craig Andrew Bush and Caroline Elston
xxvi Contents

18.11 Diffuse parenchymal lung diseases 4166 18.15 Chronic respiratory failure 4282
18.11.1 Diffuse parenchymal lung disease: An Michael I. Polkey and P.M.A. Calverley
introduction 4166 18.16 Lung transplantation 4292
F. Teo and A.U. Wells P. Hopkins and A.J. Fisher
18.11.2 Idiopathic pulmonary fibrosis 4177
P.L. Molyneaux, A.G. Nicholson, N. Hirani, and 18.17 Pleural diseases 4305
A.U. Wells D. de Fonseka, Y.C. Gary Lee, and N.A. Maskell

18.11.3 Bronchiolitis obliterans and cryptogenic 18.18 Disorders of the thoracic cage and
organizing pneumonia 4185 diaphragm 4328
Vasilis Kouranos and A.U. Wells John M. Shneerson and Michael I. Polkey
18.11.4 The lung in autoimmune rheumatic
18.19 Malignant diseases 4338
disorders 4191
M.A. Kokosi and A.U. Wells 18.19.1 Lung cancer 4338
S.G. Spiro and N. Navani
18.11.5 The lung in vasculitis 4200
G.A. Margaritopoulos and A.U. Wells 18.19.2 Pulmonary metastases 4360
S.G. Spiro
18.12 Sarcoidosis 4208 18.19.3 Pleural tumours 4361
Robert P. Baughman and Elyse E. Lower Y.C. Gary Lee
18.13 Pneumoconioses 4219 18.19.4 Mediastinal tumours and cysts 4368
P.T. Reid Y.C. Gary Lee and Helen E. Davies

18.14 Miscellaneous conditions 4235

18.14.1 Diffuse alveolar haemorrhage 4235
S.J. Bourke and G.P. Spickett SECTION 19
18.14.2 Eosinophilic pneumonia 4238 Rheumatological disorders
S.J. Bourke and G.P. Spickett Section editor: Richard A. Watts
18.14.3 Lymphocytic infiltrations of the
lung 4241 19.1 Joints and connective tissue—​structure and
S.J. Bourke function 4379
Thomas Pap, Adelheid Korb-​Pap, Christine Hartmann, and
18.14.4 Hypersensitivity pneumonitis 4244
Jessica Bertrand
S.J. Bourke and G.P. Spickett
18.14.5 Pulmonary Langerhans’ cell 19.2 Clinical presentation and diagnosis of
histiocytosis 4256 rheumatological disorders 4386
S.J. Bourke Christopher Deighton and Fiona Pearce
18.14.6 Lymphangioleiomyomatosis 4257 19.3 Clinical investigation 4395
S.J. Bourke Michael Doherty and Peter C. Lanyon
18.14.7 Pulmonary alveolar proteinosis 4259
19.4 Back pain and regional disorders 4406
S.J. Bourke
Carlo Ammendolia and Danielle Southerst
18.14.8 Pulmonary amyloidosis 4261
S.J. Bourke 19.5 Rheumatoid arthritis 4415
Kenneth F. Baker and John D. Isaacs
18.14.9 Lipoid (lipid) pneumonia 4263
S.J. Bourke 19.6 Spondyloarthritis and related conditions 4441
18.14.10 Pulmonary alveolar microlithiasis 4265 Jürgen Braun and Joachim Sieper
S.J. Bourke
19.7 Infection and arthritis 4457
18.14.11 Toxic gases and aerosols 4267 Graham Raftery and Muddassir Shaikh
Chris Stenton
19.8 Reactive arthritis 4464
18.14.12 Radiation pneumonitis 4271
Carmel B. Stober and Hill Gaston
S.J. Bourke
18.14.13 Drug-​induced lung disease 4272 19.9 Osteoarthritis 4470
S.J. Bourke Andrew J. Barr and Philip G. Conaghan
 Contents xxvii

19.10 Crystal-​related arthropathies 4482 20.3 Osteomyelitis 4688

Edward Roddy and Michael Doherty Martin A. McNally and Anthony R. Berendt

19.11 Autoimmune rheumatic disorders and 20.4 Osteoporosis 4696

vasculitides 4495 Nicholas C. Harvey, Juliet Compston, and Cyrus Cooper
19.11.1 Introduction 4495 20.5 Osteonecrosis, osteochondrosis, and
David A. Isenberg and Ian Giles osteochondritis dissecans 4703
19.11.2 Systemic lupus erythematosus and related Gavin Clunie
disorders 4499
Anisur Rahman and David A. Isenberg 20.6 Bone cancer 4709
Helen Hatcher
19.11.3 Systemic sclerosis (scleroderma) 4513
Christopher P. Denton and Carol M. Black
19.11.4 Sjögren’s syndrome 4532
Wan-​Fai Ng SECTION 21
19.11.5 Inflammatory myopathies 4537 Disorders of the kidney and
Ingrid E. Lundberg, Hector Chinoy, and urinary tract
Robert Cooper
Section editor: John D. Firth
19.11.6 Large vessel vasculitis 4546
Raashid Luqmani and Cristina Ponte 21.1 Structure and function of the kidney 4717
Steve Harper and Robert Unwin
19.11.7 ANCA-​associated vasculitis 4556
David Jayne 21.2 Electrolyte disorders 4729
19.11.8 Polyarteritis nodosa 4569 21.2.1 Disorders of water and sodium homeostasis 4729
Loïc Guillevin Michael L. Moritz and Juan Carlos Ayus
19.11.9 Small vessel vasculitis 4573 21.2.2 Disorders of potassium homeostasis 4748
Richard A. Watts John D. Firth
19.11.10 Behçet’s syndrome 4579
21.3 Clinical presentation of renal disease 4764
Sebahattin Yurdakul, Izzet Fresko, and
Richard E. Fielding and Ken Farrington
Hasan Yazici
19.11.11 Polymyalgia rheumatica 4584 21.4 Clinical investigation of renal disease 4781
Bhaskar Dasgupta and Eric L. Matteson Andrew Davenport
19.11.12 Kawasaki disease 4590 21.5 Acute kidney injury 4807
Brian W. McCrindle John D. Firth
19.12 Miscellaneous conditions presenting to the 21.6 Chronic kidney disease 4830
rheumatologist 4598 Alastair Hutchison
Stuart Carter, Lisa Dunkley, and Ade Adebajo
21.7 Renal replacement therapy 4861
21.7.1 Haemodialysis 4861
Robert Mactier
SECTION 20
21.7.2 Peritoneal dialysis 4874
Disorders of the skeleton Simon Davies
Section editor: Cyrus Cooper 21.7.3 Renal transplantation 4879
Nicholas Torpey and John D. Firth
20.1 Skeletal disorders—​general approach and clinical
conditions 4615 21.8 Glomerular diseases 4909
B. Paul Wordsworth and M.K. Javaid 21.8.1 Immunoglobulin A nephropathy and IgA
20.2 Inherited defects of connective tissue: vasculitis (HSP) 4909
Jonathan Barratt and John Feehally
Ehlers–​Danlos syndrome, Marfan’s syndrome,
and pseudoxanthoma elasticum 4670 21.8.2 Thin membrane nephropathy 4918
N.P. Burrows Peter Topham and John Feehally
xxviii Contents

21.8.3 Minimal-​change nephropathy and focal 21.10.6 Haemolytic uraemic syndrome 5027
segmental glomerulosclerosis 4919 Edwin K.S. Wong and David Kavanagh
Moin Saleem and Lisa Willcocks 21.10.7 Sickle cell disease and the kidney 5032
21.8.4 Membranous nephropathy 4928 Claire C. Sharpe
An S. De Vriese and Fernando C. Fervenza 21.10.8 Infection-​associated nephropathies 5034
21.8.5 Proliferative glomerulonephritis 4933 A. Neil Turner
Alan D. Salama and Mark A. Little 21.10.9 Malignancy-​associated renal disease 5041
21.8.6 Membranoproliferative glomerulonephritis 4937 A. Neil Turner
Tabitha Turner-​Stokes and Mark A. Little 21.10.10 Atherosclerotic renovascular disease 5044
21.8.7 Antiglomerular basement membrane Philip A. Kalra and Diana Vassallo
disease 4943
21.11 Renal diseases in the tropics 5049
Mårten Segelmark and Thomas Hellmark
Vivekanand Jha
21.9 Tubulointerstitial diseases 4951
21.12 Renal involvement in genetic disease 5065
21.9.1 Acute interstitial nephritis 4951 D. Joly and J.P. Grünfeld
Simon D. Roger
21.13 Urinary tract infection 5074
21.9.2 Chronic tubulointerstitial nephritis 4956
Charles Tomson and Neil Sheerin
Marc E. De Broe, Channa Yamasumana,
Patrick C. D’Haese, Monique M. Elseviers, and 21.14 Disorders of renal calcium handling, urinary
Benjamin Vervaet stones, and nephrocalcinosis 5093
21.10 The kidney in systemic disease 4975 Christopher Pugh, Elaine M. Worcester, Andrew P. Evan, and
Fredric L. Coe
21.10.1 Diabetes mellitus and the kidney 4975
Rudolf Bilous 21.15 The renal tubular acidoses 5104
21.10.2 The kidney in systemic vasculitis 4988 John A. Sayer and Fiona E. Karet
David Jayne 21.16 Disorders of tubular electrolyte handling 5112
21.10.3 The kidney in rheumatological Nine V.A.M. Knoers and Elena N. Levtchenko
disorders 5001
Liz Lightstone and Hannah Beckwith
21.17 Urinary tract obstruction 5124
Muhammad M. Yaqoob and Kieran McCafferty
21.10.4 The kidney in sarcoidosis 5012
Ingeborg Hilderson and Jan Donck 21.18 Malignant diseases of the urinary tract 5136
21.10.5 Renal involvement in plasma cell dyscrasias, Tim Eisen, Freddie C. Hamdy, and Robert A. Huddart
immunoglobulin-​based amyloidoses, and 21.19 Drugs and the kidney 5150
fibrillary glomerulopathies, lymphomas, and Aine Burns and Caroline Ashley
leukaemias 5016
Pierre Ronco, Frank Bridoux, and Arnaud Jaccard Index

Volume 4

List of abbreviations xxxv 22.1 Introduction to haematology 5169

List of contributors xlv Chris Hatton

22.2 Haematopoiesis 5172

22.2.1 Cellular and molecular basis of haematopoiesis 5172
SECTION 22 Paresh Vyas and N. Asger Jakobsen
Haematological disorders 22.2.2 Diagnostic techniques in the assessment of
Section editors: Chris Hatton and Deborah Hay haematological malignancies 5181
Wendy N. Erber
 Contents xxix

22.3 Myeloid disease 5189 22.6 Erythroid disorders 5354

22.3.1 Granulocytes in health and disease 5189 22.6.1 Erythropoiesis 5354
Joseph Sinning and Nancy Berliner Vijay G. Sankaran
22.3.2 Myelodysplastic syndromes 5197 22.6.2 Anaemia: pathophysiology, classification, and
Charlotte K. Brierley and David P. Steensma clinical features 5359
22.3.3 Acute myeloid leukaemia 5205 David J. Weatherall† and Chris Hatton
Nigel Russell and Alan Burnett 22.6.3 Anaemia as a challenge to world health 5366
22.3.4 Chronic myeloid leukaemia 5213 David J. Roberts and David J. Weatherall†
Mhairi Copland and Tessa L. Holyoake† 22.6.4 Iron metabolism and its disorders 5371
22.3.5 The polycythaemias 5227 Timothy M. Cox and John B. Porter
Daniel Aruch and Ronald Hoffman 22.6.5 Anaemia of inflammation 5402
22.3.6 Thrombocytosis and essential Sant-​Rayn Pasricha and Hal Drakesmith
thrombocythaemia 5239 22.6.6 Megaloblastic anaemia and miscellaneous
Daniel Aruch and Ronald Hoffman deficiency anaemias 5407
22.3.7 Primary myelofibrosis 5247 A.V. Hoffbrand
Evan M. Braunstein and Jerry L. Spivak 22.6.7 Disorders of the synthesis or function of
22.3.8 Eosinophilia 5254 haemoglobin 5426
Peter F. Weller Deborah Hay and David J. Weatherall†
22.6.8 Anaemias resulting from defective maturation
22.3.9 Histiocytosis 5259
Chris Hatton of red cells 5450
Stephen J. Fuller and James S. Wiley
22.4 Lymphoid disease 5263 22.6.9 Disorders of the red cell membrane 5456
22.4.1 Introduction to lymphopoiesis 5263 Patrick G. Gallagher
Caron A. Jacobson and Nancy Berliner 22.6.10 Erythrocyte enzymopathies 5463
22.4.2 Acute lymphoblastic leukaemia 5269 Alberto Zanella and Paola Bianchi
H. Josef Vormoor, Tobias F. Menne, and 22.6.11 Glucose-​6-​phosphate dehydrogenase
Anthony V. Moorman deficiency 5472
22.4.3 Hodgkin lymphoma 5280 Lucio Luzzatto
Vijaya Raj Bhatt and James O. Armitage 22.6.12 Acquired haemolytic anaemia 5479
22.4.4 Non-​Hodgkin lymphoma 5288 Amy Powers and Leslie Silberstein
Vijaya Raj Bhatt and James O. Armitage
22.7 Haemostasis 5490
22.4.5 Chronic lymphocytic leukaemia 5302
22.7.1 The biology of haemostasis and
Clive S. Zent and Aaron Polliack
thrombosis 5490
22.4.6 Plasma cell myeloma and related monoclonal
Gilbert C. White, II, Harold R. Roberts,
gammopathies 5310 and Nigel S. Key
S. Vincent Rajkumar and Robert A. Kyle
22.7.2 Evaluation of the patient with a bleeding
22.5 Bone marrow failure 5325 tendency 5509
22.5.1 Inherited bone marrow failure syndromes 5325 Trevor Baglin
Irene Roberts and Inderjeet S. Dokal 22.7.3 Thrombocytopenia and disorders of platelet
22.5.2 Acquired aplastic anaemia and pure red cell function 5520
aplasia 5336 Nicola Curry and Susie Shapiro
Judith C.W. Marsh, Shreyans Gandhi, 22.7.4 Genetic disorders of coagulation 5532
and Ghulam J. Mufti Eleanor S. Pollak and Katherine A. High
22.5.3 Paroxysmal nocturnal haemoglobinuria 5348 22.7.5 Acquired coagulation disorders 5546
Lucio Luzzatto T.E. Warkentin

†
It is with great regret that we report that Tessa L. Holyoake died on 30 August, †
It is with great regret that we report that David J. Weatherall died on 8 December,
2017. 2018.
xxx Contents

22.8 Transfusion and transplantation 5563 23.16 Cutaneous reactions to drugs 5752
22.8.1 Blood transfusion 5563 Sarah Walsh, Daniel Creamer, and Haur Yueh Lee
D.S. Giovanniello and E.L. Snyder 23.17 Management of skin disease 5761
22.8.2 Haemopoietic stem cell transplantation 5579 Rod Sinclair
E.C. Gordon-​Smith and Emma C. Morris

SECTION 24
SECTION 23 Neurological disorders
Disorders of the skin Section editor: Christopher Kennard
Section editor: Roderick J. Hay
24.1 Introduction and approach to the patient with
23.1 Structure and function of skin 5591 neurological disease 5775
John A. McGrath Alastair Compston and Christopher Kennard

23.2 Clinical approach to the diagnosis of skin 24.2 Mind and brain: Building bridges
disease 5596 between neurology, psychiatry, and
Vanessa Venning psychology 5778
Adam Zeman
23.3 Inherited skin disease 5602
Thiviyani Maruthappu and David P. Kelsell 24.3 Clinical investigation of neurological disease 5781
23.4 Autoimmune bullous diseases 5612 24.3.1 Lumbar puncture 5781
Kathy Taghipour and Fenella Wojnarowska R. Rhys Davies and Andrew J. Larner
24.3.2 Electrophysiology of the central and peripheral
23.5 Papulosquamous disease 5621
nervous systems 5785
Christopher E.M. Griffiths
Christian Krarup
23.6 Dermatitis/​eczema 5630 24.3.3 Imaging in neurological diseases 5802
Peter S. Friedmann, Michael J. Arden-​Jones, and Roderick J. Hay Andrew J. Molyneux, Shelley Renowden, and
Marcus Bradley
23.7 Cutaneous vasculitis, connective tissue
diseases, and urticaria 5639 24.3.4 Investigation of central motor pathways:
Volha Shpadaruk and Karen E. Harman Magnetic brain stimulation 5817
K.R. Mills
23.8 Disorders of pigmentation 5677
Eugene Healy 24.4 Higher cerebral function 5821
24.4.1 Disturbances of higher cerebral function 5821
23.9 Photosensitivity 5688
Peter J. Nestor
Hiva Fassihi and Jane McGregor
24.4.2 Alzheimer’s disease and other dementias 5830
23.10 Infections of the skin 5695 Jonathan M. Schott
Roderick J. Hay
24.5 Epilepsy and disorders of consciousness 5860
23.11 Sebaceous and sweat gland disorders 5699
24.5.1 Epilepsy in later childhood and adulthood 5860
Alison M. Layton
Arjune Sen and M.R. Johnson
23.12 Blood and lymphatic vessel disorders 5709 24.5.2 Narcolepsy 5882
Peter S. Mortimer and Roderick J. Hay Matthew C. Walker
23.13 Hair and nail disorders 5724 24.5.3 Sleep disorders 5886
David de Berker Paul J. Reading
24.5.4 Syncope 5896
23.14 Tumours of the skin 5732
Andrew J. Larner
Edel O’Toole
24.5.5 The unconscious patient 5901
23.15 Skin and systemic diseases 5743 David Bates
Clive B. Archer and Charles M.G. Archer
 Contents xxxi

24.5.6 Brainstem death and prolonged disorders of 24.11.3 Intracranial abscesses 6097
consciousness 5908 Tim Lawrence and Richard S.C. Kerr
Ari Ercole, Peter J. Hutchinson, and John D. Pickard 24.11.4 Neurosyphilis and neuro-​AIDS 6100
Hadi Manji
24.6 Disorders of the special senses 5913
24.11.5 Human prion diseases 6109
24.6.1 Visual pathways 5913
Simon Mead and R.G. Will
Sara Ajina and Christopher Kennard
24.6.2 Eye movements and balance 5922 24.12 Disorders of cranial nerves 6120
Michael Strupp and Thomas Brandt Robert D.M. Hadden
24.6.3 Hearing loss 5931 24.13 Disorders of the spinal cord 6127
Linda Luxon
24.13.1 Diseases of the spinal cord 6127
24.7 Disorders of movement 5937 Anu Jacob and Andrew J. Larner
24.7.1 Subcortical structures: The cerebellum, basal 24.13.2 Spinal cord injury and its management 6135
ganglia, and thalamus 5937 Wagih El Masri(y) and Michael Barnes
Mark J. Edwards and Penelope Talelli
24.14 Diseases of the autonomic nervous system 6150
24.7.2 Parkinsonism and other extrapyramidal Christopher J. Mathias and David A. Low
diseases 5946
Elisaveta Sokolov, Vinod K. Metta, and K. Ray 24.15 The motor neuron diseases 6166
Chaudhuri Tom Jenkins, Alice Brockington, and Pamela J. Shaw
24.7.3 Movement disorders other than Parkinson’s 24.16 Diseases of the peripheral nerves 6176
disease 5956 Robert D.M. Hadden
Bettina Balint and Kailash Bhatia
24.17 Inherited neurodegenerative diseases 6197
24.7.4 Ataxic disorders 5976
Swati Sathe
Nicholas Wood
24.18 Disorders of the neuromuscular junction 6295
24.8 Headache 5987
David Hilton-​Jones and Jacqueline Palace
Peter J. Goadsby
24.19 Disorders of muscle 6304
24.9 Brainstem syndromes 6006
David Bates 24.19.1 Structure and function of muscle 6304
Michael G. Hanna and Enrico Bugiardini
24.10 Specific conditions affecting the central
24.19.2 Muscular dystrophy 6310
nervous system 6010 Kate Bushby and Chiara Marini-​Bettolo
24.10.1 Stroke: Cerebrovascular disease 6010
24.19.3 Myotonia 6328
J. van Gijn (revised by Peter M. Rothwell)
David Hilton-​Jones
24.10.2 Demyelinating disorders of the central nervous
24.19.4 Metabolic and endocrine disorders 6334
system 6026
David Hilton-​Jones and Richard Edwards
Alasdair Coles and Siddharthan Chandran
24.19.5 Mitochondrial disease 6343
24.10.3 Traumatic brain injury 6042
Patrick F. Chinnery and D.M. Turnbull
Tim Lawrence and Laurence Watkins
24.10.4 Intracranial tumours 6048 24.20 Developmental abnormalities of the central
Jeremy Rees nervous system 6350
Chris M. Verity, Jane A. Hurst, and Helen V. Firth
24.10.5 Idiopathic intracranial hypertension 6054
Alexandra Sinclair 24.21 Acquired metabolic disorders and the nervous
24.11 Infections of the central nervous system 6060 system 6368
Neil Scolding
24.11.1 Bacterial infections 6060
Diederik van de Beek and Guy E. Thwaites 24.22 Neurological complications of systemic
24.11.2 Viral infections 6082 disease 6376
Fiona McGill, Jeremy Farrar, Bridget Wills, Menno Neil Scolding
De Jong, David A. Warrell, and Tom Solomon
xxxii Contents

24.23 Paraneoplastic neurological syndromes 6384 26.5.3 Organic psychoses 6482

Jeremy Rees Curtis McKnight and Jason Caplan
26.5.4 Alcohol misuse 6486
24.24 Autoimmune encephalitis and Morvan’s
Jonathan Wood
syndrome 6393
Camilla Buckley and Angela Vincent 26.5.5 Substance misuse 6490
Stephen Potts
26.5.6 Depressive disorder 6493
Joseph Cerimele and Lydia Chwastiak
SECTION 25
26.5.7 Bipolar disorder 6498
Disorders of the eye Kate E.A. Saunders and John Geddes
Section editor: Christopher P. Conlon 26.5.8 Anxiety disorders 6501
Ted Liao and Steve Epstein
25.1 The eye in general medicine 6399
Tasanee Braithwaite, Richard W.J. Lee, and Peng T. Khaw 26.5.9 Acute stress disorder, adjustment disorders,
and post-​traumatic stress disorder 6506
Jonathan I. Bisson
26.5.10 Eating disorders 6509
SECTION 26 Christopher G. Fairburn
Psychiatric and drug-​related disorders 26.5.11 Schizophrenia 6513
Section editor: Michael Sharpe Stephen M. Lawrie
26.5.12 Somatic symptom and related
26.1 General introduction 6445
disorders 6517
Michael Sharpe
Michael Sharpe
26.2 The psychiatric assessment of the medical 26.5.13 Personality disorders 6520
patient 6447 Iain Jordan
Jane Walker, Roger Smyth, and Michael Sharpe
26.6 Changing unhealthy behaviours 6524
26.3 Common psychiatric presentations in medical
26.6.1 Brief interventions for excessive alcohol
patients 6454 consumption 6524
26.3.1 Confusion 6454 Amy O’Donnell, Eileen Kaner, and Nick Heather
Bart Sheehan and Thomas Jackson
26.6.2 Obesity and weight management 6529
26.3.2 Self-​harm 6457 Susan Jebb and Paul Aveyard
Kate E.A. Saunders and Keith Hawton
26.6.3 Smoking cessation 6533
26.3.3 Medically unexplained symptoms 6460 Paul Aveyard
Michael Sharpe
26.7 Psychiatry, liaison psychiatry, and
26.3.4 Low mood 6462
psychological medicine 6536
Jane Walker
Michael Sharpe
26.4 Psychiatric treatments in the medically ill 6465
26.4.1 Psychopharmacology in medical practice 6465
Philip J. Cowen SECTION 27
26.4.2 Psychological treatments 6470
Forensic medicine
Michael Sharpe and Simon Wessely
Section editor: John D. Firth
26.5 Specific psychiatric disorders 6475
27.1 Forensic and legal medicine 6541
26.5.1 Delirium 6475
Jason Payne-​James, Paul Marks, Ralph Bouhaidar, and
Bart Sheehan
Steven B. Karch
26.5.2 Dementia 6478
Bart Sheehan
 Contents xxxiii

SECTION 28 SECTION 30
Sport and exercise medicine Acute medicine
Section editor: John D. Firth Section editor: John D. Firth
28.1 Sport and exercise medicine 6565 30.1 Acute medical presentations 6591
Cathy Speed Sian Coggle, Elaine Jolly, and John D. Firth

30.2 Practical procedures 6644

Elaine Jolly, Sian Coggle, and John D. Firth
SECTION 29
Index
Biochemistry in medicine
Section editor: Christopher P. Conlon
29.1 The use of biochemical analysis for diagnosis
and management 6577
Brian Shine and Nishan Guha
Abbreviations

5-​FU 5-​fluorouracil ALF acute liver failure

5-​HIAA 5-​hydroxyindoleacetic acid ALL acute lymphoblastic leukaemia
5-​HT 5-​hydroxytryptamine alloSCT allogeneic stem cell transplantation
5-​HT 5-​hydroxytryptamine ALP alkaline phosphatase
AAA acquired aplastic anaemia ALS amyotrophic lateral sclerosis
AAFB acid-​and alcohol-​fast bacilli ALT alanine aminotransferase
AASLD American Association for the Study of Liver Diseases AMA antimitochondrial antibody
AAV antineutrophil cytoplasm autoantibody-associated AML acute myeloid leukaemia
vasculitis (also aplastic anaemia AMLR autologous mixed lymphocyte reactions
ABC ATP-​binding cassette AMT Abbreviated Mental Test
ABCDE airway, breathing, circulation, disability, and exposure ANA antinuclear autoantibodies
ABG arterial blood gas ANC absolute neutrophil count
ABMR antibody-​mediated rejection ANCA antineutrophil cytoplasmic antibodies
ABPA allergic bronchopulmonary aspergillosis ANP atrial natriuretic peptide
ABPM ambulatory blood pressure measurement AOSD adult-​onset Still’s disease
ACE angiotensin-​converting enzyme AP alternative pathway
AChE acetylcholinesterase, define at first mention APA aldosterone-​producing adenoma
ACPA anticitrullinated peptide/​protein antibodies APC antigen presenting cell
ACR American College of Rheumatology (also APCM active physiological conservative management
albumin:creatinine ratio) APL acute promyelocytic leukaemia
ACS acute coronary syndromes APS antiphospholipid syndrome
ACTH adrenocorticotropic hormone APTT activated partial thromboplastin time
AD Alzheimer’s disease AR androgen receptor
ADEM acute disseminated encephalomyelitis ara-​C cytosine arabinoside
ADH antidiuretic hormone ARB angiotensin receptor blocker
ADL activities of daily living ARDS adult respiratory distress syndrome
ADME absorption, distribution, metabolism, and excretion ARF acute renal failure
ADPKD autosomal dominant polycystic kidney disease ARH autosomal recessive hypercholesterolaemia
ADR adverse drug reaction ARPKD autosomal recessive polycystic kidney disease
ADRT advanced decision to refuse treatment ART antiretroviral therapy
AECA antiendothelial cell antibodies ARVC arrhythmogenic right ventricular cardiomyopathy
AF atrial fibrillation ARVD atherosclerotic renovascular disease
AFP α-​fetoprotein AS ankylosing spondylitis
AGT alanine–​glyoxylate aminotransferase ASAS Assessment of SpondyloArthritis International
aGVHD acute graft-​versus-​host disease Society
AHA American Heart Association ASCT autologous stem cell transplantation
aHUS atypical haemolytic uraemic syndrome ASD atrial septal defect
AIF apoptosis-​inducing factor ASH Action on Smoking and Health
AIHA autoimmune haemolytic anaemia ASOT antistreptolysin O titre
AIN acute interstitial nephritis AST aspartate aminotransferase
AIP autoimmune pancreatitis (also acute interstitial ATG antithymocyte globulin
pneumonia) ATP adenosine triphosphate
AIS androgen insensitivity syndromes ATRA all-​trans-​retinoic acid
AKI acute kidney injury AV aortic valve
ALD alcoholic liver disease AVN arteriovenous nipping
xxxvi Abbreviations

AVSD atrioventricular septal defect CHAD cold haemagglutinin disease

AZA azacitidine CHD coronary heart disease
BCAA branched-​chain amino acid CHF congestive heart failure
BCC basal cell carcinoma CHM Commission on Human Medicines
BCG bacillus Calmette–​Guérin CINAC chronic interstitial nephritis in agricultural
BEN Balkan endemic nephropathy communities
BH4 tetrahydrobiopterin CINCA chronic infantile neurological, cutaneous, and
BHS British Hypertension Society articular syndrome
BICC betaferon in chronic viral cardiomyopathy CISN coumarin-​induced skin necrosis
BKV BK polyomavirus CK creatine kinase
BM bone marrow CKD chronic kidney disease
BMD bone mineral density CKD-​EPI Chronic Kidney Disease Epidemiology Collaboration
BMF bone marrow failure CLL chronic lymphocytic leukaemia
BMI body mass index CML chronic myeloid leukaemia
BMP bone morphogenic protein CMR cardiac magnetic resonance
BNF British National Formulary CMS congenital myasthenic syndrome
BNP B-​type natriuretic peptide CMT Charcot–​Marie–​Tooth disease
BOS bronchiolitis obliterans syndrome CMV cytomegalovirus
BP blood pressure CNI calcineurin inhibitor
BPG biphosphoglycerate CNS central nervous system
BRAO branch artery occlusion CNSHA congenital non-​spherocytic haemolytic anaemia
BRVO branch retinal vein occlusion CO cardiac output
BSEP haemolysis, elevated liver enzymes, and low CoA coenzyme A
platelet count COPD chronic obstructive pulmonary disease
BSP bromosulphthalein COX cyclooxygenase
BTS British Thoracic Society CPAP continuous positive airway pressure
BUN blood urea nitrogen CPM central pontine myelosis
CA carbohydrate antigen CPP central precocious puberty
CABG coronary artery bypass grafting CPPS chronic pelvic pain syndrome
CAF Comprehensive Assessment for Frailty CPR cardiopulmonary resuscitation
CAH congenital adrenal hyperplasia CR complete remission
CAM Confusion Assessment Method CRDQ Chronic Respiratory Disease Questionnaire
CAMT congenital amegakaryocytic thrombocytopenia CREST calcinosis, Raynaud’s, oesophageal dysmotility,
CAP community-​acquired pneumonia sclerodactyly, telangiectasia
CAPS cryopyrin-​associated periodic syndromes CRF chronic renal failure
CaR calcium-​sensing receptor CRH corticotropin-​releasing hormone
CAT COPD assessment test CRIM cross-​immunoreactive material
CBT cognitive behaviour therapy CRP C-​reactive protein
CCB calcium channel blocker CRT cardiac resynchronization therapy
CCK cholecystokinin CS continuous smokers
CCP anticyclic citrullinated peptide CSF cerebrospinal fluid/​colony-​stimulating factor
CCQ Clinical COPD questionnaire CT computed tomography
CCV clathrin-​coated vesicles CTA computed tomography angiography
CCyR complete cytogenetic response CTCA computed tomography coronary angiography
CD cluster of differentiation CTD connective tissue disease
CDA congenital dyserythropoietic anaemia CTEPH chronic thromboembolic pulmonary hypertension
CDC donation after circulatory death CTL cytotoxic T-​lymphocyte
CEA carcinoembryonic antigen CVD cardiovascular disease
CETP cholesteryl ester transfer protein CVID common variable immunodeficiency
CF cystic fibrosis CVS chorionic villus sampling
CFA cryptogenic fibrosing alveolitis CXR chest radiograph
cfDNA cell-​free DNA CYP cytochrome P450
CFS Clinical Frailty Scale CZT cadmium zinc telluride
CFTR cystic fibrosis transmembrane regulator DAEC diffusely adherent Escherichia coli
CFU colony forming unit DALY disability-​adjusted life year
CGA comprehensive geriatric assessment DAMP damage-​associated molecular pattern
CGRP calcitonin gene-​related peptide DASH Dietary Approaches to Stop Hypertension
cGVHD chronic graft-​versus-​host disease DAT direct antiglobulin test
  Abbreviations xxxvii

DBA Diamond–​Blackfan anaemia ECV extracellular volume

DBD donation after brain death EDMD Emery–​Dreifuss muscular dystrophy
DBP diastolic blood pressure EDRF endothelial-​derived relaxing factor
DC dyskeratosis congenita (also dendritic cell) EDTA European Dialysis and Transplant Association
DCA directional coronary atherectomy EDV end-​diastolic volume
DCCT Diabetes Control and Complications Trial EEG electroencephalography
DCD donation after circulatory death EELV end expiratory lung volume
DCI decompression illness EGF epidermal growth factor
dcSSc diffuse cutaneous systemic sclerosis eGFR estimated glomerular filtration rate
DCT distal convoluted tubule EGPA eosinophilic granulomatosis with polyangiitis
DDAVP 1-​deamino-​8-​d-​arginine vasopressin EIEC enteroinvasive Escherichia coli
DDD dense deposit disease EIS endoscopic injection sclerotherapy
DECAF dyspnoea, eosinopenia, consolidation, acidosis, and ELCA excimer laser coronary atherectomy
atrial fibrillation ELISA enzyme-​linked immunosorbent assay
DGP deamidated gliadin peptide EM erythema multiforme (also electron microscopy)
DHG dihydroxyglutarate EMA endomysial antibody
DIC disseminated intravascular coagulation EMG electromyography
DIC disseminated intravascular coagulation EMS early morning urethral smear
DILI drug-​induced liver injury ENA extractable nuclear antigens
DILV double-​inlet left ventricle ENaC epithelial sodium channel
DIP desquamative interstitial pneumonia ENT ear, nose, or throat
DISC death-​initiating signalling complex EOL end of life
DISH diffuse idiopathic skeletal hyperostosis EoO eosinophilic oesophagitis
DLB dementia with Lewy bodies EPCR endothelial cell protein C receptor
DLBCL diffuse large B-​cell lymphoma EPEC enteropathogenic Escherichia coli
DMARD disease-​modifying antirheumatic drug EPO erythropoietin
DMD disease-​modifying drugs (can also mean Duchenne ER endoplasmic reticulum
muscular dystrophy) ERA European Renal Association
DMSA dimercaptosuccinic acid ERC endoscopic retrograde cholangiography
DNACPR do-​not-​attempt-​cardiopulmonary resuscitation ERCP endoscopic retrograde cholangiopancreatography
DNR do not resuscitate ERNV equilibrium radionuclide ventriculography
DOAC direct oral anticoagulant ERS European Respiratory Society
DOCA desoxycorticosterone ESA erythropoiesis-​stimulating agent
DOPPS Dialysis Outcomes and Practice Patterns Study ESC European Society of Cardiology
DORV double-​outlet right ventricle ESGE European Society of Gastrointestinal Endoscopy
DPI dry powder inhalers ESH European Society of Hypertension
DRE digital rectal examination ESKD end-​stage kidney disease
DRESS drug reaction with eosinophilia and systemic ESR erythrocyte sedimentation rate
symptoms ESRD end-​stage renal disease
dRTA distal renal tubular acidosis ESS EULAR sicca score
DSA donor-​specific antibodies ESWL extracorporeal shock-​wave lithotripsy
DTC direct to consumer ETEC enterotoxigenic Escherichia coli
DTPA diethylenetriaminepentaacetic acid EUS endoscopic ultrasonography
DVT deep vein thrombosis EVLP ex-​vivo lung perfusion
DXA dual energy X-​ray absorptiometry EVO endoscopic variceal obturation
EACTS European Association for Cardio-​Thoracic Surgery FA Fanconi’s anaemia
EAggEC enteroaggregative Escherichia coli FACIT fibril-​associated collagen with interrupted triple
EANM European Association of Nuclear Medicine FAK focal adhesion kinase
EAPCI European Association of Percutaneous FAP familial adenomatous polyposis
Cardiovascular Interventions FBC full blood count
EASL European Association for the Study of the Liver FCAS familial cold autoinflammatory syndrome
EATL enteropathy-​associated T-​cell lymphoma FCHL familial combined hyperlipidaemia
EBV Epstein–​Barr virus FDA Food and Drug Administration
ECD extended criteria donor FDG fluorodeoxyglucose
ECF extracellular fluid FDG-​PET fluorodeoxyglucose-​positron emission tomography
ECG electrocardiogram FDP fibrinogen-​degradation product
ECLAM European community lupus activity measure FEV forced expiratory volume
ECM extracellular matrix FEV1 forced expiratory volume in 1 s
xxxviii Abbreviations

FFR fractional flow reserve GSD glycogen storage disease

FGF fibroblast growth factor GSGS focal segmental glomerulosclerosis
FH familial hypercholesterolaemia GSH glutathione
FISH fluorescent in situ hybridization GU gonococcal urethritis
FL follicular lymphoma GUM genitourinary medicine
FLC free light chain GVHD graft-​versus-​host disease
FMF familial Mediterranean fever GVL graft-​versus-​leukaemia
FMTC familial medullary thyroid carcinoma GWAS genome-​wide association study
FNAB fine needle aspiration biopsy H&E haematoxylin and eosin stain
FNH focal nodular hyperplasia HAART highly active antiretroviral therapy
FOB faecal occult blood HAND HIV-​associated neurocognitive disorder
FODMAPs fermentable oligosaccharides, disaccharides, HAV hepatitis A virus
monosaccharides, and polyols HBc hepatitis B core
FRC functional residual capacity HBeAG hepatitis B e antigen
FSGS focal segmental glomerulosclerosis HBIg hepatitis B immunoglobulin
FSH follicular stimulating hormone HBPM home blood pressure measurement
FTD frontotemporal dementia HBsAG hepatitis B surface antigen
FVC forced vital capacity HBV hepatitis B virus
FVU first voided urine HCC hepatocellular carcinoma
G6PD glucose-​6-​phosphate dehydrogenase HCG human chorionic gonadotropin
GABA γ-​aminobutyric acid HCV hepatitis C virus
GAD generalized anxiety disorder HD haemodialysis
GALT gut-​associated lymphoid tissue HDF haemodiafiltration
GAVE gastric antral vascular ectasia HDL high-​density lipoprotein
GBD Global Burden of Disease HDL-​C high-​density lipoprotein cholesterol
GBM glomerular basement membrane HDU high-​dependency unit
G-​CSF granulocyte colony-​stimulating factor HDV hepatitis D virus
GCA giant cell arteritis HE hepatic encephalopathy or hereditary elliptocytosis
GCS Glasgow Coma Score HELLP haemolysis, elevated liver enzymes and low platelets
GDF growth differentiation factors HES hypereosinophilic syndrome
GEP gastroenteropancreatic hESC human embryonic stem cell
GFB glomerular filtration barrier HETE hydroxyeicosatetraenoic acid
GFR glomerular filtration rate HEV hepatitis E virus
GH growth hormone HF haemofiltration
GI gastrointestinal HFA Heart Failure Association
GIB gastrointestinal bleeding HFnEF heart failure with a normal ejection fraction
GIE glucocorticoid inhibitory element HFOV high-​frequency oscillatory ventilation
GIP gastric inhibitor peptide HFV high-​frequency ventilation
GIST gastrointestinal stromal tumour HHT hereditary haemorrhagic telangiectasis/​
GLP glucagon-​like peptide 15-​hydroxy-​5,8,10-​hepatrotrienoic acid
GM-​CSF granulocyte–​macrophage colony-​stimulating factor HHV human herpesvirus
GM/​MS gas chromatography–​mass spectrometry HIF hypoxia-​inducible factors
GN glomerulonephritis HIV human immunodeficiency virus
GnRH gonadotropin-​releasing hormone HIV-​OL human immunodeficiency virus oral lesion
GOLD Global Initiative for Obstructive Lung Disease HK high molecular weight kininogen
GOMMID glomerulonephritis with organized microtubular HL hepatic lipase
monoclonal immunoglobulin deposits HLA human leucocyte antigen
GORD gastro-​oesophageal reflux disease HLH haemophagocytic lymphohistiocytosis
GOV gastro-​oesophageal varices HLHS hypoplastic left heart syndrome
GP glycoprotein (also general practitioner) HMA hypomethylating agent
GPA granulomatosis with polyangiitis HOGA 4-​hydroxy-​2-​oxoglutarate aldolase
GPCR G-​protein-​coupled-​receptors HPA hypothalamic-​pituitary-​adrenal
GPI glycosylphosphatidylinositol HPG hypothalamic-​pituitary-​gonadal
GRACE Global Registry of Acute Coronary Events HPLC high-​performance liquid chromatography
GRADE Grading of Recommendations, Assessment, HPP hereditary pyropoikilocytosis
Development and Evaluations HPRT hypoxanthine-​guanine phosphoribosyltransferase
GRHPR glyoxylate/​hydroxypyruvate reductase HPV human papillomavirus
  Abbreviations xxxix

HRA high-​resolution anoscopy ISH International Society of Hypertension

HRCT high-​resolution computed tomography ISHLT International Society for Heart and Lung
HRT hormone replacement therapy Transplantation
HS hereditary spherocytosis ISIS International Study of Infarct Survival
HSC haematopoietic stem cell or hepatic stellate cell ISWT incremental shuttle walking test
HSCT haemopoietic stem cell transplantation ITP immune thrombocytopenia
HSP Henoch–​Schönlein purpura ITU intensive care unit
HSPC haematopoietic stem and progenitor cell IV intravenous
HSV herpes simplex virus IVC inferior vena cava
HUS haemolytic uraemic syndrome IVF in vitro fertilization
HUV hypocomplementaemic urticarial vasculitis IVIG intravenous immunoglobulin
IADL instrumental activities of daily living IVU intravenous urography
IAS insulin autoimmune syndrome JE Japanese encephalitis
IBD irritable bowel disease JIA juvenile idiopathic arthritis
IBS irritable bowel syndrome JNC Joint National Committee
IBS-​C irritable bowel syndrome with constipation KDIGO Kidney Disease: Improving Global Outcomes
IBS-​D irritable bowel syndrome with diarrhoea LA left atrium
IBS-​M irritable bowel syndrome with alternating LAMA long-​acting antimuscarinic agents
constipation and diarrhoea LBBB left bundle branch block
IC intercalated cell LCAT lecithin–​cholesterol acyltransferase
ICAM intercell adhesion molecules LCH Langerhans’ cell histiocytosis
ICD implantable cardioverter-​defibrillator lcSSc limited cutaneous systemic sclerosis
ICP intracranial pressure LDH lactate dehydrogenase
ICS inhaled oral corticosteroids LDL low-​density lipoprotein
ICU intensive care unit LDL-​C low-​density lipoprotein cholesterol
IDA iminodiacetic acid LFT liver function test
IDL intermediate-​density lipoprotein LGE late gadolinium enhancement
IEC intestinal epithelial cell LGMD limb-​girdle muscular dystrophy
IF intrinsic factor LGV lymphogranuloma venereum
IFG impaired fasting glucose LH luteinizing hormone
IFN interferon LIC liver iron content
Ig immunoglobulin LINQ Lung Information Needs Questionnaire
IgAN immunoglobulin A nephropathy LIP lymphocytic interstitial pneumonia
IgE immunoglobulin E LKM liver–​kidney microsomal
IGF insulin-​like growth factors LMICs low-​and middle-​income countries
IgG4-​RD immunoglobulin G4-​related disease LMN lower motor neuron
IgG4-​SC immunoglobulin G4-​related sclerosing cholangitis LMWH low molecular weight heparin
IGV isolated gastric varices LMWP low molecular weight protein
IHD ischaemic heart disease LOLA l-​ornithine l-​arginine
IHME Institute for Health Metrics and Evaluation LP lumbar puncture
IIH idiopathic intracranial hypertension LPL lipoprotein lipase
IIP idiopathic interstitial pneumonias LPLR lipoprotein lipase receptor
IL interleukin LTOT long-​term oxygen therapy
ILC innate lymphoid cell LV left ventricle
ILD interstitial lung disease LVDD left ventricular diastolic dysfunction
IMA inferior mesenteric artery LVEF left ventricular ejection fraction
INR international normalized ratio LVOT left ventricular outflow tract
IPAF interstitial pneumonitis with autoimmune features LVRS lung volume reduction surgery
IPEX immunodysregulation polyendocrinopathy LVSD left ventricular systolic dysfunction
enteropathy X-​linked MAG3 mercaptoacetyltriglycine
IPF idiopathic pulmonary fibrosis MAGIC MAGnesium in Coronaries
IPI International Prognostic Index MAHA microangiopathic haemolytic anaemia
iPSC induced pluripotent stem cell MALT mucosa-​associated lymphoid tissue
IPSID immunoproliferative small intestinal disease MAO monoamine oxidase inhibitor
IRIDA iron-​refractory iron deficiency anaemia MAP mean arterial pressure
IRIS immune reconstitution inflammatory syndrome MAPK mitogen-​activated protein kinase
IRM immunoradiographic assay MBD mineral and bone disorder
IRV Inspiratory and expiratory reserve volume M-​CSF macrophage colony-​stimulating factor
xl Abbreviations

MCHC mean cell haemoglobin concentration NAFLD nonalcoholic fatty liver disease
MCL mantle cell lymphoma NAIT neonatal alloimmune thrombocytopenia
MCNS minimal change nephrotic syndrome NASH nonalcoholic steatohepatitis
MCpEF myocarditis with preserved left ventricular ejection NCAM neural-​cell adhesion molecule
fraction NEP neutral endopeptidase
MCV mean corpuscular volume NET neuroendocrine tumour or neutrophil
MDE myeloma-​defining event extracellular trap
MDI metered dose inhalers NETT National Emphysema Therapy Trial
MDRD Modification of Diet in Renal Disease NEWS National Early Warning Score
MDS myelodysplastic syndrome NGF nerve growth factor
MED minimal erythema dose NGS next-​generation sequencing
MELD Model for End-​Stage Liver Disease NHDL-​C non-​high-​density lipoprotein cholesterol
MEN multiple endocrine neoplasia NHL non-​Hodgkin’s lymphoma
MERFF myoclonic epilepsy and ragged red fibres NHS National Health Service (UK)
mESC mouse embryonic stem cell NICE National Institute for Health and Care Excellence
MGRS monoclonal gammopathy of renal significance NIPPV non-​invasive nasal positive-​pressure ventilation
MGUS monoclonal gammopathy of undetermined NIPT non-​invasive prenatal testing
significance NIV non-​invasive ventilation
MHC major histocompatibility complex NK natural killer
MHRA Medicines and Healthcare Products NKT natural killer T
Regulatory Agency NLST National Lung Screening Trial
MIC minimum inhibitory concentration NMS neuroleptic malignant syndrome
MIDD monoclonal immunoglobulin deposition diseases NMSC non-​melanoma skin cancer
MKD mevalonate kinase deficiency NNH number needed to harm
MM malignant melanoma NNT number needed to treat
MMA methylmalonic acid NOTT Nocturnal Oxygen Treatment Trial
MMF mycophenolate mofetil NREM non-​rapid eye movement
MMP matrix metalloproteinase NRT nicotine replacement therapy
MMR mismatch repair NSAID non-​steroidal anti-​inflammatory drug
MN membranous nephropathy NSCLC non-​small cell lung cancer
MND motor neuron disease NSIP non-​specific interstitial pneumonia
MoCA Montreal Cognitive Assessment NSTEMI non-​ST-​elevation myocardial infarction
MPA microscopic polyangiitis NTD neural tube defect
MPO myeloperoxidase NTM non-​tuberculous mycobacterial
MPS mucopolysaccharidosis (also myocardial perfusion NT-​proBNP N-​terminal B-​type natriuretic peptide
scintigraphy) NYHA New York Heart Association
MR magnetic resonance OAF osteoclast-​activating factor
MRA magnetic resonance angiography (can also be OAPR odds of being affected given a positive result
medicine regulatory authority) OB obliterative bronchiolitis
MRC Medical Research Council OCD obsessive–​compulsive disorder
MRCP magnetic resonance cholangiopancreatography OCT optical coherence tomography
MRI magnetic resonance imaging OD once daily
MRSA methicillin-​resistant Staphylococcus aureus OECD Organisation for Economic Cooperation and
MS multiple sclerosis Development
MS/​MS tandem mass spectroscopy OED other eating disorders
MSA multiple-​system atrophy OLP oral lichen planus
MSC mesenchymal stromal cell OMIM Online Mendelian Inheritance in Man
MSH melanocyte-​stimulating hormone OMT optimal medical therapy
MSU midstream urine OPAT outpatient parenteral antibiotic therapy
MTC medullary thyroid carcinoma OR odds ratio
mTOR mammalian target of rapamycin OS overall survival
MUS medically unexplained symptoms OSA obstructive sleep apnoea
MWS Muckle–​Wells syndrome OTB oral tuberculosis
NAAT nucleic acid amplification testing PA pernicious anaemia (also pulmonary artery)
NABQI N-​acetyl-​p-​benzoquinone imine PACAP pituitary adenylate cyclase activating polypeptide
NADH reduced nicotinamide-​adenine dinucleotide PAF platelet activating factor
NADPH reduced nicotinamide-​adenine dinucleotide PAH polycyclic aromatic hydrocarbons (can also mean
phosphate pulmonary hypertension)
  Abbreviations xli

PAOP pulmonary artery occlusion pressure PRR pattern-​recognition receptor

PAS periodic acid–​Schiff PRrP parathyroid-​hormone-​related protein
PASI Psoriasis Area and Severity Index PSA prostate-​specific antigen
PASP pulmonary artery systolic pressure PSC primary sclerosing cholangitis
PBD polyglucosan body disease PSP primary spontaneous pneumothorax
PBM peripheral blood mononuclear cell PT prothrombin time
PCC prothrombin complex concentrate PTC percutaneous transhepatic cholangiography
PCH paroxysmal cold haemoglobinuria (also pulmonary PTCA percutaneous transluminal coronary angioplasty
capillary haemangiomatosis) PTH parathyroid hormone
PCI percutaneous coronary intervention PTHrP PTH/​PTH-​related peptide
PCNSL primary central nervous system lymphoma PTLD post-​transplant lymphoproliferative disorder
Pco partial pressure of carbon dioxide PTP post-​transfusion purpura
PCP Pneumocystis jirovecii pneumonia PTSD post-​traumatic stress disorder
PCR polymerase chain reaction (also PUVA psoralen ultraviolet A
protein:creatinine ratio) PV pemphigus vulgaris (also plasmas viscosity test)
PCT proximal convoluted tubule PVE prosthetic valve endocarditis
PCV pneumococcal conjugate vaccine PVOD pulmonary veno-​occlusive disease
PCWP pulmonary capillary wedge pressure PVR pulmonary vascular resistance
PD peritoneal dialysis (also Parkinson’s disease) PYY peptide tyrosine-​tyrosine
PDA patent ductus arteriosus QALY quality-​adjusted life year
PDC pyruvate dehydrogenase complex RA rheumatoid arthritis (can also mean right atrium)
PDD Parkinson’s disease dementia RAAS renin–​angiotensin–​aldosterone system
PDGF platelet-​derived growth factor RAS renin–​angiotensin system (also renal artery stenosis
PE pleural effusion (can also mean pulmonary embolism) or restrictive allograft syndrome
PEACH Pelvic Inflammatory Disease Evaluation and RAVV right atrioventricular valve
Clinical Health RBBB right bundle branch block
PEEP positive end expiratory pressure RBF rat bite fevers
PEF peak expiratory flow RCA right coronary artery
PEG percutaneous endoscopic gastrostomy RCC renal cell carcinoma
PET position emission tomography RCDP rhizomelic chondrodysplasia punctata
PFO patent foramen ovale RCT randomized controlled trial
PFS progression-​free survival RDA recommended dietary allowance
PGK phosphoglycerate kinase REM rapid eye movement
PHARC polyneuropathy, hearing loss, ataxia, retinitis RF rheumatoid factor
pigmentosa, and cataract RI resistivity index
PICS post-​intensive care syndrome RNA ribonucleic acid
PID pelvic inflammatory disease RNI reference nutrient intake
PIGN postinfectious glomerulonephritis RNP ribonucleoprotein
PK pyruvate kinase ROC receiver–​operator characteristic
PKD pyruvate kinase deficiency (also polycystic kidney RP ribosomal protein
disease) RRT renal replacement therapy
PKU phenylketonuria RTA renal tubular acidosis
PLA2R phospholipase A2 receptor RV residual volume (also right ventricle)
PMN polymorphonuclear neutrophil RVOTO right ventricular outflow tract obstruction
PMR polymyalgia rheumatica SA short-​axis
PNH paroxysmal nocturnal haemoglobinuria SABR stereotactic ablative body radiotherapy
Po2 partial pressure of oxygen SBP spontaneous bacterial peritonitis (also systolic blood
POC point of care pressure)
POMC pro-​opiomelanocortin SCC squamous cell carcinoma
PP polypeptide SCD sickle cell disease (also sudden cardiac death)
PPI proton pump inhibitor SCI spinal cord injuries
ppm parts per million SCID severe combined immunodeficiency
PPS Palliative Performance Scale SCLC small cell lung cancer
PPV porcine parvovirus SCMR Society for Cardiovascular Magnetic Resonance
PR3 proteinase 3 SCN sickle cell nephropathy or severe congenital
PRCA pure red cell aplasia neutropenia
PRI population reference intake sdLDL small dense low-​density lipoprotein
PRPP phosphoribosyl pyrophosphate SDS Shwachman–​Diamond syndrome
xlii Abbreviations

SEER Surveillance, Epidemiology, and End Results THR total hip replacement
SGRQ St George’s Respiratory Questionnaire THRIVE Treatment of HDL to Reduce the Incidence of
SHBG sex hormone binding globulin Vascular Events
SHEC Shiga toxin-​producing Escherichia coli TIA transient ischaemic attack
SIADH syndrome of inappropriate antidiuretic hormone TIBC total iron-​binding capacity
secretion TIMI thrombolysis in myocardial infarction
SIRS systemic inflammatory response syndrome TINU tubulointerstitial nephritis uveitis
SLB surgical lung biopsy TIPS transjugular intrahepatic portosystemic shunt
SLE systemic lupus erythematosus TK tyrosine kinase
SM smouldering myeloma TKI tyrosine kinase inhibitor
SMA superior mesenteric artery (also smooth muscle TKR total knee replacement
antibody) TLC total lung capacity
SMC smooth muscle cell TLR Toll-​like receptor
sMDRD simplified Modification of Diet in Renal Disease TMA thrombotic microangiopathy
SMR standardized mortality ratio t-​MDS therapy-​related myelodysplastic syndrome(s)
SNGFR single-​nephron glomerular filtration rate TNF tumour necrosis factor
SNP single nucleotide polymorphism TNFα tumour necrosis factor-​α
SNS sympathetic nervous system tPA tissue plasminogen activator
SOD sphincter of Oddi disorder TPN total parenteral nutrition
SPC Summary of Product Characteristics TPN total parenteral nutrition
SPD storage pool deficiency TRAIL TNF-​related apoptosis-​inducing ligand
SPECT single-​positron emission computed tomography TRAPS tumour necrosis factor receptor-​associated
SPF sun protection factor periodic syndrome
SSc systemic sclerosis Treg regulatory T (cell)
SSD somatic symptom disorder TROPHY Trial of Preventing Hypertension
SSFP steady-​state free precession TSH thyroid-​stimulating hormone
SSRI selective serotonin reuptake inhibitor TTD thiazide-​type diuretic
STEMI ST elevation myocardial infarction tTG tissue transglutaminase
STI sexually transmitted infection TTIP Transatlantic Trade and Investment Partnership
STOPP/​START set of inappropriate combinations of medicines TTKG transtubular potassium concentration gradient
and disease (STOPP) and a set of recommended TTP thrombotic thrombocytopenic purpura
treatments for given conditions (START) TURBT transurethral resection of bladder tumour
suPAR soluble urokinase plasminogen activating TV tricuspid valve
receptor UAER urinary albumin excretion rate
SVC superior vena cava UCB umbilical cord blood
SVR systemic vascular resistance UDCA ursodeoxycholic acid
TACE transarterial chemoembolization UDP uridine diphosphate
TAE transarterial embolization UI urinary incontinence
TALH thick ascending limb of Henle UIP usual interstitial pneumonia
TAR thrombocytopenia with absent radii UKELD United Kingdom Model for End-​Stage Liver
TAVI transcatheter aortic valve implantation Disease
TB tuberculosis UKM urea kinetic modelling
TBLC transbronchial lung cryobiopsy UKMEC UK Medical Eligibility Criteria
TBM tuberculous meningitis UKPDS United Kingdom Prospective Diabetes Study
TC total cholesterol ULN upper limit of normal
TCA tricyclic antidepressant UMN upper motor neuron
TCPC total cavopulmonary connection UPR unfolded protein response
TCR T-​cell receptor URR urea reduction ratio
TCT thrombin clotting time URTI upper respiratory tract infection
TdT terminal deoxyribonucleotidyl transferase UTI urinary tract infection
TEC transient erythroblastopenia of childhood UV ultraviolet
TEN toxic epidermal necrolysis UVL ultraviolet light
TF transcription factor (also tissue factor) UVR ultraviolet radiation
TFPI tissue factor pathway inhibitor V/​Q ventilation/​perfusion
TG triglyceride VARD video-​assisted retroperitoneal debridement
TGF transforming growth factor VATS video-​assisted thoracoscopic surgery
TGFα, TGFβ transforming growth factor-​α, -​β VC vital capacity
TGN trans Golgi network vCJD variant Creutzfeldt–​Jakob disease
  Abbreviations xliii

VDRL Venereal Diseases Research Laboratory VZV varicella zoster virus

VEGF vascular endothelial growth factor WBC white blood cell
VEOIBD very early-​onset inflammatory bowel disease WCC white cell count
VIP vasoactive intestinal peptide WGS whole genome sequencing
VKA vitamin K antagonist WHO World Health Organization
VLA vertical long axis WM Waldenström’s macroglobulinaemia
VLCFA very long-​chain fatty acid X-​ALD X-​linked adrenoleukodystrophy
VLDL very low-​density lipoprotein XLH X-​linked hypophosphataemia
VSD ventricular septal defect YLDs years lived with disability
VTE venous thromboembolism YLL years of life lost
VWD von Willebrand’s disease ZASP Z-​line associated protein
VWF von Willebrand factor
Contributors

Peter Aaby Bandim Health Project, INDEPTH Graeme J.M. Alexander UCL Professor, UCL Clive B. Archer Consultant Dermatologist and
Network, Bissau, Guinea-​Bissau, West Africa Institute for Liver and Digestive Health, Royal Honorary Senior Clinical Lecturer, St John’s
8.5.6: Measles Free Hospital, London, UK Institute of Dermatology, Guy’s and St Thomas’
Emma Aarons Consultant Virologist and Infectious 15.23.1: Hepatitis A to E; 15.24.6: Primary and NHS Foundation Trust & King’s College London,
Disease Physician, Rare and Imported Pathogens secondary liver tumours Guy’s Hospital, London, UK
Laboratory, Public Health England, Salisbury, Michael E.D. Allison Liver Unit, Cambridge 23.15: Skin and systemic diseases
Wiltshire, UK Biomedical Research Centre, Addenbrooke’s Michael J. Arden-​Jones Consultant
8.5.27: Orf and Milker’s nodule Hospital, Cambridge, UK Dermatologist, University of Southampton,
Tom Abbott William Harvey Research Institute, 15.24.6: Primary and secondary liver tumours Southampton, UK
Queen Mary University of London, UK Carlo Ammendolia Faculty of Medicine, 23.6: Dermatitis/​eczema
17.4: Assessing and preparing patients with University of Toronto, Toronto, Canada; Mark J. Arends University of Edinburgh Division
medical conditions for major surgery Rebecca MacDonald Centre for Arthritis of Pathology, Cancer Research UK Edinburgh
Ade Adebajo Faculty of Medicine, Dentistry and and Autoimmune Diseases, Division of Centre, Institute of Genetics and Molecular
Health, University of Sheffield, UK Rheumatology, Mount Sinai Hospital, Medicine, Western General Hospital,
19.12: Miscellaneous conditions presenting to the Toronto, Canada Edinburgh, UK
rheumatologist 19.4: Back pain and regional disorders 3.6: Apoptosis in health and disease
Raymond Agius Occupational Medicine, University Chris Andrews Faculty of Medicine, University of J. Arendt Emeritus Professor of
of Manchester, UK Queensland, Herston, Qld 4029, Australia Endocrinology, University of Surrey,
10.2.1: Occupational and environmental health 10.3.5: Lightning and electrical injuries Guildford, UK
Ross H. Andrews Professor, Cholangiocarcinoma 13.11: The pineal gland and melatonin
S. Faisal Ahmed School of Medicine, University
of Glasgow, Royal Hospital for Children, Research Institute (CARI), Cholangiocarcinoma James O. Armitage The Joe Shapiro Professor of
Glasgow, UK Screening and Care Program (CASCAP), Faculty Medicine, Division of Oncology/​Hematology,
13.7.3: Normal and abnormal sexual of Medicine, Khon Kaen University, Khon Kaen, University of Nebraska Medical Center, Omaha,
differentiation Thailand; Professor of Parasitology, Imperial NE, USA
College London, Faculty of Medicine, St Mary’s 22.4.3: Hodgkin lymphoma; 22.4.4: Non-​Hodgkin
Shahzada K. Ahmed Department of
Campus, London, UK lymphoma
Otorhinolaryngology, Queen Elizabeth Hospital,
8.11.2: Liver fluke infections Vicente Arroyo Professor of Medicine at the
Birmingham, UK
13.2.2: Disorders of the posterior pituitary gland Jervoise Andreyev Consultant Gastroenterologist, University of Barcelona Medical School;
United Lincolnshire Hospitals Trust; Honorary Chairman of the European Association
Vineet Ahuja Department of Gastroenterology and
Professor, The School of Medicine, University of for the Study of the Liver Chronic Liver
Human Nutrition, All India Institute of Medical
Nottingham, UK Failure Consortium (EASL-​CLIF
Sciences, New Delhi, India
15.3.4: Investigation of gastrointestinal Consortium) and President of the European
15.10.8: Malabsorption syndromes in the tropics
function Foundation for the Study of Chronic Liver
Guruprasad P. Aithal NIHR Nottingham Biomedical
Gregory M. Anstead Division of Infectious Failure (EF-​C LIF), Barcelona, Spain
Research Centre, Nottingham University Hospitals
Diseases, Department of Medicine, University 15.22.2: Cirrhosis and ascites
NHS Trust and the University of Nottingham;
of Texas Health Science Center at San Antonio, Daniel Aruch Icahn School of Medicine at Mount
Nottingham Digestive Diseases Centre, The
San Antonio, TX, USA; Immunosuppression Sinai, New York, NY, USA
University of Nottingham, Nottingham, UK
and Infectious Diseases Clinics, Department 22.3.5: The polycythaemias; 22.3.6: Thrombocytosis
15.24.3: Drug-​induced liver disease
of Medicine, South Texas Veterans Health Care and essential thrombocythaemia
Sara Ajina Nuffield Department of Clinical
System, San Antonio, TX, USA Frances Ashcroft Professor of Physiology,
Neurosciences, University of Oxford, Oxford, UK 8.7.3: Coccidioidomycosis Department of Physiology, Anatomy and
24.6.1: Visual pathways
Quentin M. Anstee Professor of Experimental Genetics, University of Oxford, Oxford, UK
Tyler Albert VA Puget Sound Health Care System,
Hepatology and Honorary Consultant 3.4: Ion channels and disease
Division of General Internal Medicine, University Hepatologist, Faculty of Medical Sciences, Caroline Ashley Lead Specialist Pharmacist,
of Washington, Seattle, WA, USA Newcastle University and Freeman Hospital Centre for Nephrology, Royal Free Hospital,
10.3.6: Diseases of high terrestrial altitudes Liver Unit, Newcastle upon Tyne Hospitals NHS London, UK
Maha Albur University of Bristol, Bristol, UK Foundation Trust, Newcastle upon Tyne, UK 21.19: Drugs and the kidney
8.2.5: Antimicrobial chemotherapy 15.24.2: Non​alcoholic fatty liver disease Shazad Q. Ashraf Consultant Colorectal Surgeon,
Michael J. Aldape Veterans Affairs Medical Center, Charles M.G. Archer Department of Dermatology, Department of Colorectal Surgery, Queen
Infectious Diseases Section, Boise, ID, USA Oxford University Hospitals NHS Trust, Elizabeth Hospital, Birmingham University
8.6.25: Botulism, gas gangrene, and clostridial Oxford, UK Hospitals, Birmingham, UK
gastrointestinal infections 23.15: Skin and systemic diseases 15.14: Colonic diverticular disease
xlvi Contributors

Paul Aveyard Nuffield Department of Primary Care E.J. Barnes Nuffield Department of Medicine, Nancy Berliner H. Franklin Bunn Professor of
Health Sciences, University of Oxford, Oxford, UK University of Oxford, Oxford, UK Medicine, Brigham and Women’s Hospital and
26.6.2: Obesity and weight management; 8.5.22: Hepatitis C virus Harvard Medical School, Boston, MA
26.6.3: Smoking cessation Michael Barnes University of Newcastle, Newcastle 22.3.1: Granulocytes in health and disease;
Tar-​Ching Aw† Abu Dhabi National Oil Company, upon Tyne, UK; Christchurch Group, Janet 22.4.1: Introduction to lymphopoiesis
United Arab Emirates Barnes Unit, Birmingham, UK Jessica Bertrand Experimental Orthopedics,
10.2.5: Noise; 10.2.6 Vibration 24.13.2: Spinal cord injury and its management University Hospital Magdeburg, Magdeburg,
Jon G. Ayres Emeritus Professor of Environmental Andrew J. Barr Leeds Institute of Rheumatic and Germany
and Respiratory Medicine, Universty of Musculoskeletal Medicine, Leeds, UK 19.1: Joints and connective tissue—​structure
Birmingham, Birmingham, UK 19.9: Osteoarthritis and function
10.1: Environmental medicine, occupational Jonathan Barratt Professor of Renal Medicine, J.M. Best King’s College London, London, UK
medicine, and poisoning; 10.3.1: Air pollution University of Leicester; Honorary Consultant 8.5.13: Rubella
and health Nephrologist, University Hospitals of Leicester, Delia B. Bethell Oxford University Hospitals NHS
Juan Carlos Ayus Renal Consultants of Houston, Leicester, UK Foundation Trust, Oxford, UK
Houston, TX, USA; University of California 21.8.1: Immunoglobulin A nephropathy and 8.6.1: Diphtheria
Irvine, Orange, CA, USA IgA vasculitis (HSP) Kailash Bhatia Sobell Department of Motor
21.2.1: Disorders of water and sodium homeostasis Buddha Basnyat Oxford University Clinical Neuroscience and Movement Disorders,
Qasim Aziz Centre for Neuroscience, Research Unit -​Nepal; Patan Academy of Health University College London (UCL) Institute of
Surgery and Trauma, Wingate Institute of Sciences, Nepal Neurology, Queen Square, London, UK
Neurogastroenterology, Blizard Institute, Barts 8.6.9 Typhoid and paratyphoid fevers; 24.7.3: Movement disorders other than
and the London School of Medicine and Dentistry, 10.3.6: Diseases of high terrestrial altitudes Parkinson’s disease
Queen Mary University of London, London, UK D. Nicholas Bateman, Pharmacology, Toxicology Vijaya Raj Bhatt Assistant Professor, Division of
15.13: Irritable bowel syndrome and Therapeutics, University of Edinburgh, Hematology-​Oncology, University of Nebraska
Trevor Baglin Previously Cambridge Haemophilia Edinburgh, UK Medical Center, Omaha, NE, USA
and Thrombophilia Centre, Department of 10.4.1: Poisoning by drugs and chemicals 22.4.3: Hodgkin lymphoma; 22.4.4: Non-​Hodgkin
Haematology, Addenbrooke’s Hospital, Cambridge David Bates Clinical Neurology, Newcastle lymphoma
University Hospitals, Cambridge, UK University, Newcastle on Tyne, UK Joya Bhattacharyya Division of Gastroenterology
22.7.2: Evaluation of the patient with a bleeding 24.5.5: The unconscious patient; 24.9: Brainstem and Hepatology, Department of Medicine,
tendency syndromes University of Cambridge, Addenbrooke’s
Michael Bagshaw Aviation Medicine, King’s Robert P. Baughman University of Cincinnati Hospital, Cambridge, UK
College, London, UK Medical Center, Cincinnati, OH, USA 15.5: Immune disorders of the
10.2.3: Aviation medicine 18.12: Sarcoidosis gastrointestinal tract
Colin Baigent Clinical Trial Service Unit and Peter J. Baxter School of Clinical Medicine, Paola Bianchi Oncohematology Unit—​
Epidemiological Studies Unit (CTSU), University Public Health and Primary Care, Pathophysiology of Anemias Unit, Foundation
of Oxford, Oxford, UK Institute of Public Health, University of IRCCS Ca’ Granda Ospedale Maggiore,
2.4: Large-​scale randomized evidence: Trials and Cambridge, Cambridge, UK Milan, Italy
meta-​analyses of trials 10.3.8: Disasters: Earthquakes, hurricanes, floods, 22.6.10: Erythrocyte enzymopathies
Kenneth F. Baker Faculty of Medical Sciences, and volcanic eruptions Rudolf Bilous Professor of Clinical Medicine,
Newcastle University and Musculoskeletal Unit, Hannah Beckwith Specialist Registrar, Imperial Newcastle University, Newcastle upon Tyne;
Newcastle upon Tyne Hospitals NHS Foundation College Healthcare NHS Trust Renal and Academic Centre, James Cook University
Trust, Newcastle upon Tyne, UK Transplant Centre, Hammersmith Hospital, Hospital, Middlesbrough, UK
19.5: Rheumatoid arthritis London, UK 21.10.1: Diabetes mellitus and the kidney
Bettina Balint Sobell Department of Motor 21.10.3: The kidney in rheumatological D. Bilton Faculty of Medicine, National Heart
Neuroscience and Movement Disorders, disorders and Lung Institute, Imperial College London,
University College London Institute of Diederik van de Beek Academic Medical Center, London, UK
Neurology, Queen Square, London, UK; University of Amsterdam, Amsterdam, the 18.9: Bronchiectasis
Department of Neurology, University Hospital Netherlands Jonathan I. Bisson Division of Psychological
Heidelberg, University of Heidelberg, Germany 24.11.1: Bacterial infections Medicine and Clinical Neurosciences, University
24.7.3: Movement disorders other than of Cardiff, Cardiff, UK
David A. Bender University College London,
Parkinson’s disease 26.5.9: Acute stress disorder, adjustment disorders,
London, UK
Jay Banerjee College of Life Sciences, University of 11.2: Vitamins and post-​traumatic stress disorder
Leicester, Leicester, UK Carol M. Black Newnham College, Cambridge, UK
D.A. Bente University of Texas Medical Branch,
6.4: Older people and urgent care 19.11.3: Systemic sclerosis (scleroderma)
Galveston, TX, USA
Adrian P. Banning Oxford University Hospitals NHS 8.5.16: Bunyaviridae S.R. Bloom Head of Division of Diabetes,
Trust, Oxford, UK Endocrinology and Metabolism,
Anthony R. Berendt Oxford University Hospitals
16.3.2: Echocardiography; Hammersmith Hospital, Imperial College
NHS Foundation Trust, Oxford, UK
16.14.1 Acute aortic syndromes London, London, UK
20.3: Osteomyelitis
George Banting Medical Sciences Building, 13.8: Pancreatic endocrine disorders and multiple
Stefan Berg Consultant in Pediatric Rheumatology
University of Bristol, Bristol, UK endocrine neoplasia; 15.9.1: Hormones and the
and Immunology, Queen Silvia Children’s
3.1: The cell gastrointestinal tract;
Hospital, Goteborg, Sweden
Thomas M. Barber University of Warwick, University 15.9.2: Carcinoid syndrome
12.12.2 Hereditary periodic fever syndromes
Hospitals Coventry and Warwickshire NHS Trust, Johannes Blum Medical Services, Swiss
David de Berker Bristol Dermatology
Coventry, UK Tropical and Public Health Institute, Basel,
Centre, University Hospitals Bristol,
13.10: Hormonal manifestations of non-​endocrine Switzerland
Bristol, UK
disease 8.8.11: Human African trypanosomiasis
23.13: Hair and nail disorders

†
It is with great regret that we report that Tar-Ching Aw died on 18 July, 2017.
 Contributors xlvii

Kristien Boelaert University of Birmingham, Birmingham; School of Biosciences, University of Anthony F.T. Brown Department of Emergency
Birmingham, UK Birmingham, Birmingham, UK Medicine, Royal Brisbane and Women’s Hospital,
13.3.1: The thyroid gland and disorders of thyroid 10.4.1: Poisoning by drugs and chemicals Brisbane, Qld, Australia
function; 13.3.2: Thyroid cancer Marcus Bradley North Bristol NHS Trust, 17.3: Anaphylaxis
Eva Boonen Clinical Division and Laboratory of Bristol, UK Kevin E. Brown Virus Reference Department, Public
Intensive Care Medicine, Department of Cellular 24.3.3: Imaging in neurological diseases Health England, London, UK
and Molecular Medicine, KU Leuven University, Tasanee Braithwaite Locum Consultant, Moorfields 8.5.20: Parvovirus B19
B-​3000 Leuven, Belgium Eye Hospital NHS Foundation Trust, London, UK Michael Brown Department of Infectious and
17.9: Metabolic and endocrine changes in acute 25.1: The eye in general medicine Tropical Diseases, London School of Hygiene and
and chronic critical illness Tropical Medicine, London, UK
Thomas Brandt Ludwig Maximilians University,
Christopher Booth† Wellcome Institute for the Munich, Germany 8.9.4: Strongyloidiasis, hookworm, and other gut
History of Medicine, Wellcome Building, 24.6.2: Eye movements and balance strongyloid nematodes
London, UK Morris J. Brown Professor of Endocrine
Petter Brandtzaeg Emeritus Professor, Department
1.1: On being a patient Hypertension, Queen Mary University of London,
of Paediatrics, Oslo University Hospital,
Marina Botto Professor, Imperial College London, Oslo, Norway William Harvey Heart Centre, London, UK
London, UK 8.6.5: Meningococcal infections 16.17.3: Secondary hypertension
4.2: The complement system Vanessa Brown Specialist Registrar, Royal Surrey
Philippe Brasseur Institut de Recherche pour le
Ralph Bouhaidar Consultant Forensic Pathologist, Développement, Dakar, Sénégal, West Africa County Hospital, Guildford, UK
NHS Lothian; Honorary Senior Lecturer, 8.8.3: Babesiosis 15.4.2: Gastrointestinal bleeding
Edinburgh University, Edinburgh; Training Reto Brun Parasite Chemotherapy Unit, Medical
Jürgen Braun Medical Director, Rheumazentrum
Programme Director for Forensic Histopathology Parasitology and Infection Biology, Swiss Tropical
Ruhrgebiet, Herne, Germany; Chair of
(Scotland), UK and Public Health Institute, Basel, Switzerland
Rheumatology, Ruhr University, Bochum,
27.1: Forensic and legal medicine 8.8.11: Human African trypanosomiasis
Germany
Henri-​Jean Boulouis Ecole Nationale Vétérinaire 19.6: Spondyloarthritis and related Marco J. Bruno Erasmus Medical Center, University
d’Alfort, Maisons-​Alfort, France conditions Medical Center Rotterdam, Department of
8.6.43: Bartonellas excluding B. bacilliformis Gastroenterology and Hepatology, Rotterdam,
Evan M. Braunstein Hematology Division, Johns
P.-​M.G. Bouloux Centre for Neuroendocrinology, Hopkins University School of Medicine, the Netherlands
University College London Medical School, Baltimore, MD, USA 15.26.2: Chronic pancreatitis
London, UK 22.3.7: Primary myelofibrosis Amy E. Bryant Research Professor, Department
13.6.2: Disorders of male reproduction and male of Biomedical and Pharmaceutical Sciences,
James D. Brenton Cancer Research UK
hypogonadism College of Pharmacy, Idaho State University,
Cambridge Institute, University of Cambridge,
S.J. Bourke Royal Victoria Infirmary, Newcastle Cambridge, UK ID, USA
upon Tyne, UK 5.2: The nature and development of cancer: Cancer 8.6.25: Botulism, gas gangrene, and clostridial
18.14.1: Diffuse alveolar haemorrhage; mutations and their implications gastrointestinal infections
18.14.2: Eosinophilic pneumonia; Antony D.M. Bryceson London School of Hygiene
J.A. Bridgewater Professor and Consultant in
18.14.3: Lymphocytic infiltrations of the lung; and Tropical Medicine, London, UK
Medical Oncology, UCL Cancer Institute,
18.14.4: Hypersensitivity pneumonitis; 8.8.13: Leishmaniasis
London, UK
18.14.5: Pulmonary Langerhans’ cell Nicolas C. Buchs Consultant Colorectal Surgeon,
15.16: Cancers of the gastrointestinal tract
histiocytosis; 18.14.6: Lymphangioleiomyomatosis; Clinic for Visceral and Transplantation Surgery,
Frank Bridoux Professor of Nephrology,
18.14.7: Pulmonary alveolar proteinosis; Department of Surgery, University Hospitals of
Department of Nephrology, Hôpital Jean
18.14.8: Pulmonary amyloidosis; 18.14.9: Lipoid Geneva, Geneva, Switzerland
Bernard, Poitiers, France
(lipid) pneumonia; 18.14.10: Pulmonary 15.14: Colonic diverticular disease
21.10.5: Renal involvement in plasma cell
alveolar microlithiasis; 18.14.12: Radiation
dyscrasias, immunoglobulin-​based amyloidoses, Camilla Buckley MRC Clinician Scientist and
pneumonitis; 18.14.13: Drug-​induced
and fibrillary glomerulopathies, lymphomas, and Honorary Consultant, Department of Clinical
lung disease
leukaemias Neurology, University of Oxford, Oxford, UK
Ian C.J.W. Bowler Oxford University Hospitals NHS 24.24: Autoimmune encephalitis and Morvan’s
Charlotte K. Brierley Department of Haematology,
Foundation Trust, Oxford, UK; University of syndrome
Cancer and Haematology Centre, Churchill
Oxford, Oxford, UK
Hospital, Oxford University Hospitals NHS Trust, Simon J.A. Buczacki Honorary Consultant
8.2.3: Nosocomial infections
Oxford, UK Colorectal Surgeon, Cambridge Colorectal Unit,
Louise Bowles Consultant Haematologist, Barts Addenbrooke’s Hospital, Cambridge, UK
22.3.2: Myelodysplastic syndromes
Health NHS Trust, London, UK 15.4.1: The acute abdomen
Alice Brockington University of Sheffield,
14.7: Thrombosis in pregnancy
Sheffield, UK Enrico Bugiardini MRC Centre for Neuromuscular
Paul Bowness Oxford University Hospitals Disease, University College London, London, UK
24.15: The motor neuron diseases
NHS Foundation Trust, Oxford, UK; Nuffield 24.19.1: Structure and function of muscle
Max Bronstein Advocacy and Science
Department of Orthopaedics, Rheumatology and
Policy, Every Life Foundation, Washington, Alan Burnett Former Professor of Haematology,
Musculoskeletal Science, University of Oxford,
DC, USA Cardiff University, Cardiff, UK
Oxford, UK
2.9: Engaging patients in therapeutic 22.3.3: Acute myeloid leukaemia
4.1: The innate immune system
development Gilbert Burnham John Hopkins Bloomberg School
Ray Boyapati Department of Gastroenterology,
Gary Brook London North West University of Public Health, Baltimore, MD, USA
Monash Health, Victoria, Australia; Faculty of
Healthcare NHS Trust, London, UK 8.9.1: Cutaneous filariasis
Medicine, Nursing and Health Sciences, Monash
9.3: Sexual history and examination Aine Burns Consultant Nephrologist and Director
University, Vic, Australia
15.17: Vascular disorders of the Arthur E. Brown Research Consultant, Faculty of Postgraduate Medical Education, Centre
gastrointestinal tract of Medical Technology, Mahidol University, for Nephrology, Royal Free NHS Trust and
Nakhon Pathom, Thailand University College Medical School, London, UK
Sally M. Bradberry NPIS (Birmingham Unit) and
8.6.21: Anthrax 21.19: Drugs and the kidney
West Midlands Poisons Unit, City Hospital,
†
It is with great regret that we report that Christopher Booth died on 13 July, 2012.
xlviii Contributors

Eileen Burns Leeds Centre for Older People’s R. Carter Consultant Pancreaticobiliary Surgeon, Hector Chinoy University of Manchester,
Medicine, Leeds Teaching Hospitals NHS Trust, West of Scotland Pancreatic Unit, Glasgow Royal Manchester, UK
Leeds, UK Infirmary, Glasgow, UK 19.11.5: Inflammatory myopathies
6.11: Promotion of dignity in the life and death of 15.26.1: Acute pancreatitis Peter L. Chiodini Hospital for Tropical Diseases,
older patients Stuart Carter Sheffield Teaching Hospitals NHS University College London Hospitals,
Harry Burns University of Strathclyde, UK Foundation Trust, Sheffield, UK London, UK
2.14: Deprivation and health 19.12: Miscellaneous conditions presenting to the 8.9.5: Gut and tissue nematode infections acquired
N.P. Burrows Consultant Dermatologist, Cambridge rheumatologist by ingestion
University Hospitals NHS Foundation Trust, David Carty Department of Diabetes, Rossa W.K. Chiu Choh-​Ming Li Professor of
Cambridge, UK Endocrinology and Clinical Pharmacology, Chemical Pathology, Department of Chemical
20.2: Inherited defects of connective tissue: Glasgow Royal Infirmary, Glasgow, UK Pathology, The Chinese University of Hong
Ehlers–​Danlos syndrome, Marfan syndrome, and 14.11: Endocrine disease in pregnancy Kong, Hong Kong, China
pseudoxanthoma elasticum Jaimini Cegla Imperial College London, 3.9: Circulating DNA for molecular diagnostics
Rosie Burton Khayelitsha District Hospital, London, UK Bruno B. Chomel School of Veterinary Medicine,
Corner of Walter Sisulu and Streve Biko 12.6: Lipid disorders University of California, CA, USA
Roads, Khayelitsha, Cape Town, Africa; Joseph Cerimele University of Washington, 8.6.43: Bartonellas excluding B. bacilliformis
Department of Medicine, University of Cape Washington, DC, USA Robin P. Choudhury University of Oxford,
Town, Cape Town, Africa 26.5.6: Depressive disorder Oxford, UK
14.15: Maternal infection in pregnancy 16.13.1: Biology and pathology of atherosclerosis
Joshua T. Chai Department of Cardiovascular
Andrew Bush Imperial College London, London, Medicine, University of Oxford, Julia Choy National Health Service, London, UK
UK; National Heart and Lung Institute, London, Oxford, UK 18.4.5: Pulmonary complications of HIV infection
UK; Royal Brompton and Harefield NHS 16.13.1: Biology and pathology of Lydia Chwastiak Department of Psychiatry and
Foundation Trust, London, UK atherosclerosis Behavioral Sciences, University of Washington
18.10: Cystic fibrosis Richard E. Chaisson Center for Tuberculosis School of Medicine, Seattle, WA, USA
Kate Bushby Newcastle University John Walton Research, Johns Hopkins University School of 26.5.6: Depressive disorder
Centre for Muscular Dystrophy Research, MRC Medicine, Baltimore, MD, USA Andrew L. Clark Chair of Clinical Cardiology
Centre for Neuromuscular Diseases, Institute of 8.6.26: Tuberculosis and Honorary Consultant Cardiologist,
Genetic Medicine, International Centre for Life, Romanee Chaiwarith Division of Infectious Hull York Medical School, Castle Hill Hospital,
Newcastle upon Tyne, UK Diseases, Department of Medicine, Faculty of Hull, UK
24.19.2: Muscular dystrophy Medicine, Chiang Mai University, Chiang Mai, 16.5.2: Acute cardiac failure: Definitions,
Gary Butler University College London Hospital Thailand investigation, and management; 16.5.3: Chronic
and UCL Great Ormond Street Institute of Child 8.7.6: Talaromyces (Penicillium) marneffei heart failure: Definitions, investigation, and
Health, London, UK infection management
13.7.1: Normal growth and its disorders Ben Challis University of Cambridge Medical Andrew Clegg Academic Unit of Elderly Care and
William F. Bynum Professor Emeritus, University School, Cambridge, UK Rehabilitation, University of Leeds, Bradford
College London, London, UK 13.9.2: Hypoglycaemia Teaching Hospitals NHS Foundation Trust,
2.1: Science in medicine: When, how, Bradford, UK
Siddharthan Chandran Euan MacDonald Centre
and what 6.2: Frailty and sarcopenia
for Clinical Brain Sciences (CCBS), University of
Simone M. Cacciò European Union Reference Edinburgh, Edinburgh, UK John G.F. Cleland National Heart and Lung Institute,
Laboratory for Parasites, Department of 3.7: Stem cells and regenerative medicine; Royal Brompton and Harefield Hospitals
Infectious, Parasitic and Immunomediated 24.10.2: Demyelinating disorders of the central Trust London, UK; Hull York Medical School,
Diseases, Istituto Superiore di Sanità, nervous system University of Hull, Hull, UK
Rome, Italy 16.5.2: Acute cardiac failure: Definitions,
Keith Channon John Radcliffe Hospital,
8.8.5: Cryptosporidium and cryptosporidiosis investigation, and management; 16.5.3 Chronic
Oxford, UK
Djuna L. Cahen Erasmus Medical Center, University 16.1.1: Blood vessels and the endothelium heart failure: Definitions, investigation, and
Medical Center Rotterdam, Department of management
Roger W. Chapman Translational Gastroenterology
Gastroenterology and Hepatology, Rotterdam, Gavin Clunie Cambridge University Hospitals NHS
Unit, John Radcliffe Hospital, Oxford; Nuffield
the Netherlands Foundation Trust, Cambridge, UK
Department of Medicine, University of Oxford,
15.26.2: Chronic pancreatitis 20.5: Osteonecrosis, osteochondrosis, and
Oxford, UK
P.M.A. Calverley School of Clinical Sciences, 15.23.4: Primary sclerosing cholangitis osteochondritis dissecans
University of Liverpool, Liverpool, UK V. Krishna Chatterjee University of Cambridge S.M. Cobbe Previously Consultant Cardiologist,
18.15: Chronic respiratory failure Medical School, Cambridge, UK Glasgow Royal Infirmary; former BHF Walton
Jason Caplan Dignity Health Medical Group; St. 13.1: Principles of hormone action Professor of Medical Cardiology, University of
Joseph’s Hospital and Medical Center; Creighton Glasgow, Glasgow, UK
Afzal Chaudhry Chief Clinical Information
University School of Medicine; Phoenix, 16.2.2: Syncope and palpitation
Officer, Cambridge University Hospitals,
AZ, USA Cambridge, UK Fredric L. Coe The University of Chicago Medicine,
26.5.3: Organic psychoses 2.5: Bioinformatics Chicago, IL, US
Jonathan R. Carapetis Telethon Kids Institute, 21.1: Structure and function of the kidney
K. Ray Chaudhuri National Parkinson Foundation
University of Western Australia and Perth Centre of Excellence, King’s College, Denmark Sian Coggle Consultant Physician, Cambridge
Children’s Hospital, Perth, Australia Hill Campus, London, UK University Hospitals, Cambridge, UK
16.9.1: Acute rheumatic fever 24.7.2: Parkinsonism and other extrapyramidal 30.1: Acute medical presentations; 30.2: Practical
Jordi Carratalà Department of Infectious Diseases, diseases procedures
Hospital Universitari de Bellvitge -​IDIBELL, Patrick F. Chinnery University of Newcastle, Jon Cohen Brighton and Sussex Medical School,
Division of Health Sciences, Faculty of Medicine, Newcastle upon Tyne, UK Brighton, UK
University of Barcelona, Barcelona, Spain 24.19.5: Mitochondrial disease 8.2.4: Infection in the immunocompromised host
8.6.39: Legionellosis and Legionnaires’ disease
 Contributors xlix

Alasdair Coles Cambridge School of Clinical Timothy M. Cox Professor of Medicine Emeritus, Andrew Davenport Professor of Dialysis and ICU
Medicine, Cambridge, UK Director of Research, University of Cambridge; Nephrology, UCL Department of Nephrology,
24.10.2: Demyelinating disorders of the central Honorary Consultant Physician, Addenbrooke’s Royal Free Hospital, University College London,
nervous system Hospital, Cambridge, UK London, UK
Jane Collier Consultant Hepatologist, John Radcliffe 1.1: An older patient’s story; 12.1: The inborn errors 21.4: Clinical investigation of renal disease
Hospital, Oxford, UK of metabolism: General aspects; 12.3.1: Glycogen Gail Davey Centre for Global Health Research,
8.5.22: Hepatitis C virus; 15.22.1: Investigation storage diseases; 12.3.2: Inborn errors of fructose Brighton and Sussex Medical School,
and management of jaundice metabolism; 12.3.3: Disorders of galactose, pentose, Brighton, UK
and pyruvate metabolism; 12.5: The porphyrias; 10.5: Podoconiosis
Rory Collins Clinical Trial Service Unit and
12.7.1: Hereditary haemochromatosis;
Epidemiological Studies Unit (CTSU), University Alun Davies Imperial College School of Medicine,
12.8: Lysosomal disease; 13.11: The pineal gland
of Oxford, Oxford, UK London, UK
and melatonin; 15.10.5: Disaccharidase deficiency;
2.4: Large-​scale randomized evidence: Trials and 16.14.2: Peripheral arterial disease
22.6.4: Iron metabolism and its disorders
meta-​analyses of trials Helen E. Davies University Hospital of Wales,
S.E. Craig Oxford Sleep Unit, Churchill Hospital,
Juan D. Colmenero Infectious Diseases Cardiff, UK
Oxford, UK
Service, Regional University Hospital, 18.19.4: Mediastinal tumours and cysts
18.1.1: The upper respiratory tract
Málaga, Spain R Justin Davies Consultant Colorectal Surgeon,
8.6.22: Brucellosis Matthew Cramp South West Liver Unit and
Cambridge Colorectal Unit, Addenbrooke’s
Peninsula Schools of Medicine and Dentistry,
Alastair Compston Department of Clinical Hospital, Cambridge, UK
Derriford Hospital, Plymouth, UK
Neurosciences, University of Cambridge, 15.4.1: The acute abdomen
8.5.21: Hepatitis viruses (excluding hepatitis
Cambridge, UK P.D.O. Davies Liverpool Heart and Chest Hospital
C virus)
24.1: Introduction and approach to the patient NHS Foundation Trust, Liverpool, UK
with neurological disease Robin A.F. Crawford Addenbrooke’s Hospital,
8.6.27: Disease caused by environmental
Cambridge, UK
Juliet Compston University of Cambridge mycobacteria
14.18: Malignant disease in pregnancy
School of Clinical Medicine and Cambridge R. Rhys Davies Cognitive Function Clinic, Walton
University Hospitals NHS Foundation Trust, Daniel Creamer King’s College Hospital,
Centre for Neurology and Neurosurgery,
Cambridge, UK London, UK Liverpool, UK
20.4: Osteoporosis 23.16: Cutaneous reactions to drugs 24.3.1: Lumbar puncture
Philip G. Conaghan Leeds University, Tim Crook North Middlesex Hospital,
Simon Davies Professor of Nephrology and Dialysis
Leeds, UK London, UK Medicine, Institute for Science and Technology
19.9: Osteoarthritis 5.7: Medical management of breast cancer in Medicine, Keele University, Keele; Consultant
Christopher P. Conlon Professor of Infectious Paul Cullinan Faculty of Medicine, National Heart Nephrologist, University Hospital of North
Diseases, Nuffield Department of Medicine, and Lung Institute, Imperial College London, Midlands, Stoke-​on-​Trent, UK
University of Oxford, Oxford, UK London, UK 21.7.2: Peritoneal dialysis
8.4: Travel and expedition medicine; 8.5.23: HIV/​ 18.7: Asthma Richard Dawkins New College, University of
AIDS; 8.5.28: Molluscum contagiosum Peter F. Currie Perth Royal Infirmary, Perth Oxford, Oxford, UK
Simon Conroy Department of Health Sciences, and Ninewells Hospital and Medical School, 2.2: Evolution: Medicine’s most basic science
University of Leicester, Leicester, UK Dundee, UK Christopher P. Day Vice-​Chancellor and
6.4: Older people and urgent care 16.9.3: Cardiac disease in HIV infection President, Newcastle University and Freeman
Cyrus Cooper MRC Lifecourse Epidemiology Unit, Nicola Curry Consultant Haematologist, Oxford Hospital Liver Unit, Newcastle upon Tyne
University of Southampton, Southampton, UK; University Hospitals NHS Foundation Trust, Hospitals NHS Foundation Trust, Newcastle
NIHR Oxford Biomedical Research Centre, Oxford Haemophilia and Thrombosis Centre, upon Tyne, UK
University of Oxford, Oxford, UK Churchill Hospital, Oxford, UK 15.24.2: Non​alcoholic fatty liver disease
20.4: Osteoporosis 22.7.3: Thrombocytopenia and disorders of Nicholas P.J. Day Mahidol-​Oxford Tropical
platelet function
John E. Cooper University of Cambridge, Medicine Research Unit, Faculty of Tropical
Cambridge, UK Goodarz Danaei Department of Global Health Medicine, Mahidol University, Bangkok,
8.8.8: Sarcocystosis (sarcosporidiosis) and Population, Department of Epidemiology, Thailand; Nuffield Department of Clinical
Harvard T.H. Chan School of Public Health, Medicine, University of Oxford, Oxford, UK
Robert Cooper University of Liverpool,
Boston, MA, USA 8.6.35: Leptospirosis; 8.6.41: Scrub typhus
Liverpool, UK
16.13.2: Coronary heart disease: Epidemiology and
19.11.5: Inflammatory myopathies Colin Dayan University of Cardiff, Wales, UK
prevention
Mhairi Copland Professor of Translational 13.9.1: Diabetes
Christopher J. Danpure Emeritus Professor of
Haematology, Section of Experimental Marc E. De Broe Professor of Medicine, Laboratory
Molecular Cell Biology, University College
Haematology, Paul O’Gorman Leukaemia of Pathophysiology, University of Antwerp,
London, London, UK
Research Centre, Institute of Cancer Sciences, Antwerp, Belgium
12.10: Hereditary disorders of oxalate
College of Medical, Veterinary and Life Sciences, 21.9.2: Chronic tubulointerstitial nephritis
metabolism: The primary hyperoxalurias
University of Glasgow, Glasgow, UK Kevin M. De Cock Center for Global Health, Atlanta,
22.3.4: Chronic myeloid leukaemia Bhaskar Dasgupta University of Essex, Essex, UK;
GA, USA
Anglia Ruskin University, East Anglia, UK;
Susan J. Copley Imperial College Healthcare NHS 8.5.24: HIV in low-​and middle-​income
Southend University Hospital NHS Foundation
Trust, London, UK countries
Trust, Essex, UK
18.3.2: Thoracic imaging An S. De Vriese Division of Nephrology, AZ Sint-​Jan
19.11.11: Polymyalgia rheumatica
Jeremy Cordingley Peri-​Operative Medicine, St Brugge-​Oostende AV, Brugge, Belgium
Pooja Dassan Consultant Neurologist, Imperial
Bartholomew’s Hospital, London, UK 21.8.4: Membranous nephropathy
College Healthcare NHS Trust and London
17.5: Acute respiratory failure Patrick B. Deegan Consultant Metabolic Physician,
North West University Healthcare NHS Trust,
Philip J. Cowen University of Oxford Department Lysosomal Disorders Unit, Cambridge University
London, UK
of Psychiatry, Warneford Hospital, Oxford, UK Hospitals, Cambridge, UK
14.12: Neurological conditions in
26.4.1: Psychopharmacology in medical practice 12.8 Lysosomal disease
pregnancy
l Contributors

Christopher Deighton Royal Derby Hospital, Hal Drakesmith MRC Human Immunology Unit, Tim Eisen Department of Oncology, University
Derby, UK Weatherall Institute of Molecular Medicine, John of Cambridge, Cambridge, UK; Oncology
19.2 Clinical presentation and diagnosis of Radcliffe Hospital and University of Oxford, Early Clinical Development, AstraZeneca,
rheumatological disorders Oxford, UK Cambridge, UK
David M. Denison Emeritus Professor of Clinical 22.6.5: Anaemia of inflammation 5.2: The nature and development of cancer: Cancer
Physiology, Royal Brompton Hospital and Christopher Dudley Consultant Nephrologist, The mutations and their implications; 5.5: Clinical
Imperial College London, London, UK Richard Bright Renal Unit, Southmead Hospital, features and management; 21.18: Malignant
10.2.4: Diving medicine North Bristol NHS Trust, Bristol, UK diseases of the urinary tract
Christopher P. Denton Centre for Rheumatology, 16.14.3: Cholesterol embolism Wagih El Masri(y) Keele University, Newcastle-​
Division of Medicine, University College London Susanna Dunachie Oxford University Hospitals under-​Lyme, UK; The Robert Jones and Agnes
(UCL) Medical School, Royal Free Hospital, NHS Trust, Oxford, UK Hunt Orthopaedic Hospital, Oswestry, UK
London, UK 8.4: Travel and expedition medicine 24.13.2: Spinal cord injury and its management
19.11.3: Systemic sclerosis (scleroderma) Lisa Dunkley Sheffield Teaching Hospitals NHS Carole Eldin University Hospital Institute
Ulrich Desselberger University of Cambridge, Foundation Trust, Sheffield, UK Méditerranée Infection, Marseille, France
Cambridge, UK 19.12: Miscellaneous conditions presenting to the 8.6.40: Rickettsioses
8.5.8: Enterovirus infections; 8.5.9: Virus rheumatologist Perry Elliott St Bartholomew’s Hospital, London,
infections causing diarrhoea and vomiting David Dunne University of Cambridge, UK; Institute of Cardiovascular Science,
Patrick C. D’Haese Head of Laboratory of Cambridge, UK; Wellcome Trust-​Cambridge, University College London, London, UK
Pathophysiology, University of Antwerp, Campus Centre for Global Health Research, UK; 16.7.2: The cardiomyopathies: Hypertrophic,
Drie Eiken, Wilrijk, Belgium CAPREx, THRiVE-​Cambridge, and dilated, restrictive, and right ventricular;
21.9.2: Chronic tubulointerstitial nephritis Cambridge-​Africa 16.7.3: Specific heart muscle disorders
Ashwin Dhanda Plymouth Hospitals NHS Trust, 8.11.1: Schistosomiasis Christopher J. Ellis Heart of England Foundation
Plymouth, UK Stephen R. Durham National Heart and Lung Trust, Birmingham, UK; University of
8.5.21: Hepatitis viruses (excluding hepatitis Institute, Imperial College and Royal Brompton Birmingham, Birmingham, UK
C virus) Hospital, London, UK 8.2.1: Clinical approach
Jugdeep Dhesi Guys and St Thomas’ Hospitals, 18.6: Allergic rhinitis Graham Ellis Monklands Hospital, Airdrie,
London, UK Jeremy Dwight John Radcliffe Hospital, Oxford, UK Lanarkshire, UK
6.6: Supporting older peoples’ care in surgical and 16.2.1: Chest pain, breathlessness, and fatigue 6.5: Older people in hospital
oncological services Jessica K. Dyson Newcastle University and Liver Unit, Monique M. Elseviers Centre for Research and
Euan J. Dickson Consultant Pancreaticobiliary Freeman Hospital, Newcastle upon Tyne, UK Innovation in Care (CRIC), University of
Surgeon, West of Scotland Pancreatic Unit, 15.23.3: Primary biliary cholangitis Antwerp, Antwerp; Heymans Institute of
Glasgow Royal Infirmary, Glasgow, UK Clinical Pharmacology, Ghent University, Ghent,
Christopher P. Eades University College London,
15.26.1: Acute pancreatitis Belgium
London, UK
Michael Doherty University of Nottingham, 21.9.2: Chronic tubulointerstitial nephritis
8.7.5: Pneumocystis jirovecii
Nottingham, UK Caroline Elston Respiratory Medicine and Adult Cystic
Ian Eardley St James’s Hospital, Leeds, UK
19.3: Clinical investigation; 19.10: Crystal-​related Fibrosis, King’s College Hospital, London, UK
13.6.4: Sexual dysfunction
arthropathies 18.10: Cystic fibrosis
James E. East Consultant Gastroenterologist,
Inderjeet S. Dokal Barts and The London School M.A. Epstein Nuffield Department of Clinical
Translational Gastroenterology Unit, John
of Medicine and Dentistry, Queen Mary Medicine, John Radcliffe Hospital, Oxford, UK
Radcliffe Hospital; Associate Professor of
University of London, Barts Health NHS Trust, 8.5.3: Epstein–​Barr virus
Gastroenterology and Endoscopy, Nuffield
London, UK Department of Clinical Medicine, University of Steve Epstein MedStar Georgetown University
22.5.1: Inherited bone marrow failure Oxford, Oxford, UK Hospital and Georgetown University School of
syndromes 15.3.1: Colonoscopy and flexible Medicine, Washington, DC, USA
Jan Donck Department of Nephrology, AZ Sint-​ sigmoidoscopy; 15.3.2: Upper gastrointestinal 26.5.8: Anxiety disorders
Lucas, Ghent, Belgium endoscopy Wendy N. Erber Medical School, Faculty of Health
21.10.4: The kidney in sarcoidosis Lars Eckmann Department of Medicine, School of and Medical Sciences, The University of Western
Arjen M. Dondorp Mahidol-​Oxford Tropical Medicine, University of California, San Diego, La Australia, Perth, WA, Australia
Medicine Research Unit, Bangkok, Jolla, CA, USA 22.2.2: Diagnostic techniques in the assessment of
Thailand 8.8.9: Giardiasis and balantidiasis haematological malignancies
8.8.2: Malaria Michael Eddleston Pharmacology, Toxicology and Ari Ercole Neurosciences Critical Care Unit,
Basil Donovan University of New South Wales, Therapeutics, Centre for Cardiovascular Science, Cambridge University Hospitals NHS
NSW, Australia University of Edinburgh, Edinburgh, UK Foundation Trust, Cambridge, UK
8.6.37: Syphilis 10.4.4: Poisonous plants 24.5.6: Brainstem death and prolonged disorders of
Philip R. Dormitzer Pfizer Vaccine Research and consciousness
Mark J. Edwards St George’s University of London,
Development, Pearl River, NY, USA London, UK Edzard Ernst Emeritus Professor, University of
8.5.9: Virus infections causing diarrhoea and 24.7.1: Subcortical structures: The cerebellum, Exeter, Exeter, UK
vomiting basal ganglia, and thalamus 2.22: Complementary and alternative medicine
Anne Dornhorst Imperial College Hospital, Richard Edwards School of Clinical Sciences, Andrew P. Evan Indiana University School of
London, UK University of Bristol, Bristol, UK Medicine, Indianapolis, IN, USA
14.10: Diabetes in pregnancy 24.19.4: Metabolic and endocrine disorders 21.14: Disorders of renal calcium handling, urinary
Charles G. Drake New York Presbyterian stones, and nephrocalcinosis
Rosalind A. Eeles The Institute of Cancer Research
and Columbia University Medical Center, and Royal Marsden NHS Foundation Trust, Mark Evans University of Cambridge Medical
New York, USA London, UK School, Cambridge, UK
5.4: Cancer immunity and immunotherapy 5.3: The genetics of inherited cancers 13.9.2: Hypoglycaemia
 Contributors li

Rhys D. Evans Department of Physiology, Anatomy Javier Fernández Consultant Hepatologist, Head of UK; Cambridge Centre for Lung Infection, Royal
and Genetics, University of Oxford, Oxford, UK Liver ICU, Liver Unit, Hospital Clinic Barcelona; Papworth Hospital, Cambridge, UK
11.1 Nutrition: Macronutrient metabolism; Associate Professor, University of Barcelona 3.5: Intracellular signalling
16.1.2: Cardiac physiology Medical School, Barcelona, Spain; Member of the Edward D. Folland University of Massachusetts
Pamela Ewan Allergy Department, Cambridge European Foundation for the Study of Chronic Medical School, MA, USA
University Hospitals NHS Foundation Trust, Liver Failure (EF-​CLIF) 16.3.4: Cardiac catheterization and angiography;
Cambridge, UK 15.22.2: Cirrhosis and ascites 16.13.5: Percutaneous interventional cardiac
4.5: Allergy Fernando C. Fervenza Professor of Medicine, procedures
David W. Eyre Nuffield Department of Clinical Division of Nephrology and Hypertension, D. de Fonseka Academic Respiratory Unit,
Medicine, University of Oxford, John Radcliffe Mayo Clinic College of Medicine, Rochester, University of Bristol, Bristol, UK
Hospital, Oxford, UK MN, USA 18.17: Pleural diseases
8.6.24 Clostridium difficile 21.8.4: Membranous nephropathy Carole Foot Royal North Shore Hospital, NSW,
Lynette D. Fairbanks Purine Research Laboratory, Sarah Fidler Professor of HIV Medicine, Imperial Australia
Viapath, St Thomas’ Hospital, London, UK College London, London, UK 17.1: The seriously ill or deteriorating patient
12.4 Disorders of purine and pyrimidine 8.5.23: HIV/​AIDS Alastair Forbes Norwich Medical School, University
metabolism Richard E. Fielding Newcastle upon Tyne Hospitals of East Anglia, Norwich, UK
Christopher G. Fairburn Oxford University NHS Foundation Trust, Newcastle upon 15.10.1: Differential diagnosis and investigation of
Hospitals NHS Foundation Trust, Oxford, UK Tyne, UK malabsorption
26.5.10: Eating disorders 21.3: Clinical presentation of renal disease Ewan Forrest Consultant Hepatologist and Honorary
Carole Fakhry Johns Hopkins Medical Institution, Roger G. Finch Nottingham University Hospitals, Clinical Associate Professor, Department of
Baltimore, MD, USA NHS Trust, Nottingham, UK Gastroenterology, Glasgow Royal Infirmary and
8.5.19: Papillomaviruses and polyomaviruses 8.2.5: Antimicrobial chemotherapy the University of Glasgow, Glasgow UK
Marie Fallon St Columba’s Hospice Chair of Simon Finney Peri-​Operative Medicine, St 15.24.1: Alcoholic liver disease
Palliative Medicine, University of Edinburgh, Bartholomew’s Hospital, London, UK Rob Fowkes Royal Veterinary College,
Edinburgh, UK 17.5: Acute respiratory failure London, UK
7.2: Pain management Helen V. Firth Addenbrookes Hospital Cambridge, 13.1: Principles of hormone action
Sonia Fargue University of Alabama at Birmingham, Cambridge, UK Keith A.A. Fox Centre for Cardiovascular Science,
Birmingham, AL, USA 24.20: Developmental abnormalities of the central University of Edinburgh, Edinburgh, UK
12.10: Hereditary disorders of oxalate nervous system 16.13.4: Management of acute coronary
metabolism: The primary hyperoxalurias John D. Firth Consultant Physician and syndrome
Adam D. Farmer Wingate Institute of Nephrologist, Cambridge University Stephen Franks Imperial College London,
Neurogastroenterology, Blizard Institute, Barts Hospitals, Cambridge, UK London, UK
and the London School of Medicine and Dentistry, 16.16.1: Deep venous thrombosis and 13.6.1: Ovarian disorders
Queen Mary University of London, London; pulmonary embolism; 16.17.1: Essential Keith N. Frayn Radcliffe Department of Medicine,
Department of Gastroenterology, University hypertension: Definition, epidemiology, University of Oxford, Oxford, UK
Hospitals of North Midlands, Stoke-​on-​Trent, UK and pathophysiology; 16.17.2: Essential 11.1: Nutrition: Macronutrient metabolism
15.13: Irritable bowel syndrome hypertension: Diagnosis, assessment, and
Patrick French Mortimer Market Centre,
treatment; 16.19: Idiopathic oedema of women;
I. Sadaf Farooqi Wellcome-​MRC Institute of Central and North West London NHS Trust,
21.2.2: Disorders of potassium homeostasis;
Metabolic Science, University of Cambridge, UK London, UK; University College London,
21.5: Acute kidney injury; 21.7.3: Renal
11.6: Obesity London, UK
transplantation; 30.1: Acute medical presentations;
Jeremy Farrar Wellcome Trust, London, UK 9.6: Genital ulceration
30.2: Practical procedures
2.17: Research in the developed world; Izzet Fresko Division of Rheumatology, Department
A.J. Fisher Professor of Respiratory Transplant
24.11.2: Viral infections of Medicine, Cerrahpasa Medical Faculty,
Medicine, Newcastle University Translational
Ken Farrington Lister Hospital, East and North University of Istanbul, Istanbul, Turkey
and Clinical Research Institute, Newcastle upon
Hertfordshire NHS Trust, Stevenage, UK 19.11.10: Behçet’s syndrome
Tyne, UK
21.3: Clinical presentation of renal disease Peter S. Friedmann Emeritus Professor of
18.16: Lung transplantation
Hiva Fassihi King’s College London, Dermatology, University of Southampton,
Edward A. Fisher Departments of Medicine,
London, UK Southampton, UK
Pediatrics, and Cell Biology, Smilow Research
23.9: Photosensitivity 23.6: Dermatitis/​eczema
Centre, New York, NY, USA
John Feehally Emeritus Consultant Nephrologist, 16.13.1: Biology and pathology of atherosclerosis Charlotte Frise Obstetric Medicine and Acute
University Hospitals of Leicester; Honorary General Medicine, Oxford University Hospitals
Rebecca C. Fitzgerald Professor of Cancer Prevention
Professor of Renal Medicine, University of NHS Foundation Trust, Oxford, UK
and MRC Programme Leader, MRC Cancer
Leicester, Leicester, UK 14.20: Prescribing in pregnancy
Unit, University of Cambridge, Hutchison/​MRC
21.8.1: Immunoglobulin A nephropathy and Susannah J.A. Froude Consultant Microbiology
Research Centre, Cambridge, UK
IgA vasculitis (HSP); 21.8.2: Thin membrane and Infectious Diseases, Public Health Wales,
15.7: Diseases of the oesophagus
nephropathy Cardiff, UK
Michael E.B. FitzPatrick Department of
Peter J. Fenner School of Public Health, Tropical 8.5.29: Newly discovered viruses
Gastroenterology, Oxford University
Medicine and Rehabilitation Sciences, James Stephen J. Fuller Associate Professor, Medicine
Hospitals, Oxford; Senior Research Fellow,
Cook University, Townsville, Qld, Australia Sydney Medical School Nepean, The University of
Translational Gastroenterology Unit, Nuffield
10.3.4: Drowning Sydney, Sydney, Australia
Department of Medicine, University of
Florence Fenollar Aix-​Marseille Université, Oxford, Oxford, UK 22.6.8: Anaemias resulting from defective
URMITE, UM63, CNRS 7278, IRD 198, 15.1: Structure and function of the maturation of red cells
INSERM 1095, IHU Méditerranée Infection, gastrointestinal tract David A. Gabbott Gloucestershire Hospitals NHS
Marseille, France Foundation Trust, Gloucester, UK
R. Andres Floto Molecular Immunity Unit,
15.10.6: Whipple’s disease 17.2: Cardiac arrest
Department of Medicine, University of Cambridge,
lii Contributors

Simon M. Gabe Consultant Gastroenterologist, D.S. Giovanniello Medical Director, American Red Christopher D. Gregory University of Edinburgh
Intestinal Failure and Academic Unit, St Mark’s Cross, Biomedical Services, Connecticut Blood Centre for Inflammation Research, Queen’s
Hospital, London, UK Services Region, Farmington, CT, USA Medical Research Institute, Edinburgh, UK
15.10.7: Effects of massive bowel resection 22.8.1: Blood transfusion 3.6: Apoptosis in health and disease
Patrick G. Gallagher Professor of Pediatrics, Mark A. Glover Hyperbaric Medicine Unit, St Christopher E.M. Griffiths Salford Royal NHS
Genetics and Pathology, Yale University, New Richard’s Hospital, Chichester, UK Foundation Trust, University of Manchester,
Haven, CT, USA 10.2.4: Diving medicine Manchester, UK
22.6.9: Disorders of the red cell membrane Peter J. Goadsby NIHR-​Wellcome Trust King’s 23.5: Papulosquamous disease
Shreyans Gandhi King’s College Hospital/​King’s Clinical Research Facility, King’s College London, Karolina Griffiths University Hospital
College London, London, UK London, UK Institute Méditerranée Infection,
22.5.2: Acquired aplastic anaemia and pure red 24.8: Headache Marseille, France
cell aplasia David Goldblatt University College London, 8.6.40: Rickettsioses
Hector H. Garcia Center for Global Health, Tumbes London, UK Mark Griffiths Peri-​Operative Medicine, St
and Department of Microbiology, Universidad 8.3: Immunization Bartholomew’s Hospital, London, UK; Imperial
Peruana Cayetano Heredia, and Cysticercosis Armando E. Gonzalez Center for Global Health, College London, London, UK
Unit, Instituto Nacional de Ciencias Neurologicas, Tumbes, Universidad Peruana Cayetano Heredia, 17.5: Acute respiratory failure
Lima, Peru and Department of Veterinary Epidemiology William J.H. Griffiths Consultant Hepatologist,
8.10.2: Cystic hydatid disease (Echinococcus and Economics, School of Veterinary Medicine, Department of Hepatology, Addenbrooke’s
granulosus); 8.10.3: Cysticercosis Universidad Nacional Mayor de San Marcos, Hospital, Cambridge, UK
Hill Gaston University of Cambridge, Cambridge, UK Lima, Peru 12.7.1: Hereditary haemochromatosis;
19.8: Reactive arthritis 8.10.2: Cystic hydatid disease (Echinococcus 15.24.6: Primary and secondary liver tumours
Rupert Gauntlett Critical Care Medicine and granulosus) J.P. Grünfeld Hôpital Universitaire Necker, Paris,
Obstetric Anaesthesia, Royal Victoria Infirmary, E.C. Gordon-​Smith Professor of Haematology, France
Newcastle upon Tyne NHS Foundation Trust, St George’s Hospital, University of London, 21.12: Renal involvement in genetic disease
Newcastle upon Tyne, UK London, UK D.J. Gubler Director, Program on Emerging
14.19: Maternal critical care 22.8.2: Haemopoietic stem cell transplantation Infectious Disease, Duke-NUS Graduate
John Geddes University of Oxford, Oxford, UK Martin Gore† The Royal Marsden, London, UK; Medical School, Singapore; Asian Pacific
26.5.7: Bipolar disorder The Institute of Cancer Research, University of Institute of Tropical Medicine and Infectious
William Gelson Consultant Hepatologist, London, London, UK Diseases, University of Hawaii, Honolulu
Hepatobiliary and Liver Transplant Unit, 5.5: Clinical features and management 8.5.12: Alphaviruses
Addenbrooke’s Hospital, Cambridge, UK Eduardo Gotuzzo Universidad Peruana Cayetano Richard L. Guerrant Center for Global Health,
15.20: Structure and function of the liver, biliary Heredia, Lima, Peru School of Medicine, University of Virginia,
tract, and pancreas 8.5.25: HTLV-​1, HTLV-​2, and associated VA, USA
Jacob George Department of Clinical diseases 8.6.12: Cholera
Pharmacology and Therapeutics, University of Philip Goulder University of Oxford, Oxford, UK Kaushik Guha Portsmouth Hospitals NHS Trust,
Dundee, Dundee, UK 8.5.23: HIV/​AIDS Portsmouth, UK
6.7: Drugs and prescribing in the older patient Alison D. Grant Department of Clinical Research, 16.5.1: Epidemiology and general
G.J. Gibson Newcastle University, Newcastle upon London School of Hygiene and Tropical pathophysiological classification of
Tyne, UK Medicine, London, UK heart failure
18.3.1: Respiratory function tests 8.5.24: HIV in low-​and middle-​income Nishan Guha Oxford University Hospitals NHS
John Gibson Professor of Oral Medicine and Honorary countries Foundation Trust, Oxford, UK
Consultant in Oral Medicine, Institute of Dentistry, Cameron C. Grant The University of Auckland, New 29.1: The use of biochemical analysis for diagnosis
School of Medicine, Medical Sciences and Nutrition, Zealand; Starship Children’s Health, Auckland, and management
University of Aberdeen, Aberdeen, UK New Zealand Loïc Guillevin Department of Internal Medicine,
15.6: The mouth and salivary glands 8.6.15: Bordetella infection National Referral Center for Rare Autoimmune
J. van Gijn University Medical Center Utrecht, David Gray Department of Cardiovascular and Systemic Diseases, INSERM U1060,
Utrecht, the Netherlands Medicine, Nottingham University Hospitals NHS Hôpital Cochin, Assistance Publique–​
24.10.1 Stroke: Cerebrovascular disease Trust, Nottingham, UK Hôpitaux de Paris, University Paris Descartes,
16.3.1: Electrocardiography Paris, France
Ian Giles Centre for Rheumatology, Department of
Richard Gray Clinical Trial Service Unit and 19.11.8: Polyarteritis nodosa
Medicine, University College London, London, UK
19.11.1: Introduction Epidemiological Studies Unit (CTSU), University Mark Gurnell University of Cambridge Medical
of Oxford, Oxford, UK School, Cambridge, UK
Robert H. Gilman Johns Hopkins University,
2.4: Large-​scale randomized evidence: Trials and 13.1: Principles of hormone action;
Bloomberg School of Public Health, Baltimore,
meta-​analyses of trials 13.5.1 Disorders of the adrenal cortex
MD, USA
8.10.3: Cysticercosis John R. Graybill Department of Medicine, Oliver P. Guttmann St Bartholomew’s Hospital,
University of Texas Health Science Center at San London, UK; Institute of Cardiovascular
Alexander Gimson Consultant Hepatologist,
Antonio, San Antonio, TX, USA Science, University College London,
Hepatobiliary and Liver Transplant Unit,
8.7.3: Coccidioidomycosis London, UK
Addenbrooke’s Hospital, Cambridge, UK
Darren Green Division of Cardiovascular 16.7.2: The cardiomyopathies: Hypertrophic,
15.19: Miscellaneous disorders of the bowel;
Sciences, University of Manchester, dilated, restrictive, and right ventricular;
15.20: Structure and function of the liver, biliary
Manchester, UK 16.7.3: Specific heart muscle disorders
tract, and pancreas;
15.24.4: Vascular disorders of the liver 16.5.4: Cardiorenal syndrome Robert D.M. Hadden Consultant Neurologist,
Manfred S. Green Hyperbaric Medicine Unit, St King’s College Hospital, London, UK
Matthew R. Ginks Oxford University Hospitals NHS
Richard’s Hospital, Chichester, UK 24.12: Disorders of cranial nerves;
Trust, Oxford, UK
10.3.9: Bioterrorism 24.16: Diseases of the peripheral nerves
16.4: Cardiac arrhythmias

†
It is with great regret that we report that Martin Gore died on 10 January, 2019.
 Contributors liii

Zara Haider Kingston Hospital NHS Trust, Helen Hatcher Consultant Medical Oncologist, Martin F. Heyworth Department of Medicine,
Surrey, UK Cambridge University Hospitals, Cambridge, UK Perelman School of Medicine, University of
9.9: Principles of contraception 20.6: Bone cancer Pennsylvania, Philadelphia, PA, USA
Sophie Hambleton Institute of Cellular Medicine, Chris Hatton Cancer and Haematology Centre, 8.8.9: Giardiasis and balantidiasis
Newcastle University Medical School, Newcastle Churchill Hospital, Oxford, UK Liz Hickson Royal North Shore Hospital, NSW,
upon Tyne, UK; Paediatric Immunology and 22.1: Introduction to Australia
Infectious Diseases, Great North Children’s haematology; 22.3.9: Histiocytosis; 17.1: The seriously ill or deteriorating
Hospital, Newcastle upon Tyne, UK 22.6.2: Anaemia: Pathophysiology, classification, patient
4.4: Immunodeficiency and clinical features Tran Tinh Hien Oxford University Clinical Research
Freddie C. Hamdy Nuffield Department of Philip N. Hawkins Professor of Medicine, National Unit, Hospital for Tropical Diseases, Ho Chi
Surgical Sciences, University of Oxford, Amyloidosis Centre, Centre for Amyloidosis and Minh City, Vietnam
Oxford, UK Acute Phase Proteins, University College London, 8.6.1: Diphtheria
21.18: Malignant diseases of the London, UK
Katherine A. High Professor of Pediatrics Emerita,
urinary tract 12.12.2 Hereditary periodic fever syndromes;
Perelman School of Medicine, University
Michael G. Hanna National Hospital for 12.12.3 Amyloidosis
of Pennsylvania, Children’s Hospital of
Neurology and Neurosurgery, Queen Square, Keith Hawton Centre for Suicide Research, Philadelphia, Philadelphia, PA, USA; President
London, UK University of Oxford Department of Psychiatry, and Head of R&D, Spark Therapeutics,
24.19.1: Structure and function of muscle Warneford Hospital, Oxford, UK Philadelphia, PA, USA
David M. Hansell Faculty of Medicine, National 26.3.2: Self-​harm 22.7.4: Genetic disorders of coagulation
Heart and Lung Institute, Imperial College Deborah Hay Honorary Consultant Haematologist,
Ingeborg Hilderson Department of Medical
London, London, UK Nuffield Department of Medicine, University of Oncology, University Hospital Ghent, Ghent,
18.3.2: Thoracic imaging Oxford, Oxford, UK Belgium
Danielle Harari Guy’s and St Thomas’ Hospitals and 22.6.7: Disorders of the synthesis or function of 21.10.4: The kidney in sarcoidosis
King’s College London, London, UK haemoglobin; 22.6.9: Disorders of the red cell
membrane Tom R. Hill Population Health Sciences
6.9: Bladder and bowels
Institute, Newcastle University, Newcastle
Kate Hardy Faculty of Medicine, Department of Roderick J. Hay King’s College London,
upon Tyne, UK
Surgery and Cancer, Imperial College London, London, UK
11.2: Vitamins
London, UK 8.6.31: Nocardiosis; 8.7.1: Fungal infections;
23.6: Dermatitis/​eczema; 23.10: Infections of David Hilton-​Jones Muscular Dystrophy
13.6.1: Ovarian disorders
the skin; 23.12: Blood and lymphatic vessel Campaign, Muscle and Nerve Centre,
Karen E. Harman Department of Dermatology,
disorders Department of Clinical Neurology, John
University Hospitals of Leicester NHS Trust, Radcliffe Hospital, Oxford, UK
Leicester, UK Peter Hayes Professor of Hepatology, Liver Unit,
24.18: Disorders of the neuromuscular junction;
23.7: Cutaneous vasculitis, connective tissue University of Edinburgh; and Royal Infirmary of
24.19.3: Myotonia; 24.19.4 Metabolic and
diseases, and urticaria Edinburgh, Edinburgh, UK
endocrine disorders
15.22.3: Portal hypertension and variceal
Peter Harper London Oncology Centre,
bleeding Matthew Hind Royal Brompton Hospital
London, UK
Catherine E.G. Head Consultant Cardiologist, and National Heart and Lung Institute,
5.6: Systemic treatment and radiotherapy;
Guy’s and St Thomas’ NHS Foundation Trust, Imperial College School of Medicine,
5.7: Medical management of breast cancer
London, UK London, UK
Steve Harper Consultant Renal and Transplant 18.5.1: Upper airway obstruction; 18.5.2: Sleep-​
14.6: Heart disease in pregnancy
Medicine, Southmead Hospital, Bristol; related breathing disorders
Honorary Professor, School of Physiology, Eugene Healy Dermatopharmacology,
Southampton General Hospital, University John Hindle Betsi Cadwaladr University Health
Pharmacology and Neuroscience, University
of Southampton, UK Board, Llandudno Hospital; School of
of Bristol, Bristol, UK; Honorary Professor,
23.8: Disorders of pigmentation Psychology, Bangor University, Bangor, UK
School of Medicine, University of Exeter,
6.10: Neurodegenerative disorders in
Exeter, UK Nick Heather Department of Psychology, Faculty
older people
21.1: Structure and function of the kidney of Health and Life Sciences, Northumbria
James L. Harrison London Deanery, London, UK University, Newcastle upon Tyne, UK N. Hirani Royal Infirmary, Edinburgh, UK
16.9.2: Endocarditis 26.6.1: Brief interventions for excessive alcohol 18.11.2: Idiopathic pulmonary fibrosis
consumption Gideon M. Hirschfield Lily and Terry Horner
Tina Hartert Division of Pulmonary and Critical
Care, Vanderbilt University Medical Center, David W. Hecht Loyola University Health System, Chair in Autoimmune Liver Disease Research,
Nashville, TN, USA IL, USA Toronto Centre for Liver Disease,
14.8: Chest diseases in pregnancy 8.6.11: Anaerobic bacteria Department of Medicine, University of
Thomas Hellmark Department of Clinical Sciences, Toronto, Toronto General Hospital,
Christine Hartmann Institute of Musculoskeletal
Lund University, Lund, Sweden Toronto, Canada
Medicine, University of Münster, Münster,
21.8.7: Antiglomerular basement membrane 15.23.2: Autoimmune hepatitis
Germany
19.1: Joints and connective tissue—​structure and disease Sarah Hobdey Veterans Medical Hospital, Boise,
function Michael Heneghan Professor of Hepatology and ID, USA
Nicholas C. Harvey MRC Lifecourse Consultant Hepatologist, Institute of Liver 8.6.2: Streptococci and enterococci
Epidemiology Unit, University of Southampton, Studies, King’s College Hospital, London, UK Herbert Hof MVZ Labor Limbach, Heidelberg,
Southampton, UK 14.9: Liver and gastrointestinal diseases of Germany
20.4: Osteoporosis pregnancy 8.6.38: Listeriosis
Rowan Harwood Nottingham University Hospitals Michael Henein Umeå University, Sweden; Canterbury A.V. Hoffbrand Emeritus Professor of Haematology,
NHS Trust and University of Nottingham, Christ Church University, Canterbury, UK University College, London, UK
Queens Medical Centre, Nottingham, UK 16.6: Valvular heart disease; 16.8: Pericardial 22.6.6: Megaloblastic anaemia and miscellaneous
6.5: Older people in hospital disease deficiency anaemias
liv Contributors

Ronald Hoffman Albert A. and Vera G. List, Alastair Hutchison Medical Director and Professor Caron A. Jacobson Division of Hematologic
Professor of Medicine, Division of Hematology/​ of Renal Medicine, Dorset County Hospital, Malignancies, Dana-​Farber Cancer Institute,
Oncology; Director, Myeloproliferative Disorders Dorchester, UK Boston, MA, USA
Program, Tisch Cancer Institute, Department of 21.6: Chronic kidney disease 22.4.1: Introduction to lymphopoiesis
Medicine, Icahn School of Medicine at Mount Peter J. Hutchinson University of Cambridge, N. Asger Jakobsen Clinical Research Fellow, MRC
Sinai, New York, NY, USA Cambridge, UK Molecular Haematology Unit, Weatherall Institute
22.3.5: The polycythaemias; 22.3.6: Thrombocytosis 24.5.6: Brainstem death and prolonged disorders of of Molecular Medicine, Radcliffe Department of
and essential thrombocythaemia consciousness Medicine, University of Oxford, Oxford, UK
Georg F. Hoffmann Department of General Pediatrics, Steve Iliffe Research Department of Primary Care 22.2.1: Cellular and molecular basis of
University of Heidelberg, Heidelberg, Germany and Population Health, University College haematopoiesis
12.2 Protein-​dependent inborn errors of metabolism London, London, UK Rajiv Jalan Liver Failure Group, Institute for Liver
Tessa L. Holyoake† Professor of Experimental 6.3: Optimizing well-​being into old age and Digestive Health, University College London,
Haematology, Section of Experimental Lawrence Impey Obstetrics and Fetal Medicine, Royal Free Campus, London, UK
Haematology, Paul O’Gorman Leukaemia The Women’s Centre, John Radcliffe Hospital, 15.22.5: Liver failure
Research Centre, Institute of Cancer Sciences, Oxford, UK Hannah Jarvis Respiratory Medicine, St Mary’s
College of Medical, Veterinary and Life Sciences, 14.16: Fetal effects of maternal infection Hospital, Imperial College Healthcare NHS Trust,
University of Glasgow, Glasgow, UK London, UK
Jakko van Ingen Radboud University Medical
22.3.4: Chronic myeloid leukaemia 18.4.4: Mycobacteria
Centre, Nijmegen, the Netherlands
Roel Hompes Consultant Colorectal Surgeon, 8.6.27: Disease caused by environmental M.K. Javaid Nuffield Department of Orthopaedics,
Academic Medical Centre Amsterdam, mycobacteria Rheumatology and Musculoskeletal Sciences,
University of Amsterdam, the Netherlands Botnar Research Centre, Nuffield Orthopaedic
Peter Irving Department of Gastroenterology,
15.14: Colonic diverticular disease Centre, Oxford, UK
Guy’s and St Thomas’ NHS Foundation Trust,
Tony Hope St Cross College, University of Oxford, London, UK 20.1: Skeletal disorders—​general approach and
Oxford, UK 15.12: Ulcerative colitis clinical conditions
1.5: Medical ethics David Jayne Professor of Clinical Autoimmunity,
John D. Isaacs Faculty of Medical Sciences,
Julian Hopkin Medicine and Health, School of Newcastle University and Musculoskeletal Unit, Department of Medicine, School of Clinical
Medicine, Swansea University, Swansea, UK Newcastle upon Tyne Hospitals NHS Foundation Medicine, University of Cambridge, Cambridge, UK
18.2: The clinical presentation of respiratory Trust, Newcastle upon Tyne, UK 19.11.7: ANCA-​associated vasculitis; 21.10.2: The
disease 2.7 Biological therapies for immune, kidney in systemic vasculitis
P. Hopkins Medical Director, Queensland Lung inflammatory, and allergic diseases; Susan Jebb Nuffield Department of Primary
Transplant Service, Chermside, Qld, Australia 19.5: Rheumatoid arthritis Care Health Sciences, University of Oxford,
18.16: Lung transplantation David A. Isenberg Centre for Rheumatology, Oxford, UK
Nicholas S. Hopkinson National Heart and Lung Department of Medicine, University College 26.6.2: Obesity and weight management
Institute, Imperial College, London, UK London, London, UK Katie J.M. Jeffery Oxford University Hospitals NHS
18.8: Chronic obstructive pulmonary disease 19.11.1: Introduction; 19.11.2: Systemic lupus Foundation Trust, Department of Microbiology,
Patrick Horner Population Health Sciences, erythematosus and related disorders John Radcliffe Hospital, Oxford, UK
University of Bristol, Bristol, UK Theodore J. Iwashyna Department of Internal 8.5.22: Hepatitis C virus
8.6.45: Chlamydial infections; 9.5: Urethritis Medicine, University of Michigan, Ann Arbor, Rajesh Jena Cambridge University Hospitals,
Bala Hota Rush University, Chicago, IL USA MI, USA; Center for Clinical Management Cambridge, UK
8.6.4: Staphylococci Research, Department of Veterans Affairs, 5.6: Systemic treatment and radiotherapy
Ann Arbor, MI, USA; Australian and New Tom Jenkins University of Sheffield, Sheffield, UK
Andrew R. Houghton Grantham and District
Zealand Intensive Care Research Centre, 24.15: The motor neuron diseases
Hospital, Grantham, UK; University of Lincoln,
Department of Epidemiology and Preventive
Lincoln, UK Jørgen Skov Jensen Microbiology and Infection
Medicine, Monash University, Melbourne, Vic,
16.3.1: Electrocardiography Control, Statens Serum Institut, Copenhagen,
Australia
Robert A. Huddart The Institute of Cancer Research, Denmark
17.12: Persistent problems and recovery after
London, UK 8.6.46: Mycoplasmas
critical illness
21.18: Malignant diseases of the urinary tract Vivekanand Jha Executive Director, The George
Arnaud Jaccard Service d’hématologie clinique et
Harriet C. Hughes Consultant Microbiology Institute for Global Health, New Delhi, India;
de thérapie cellulaire, CHU de Limoges—​Hôpital
and Infectious Diseases, Public Health Wales, Professor of Nephrology, University of Oxford,
Dupuytren, Limoges, France
Cardiff, UK Oxford, UK
21.10.5: Renal involvement in plasma cell
8.5.29: Newly discovered viruses 21.11: Renal diseases in the tropics
dyscrasias, immunoglobulin-​based amyloidoses,
Ieuan A. Hughes University of Cambridge, Tingliang Jiang Professor, Department of
and fibrillary glomerulopathies, lymphomas, and
Cambridge, UK Pharmacology, Institute of Chinese Materia
leukaemias
13.5.2: Congenital adrenal hyperplasia Medica, China Academy of Chinese Medical
Alan A. Jackson Southampton General Hospital,
Sciences, Beijing, China
James H. Hull The Royal Brompton Hospital, Southampton, UK 2.8: Traditional medicine exemplified by
London, UK 11.4: Severe malnutrition traditional Chinese medicine
18.5.1: Upper airway obstruction Thomas Jackson Queen Elizabeth Hospital,
Alexis J. Joannides University of Cambridge,
Adam Hurlow Leeds Teaching Hospitals NHS Trust, Birmingham, UK Cambridge, UK
Leeds, UK 26.3.1: Confusion 3.7: Stem cells and regenerative medicine
7.4: Care of the dying person Anu Jacob National Neuromyelitis Optica Service,
Anne M. Johnson Centre for Molecular Epidemiology
Jane A. Hurst Great Ormond Street Hospital, Walton Centre for Neurology and Neurosurgery, and Translational Research, Institute for Global
London, UK Liverpool, UK Health, University College London, London, UK
24.20: Developmental abnormalities of the central 24.13.1: Diseases of the spinal cord 9.2: Sexual behaviour
nervous system

†
It is with great regret that we report that Tessa L. Holyoake died on 30 August, 2017.
 Contributors lv

Colin Johnson Emeritus Professor of Surgical Sciences, David Kavanagh Institute of Genetic Medicine, B. Khoo University College London, London, UK
University of Southampton, Southampton, UK Newcastle University, Newcastle upon Tyne, UK 13.8: Pancreatic endocrine disorders and multiple
15.15: Diseases of the gallbladder and biliary tree 21.10.6: Haemolytic uraemic syndrome endocrine neoplasia;
M.R. Johnson Professor of Neurology and Genomic Fiona Kearney Nottingham University Hospitals 15.9.2: Carcinoid syndrome
Medicine, Faculty of Medicine, Department of Trust, Nottingham, UK Nine V.A.M. Knoers Professor in Clinical Genetics,
Brain Sciences, Imperial College, London, UK 6.8: Falls, faints, and fragility fractures Department of Genetics, University Medical
24.5.1: Epilepsy in later childhood and adulthood David Keeling Oxford Haemophilia and Thrombosis Centre Utrecht, Utrecht, the Netherlands
Elaine Jolly University of Cambridge, Cambridge, UK Centre, Churchill Hospital, Oxford, UK 21.16: Disorders of tubular electrolyte handling
30.1: Acute medical presentations; 30.2: Practical 16.16.2: Therapeutic anticoagulation Stefan Kölker Consultant, Pediatric Metabolic
procedures Andrew Kelion Oxford University Hospitals NHS Medicine, University Children’s Hospital,
D. Joly Necker-​Enfants Malades Hospital, Paris, France Foundation Trust, Oxford, UK Heidelberg; Department of General Pediatrics,
21.12: Renal involvement in genetic disease 16.3.3: Cardiac investigations: Nuclear, Division of Inborn Metabolic Diseases,
MRI, and CT Heidelberg, Germany
Bryony Jones Imperial College Hospital, London, UK
12.2 Protein-​dependent inborn errors of
14.10: Diabetes in pregnancy Julia Kelly Royal Brompton and Harefield NHS
metabolism
David E.J. Jones Institute of Cellular Medicine, Trust, London, UK
18.5.2: Sleep-​related breathing disorders Nils P. Krone University of Sheffield,
Newcastle University and Liver Unit, Freeman
Sheffield, UK
Hospital, Newcastle upon Tyne, UK Paul Kelly Professor of Tropical Gastroenterology,
13.5.2: Congenital adrenal hyperplasia
15.23.3: Primary biliary cholangitis Blizard Institute, Barts and The London School
of Medicine, Queen Mary University of London, Narong Khuntikeo Director, Cholangiocarcinoma
Bouke de Jong Institute of Tropical Medicine,
London, UK; TROPGAN Group, Department of Research Institute (CARI), Director,
Antwerp, Belgium
Internal Medicine, University of Zambia School Cholangiocarcinoma Screening and Care
8.6.29: Buruli ulcer: Mycobacterium ulcerans infection
of Medicine, Lusaka, Zambia Program (CASCAP), Faculty of Medicine, Khon
Menno De Jong Department of Medical Microbiology,
8.8.6: Cyclospora and cyclosporiasis Kaen University, Thailand; Faculty of Medicine,
Academic Medical Center, University of Khon Kaen University, Thailand; Associate
Amsterdam, Amsterdam, the Netherlands David P. Kelsell London Medical School,
Professor, Department of Surgery, Faculty of
24.11.2: Viral infections London, UK
Medicine, Khon Kaen University, Thailand
23.3: Inherited skin disease
Iain Jordan Oxford University Hospitals NHS 8.11.2: Liver fluke infections
Foundation Trust, Oxford, UK Samuel Kemp Royal Brompton Hospital,
Gudula Kirtschig Tübingen, Germany
26.5.13: Personality disorders London, UK
14.13: The skin in pregnancy
18.2: The clinical presentation of respiratory
Emil Kakkis Ultragenyx Pharmaceutical Inc.,
disease Suzanne Kite Leeds Teaching Hospitals NHS Trust,
Novato, CA, USA Leeds, UK
2.9: Engaging patients in therapeutic development Christopher Kennard Nuffield Department of
7.4: Care of the dying person
Clinical Neurosciences, University of Oxford,
Philip A. Kalra Consultant and Honorary Professor
Oxford, UK John L. Klein Guy’s and St Thomas’ NHS Foundation
of Nephrology, Department of Renal Medicine,
24.1: Introduction and approach to the patient Trust, London, UK
Salford Royal NHS Foundation Trust, Salford, UK
with neurological disease; 24.6.1: Visual pathways 16.9.2: Endocarditis
16.5.4 Cardiorenal syndrome;
Richard S.C. Kerr Oxford University Hospitals NHS Paul Klenerman Nuffield Department of Medicine,
21.10.10: Atherosclerotic renovascular disease
Foundation Trust, Oxford, UK University of Oxford, Oxford, UK
Eileen Kaner Institute of Health and Society,
24.11.3: Intracranial abscesses 4.3: Adaptive immunity; 8.5.22: Hepatitis
Newcastle University, Newcastle upon Tyne, UK C virus
26.6.1: Brief interventions for excessive alcohol Satish Keshav† Department of Gastroenterology,
Oxford University Hospitals NHS Foundation Richard Knight Department of Microbiology,
consumption
Trust, Oxford; Professor of Gastroenterology, University of Nairobi, Nairobi, Kenya
Theodoros Karamitos Division of Cardiovascular
Translational Gastroenterology Unit, Nuffield 8.8.1: Amoebic infections; 8.8.10: Blastocystis
Medicine, Radcliffe Department of Medicine,
Department of Medicine, University of Oxford, infection; 8.9.2: Lymphatic filariasis;
University of Oxford, John Radcliffe Hospital,
Oxford, UK 8.9.3: Guinea worm disease (dracunculiasis);
Oxford, UK
15.1: Structure and function of the 8.9.6: Angiostrongyliasis; 8.10.1: Cestodes
16.3.3: Cardiac investigations: Nuclear,
gastrointestinal tract (tapeworms)
MRI, and CT
Nigel S. Key Harold R. Roberts Professor of Medicine, David Koh PAPRSB Institute of Health Sciences,
Niki Karavitaki Queen Elizabeth Hospital,
Division of Hematology-​Oncology, University of Universiti Brunei Darussalam, SSH School of
Birmingham, UK
North Carolina, Chapel Hill, NC, USA Public Health, National University of Singapore,
13.2.1: Disorders of the anterior pituitary
22.7.1: The biology of haemostasis and thrombosis Singapore
gland; 13.2.2: Disorders of the posterior 10.2.5: Noise
pituitary gland Rajesh K. Kharbanda John Radcliffe Hospital,
Oxford, UK G.C.K.W. Koh Diseases of the Developing
Steven B. Karch Consultant in Cardiac Pathology
16.13.4: Management of acute coronary syndrome World, Alternative Drug Development,
and Toxicology, Berkeley, CA, USA GlaxoSmithKline, UK
27.1: Forensic and legal medicine Elham Khatamzas Regional Infectious Diseases
8.6.8: Pseudomonas aeruginosa
Unit, NHS Lothian, Edinburgh, UK
Fiona E. Karet Cambridge University Hospitals NHS
8.2.4: Infection in the immunocompromised host M.A. Kokosi Royal Brompton and Harefield NHS
Foundation Trust, Cambridge, UK Trust, London, UK
21.15: The renal tubular acidoses Peng T. Khaw Professor and Consultant Ophthalmic
18.11.4: The lung in autoimmune rheumatic
Surgeon; Director of Research, Development
Arthur Kaser Division of Gastroenterology and disorders
and Innovation; Director, NIHR Biomedical
Hepatology, Department of Medicine, University
Research Centre at Moorfields Eye Hospital Onn Min Kon Respiratory Medicine, St Mary’s
of Cambridge, Addenbrooke’s Hospital,
NHS Foundation Trust and UCL Institute of Hospital, Imperial College Healthcare NHS Trust,
Cambridge, UK
Ophthalmology, London, UK London, UK; National Heart and Lung Institute,
15.5: Immune disorders of the
25.1: The eye in general medicine Imperial College London, London, UK
gastrointestinal tract 18.4.4: Mycobacteria

†
It is with great regret that we report that Satish Keshav died on 23 January, 2019.
lvi Contributors

Adelheid Korb-​Pap Institute of Experimental Malcolm Law Wolfson Institute of Preventive Ted Liao MedStar Georgetown University Hospital
Musculoskeletal Medicine, University Hospital Medicine, St Bartholomew’s and the Royal and Georgetown University School of Medicine,
Münster, Münster, Germany London School of Medicine and Dentistry, Queen Washington DC, USA
19.1: Joints and connective tissue—​structure and Mary University of London, London, UK 26.5.8: Anxiety disorders
function 2.12 Medical screening Oliver Liesenfeld Roche Molecular Systems,
Vasilis Kouranos Royal Brompton and Harefield Tim Lawrence Nuffield Department of Clinical Pleasanton, CA, USA
NHS Trust, London, UK Neurosciences, University of Oxford, Oxford, UK 8.8.4: Toxoplasmosis
18.11.3: Bronchiolitis obliterans and cryptogenic 24.10.3: Traumatic brain injury; Liz Lightstone, Professor of Renal Medicine,
organizing pneumonia 24.11.3: Intracranial abscesses Centre for Inflammatory Disease, Faculty
Christian Krarup Region Hovedstaden, Denmark Stephen M. Lawrie Division of Psychiatry, of Medicine, Imperial College London,
24.3.2: Electrophysiology of the central and University of Edinburgh, Edinburgh, UK London, UK
peripheral nervous systems 26.5.11: Schizophrenia 21.10.3: The kidney in rheumatological disorders
Amy S. Kravitz United States Agency for Alison M. Layton Harrogate and District NHS Wei Shen Lim Consultant Respiratory Physician and
International Development (USAID), Foundation Trust, Harrogate, UK Honorary Professor of Medicine, Nottingham
Washington DC, USA 23.11: Sebaceous and sweat gland disorders University Hospitals NHS Trust and University of
2.21: Humanitarian medicine James W. Le Duc Galveston National Laboratory, Nottingham, Nottingham, UK
Dinakantha S. Kumararatne Depatment of Clinical University of Texas Medical Branch, Galveston, 18.4.2: Pneumonia in the normal host;
Immunology, Cambridge University Hospitals TX, USA 18.4.3: Nosocomial pneumonia
NHS Foundation Trust, Cambridge, UK 8.5.16: Bunyaviridae Aldo A.M. Lima Biomedicine Center and
4.4: Immunodeficiency Susannah Leaver St George’s NHS Foundation Department of Physiology and Pharmacology,
Om P. Kurmi Hyperbaric Medicine Unit, Trust, London, UK School of Medicine, Federal University of Ceará,
St Richard’s Hospital, Chichester, UK 17.5: Acute respiratory failure Fortaleza, Ceará, Brazil
10.3.1: Air pollution and health 8.6.12: Cholera
Y.C. Gary Lee Faculty of Health and Medical
Robert A. Kyle Professor of Medicine, Division of Sciences, UWA Medical School, University of Gregory Y.H. Lip Liverpool Centre for
Hematology, Mayo Clinic, Rochester, MN, USA Western Australia, Perth, WA, Australia Cardiovascular Science, University of Liverpool
22.4.6: Plasma cell myeloma and related 18.17: Pleural diseases; 18.19.3 Pleural tumours; and Liverpool Heart and Chest Hospital,
monoclonal gammopathies 18.19.4 Mediastinal tumours and cysts Liverpool, UK; Aalborg Thrombosis Research
Unit, Department of Clinical Medicine, Aalborg
Peter L. Labib Clinical Research Fellow, Institute Haur Yueh Lee National Heart Centre Singapore,
University, Aalborg, Denmark
for Liver and Digestive Health, Royal Singapore, China; Kings Drugs Reaction Group,
16.4: Cardiac arrhythmias; 16.17.5: Hypertensive
Free Campus, University College London, King’s College London, London, UK
urgencies and emergencies
London, UK 23.16: Cutaneous reactions to drugs
15.16: Cancers of the gastrointestinal tract Mark A. Little Professor of Nephrology and
Richard W.J. Lee Director, Uveitis and Scleritis Service,
Consultant Nephrologist, Trinity Health Kidney
Charles J.N. Lacey Hull York Medical School, National Institute for Health Research Biomedical
Centre, Trinity College Dublin; Tallaght and
University of York, York, UK Research Centre at Moorfields Eye Hospital NHS
Beaumont Hospitals, Dublin, Ireland
9.7: Anogenital lumps and bumps Foundation Trust and University College London
21.8.5: Proliferative glomerulonephritis;
Helen J. Lachmann Senior Lecturer, National Institute of Ophthalmology, London, UK
21.8.6: Membranoproliferative
Amyloidosis Centre and Centre for Acute Phase 25.1: The eye in general medicine
glomerulonephritis
Proteins, University College London Medical Evelyne de Leeuw Centre for Health Equity
P. Little University of Southampton,
School, London, UK Training, Research and Evaluation, UNSW
Southampton, UK
12.12.2: Hereditary periodic fever syndromes Sydney, South Western Sydney Local Health
18.4.1: Upper respiratory tract infections
Robin H. Lachmann Consultant in Inherited District, Ingham Institute, Australia
2.13: Health promotion William A. Littler The Priory Hospital,
Metabolic Disease, Charles Dent Metabolic
Birmingham, UK
Unit, National Hospital for Neurology and Yee-​Sin Leo National Centre for Infectious Disease,
16.9.2: Endocarditis
Neurosurgery, London, UK Tan Tock Seng Hospital, Singapore; Yong Loo Lin
12.3.1: Glycogen storage diseases School of Medicine and Saw Swee Hock School of A. Llanos-​Cuentas School of Public Health and
Public Health, National University of Singapore, Administration, Universidad Peruana Cayetano
Ralph Lainson† Ex Director, the Wellcome Parisitology
Singapore; Lee Kong Chian School of Medicine, Heredia, Lima, Peru
Unit, and research-worker, Department of
Singapore 8.6.44: Bartonella bacilliformis infection
Parasitology, Instiuto Evandro Chagas, Rodovia,
Barro Levilầndia, Ananindeua, Pará, Brazil 8.5.15: Dengue Y.M. Dennis Lo Li Ka Shing Professor of Medicine,
8.8.6: Cyclospora and cyclosporiasis Phillip D. Levin Intensive Care Unit, Shaare Zedek Department of Chemical Pathology, The Chinese
Medical Center, Jerusalem, Hebrew University of University of Hong Kong, China
Kin Bong Hubert Lam University of Oxford,
Jerusalem, Faculty of Medicine, Jerusalem, Israel 3.9: Circulating DNA for molecular diagnostics
Oxford, UK
10.3.1: Air pollution and health 17.10: Palliative and end-​of-​life care in the ICU Diana N.J. Lockwood London School of Hygiene
Elena N. Levtchenko Professor in Pediatric Nephrology, and Tropical Medicine, London, UK
D.A. Lane Faculty of Medicine, Department of
Catholic University Leuven, Leuven, the Netherlands 8.6.28: Leprosy (Hansen’s disease);
Medicine, Imperial College London,
21.16: Disorders of tubular electrolyte handling 8.8.13: Leishmaniasis
London, UK
16.4: Cardiac arrhythmias Su Li Department of Epidemiology, Guangxi David A. Lomas Vice Provost (Health) and Head of
Medical University, Nanning, Guangxi, China UCL Medical School, University College London,
Peter C. Lanyon Nottingham University Hospitals
5.7: Medical management of breast cancer London, UK
Trust, Nottingham, UK
12.13: α1-​Antitrypsin deficiency and the
19.3: Clinical investigation Fulong Liao Professor, Biomechanopharmacology,
serpinopathies; 15.24.6 Primary and secondary
Andrew J. Larner Cognitive Function Clinic, Institute of Chinese Materia Medica, China
liver tumours
Walton Centre for Neurology and Neurosurgery, Academy of Chinese Medical Sciences,
Beijing, China Alan Lopez University of Melbourne, Melbourne,
Liverpool, UK
2.8: Traditional medicine exemplified by Vic, Australia
24.3.1: Lumbar puncture; 24.5.4: Syncope;
traditional Chinese medicine 2.3: The Global Burden of Disease: Measuring the
24.13.1: Diseases of the spinal cord
health of populations

†
It is with great regret that we report that Ralph Lainson died on 5 May, 2015.
 Contributors lvii

Constantino López-Macias Mexican Society of Alasdair MacGowan Department of Medical Anthony M. Marinaki Purine Research Laboratory,
Immunology, Mexico; University of Oxford, Microbiology, North Bristol NHS Trust, Bristol, UK Viapath, St Thomas’ Hospital, London, UK
Oxford, UK 8.2.5: Antimicrobial chemotherapy 12.4: Disorders of purine and pyrimidine
4.3: Adaptive immunity Lucy Mackillop Obstetric Medicine, Oxford metabolism
David A. Low Liverpool John Moores University, University Hospitals NHS Foundation Trust, Chiara Marini-​Bettolo Newcastle University
Liverpool, UK Oxford, UK John Walton Centre for Muscular Dystrophy
24.14: Diseases of the autonomic nervous system 14.20 Prescribing in pregnancy Research, Newcastle upon Tyne Hospital NHS
Elyse E. Lower University of Cincinnati Medical Gael M. MacLean Oxford University Hospitals NHS Foundation Trust, Institute of Genetic Medicine,
Center, Cincinnati, OH, USA Foundation Trust, Oxford, UK International Centre for Life, Newcastle upon
18.12: Sarcoidosis 13.6.3: Benign breast disease Tyne, UK
Kenneth T. MacLeod National Heart and Lung 24.19.2: Muscular dystrophy
Katharine Lowndes Department of Haematology,
Royal Hampshire County Hospital, Winchester UK Institute (NHLI) Division, Faculty of Medicine, Michael Marks Department of Clinical Research,
14.17: Blood disorders in pregnancy Imperial College London, London, UK London School of Hygiene and Tropical
16.1.2: Cardiac physiology Medicine, London, UK
Angela K. Lucas-​Herald School of Medicine,
Alasdair MacLullich Edinburgh University, 8.6.36: Non-​venereal endemic treponematoses:
University of Glasgow, Royal Hospital for
Edinburgh, UK Yaws, endemic syphilis (bejel), and pinta
Children, Glasgow, UK
13.7.3: Normal and abnormal sexual differentiation 6.5: Older people in hospital Paul Marks Honorary Consultant Neurosurgeon,
Jane Macnaughtan Liver Failure Group, Institute Harrogate District Hospital, Harrogate;
Ingrid E. Lundberg Rheumatology Unit, Department
for Liver and Digestive Health, University Her Majesty’s Senior Coroner for the City
of Medicine, Sloan, Karolinska Institute,
College London, Royal Free Campus, of Kingston upon Hull and the County of
Karolinska Hospital, Stockholm, Sweden
London, UK the East Riding of Yorkshire; Vice President,
19.11.5: Inflammatory myopathies
15.22.5: Liver failure Faculty of Forensic and Legal Medicine,
James R. Lupski Department of Molecular and
London, UK; Honorary Professor of
Human Genetics, Department of Pediatrics, Robert Mactier Consultant Nephrologist,
Neurosurgery, College of Medicine,
Human Genome Sequencing Center, Baylor Glasgow Renal and Transplant Unit, South
University of Malawi, Malawi
College of Medicine, Texas Children’s Hospital, Glasgow University Hospital, NHS Greater
27.1: Forensic and legal medicine
Houston, TX, USA Glasgow and Clyde, Glasgow, UK
21.7.1: Haemodialysis Thomas J. Marrie Department of Medicine,
3.2: The genomic basis of medicine
Dalhousie University, Nova Scotia, Canada
Raashid Luqmani Nuffield Department C. Maguiña-​Vargas School of Medicine,
8.6.42: Coxiella burnetii infections (Q fever)
of Orthopaedics, Rheumatology and Universidad Peruana Cayetano Heredia,
Lima, Peru Judith C.W. Marsh King’s College Hospital, King’s
Musculoskeletal Science, University of
8.6.44: Bartonella bacilliformis infection College London, London, UK
Oxford Rheumatology Department, Nuffield
22.5.2: Acquired aplastic anaemia and pure red
Orthopaedic Centre, Oxford, UK Michael Maher Professor of Radiology, University
cell aplasia
19.11.6: Large vessel vasculitis College Cork and Consultant Radiologist,
Cork University Hospital and Mercy University Sara Marshall Wellcome Trust, London, UK
Linda Luxon National Hospital for Neurology
Hospital, Cork, Ireland 4.4: Immunodeficiency
and Neurosurgery, University College London
Hospitals NHS Foundation Trust, Queen Square, 15.3.3: Radiology of the gastrointestinal tract Steven B. Marston National Heart and Lung
London, UK Malegapuru W. Makgoba National Health Ombud, Institute (NHLI) Division, Faculty of Medicine,
24.6.3: Hearing loss Pretoria, South Africa; College of Health Science, Imperial College London, UK
University of KwaZulu-​Natal, Durban, South 16.1.2: Cardiac physiology
Jean Paul Luzio Cambridge Institute for Medical
Research, Cambridge, UK Africa; National Planning Commission of South Maria do Rosario O. Martins University Nova de
3.1: The cell Africa; Universities of Natal and KwaZulu-​Natal, Lisboa, Lisbon, Portugal
Durban, South Africa; MRC (SA), Cape Town, 2.16: Financing healthcare in low-​income
Lucio Luzzatto Department of Haematology,
South Africa developing countries: A challenge for equity
Muhimbili University of Health and Allied
2.18: Fostering medical and health research in in health
Sciences Dar es Salaam, Tanzania
22.5.3: Paroxysmal nocturnal haemoglobinuria; resource-​constrained countries Thiviyani Maruthappu Kelsell Group, Cell Biology
22.6.11: Glucose-​6-​phosphate dehydrogenase deficiency Govind K. Makharia Department of and Cutaneous Research, Blizard Institute, Barts
Gastroenterology and Human Nutrition, and The London, Queen Mary University of
Graz A. Luzzi Wycombe General Hospital, High
All India Institute of Medical Sciences, New London, London, UK
Wycombe, UK
Delhi, India 23.3: Inherited skin disease
9.3: Sexual history and examination
15.10.8: Malabsorption syndromes in Duncan J. Maskell University of Cambridge,
Kate D. Lynch Translational Gastroenterology
the tropics Cambridge, UK
Unit, John Radcliffe Hospital, Oxford; Nuffield
Hadi Manji The National Hospital for Neurology 8.1.1: Biology of pathogenic microorganisms
Department of Medicine, University of Oxford,
Oxford, UK and Neurosurgery, Queen Square, London, UK N.A. Maskell Academic Respiratory Unit,
15.23.4: Primary sclerosing cholangitis 24.11.4: Neurosyphilis and neuro-​AIDS University of Bristol, UK
J.I. Mann Edgar Diabetes and Obesity Research 18.17: Pleural diseases
David Mabey Department of Clinical Research,
London School of Hygiene and Tropical Centre (EDOR), Department of Human Jay W. Mason Cardiology Division, University
Medicine, London, UK Nutrition, University of Otago, Dunedin, New of Utah College of Medicine, Salt Lake City,
8.6.36: Non-​venereal endemic treponematoses: Zealand UT, USA
Yaws, endemic syphilis (bejel), and pinta; 11.5: Diseases of affluent societies and the need for 16.7.1: Myocarditis
8.6.45: Chlamydial infections; 9.1: Epidemiology of dietary change Tahir Masud Nottingham University Hospitals
sexually transmitted infections David Mant University of Oxford, Oxford, UK Trust, Nottingham, UK
Peter K. MacCallum Senior Lecturer in Haematology, 2.11: Preventive medicine 6.8: Falls, faints, and fragility fractures
Barts and The London School of Medicine and G.A. Margaritopoulos Royal Brompton and Christopher J. Mathias Stoke Poges, UK
Dentistry, Queen Mary University of London, UK Harefield NHS Trust, London, UK 24.14: Diseases of the autonomic nervous
14.7: Thrombosis in pregnancy 18.11.5: The lung in vasculitis system
lviii Contributors

Fadi Matta Associate Professor, Department of Alison McMillan East and North Hertfordshire NHS Stephen J. Middleton Consultant
Osteopathic Medical Specialties, Collage of Trust, Stevenage, UK Gastroenterologist, Addenbrooke’s Hospital,
Osteopathic Medicine, Michigan State University, 18.5.2: Sleep-​related breathing disorders Cambridge University Hospitals, Cambridge;
East Lansing, MI, USA Martin A. McNally The Bone Infection Unit, Consultant Gastroenterologist (Hon.) St Mark’s
16.16.1: Deep venous thrombosis and pulmonary Nuffield Orthopaedic Centre, Oxford University Hospital, Harrow, London; Associate Professor
embolism Hospitals, Oxford, UK (Hon.) Plymouth University Peninsula Schools of
Eric L. Matteson Division of Rheumatology, 20.3: Osteomyelitis Medicine and Dentistry, Plymouth, UK
Divisions of Rheumatology and Epidemiology, 15.10.2: Bacterial overgrowth of the small intestine;
Regina McQuillan St Francis Hospice and Beaumont
Mayo Clinic College of Medicine, Rochester, 15.10.7: Effects of massive bowel resection
Hospital, Dublin, Ireland
MN, USA 7.3: Symptoms other than pain Mark E. Mikkelsen Department of Medicine,
19.11.11: Polymyalgia rheumatica Perelman School of Medicine, University of
Simon Mead MRC Prion Unit, University College
Kieran McCafferty Consultant Nephrologist, Barts Pennsylvania, Philadelphia, PA, USA
London, Institute of Prion Diseases; NHS National
Health NHS Trust, London, UK 17.12: Persistent problems and recovery after
Prion Clinic, National Hospital for Neurology and
21.17: Urinary tract obstruction critical illness
Neurosurgery, UCL Hospitals NHS Foundation
Fergus McCarthy Division of Women’s Health, Trust, Queen Square, London, UK Michael A. Miles Faculty of Infectious and Tropical
Women’s Health Academic Centre KHP, St. 24.11.5: Human prion diseases Diseases, London School of Hygiene and Tropical
Thomas’ Hospital, London, UK Medicine, London, UK
Jill Meara Hyperbaric Medicine Unit, St Richard’s
14.4: Hypertension in pregnancy 8.8.12: Chagas disease
Hospital, Chichester, UK
Brian W. McCrindle University of Toronto, Toronto, 10.3.7: Radiation Robert F. Miller University College London,
Canada; The Hospital for Sick Children, Toronto, London, UK
Wajahat Z. Mehal Section of Digestive Diseases Yale
ON, Canada 8.7.5: Pneumocystis jirovecii
University, New Haven, CT, USA
19.11.12: Kawasaki disease 15.21: Pathobiology of chronic liver disease Dawn S. Milliner Emeritus Professor of Medicine
Theresa A. McDonagh King’s College Hospital, and Pediatrics at the Mayo Clinic Alix School of
Tobias F. Menne Consultant Haematologist, The
Denmark Hill, London, UK Medicine, Rochester, MN, USA
Newcastle upon Tyne Hospitals NHS Foundation
16.5.1: Epidemiology and general 12.10 Hereditary disorders of oxalate
Trust, Freeman Hospital, Newcastle upon
pathophysiological classification of heart failure metabolism: The primary hyperoxalurias
Tyne, UK
A.D. McGavigan Flinders University, 22.4.2: Acute lymphoblastic leukaemia K.R. Mills King’s College London, London, UK
SA, Australia 24.3.4: Investigation of central motor
David K. Menon Division of Anaesthesia, University
16.2.2: Syncope and palpitation; 16.4: Cardiac pathways: Magnetic brain stimulation
of Cambridge, UK; Neurosciences Critical Care
arrhythmias Unit, Royal College of Anaesthetists, London, Philip Minor National Institute for Biological
Fiona McGill Institute of Infection and Global UK; Queens’ College, Cambridge, UK; National Standards and Control (NIBSC), Ridge, UK
Health, University of Liverpool, Liverpool, UK Institute for Health Research, UK 8.5.8: Enterovirus infections
24.11.2: Viral infections 17.7: Management of raised intracranial Fraz A. Mir Department of Medicine, Cambridge
John A. McGrath Genetic Skin Disease Group, St pressure University Hospitals NHS Foundation Trust,
John’s Institute of Dermatology, King’s College Andrew Menzies-​Gow Royal Brompton Hospital, Addenbrooke’s Hospital, Cambridge, UK
London (Guy’s Campus), London, UK London, UK 16.17.3: Secondary hypertension
23.1: Structure and function of skin 18.7: Asthma Pramod K. Mistry Professor of Pediatrics and
Alastair McGregor Department of Tropical Catherine H. Mercer Professor of Sexual Medicine, Chief, Pediatric Gastroenterology
Medicine and Infectious Diseases, London Health Science, Centre for Population and Hepatology, Yale School of Medicine, New
Northwest Hospitals NHS Trust, London, UK; Research in Sexual Health and HIV, Institute Haven, CT, USA
Department of Medicine, Imperial College for Global Health, University College London, 12.7.2 Inherited diseases of copper
London, London, UK London, UK metabolism: Wilson’s disease and Menkes’ disease
8.11.4: Intestinal trematode infections 9.2: Sexual behaviour Andrew R.J. Mitchell Jersey General Hospital,
Jane McGregor Clinical Senior Lecturer and Vinod K. Metta Neurology, National Hospital for Jersey, UK
Honorary Consultant Dermatologist, Blizard Neurology and Neurosurgery, University College 16.3.2: Echocardiography; 16.14.1: Acute aortic
Institute, Barts and the London School Medicine London, London, UK syndromes
and Dentistry, London, UK 24.7.2: Parkinsonism and other extrapyramidal Oriol Mitjà Barcelona Institute for Global Health,
23.9: Photosensitivity diseases University of Barcelona, Spain; Lihir Medical
Iain B. McInnes University of Glasgow, Jan H. ter Meulen Philipps University Marburg, Centre, InternationalSOS, Lihir Island, Papua
Glasgow, UK 35043 Marburg, Germany New Guinea
3.3: Cytokines 8.5.17: Arenaviruses; 8.5.18: Filoviruses 8.6.36: Non-​venereal endemic treponematoses:
Yaws, endemic syphilis (bejel), and pinta
C.J. McKay Consultant Pancreaticobiliary Surgeon, Wayne M. Meyers Department of Environmental
West of Scotland Pancreatic Unit, Glasgow Royal and Infectious Disease Sciences, Armed Aarthi R. Mohan Obstetrics and Maternal Medicine,
Infirmary, Glasgow, UK Forces Institute of Pathology, Washington University Hospitals Bristol NHS Foundation
15.26.1: Acute pancreatitis DC, USA Trust, Bristol, UK
8.6.29: Buruli ulcer: Mycobacterium ulcerans 14.21: Contraception for women with medical
William J. McKenna The Heart Hospital, University
infection diseases
College London, London, UK
16.7.2: The cardiomyopathies: Hypertrophic, Paul K. Middleton Clinical Research Fellow, Fiachra Moloney Consultant Radiologist,
dilated, restrictive, and right ventricular Institute of Liver Studies, Inflammation Biology, Department of Radiology, Cork University
School of Immunology and Microbial Sciences, Hospital, Cork, Ireland
Curtis McKnight Dignity Health Medical Group;
Faculty of Life Sciences and Medicine, King’s 15.3.3: Radiology of the gastrointestinal tract
St. Joseph’s Hospital and Medical Center;
Creighton University School of Medicine, College London, King’s College Hospital, P.L. Molyneaux Royal Brompton and Harefield NHS
Phoenix, AZ, USA London, UK Trust, London, UK
26.5.3: Organic psychoses 15.22.4: Hepatic encephalopathy 18.11.2: Idiopathic pulmonary fibrosis
 Contributors lix

Andrew J. Molyneux The Manor Hospital, Oxford, UK David R. Murdoch Professor and Head of James D. Newton Oxford University Hospitals NHS
24.3.3: Imaging in neurological diseases Pathology, University of Otago, Christchurch, Trust, Oxford, UK
Peter D. Mooney Royal Hallamshire Hospital and New Zealand 16.3.2: Echocardiography; 16.14.1: Acute aortic
University of Sheffield, Sheffield, UK 10.3.6: Diseases of high terrestrial altitudes syndromes
15.10.3: Coeliac disease Paul Murphy NHS Blood and Transplant, Paul N. Newton Lao-​Oxford-​Mahosot Hospital-​
Anthony V. Moorman Professor of Genetic Bristol, UK Wellcome Trust Research Unit (LOMWRU),
Epidemiology, Leukaemia Research Cytogenetics 17.11: Diagnosis of death and organ donation Microbiology Laboratory, Mahosot Hospital,
Group, Northern Institute for Cancer Research, Christopher Murray University of Washington, Vientiane, Lao PDR; Nuffield Department
Newcastle University, Newcastle upon Tyne, UK WA, USA of Medicine, University of Oxford, Oxford;
22.4.2: Acute lymphoblastic leukaemia 2.3: The Global Burden of Disease: Measuring the Infectious Diseases Data Observatory (IDDO),
health of populations University of Oxford, Oxford, UK
Pilar Morata Department of Biochemistry
2.10: Medicine quality, physicians,
and Molecular Biology, School of Medicine, Jean B. Nachega Departments of Epidemiology,
and patients
University of Málaga, Málaga, Spain Infectious Diseases and Microbiology,
8.6.22: Brucellosis Graduate School of Public Health, University of Wan-​Fai Ng Newcastle University and NIHR
Pittsburgh, Pittsburgh, PA USA; Department of Newcastle Biomedical, Research Centre for
Marina S. Morgan Royal Devon and Exeter NHS
Medicine, Centre for Infectious Diseases, Ageing and Chronic Diseases, Newcastle upon
Foundation Trust, Exeter, UK
Stellenbosch University, Tygerberg, Cape Town, Tyne, UK
8.6.19: Pasteurella
South Africa 19.11.4: Sjögren’s syndrome
Michael L. Moritz Professor of Pediatrics, University
8.6.26: Tuberculosis A.G. Nicholson Royal Brompton and Harefield
of Pittsburgh School of Medicine, Clinical Director,
Robert B. Nadelman Division of Infectious NHS Trust; Professor of Respiratory Pathology,
Division of Nephrology, UPMC Children’s Hospital
Diseases, Department of Medicine, New York National Heart and Lung Institute, Imperial
of Pittsburgh, Pittsburgh, PA, USA
Medical College, Valhalla, NY, USA College School of Medicine, London, UK
21.2.1: Disorders of water and sodium homeostasis
8.6.33: Lyme borreliosis 18.11.2: Idiopathic pulmonary fibrosis
Pedro L. Moro Immunization Safety Office, Division
Alexandra Nanzer-​Kelly Guys and St Thomas’ Jerry P. Nolan Warwick Medical School, Coventry;
of Healthcare Quality Promotion, NCEZID,
Hospital, London, UK Royal United Hospital, Bath, UK
Centers for Disease Control and Prevention,
18.7: Asthma 17.2: Cardiac arrest
Atlanta, GA, USA
8.10.2: Cystic hydatid disease (Echinococcus Nikolai V. Naoumov Novartis Pharma, Basel, John Nowakowski New York Medical College,
granulosus) Switzerland NY, USA
8.5.21: Hepatitis viruses (excluding hepatitis 8.6.33: Lyme borreliosis
Mary J. Morrell Imperial College London, London, UK
18.5.2: Sleep-​related breathing disorders C virus) Paul Nyirjesy Drexel University College of
Kikkeri N. Naresh Department of Histopathology, Medicine, Philadelphia, PA, USA
Nicholas W. Morrell British Heart Foundation
Imperial College Healthcare NHS Trust and 9.4: Vaginal discharge
Professor of Cardiopulmonary Medicine,
University of Cambridge School of Clinical Imperial College, London, UK Sarah O’Brien Modelling, Evidence and Policy
Medicine, Addenbrooke’s and Papworth 15.10.4: Gastrointestinal lymphomas Group, School of Natural and Environmental
Hospitals, Cambridge, UK Kate Nash University Hospital Southampton NHS Sciences, Newcastle University, Newcastle upon
16.15.1: Structure and function of the pulmonary Foundation Trust, Southampton, UK Tyne, UK
circulation; 16.15.2: Pulmonary hypertension 15.23.1: Hepatitis A to E 15.18: Gastrointestinal infections
Emma C. Morris Professor, Division of Infection N. Navani University College Hospital, Amy O’Donnell Institute of Health and Society,
and Immunity, UCL Institute of Immunity and London, UK Newcastle University, Newcastle upon Tyne, UK
Transplantation, Royal Free Campus, Royal Free 18.19.1: Lung cancer 26.6.1: Brief interventions for excessive alcohol
Hospital, London, UK and Honorary Consultant, consumption
Catherine Nelson-​Piercy Obstetric Medicine,
University College London Medical School, Women’s Health Academic Centre, King’s Nigel O’Farrell Ealing Hospital, London North West
London, UK Health Partners, King’s College London, University Healthcare NHS Trust, London, UK
22.8.2: Haemopoietic stem cell transplantation London, UK 8.6.14: Haemophilus ducreyi and chancroid
Neil J.McC. Mortensen Professor of Colorectal 14.14: Autoimmune rheumatic disorders and John G. O’Grady Institute of Liver Studies, King’s
Surgery, Nuffield Department of Surgery, vasculitis in pregnancy College Hospital, London, UK
University of Oxford; Honorary Consultant Randolph M. Nesse Center for Evolution and 15.22.6: Liver transplantation
Colorectal Surgeon, Oxford University Hospitals Medicine, Arizona State University, AZ, USA Denis O’Mahony Department of Medicine,
NHS Foundation Trust, Oxford, UK 2.2: Evolution: Medicine’s most basic science University College Cork and Department of
15.14: Colonic diverticular disease Geriatric Medicine, Cork University Hospital,
Peter J. Nestor German Center for
Peter S. Mortimer St George’s University of London; Neurodegenerative Diseases (DZNE), Cork, Ireland
St George’s Hospital, London; Royal Marsden Magdeburg, Germany 6.7: Drugs and prescribing in the older patient
Hospital, London, UK 24.4.1: Disturbances of higher cerebral function E.E. Ooi Programme in Emerging Infectious
16.18: Chronic peripheral oedema and Diseases, Duke-NUS Medical School, Singapore
Stefan Neubauer Oxford Centre for Clinical
lymphoedema; 23.12: Blood and lymphatic vessel 8.5.12: Alphaviruses
Magnetic Resonance Research (OCMR),
disorders Division of Cardiovascular Medicine, Radcliffe Susie Orme Barnsley Hospital NHS Foundation
Ghulam J. Mufti King’s College Hospital/​King’s Department of Medicine, University of Oxford, Trust, Barnsley, UK
College London, London, UK John Radcliffe Hospital, Oxford, UK 6.9: Bladder and bowels
22.5.2: Acquired aplastic anaemia and pure red 16.3.3: Cardiac investigations: Nuclear, Kevin O’Shaughnessy Division of Experimental
cell aplasia MRI, and CT Medicine and Immunotherapeutics,
Victoria Mulcahy Norwich Medical School, James Neuberger Hon Consultant Physician, Department of Medicine, University of Cambridge,
University of East Anglia, Norwich, UK Liver Unit, Queen Elizabeth Hospital, Cambridge, UK
15.10.1: Differential diagnosis and investigation of Birmingham, UK 2.6: Principles of clinical pharmacology and drug
malabsorption 15.24.5: The liver in systemic disease therapy
lx Contributors

Edel O’Toole Centre for Cutaneous Research, John Paul SE region, National Infection Service, Hans Persson Swedish Poisons Centre,
Blizard Institute of Cell and Molecular Science, Public Health England, UK Stockholm, Sweden
Barts and the London School of Medicine and 8.6.47: A checklist of bacteria associated with 10.4.3: Poisonous fungi; 10.4.4: Poisonous plants
Dentistry; and Department of Dermatology, infection in humans; Eskild Petersen Department of Infectious Diseases
Barts and the London NHS Trust, London, UK 8.12: Non​venomous arthropods and Clinical Microbiology, Aarhus University
23.14: Tumours of the skin Jason Payne-​James Specialist in Forensic and Legal Hospital Skejby, Aarhus, Denmark
Petra C.F. Oyston Biomedical Sciences, DSTL Medicine and Consultant Forensic Physician; 8.8.4: Toxoplasmosis
Porton Down, Salisbury, UK Lead Medical Examiner, Norfolk and Norwich L.R. Petersen Director, Division of Vector-borne
8.6.20: Francisella tularensis infection University Hospital, Norfolk, UK; Honorary Infectious Diseases, Centers for Disease
Jacqueline Palace Nuffield Department of Clinical Professor, William Harvey Research Control and Prevention, Fort Collins,
Clinical Neurosciences, University of Oxford, Institute, Queen Mary University of London, Colorado, USA
Oxford, UK UK; Consultant Editor-​in-​Chief, Journal of 8.5.12: Alphaviruses
24.18: Disorders of the neuromuscular junction Forensic and Legal Medicine; Director, Forensic Trevor N. Petney Professor, Cholangiocarcinoma
Healthcare Services Ltd, Southminster, UK Research Institute (CARI), Cholangiocarcinoma
Thomas Pap Institute of Experimental
27.1: Forensic and legal medicine Screening and Care Program (CASCAP),
Musculoskeletal Medicine, University Hospital
Münster, Münster, Germany Sharon J. Peacock University of Cambridge, Faculty of Medicine, Khon Kaen University,
19.1: Joints and connective tissue—​structure and Cambridge, UK Khon Kaen, Thailand; Department of
function 8.6.8: Pseudomonas aeruginosa; Paleontology and Evolution, Organization/​
8.6.16: Melioidosis and glanders University State Museum of Natural History,
Jayan Parameshwar Consultant Cardiologist, Royal
Papworth Hospital, Cambridge, UK Fiona Pearce Clinical Lecturer, Faculty of Medicine Karlsruhe, Germany
16.5.5: Cardiac transplantation and mechanical and Health Sciences, University of Nottingham, 8.11.2: Liver fluke infections
circulatory support Nottingham City Hospital, Nottingham, UK Philippa Peto Consultant in Renal and Acute
19.2: Clinical presentation and diagnosis of Medicine, Queen Elizabeth Hospital, Lewisham
Daniel H. Paris University of Oxford, Oxford, UK;
rheumatological disorders and Greenwich NHS Trust, London, UK
Rickettsial Research (Oxford Tropical Network);
Mahidol-​Oxford Tropical Medicine Research Rupert Pearse Queen Mary University of London, 1.6: Clinical decision-​making
Unit (MORU), Faculty of Tropical Medicine, London, UK Richard Peto Nuffield Department of Population
Mahidol University, Bangkok, Thailand 17.4: Assessing and preparing patients with Health, University of Oxford, Oxford, UK
8.6.41: Scrub typhus medical conditions for major surgery 2.4: Large-​scale randomized evidence: Trials
Sarah Parish Clinical Trial Service Unit and Malik Peiris School of Public Health, The and meta-​analyses of trials; 5.1: Epidemiology
Epidemiological Studies Unit (CTSU), University University of Hong Kong, Hong Kong, Special of cancer
of Oxford, Oxford, UK Administrative Region of China Timothy E.A. Peto Nuffield Department of Clinical
2.4: Large-​scale randomized evidence: Trials and 8.5.1: Respiratory tract viruses Medicine, University of Oxford; John Radcliffe
meta-​analyses of trials Neil Pendleton School of Biological Sciences, Hospital, Oxford, UK
Mike Parker Ethox Centre, Oxford, UK Faculty Biology Medicine and Health and 1.6: Clinical decision-​making; 8.5.23: HIV/​AIDS
1.5: Medical ethics Manchester Institute for Collaborative John D. Pickard University of Cambridge,
Research in Ageing, University of Manchester, Cambridge, UK
Miles Parkes Consultant Gastroenterologist,
Manchester, UK 24.5.6: Brainstem death and prolonged disorders of
Cambridge University Hospitals,
6.1: Ageing and clinical medicine consciousness
Cambridge, UK
15.11: Crohn’s disease Hugh Pennington University of Aberdeen, Matthew C. Pickering Imperial College London,
Aberdeen, UK London, UK
Philippe Parola University Hospital Institute
8.6.7: Enterobacteria and bacterial food 4.2: The complement system
Méditerranée Infection, Marseille, France
poisoning Massimiliano di Pietro Senior Clinical Investigator
8.6.40: Rickettsioses
Mark B. Pepys Director, Wolfson Drug Discovery Scientist and Consultant Gastroenterologist,
Christopher M. Parry Clinical Sciences, Liverpool
Unit, and Honorary Consultant Physician, MRC Cancer Unit, University of Cambridge,
School of Tropical Medicine, and Institute of
National Amyloidosis Centre, Centre for Hutchison/​MRC Research Centre,
Infection and Global Health, University of
Amyloidosis and Acute Phase Proteins, Cambridge, UK
Liverpool, UK; School of Tropical Medicine and
University College London, London, UK 15.7: Diseases of the oesophagus
Global Health, Nagasaki University, Nagasaki, Japan
12.12.1 The acute phase response and C-​reactive Michael R. Pinsky Professor Critical Care Medicine,
8.6.9: Typhoid and paratyphoid fevers
protein; 12.12.3 Amyloidosis Bio­engineering, Cardiovascular Disease and
Judith Partridge Guys and St Thomas’ Hospitals
Stephen P. Pereira Professor of Hepatology Anesthesiology, Department of Critical Care
London, UK
and Gastroenterology, Institute for Liver and Medicine, University of Pittsburgh, Pittsburgh,
6.6: Supporting older peoples’ care in surgical and
Digestive Health, University College London; PA, USA
oncological services
Consultant Hepatologist and Gastroenterologist, 17.6: Circulation and circulatory support in the
Sant-​Rayn Pasricha MRC Human Immunology
University College Hospital and Royal Free critically ill
Unit, Weatherall Institute of Molecular Medicine, Hospital, London, UK Julia Platts University of Cardiff, Cardiff, UK
John Radcliffe Hospital and University of Oxford, 15.16: Cancers of the gastrointestinal tract; 13.9.1: Diabetes
Oxford, UK 15.26.3: Tumours of the pancreas
22.6.5: Anaemia of inflammation Raymond J. Playford, Professor of Medicine,
Gavin D. Perkins Warwick Medical School, University of Plymouth, Plymouth, UK; Vice
Harnish Patel Academic Geriatric Medicine,
Coventry; Intensive Care Unit, Heartlands President Research Strategy, Pantheryx Inc.,
University of Southampton, Southampton, UK Hospital, University Hospitals Birmingham NHS Boulder, CO, USA
6.2: Frailty and sarcopenia Foundation Trust, Birmingham, UK 15.10.2: Bacterial overgrowth of the small intestine;
Raj Patel Solent NHS Trust, Southampton, UK 17.2: Cardiac arrest 15.10.7: Effects of massive bowel resection
9.6: Genital ulceration David J. Perry Previously Department of Michael I. Polkey Royal Brompton and Harefield
Sejal Patel Oxford Childrens Hospital, Oxford Haematology, Addenbrooke’s Hospital, NHS Trust, London, UK
University Hospitals NHS Trust, Oxford, UK Cambridge, UK 18.15: Chronic respiratory failure; 18.18 Disorders
13.7.2: Normal puberty and its disorders 14.17: Blood disorders in pregnancy of the thoracic cage and diaphragm
 Contributors lxi

Eleanor S. Pollak Associate Professor of Pathology Michael Prentice School of Microbiology, Jeremy Rees National Hospital for Neurology and
and Laboratory Medicine (retired), Perelman University College Cork, Cork, Ireland Neurosurgery, London, UK; UCL Institute of
School of Medicine of the University of 8.6.17: Plague: Yersinia pestis; 8.6.18: Other Neurology, London, UK
Pennsylvania, Philadelphia, PA, USA Yersinia infections: Yersiniosis 24.23: Paraneoplastic neurological syndromes;
22.7.4: Genetic disorders of coagulation David Price Queen Mary University of London, 24.10.4: Intracranial tumours
Andrew J. Pollard Professor of Paediatric Infection London, UK P.T. Reid Respiratory Unit, Western General
and Immunity at the University of Oxford, 2.15: How much should rich countries’ Hospital, Edinburgh, UK
Director of the Oxford Vaccine Group, Fellow governments spend on healthcare? 18.13: Pneumoconioses
of St Cross College and Honorary Consultant Christopher Pugh Nuffield Department of Shelley Renowden North Bristol NHS Trust,
Paediatrician at the Children’s Hospital, Medicine, University of Oxford, Oxford, UK Bristol, UK
Oxford, UK 21.14: Disorders of renal calcium handling, 24.3.3: Imaging in neurological diseases
10.3.6: Diseases of high terrestrial altitudes urinary stones, and nephrocalcinosis John Richens Research Department of Infection and
Aaron Polliack Emeritus Professor, Hadassah Meredith Pugh Division of Pulmonary and Critical Population Health, University College London,
University Hospital and Hebrew University Care, Vanderbilt University Medical Center, London, UK
Medical School, Jerusalem, Israel Nashville, TN, USA 8.6.10: Intracellular klebsiella infections
22.4.5: Chronic lymphocytic leukaemia 14.8: Chest diseases in pregnancy (donovanosis and rhinoscleroma)
Allyson M. Pollock Queen Mary University of Graham Raftery South Tyneside and Sunderland Alan B. Rickinson Institute for Cancer Studies,
London, London, UK NHS Foundation Trust, Sunderland, UK University of Birmingham, Birmingham, UK
2.15: How much should rich countries’ 19.7: Infection and arthritis 8.5.3: Epstein–​Barr virus
governments spend on healthcare? Kazem Rahimi The George Institute for B.K. Rima Wellcome-​Wolfson Institute for
Cristina Ponte Department of Rheumatology, Global Health, University of Oxford, Experimental Medicine, Queen’s University
Hospital de Santa Maria -​CHLN, Lisbon Oxford, UK Belfast, Belfast, UK
Academic Medical Centre, Lisbon, Portugal; 16.13.2: Coronary heart disease: Epidemiology 8.5.5: Mumps: Epidemic parotitis
Nuffield Department of Orthopaedics, and prevention David J. Roberts Radcliffe Department of Medicine,
Rheumatology and Musculoskeletal Sciences, Anisur Rahman Centre for Rheumatology, University of Oxford; Department of
University of Oxford, Oxford, UK University College London, London, UK Haematology, Oxford University Hospitals
19.11.6: Large vessel vasculitis 19.11.2: Systemic lupus erythematosus and related NHS Trust and NHS Blood and Transplant,
Kyle J. Popovich Rush University, Chicago, disorders Oxford, UK
IL, USA 22.6.3: Anaemia as a challenge to world health
Tim Raine IBD Lead and Consultant
8.6.4: Staphylococci Gastroenterologist, Cambridge University Harold R. Roberts Sarah Graham Kenan Professor
Françoise Portaels Institute of Tropical Medicine, Hospital, Cambridge, UK of Medicine, Division of Hematology-​Oncology,
Antwerp, Belgium 15.11: Crohn’s disease University of North Carolina, Chapel Hill,
8.6.29: Buruli ulcer: Mycobacterium ulcerans NC, USA
K. Rajappan Oxford University Hospitals NHS
infection 22.7.1: The biology of haemostasis and thrombosis
Foundation Trust, Oxford, UK
John B. Porter Professor of Haematology and 16.2.2: Syncope and palpitation Irene Roberts Department of Paediatrics and
Consultant Haematologist, University College MRC Molecular Haematology Unit, Weatherall
S. Vincent Rajkumar Edward W. and Betty Knight
London Hospitals, London, UK Institute of Molecular Medicine, University of
Scripps Professor of Medicine, Division of
22.6.4: Iron metabolism and its disorders Oxford, Oxford, UK
Hematology, Mayo Clinic, Rochester, MN, USA
Stephen Potts Department of Psychological 22.4.6: Plasma cell myeloma and related 22.5.1: Inherited bone marrow failure syndromes
Medicine, Edinburgh Royal Infirmary, monoclonal gammopathies Douglas Robertson Senior Lecturer and Honorary
Edinburgh, UK Consultant in Restorative Dentistry, University of
Mary Ramsay Health Protection Agency,
26.5.5: Substance misuse Glasgow, Glasgow, UK
London, UK
William G. Powderly Division of Infectious Diseases 8.3: Immunization 15.6: The mouth and salivary glands
and Institute for Public Health, Washington Marcus Robertson Gastroenterologist and
A.C. Rankin Glasgow Royal Infirmary, Glasgow, UK
University in St. Louis, MO, USA Hepatologist, Monash Health, Vic, Australia;
16.2.2: Syncope and palpitation
8.7.2: Cryptococcosis Monash University Department of Medicine,
Didier Raoult University Hospital Institute
Janet Powell Department of Surgery and Cancer, Vic, Australia
Méditerranée Infection, Marseille, France
Imperial College, London, UK 15.22.3: Portal hypertension and variceal
8.6.40: Rickettsioses; 15.10.6: Whipple’s disease
16.14.2: Peripheral arterial disease bleeding
Michael Rawlins Medicines and Healthcare
Amy Powers Associate Professor of Pathology, Esther Robinson Public Health England,
Products Regulatory Agency, London, UK
John A Burns School of Medicine, University Birmingham, UK
2.19: Regulation versus innovation in medicine
of Hawaii, Department of Pathology, Honolulu, 8.6.13: Haemophilus influenzae
Phillip Read University of New South Wales,
HI, USA T.A. Rockall Professor of Colorectal Surgery,
Kensington, NSW, Australia
22.6.12: Acquired haemolytic anaemia University of Surrey; Consultant Colorectal
8.6.37: Syphilis
Ann M. Powers Centers for Disease Control and Surgeon, Royal Surrey County Hospital
Michael C. Reade Burns, Trauma and Critical
Prevention, Atlanta, GA, USA Guildford, UK
Care Research Centre, Royal Brisbane and
8.5.12: Alphaviruses 15.4.2: Gastrointestinal bleeding
Women’s Hospital, University of Queensland,
Anton Pozniak Department of HIV and GUM, Edward Roddy Keele University, Keele, UK
Brisbane, Qld, Australia; Joint Health Command,
Chelsea and Westminster Hospital NHS 19.10: Crystal-​related arthropathies
Australian Defence Force, Canberra, ACT,
Foundation Trust, London, UK Simon D. Roger Renal Physician, Conjoint
Australia
18.4.5: Pulmonary complications of Professor, School of Medicine and Public Health,
17.8: Sedation and analgesia in the ICU
HIV infection University of Newcastle, Newcastle; Director,
Paul J. Reading Department of Sleep Medicine,
Bernard D. Prendergast John Radcliffe Hospital, Department of Renal Medicine, Central Coast
The James Cook University Hospital,
Oxford, UK Local Health District, Gosford, NSW, Australia
Middlesbrough, UK
16.9.2: Endocarditis 21.9.1: Acute interstitial nephritis
24.5.3: Sleep disorders
lxii Contributors

Jean-​Marc Rolain IHU Méditerranée Infection, Jeremy Sanderson Department of Gastroenterology, Anthony Scott KEMRI-​Wellcome Trust Research
Marseille, France Guy’s and St Thomas’ NHS Foundation Trust, Programme, Kilifi, Kenya; London School of
8.6.43: Bartonellas excluding B. bacilliformis London, UK Hygiene and Tropical Medicine,
Pierre Ronco Professor of Renal Medicine, 15.12: Ulcerative colitis London, UK
University Pierre et Marie Curie, and Inserm Unit Vijay G. Sankaran Associate Professor of 8.6.3: Pneumococcal infections
UMR_​S1155, Tenon Hospital, Paris, France Pediatrics, Harvard Medical School, Division James Scott Imperial College London,
21.10.5: Renal involvement in plasma cell of Hematology/​Oncology, Boston Children’s London, UK
dyscrasias, immunoglobulin-​based amyloidoses, Hospital, Dana-​Farber/​Boston Children’s Cancer 12.6: Lipid disorders
and fibrillary glomerulopathies, lymphomas, and and Blood Disorders Center, Boston, MA, USA Rebecca Scott Department of Metabolism,
leukaemias 22.6.1: Erythropoiesis Digestion and Reproduction, Imperial College
Antony Rosen Division of Rheumatology, Johns Swati Sathe Rutgers New Jersey Medical School, London, London, UK
Hopkins University School of Medicine, Newark, NJ, USA 15.9.1: Hormones and the gastrointestinal tract
Baltimore, MD, USA 24.17: Inherited neurodegenerative diseases Mårten Segelmark Professor of Nephrology,
4.6: Autoimmunity Brian P. Saunders Consultant Gastroenterologist, St Department of Clinical Sciences, Lund
Jonathan D.C. Ross University Hospitals Mark’s Hospital, North West London Hospitals University and Department of Nephrology
Birmingham NHS Trust, Birmingham, UK Trust; Adjunct Professor of Endoscopy, Imperial Skane University Hospital, Lund, Sweden
9.8: Pelvic inflammatory disease College London, London, UK 21.8.7: Antiglomerular basement membrane
Shannan Lee Rossi Department of Pathology, Center 15.3.1: Colonoscopy and flexible sigmoidoscopy disease
for Biodefense and Emerging Infectious Diseases; Kate E.A. Saunders University of Oxford Julian Seifter Associate Professor of Medicine,
Member, Center for Tropical Diseases, Institute Department of Psychiatry, Warneford Hospital, Department of Medicine, Brigham and Women’s
for Human Infections and Immunity, University Oxford, UK Hospital, Boston, USA
of Texas Medical Branch, Galveston, TX, USA 26.3.2: Self-​harm; 26.5.7: Bipolar disorder 12.11: A physiological approach to acid–base
8.5.14: Flaviviruses excluding dengue Rana Sayeed Oxford Heart Centre, Oxford disorders: The roles of ion transport and body fluid
Peter M. Rothwell Nuffield Department of Clinical University Hospitals NHS Trust, Oxford, UK compartments
Neurosciences, University of Oxford, Oxford, UK 16.13.6: Coronary artery bypass and valve surgery Bhuvaneish T. Selvaraj University of Edinburgh,
24.10.1 Stroke: Cerebrovascular disease John A. Sayer Institute Of Genetic Medicine, Edinburgh, UK
Simon M. Rushbrook Department of Hepatology, Newcastle University, Central Parkway, Newcastle 3.7: Stem cells and regenerative medicine
Norfolk and Norwich University Hospitals NHS upon Tyne, UK Amartya Sen Harvard University, Cambridge,
Trust, Norwich, UK 21.15: The renal tubular acidoses MA, USA
15.24.6: Primary and secondary liver tumours Claire Scampion Bradford Teaching Hospitals NHS 2.20: Human disasters
Nigel Russell Professor of Haematology, Foundation Trust, Bradford, UK Arjune Sen Oxford Epilepsy Research Group,
Nottingham University, Nottingham, UK 6.11: Promotion of dignity in the life and death of NIHR Oxford Biomedical Research Centre,
22.3.3: Acute myeloid leukaemia older patients John Radcliffe Hospital, Oxford, UK
Fiona Ryan Oxford Childrens Hospital, Oxford Matthew Scarborough Oxford University Hospitals 24.5.1: Epilepsy in later childhood and
University Hospitals NHS Foundation Trust, NHS Foundation Trust, Oxford, UK; University adulthood
Oxford, UK of Oxford, Oxford, UK Debasish Sen Occupational Medicine, University of
13.7.2: Normal puberty and its disorders 8.2.3: Nosocomial infections Manchester, UK
Nikant Sabharwal Department of Cardiology, John Klaus P. Schaal Institute for Medical Microbiology, 10.2.1: Occupational and environmental health
Radcliffe Hospital, Oxford, UK Immunology and Parasitology, University Nicholas J. Severs National Heart and Lung
16.3.3: Cardiac investigations: Nuclear, MRI, and CT Hospital of Bonn, Bonn, Germany Institute (NHLI) Division, Faculty of Medicine,
Alan D. Salama University College London, 8.6.30: Actinomycoses Imperial College London, London, UK
London, UK Michael L. Schilsky Associate Professor of 16.1.2: Cardiac physiology
21.8.5: Proliferative glomerulonephritis Medicine, Medical Director, Adult Liver Pallav L. Shah Imperial College London,
Moin Saleem Professor of Paediatric Renal Medicine, Transplant, Yale-​New Haven Transplantation London, UK
University of Bristol Children’s Renal Unit, Bristol Center, Department of Internal Medicine, Yale 18.1.1: The upper respiratory tract; 18.1.2: Airways
Royal Hospital for Children, Bristol, UK School of Medicine, New Haven, CT, USA and alveoli; 18.3.3: Bronchoscopy, thoracoscopy,
21.8.3: Minimal change nephropathy and focal 12.7.2: Inherited diseases of copper metabolism: and tissue biopsy
segmental glomerulosclerosis Wilson’s disease and Menkes’ disease Muddassir Shaikh James Cook University Hospital,
Hesham A. Saleh Charing Cross Hospital and Royal Jonathan M. Schott Dementia Research Centre, Middlesbrough, UK
Brompton Hospital, London; Imperial College UCL Institute of Neurology, Queen Square, 19.7: Infection and arthritis
London, London, UK London, UK Alena Shantsila University of Liverpool,
18.6: Allergic rhinitis 24.4.2: Alzheimer’s disease and other dementias Liverpool, UK
Susan Salt Trinity Hospice, Blackpool, UK Heinz-​Peter Schultheiss Institut Kardiale 16.17.5: Hypertensive urgencies and
7.1: Introduction to palliative care Diagnostik und Therapie (IKDT), Berlin, emergencies
Germany Susie Shapiro Consultant Haematologist,
Nilesh J. Samani Department of Cardiovascular
16.7.1: Myocarditis Oxford University Hospitals NHS Foundation
Sciences, University of Leicester, Leicester, UK
16.17.4: Mendelian disorders causing hypertension Jane Schwebke University of Alabama at Trust, Oxford Haemophilia and
Birmingham, AL, USA Thrombosis Centre, Churchill Hospital,
Luis G. Sambo University Nova de Lisboa, Lisbon,
8.8.14: Trichomoniasis Oxford, UK
Portugal
Neil Scolding University of Bristol Institute of 22.7.3: Thrombocytopenia and disorders of
2.16: Financing healthcare in low-​income
Clinical Neurosciences, Southmead Hospital, platelet function
developing countries: A challenge for equity
in health Bristol, UK Claire C. Sharpe Professor of Renal Medicine,
24.21: Acquired metabolic disorders and the Faculty of Life Sciences and Medicine, King’s
David S. Sanders Royal Hallamshire Hospital and
nervous system; 24.22: Neurological complications College London, London, UK
University of Sheffield, Sheffield, UK
of systemic disease 21.10.7: Sickle cell disease and the kidney
15.10.3: Coeliac disease
 Contributors lxiii

Michael Sharpe Psychological Medicine Research, Alexandra Sinclair Institute of Metabolism and Krishna Somers Royal Perth Hospital, Perth, WA,
University of Oxford Department of Psychiatry, Systems Research, School of Clinical and Australia
Warneford Hospital, Oxford, UK Experimental Medicine, College of Medical and 16.9.4: Cardiovascular syphilis
26.1: General introduction; 26.2: The psychiatric Dental Sciences, The Medical School, University Danielle Southerst NYU Langone Health,
assessment of the medical patient; 26.3.3: Medically of Birmingham, Birmingham, UK New York, NY, USA
unexplained symptoms; 26.4.2: Psychological 24.10.5: Idiopathic intracranial hypertension 19.4: Back pain and regional disorders
treatments; 26.5.12: Somatic symptom and related Rod Sinclair Department of Dermatology, University Cathy Speed Consultant in Rheumatology, Sport
disorders; 26.7: Psychiatry, liaison psychiatry, and of Melbourne, Melbourne, Vic, Australia; Epworth and Exercise Medicine, Senior Physician, English
psychological medicine Healthcare, Sinclair Dermatology Investigational Institute of Sport, Cambridge Centre for Health
Pamela J. Shaw Sheffield Institute for Translational Research, Education and Clinical Trials, East and Performance, Cambridge, UK
Neuroscience (SITraN), University of Sheffield, Melbourne, Vic, Australia 28.1: Sport and exercise medicine
Sheffield; Sheffield Teaching Hospitals NHS 23.17: Management of skin disease Des Spence Barclay Medical Centre, Maryhill
Foundation Trust, Sheffield, UK Joseph Sinning Regional Cancer Care Associates, Health Centre, Glasgow, UK
24.15: The motor neuron diseases Hartford, CT, USA 1.4: Why do patients attend and what do they want
Debbie L. Shawcross Professor of Hepatology and 22.3.1: Granulocytes in health and disease from the consultation?
Chronic Liver Failure, Institute of Liver Studies, Thira Sirisanthana Research Institute for Health G.P. Spickett Regional Department of Immunology,
Inflammation Biology, School of Immunology Sciences, Chiang Mai University, Chiang Mai, Royal Victoria Infirmary, Newcastle upon
and Microbial Sciences, Faculty of Life Sciences Thailand Tyne, UK
and Medicine, King’s College London, King’s 8.7.6: Talaromyces (Penicillium) marneffei infection 18.14.1: Diffuse alveolar haemorrhage;
College Hospital, London, UK J.G.P. Sissons† University of Cambridge School of 18.14.2: Eosinophilic pneumonia;
15.22.4: Hepatic encephalopathy Clinical Medicine, Cambridge, UK 18.14.4: Hypersensitivity pneumonitis
Bart Sheehan Oxford University Hospitals NHS 8.5.2: Herpesviruses (excluding S.G. Spiro University College Hospital,
Foundation Trust, Oxford, UK Epstein–​Barr virus) London, UK
26.3.1: Confusion; 26.5.1: Delirium; Paiboon Sithithaworn Professor, 18.19.1: Lung cancer; 18.19.2: Pulmonary
26.5.2: Dementia Cholangiocarcinoma Research Institute (CARI), metastases
Neil Sheerin Professor of Nephrology, Institute Cholangiocarcinoma Screening and Care David P. Steensma Institute Physician, Division
of Cellular Medicine, Newcastle University, Program (CASCAP), Faculty of Medicine, Khon of Hematologic Malignancies, Department of
Newcastle upon Tyne, UK Kaen University, Thailand; Professor Parasitology, Medical Oncology, Dana-​Farber Cancer Institute;
21.13: Urinary tract infection Department of Parasitology, Faculty of Medicine, Associate Professor of Medicine, Harvard
Mark Sherlock General Medicine and Emergency Khon Kaen University, Thailand Medical School, Boston, MA, USA
Medicine, NHS, UK; Médecins Sans Frontières 8.11.2: Liver fluke infections 22.3.2: Myelodysplastic syndromes
(MSF), Paris, France James R.A. Skipworth Consultant HPB and General Jerry L. Spivak Hematology Division,
13.5.1: Disorders of the adrenal cortex Surgeon, Bristol Royal Infirmary, University Johns Hopkins University School of Medicine,
Jackie Sherrard Wycombe General Hospital, High Hospitals Bristol NHS Trust, Bristol, UK Baltimore, MD, USA
Wycombe, UK 15.26.3: Tumours of the pancreas 22.3.7: Primary myelofibrosis
8.6.6: Neisseria gonorrhoeae; 9.3: Sexual history Geoffrey L. Smith University of Cambridge, Charles L. Sprung Department of Anesthesiology,
and examination Cambridge, UK Critical Care Medicine and Pain Medicine,
M.A. Shikanai-​Yasuda Faculdade Medicina, 8.5.4: Poxviruses Hadassah Medical Center, Hebrew
University of São Paulo (FMUSP), Brazil Roger Smyth Department of Psychological University of Jerusalem, Faculty of Medicine,
8.7.4: Paracoccidioidomycosis Medicine, Edinburgh Royal Infirmary, Jerusalem, Israel
Brian Shine Oxford University Hospitals NHS Edinburgh, UK 17.10: Palliative and end-​of-​life care in the ICU
Foundation Trust, Oxford, UK 26.2: The psychiatric assessment of the medical Paweł Stankiewicz Department of Molecular and
29.1: The use of biochemical analysis for diagnosis patient Human Genetics, Baylor College of Medicine,
and management Rosamund Snow† BMJ, Tavistock Square, Houston, TX, USA
John M. Shneerson Papworth Hospital, Papworth London, UK 3.2: The genomic basis of medicine
Everard, UK 1.3: What patients wish you understood Natalie Staplin Clinical Trial Service Unit,
18.18: Disorders of the thoracic cage and diaphragm E.L. Snyder Professor, Laboratory Medicine, Yale University of Oxford, Oxford, UK
Volha Shpadaruk Department of Dermatology, University Medical School; Director, Transfusion/​ 2.4: Large-​scale randomized evidence: Trials and
University Hospitals of Leicester NHS Trust, Apheresis/​Tissue/​Cell Processing Services, meta-​analyses of trials
Leicester, UK Yale-​New Haven Hospital, New Haven, CT, USA Paul D. Stein Professor, Department of Osteopathic
23.7: Cutaneous vasculitis, connective tissue 22.8.1: Blood transfusion Medical Specialties, College of Osteopathic
diseases, and urticaria Jasmeet Soar Intensive Care Unit, Southmead Medicine, Michigan State University, East
Joachim Sieper Free University, Berlin, Germany Hospital, North Bristol NHS Trust, Bristol, UK Lansing, MI, USA
19.6: Spondyloarthritis and related conditions 17.2: Cardiac arrest 16.16.1: Deep venous thrombosis and pulmonary
Udomsak Silachamroon Department of Clinical May Ching Soh Silver Star Unit, Women’s Centre, embolism
Tropical Medicine, Faculty of Tropical Medicine, John Radcliffe Hospital, Oxford University Chris Stenton Newcastle upon Tyne Hospitals NHS
Mahidol University, Bangkok, Thailand Hospitals NHS Trust, Oxford, UK Trust, Newcastle upon Tyne, UK
8.11.3: Lung flukes (paragonimiasis) 14.14: Autoimmune rheumatic disorders and 18.14.11: Toxic gases and aerosols
Leslie Silberstein Director, Transfusion Medicine, vasculitis in pregnancy Dennis L. Stevens Infectious Diseases Section, VA
Boston Children’s Hospital, Boston, MA, USA Elisaveta Sokolov Kings College Hospital, London, UK Medical Center, Boise, ID, USA
22.6.12: Acquired haemolytic anaemia 24.7.2: Parkinsonism and other extrapyramidal 8.6.2: Streptococci and enterococci;
Jorge Simões University Nova de Lisboa, Lisbon, diseases 8.6.25: Botulism, gas gangrene, and clostridial
Portugal Tom Solomon Institute of Infection and Global gastrointestinal infections
2.16: Financing healthcare in low-​income developing Health, University of Liverpool, Liverpool, UK Claire Steves King’s College London, London, UK
countries: A challenge for equity in health 24.11.2: Viral infections 6.1: Ageing and clinical medicine

†
It is with great regret that we report that J.G.P. Sissons died on 25 September, 2016 and Rosamund Snow died on 2 February, 2017.
lxiv Contributors

Carmel B. Stober University of Cambridge, Chen Sabrina Tan Harvard Medical School, Boston, Charles Tomson Consultant Nephrologist,
Cambridge, UK MA, USA Freeman Hospital, Newcastle upon
19.8: Reactive arthritis 8.5.19: Papillomaviruses and polyomaviruses Tyne, UK
Nicole Stoesser Nuffield Department of Medicine T.M. Tan Consultant in Diabetes, Endocrinology, 21.13: Urinary tract infection
Medical Sciences Division, University of Oxford, and Metabolic Medicine, Imperial College Pat Tookey Honorary Associate Professor,
Oxford, UK London, London, UK Population, Policy and Practice Research
8.6.10: Intracellular klebsiella infections 13.8: Pancreatic endocrine disorders and multiple and Teaching Department, University College
(donovanosis and rhinoscleroma) endocrine neoplasia; 15.9.1: Hormones and the London Institute of Child Health,
John R. Stradling Oxford Centre for gastrointestinal tract; 15.9.2: Carcinoid syndrome London, UK
Respiratory Medicine, John Radcliffe Hospital, David Taylor-​Robinson Section of Retrovirology 8.5.13: Rubella
Oxford, UK and GU Medicine, Department of Infectious Peter Topham Consultant Nephrologist,
18.1.1: The upper respiratory tract Diseases, Wright-​Fleming Institute, Faculty of John Walls Renal Unit, University Hospitals
Michael A. Stroud Department of Medicine, Medicine, Imperial College London, London, UK of Leicester NHS Trust, Leicester, UK
University of Southampton, Southampton, UK 8.6.45: Chlamydial infections; 8.6.46: Mycoplasmas 21.8.2: Thin membrane nephropathy
10.3.2: Heat; 10.3.3: Cold F. Teo National University Hospital, National Nicholas Torpey Consultant Physician and
Michael Strupp Ludwig Maximilians University, University Health System, Singapore, China Nephrologist, Cambridge University Hospitals,
Munich, Germany 18.11.1: Diffuse parenchymal lung disease: An Cambridge, UK
24.6.2: Eye movements and balance introduction 21.7.3: Renal transplantation
Matthew J. Stuckey School of Veterinary Medicine, R.V. Thakker Academic Endocrine Unit, University Thomas A. Traill Division of Cardiology, Johns
University of California, CA, USA of Oxford, OCDEM, Churchill Hospital, Hopkins Hospital, Baltimore, MD, USA
8.6.43: Bartonellas excluding B. bacilliformis Oxford, UK 16.10: Tumours of the heart; 16.11: Cardiac
13.4: Parathyroid disorders and diseases altering involvement in genetic disease
Peter H. Sugden National Heart and Lung Institute
calcium metabolism A.S. Truswell University of Sydney, Sydney, NSW,
(NHLI) Division, Faculty of Medicine, Imperial
College London, UK Nishanthi Thalayasingam Faculty of Medical Sciences, Australia
16.1.2: Cardiac physiology Newcastle University and Musculoskeletal Unit, 11.5: Diseases of affluent societies and the need for
Newcastle upon Tyne Hospitals NHS Foundation dietary change
Mehrunisha Suleman Ethox Centre,
Trust, Newcastle upon Tyne, UK Steven Tsui Consultant Cardiac Surgeon, Royal
Oxford, UK
2.7: Biological therapies for immune, Papworth Hospital, Cambridge, UK
1.5: Medical ethics
inflammatory, and allergic diseases 16.5.5: Cardiac transplantation and mechanical
Joseph Sung Professor of Medicine, lately President
Richard J. Thompson Professor of Molecular circulatory support
and Vice Chancellor, The Chinese University of
Hepatology, Institute of Liver Studies, King’s Youyou Tu Professor, Department of Chemistry,
Hong Kong, Shatin, Hong Kong, China
College London, London, UK Institute of Chinese Materia Medica, China
15.8: Peptic ulcer disease
15.24.7: Liver and biliary diseases in infancy and Academy of Chinese Medical Sciences,
Khuanchai Supparatpinyo Division of Infectious
childhood Beijing, China
Diseases, Department of Medicine, Faculty
S.A. Thorne University Hospital, Birmingham, UK 2.8: Traditional medicine exemplified by
of Medicine, Chiang Mai University, Chiang
16.12: Congenital heart disease in the adult traditional Chinese medicine
Mai, Thailand; Research Institute for Health
Sciences, Chiang Mai University, Chiang Mai, Guy E. Thwaites Oxford University Clinical Research D.M. Turnbull Wellcome Trust Centre for
Thailand Unit (OUCRU), Ho Chi Minh City, Vietnam Mitochondrial Research, Newcastle University,
8.7.6: Talaromyces (Penicillium) marneffei 24.11.1: Bacterial infections Newcastle upon Tyne, UK
infection C. Louise Thwaites Oxford University Clinical 24.19.5: Mitochondrial disease
Erik R. Swenson VA Puget Sound Health Care Research Unit, Hospital for Tropical Diseases, A. Neil Turner Professor of Nephrology,
System, Division of Pulmonary and Critical Care Ho Chi Minh City, Vietnam; Centre for University of Edinburgh, Queen’s Medical
Medicine, University of Washington, Seattle, Tropical Medicine and Global Health, Nuffield Research Institute (CIR), Edinburgh, UK
WA, USA Department of Medicine, University of Oxford, 21.10.8: Infection-​associated nephropathies;
10.3.6: Diseases of high terrestrial altitudes Oxford, UK 21.10.9: Malignancy-​associated renal disease
8.6.23: Tetanus Tabitha Turner-​Stokes MRC Clinical Research
Anthony Swerdlow The Institute of Cancer
Research, University of London, London, UK Adam D. Timmis Barts Heart Centre, Queen Mary Fellow, Centre for Inflammatory Disease,
5.1: Epidemiology of cancer University London, London, UK Department of Medicine, Imperial College
16.13.3: Management of stable angina London, London, UK
David Taggart University of Oxford, Oxford, UK
Stephen M. Tollman University of the 21.8.6: Membranoproliferative
16.13.6: Coronary artery bypass and valve
Witwatersrand, Johannesburg, South Africa; glomerulonephritis
surgery
MRC/​Wits Rural Public Health and Health Holm H. Uhlig Translational Gastroenterology
Kathy Taghipour The Whittington Health NHS
Transitions Research Unit, School of Public Unit and Department of Paediatrics,
Trust, London, UK
Health, Faculty of Health Sciences; INDEPTH University of Oxford, John Radcliffe Hospital,
23.4: Autoimmune bullous diseases
Network (International Network for the Oxford, UK
Penelope Talelli Homerton University Hospitals
Demographic Evaluation of Populations and 15.15: Congenital abnormalities of the
NHS Trust, UK Their Health), Accra, Ghana, South Africa; gastrointestinal tract
24.7.1: Subcortical structures: The cerebellum, basal Centre for Global Health Research, Umeå Magnus Unemo WHO Collaborating Centre for
ganglia, and thalamus University, Sweden Gonorrhoea and other STIs, Örebro University
Paolo Tammaro Associate Professor, Department 2.18: Fostering medical and health research in Hospital, Örebro, Sweden
of Pharmacology, University of Oxford, resource-​constrained countries 8.6.6: Neisseria gonorrhoeae; 8.6.45 Chlamydial
Oxford, UK Maciej Tomaszewski Division of Cardiovascular infections
3.4: Ion channels and disease Sciences, University of Manchester, Robert Unwin Department of Renal Medicine,
C.T. Tan University of Malaya, Kuala Lumpur, Manchester, UK University College London, London, UK
Malaysia 16.17.4: Mendelian disorders causing 21.1: Structure and function of the kidney
8.5.7: Nipah and Hendra virus encephalitides hypertension
 Contributors lxv

John A. Vale National Poisons Information Service Diego Viasus Division of Health Sciences, Faculty of T.E. Warkentin Professor, Department of Pathology and
(Birmingham Unit) and West Midlands Poisons Medicine, Universidad del Norte, Barranquilla, Molecular Medicine and Department of Medicine,
Unit; City Hospital, Birmingham; School Colombia Michael G. DeGroote School of Medicine, McMaster
of Biosciences, University of Birmingham, 8.6.39: Legionellosis and Legionnaires’ disease University, Hamilton, ON, Canada
Birmingham, UK Angela Vincent Hon Cons Immunology, Nuffield 22.7.5: Acquired coagulation disorders
10.4.1: Poisoning by drugs and chemicals Department of Clinical Neurosciences, John David A. Warrell Nuffield Department of Clinical
Patrick Vallance GlaxoSmithKline, London, UK Radcliffe Hospital, Oxford, UK Medicine, University of Oxford, Oxford, UK
16.1.1: Blood vessels and the endothelium 24.24: Autoimmune encephalitis and Morvan’s 8.5.10: Rhabdoviruses: Rabies and rabies-​related
Greet Van den Berghe Clinical Division and syndrome lyssaviruses; 8.5.11: Colorado tick fever and other
Laboratory of Intensive Care Medicine, Raphael P. Viscidi Johns Hopkins Medical arthropod-​borne reoviruses; 8.5.27: Orf and
Department of Cellular and Molecular Institution, Baltimore, MD, USA Milker’s nodule; 8.5.28: Molluscum contagiosum;
Medicine, KU Leuven University, B-​3000 Leuven, 8.5.19: Papillomaviruses and polyomaviruses 8.6.34: Relapsing fevers; 8.13: Pentastomiasis
Belgium (porocephalosis, linguatulosis/​linguatuliasis,
H. Josef Vormoor Clinical Director,
17.9: Metabolic and endocrine changes in acute or tongue worm infection); 10.4.2: Injuries,
Department of Hemato-​oncology, Princess
and chronic critical illness envenoming, poisoning, and allergic reactions
Máxima Center for Pediatric Oncology,
caused by animals; 10.4.3: Poisonous fungi;
Steven Vanderschueren Leuven Research Utrecht, the Netherlands
24.11.2: Viral infections
Department of Microbiology, Immunology 22.4.2: Acute lymphoblastic leukaemia
and Transplantation, Laboratory for Clinical Mary J. Warrell Oxford Vaccine Group, University of
Theo Vos University of Washington, WA, USA
Infectious and Inflammatory Disorders, Clinical Oxford, Oxford, UK
2.3: The Global Burden of Disease: Measuring the
Department of General Internal Medicine, 8.5.10: Rhabdoviruses: Rabies and rabies-​related
health of populations
University Hospital Leuven, B-​3000 Leuven, lyssaviruses; 8.5.11: Colorado tick fever and other
Henry J.C. de Vries Academic Medical Centre,
Belgium arthropod-​borne reoviruses
University of Amsterdam, Amsterdam, the
8.2.2: Fever of unknown origin John A.H. Wass University of Oxford, Oxford, UK
Netherlands
Sirivan Vanijanonta Department of Clinical 13.2.1: Disorders of the anterior pituitary gland;
9.7: Anogenital lumps and bumps
Tropical Medicine, Faculty of Tropical 13.2.2: Disorders of the posterior pituitary gland;
Paresh Vyas Professor of Haematology, MRC
Medicine, Mahidol University, 13.10: Hormonal manifestations of non-​endocrine
Molecular Haematology Unit, Weatherall
Bangkok, Thailand disease
Institute of Molecular Medicine, Radcliffe
8.11.3: Lung flukes (paragonimiasis) Lawrence Waterman Loughborough University,
Department of Medicine, University of Oxford;
Anita Vas-​Falcao London School of Hygiene and Loughborough, UK; Park Health and Safety
Consultant Haematologist, Department of
Tropical Medicine, London, UK Partnership, Aylesbury, UK
Haematology, Cancer and Haematology
9.1: Epidemiology of sexually transmitted 10.2.2: Occupational safety
Centre, Churchill Hospital, Oxford
infections University Hospitals NHS Foundation Trust, Laurence Watkins The National Hospital for
Nikos Vasilakis Department of Pathology, Oxford, UK Neurology and Neurosurgery, London, UK
Center for Biodefense and Emerging Infectious 22.2.1: Cellular and molecular basis of 24.10.3: Traumatic brain injury
Diseases, Center for Tropical Diseases, haematopoiesis Peter Watkinson Nuffield Department of Clinical
Institute for Human Infections and Immunity, Peter D. Wagner Division of Physiology at the Neurosciences, University of Oxford, Oxford, UK
University of Texas Medical Branch, Galveston, Department of Medicine, University of California 8.1.2: Clinical features and general management of
TX, USA San Diego, CA, USA patients with severe infections
8.5.14: Flaviviruses excluding dengue 18.1.2: Airways and alveoli Richard A. Watts Department of Rheumatology,
Diana Vassallo Specialist Registrar, Department of Nicholas Wald Institute of Health Informatics, Ipswich Hospital, Ipswich; Norwich Medical
Renal Medicine, Salford Royal NHS Foundation University College London, London; Population School, University of East Anglia, Norwich, UK
Trust, Salford, UK Health Research Institute, St George’s University of 19.11.9: Small vessel vasculitis
21.10.10: Atherosclerotic renovascular disease London, London; Division of Medical Screening Richard W.E. Watts† Division of Inherited Metabolic
Birgitte Vennervald Section for Parasitology and Special Testing, Department of Pathology and Diseases, Northwick Park Hospital, London, UK
and Aquatic Diseases, Faculty of Health and Laboratory Medicine, The Warren Alpert Medical 12.1: The inborn errors of metabolism: general
Medical Sciences, University of Copenhagen, School of Brown University, Rhode Island, USA aspects; 12.4: Disorders of purine and pyrimidine
Copenhagen, Denmark 2.12: Medical screening metabolism
8.11.1: Schistosomiasis Herman Waldmann Sir William Dunn School of David J. Weatherall† Weatherall Institute of
Vanessa Venning Department of Dermatology, Pathology, University of Oxford, Oxford, UK Molecular Medicine, Radcliffe Department of
Churchill Hospital, Oxford, UK 3.8: The evolution of therapeutic antibodies Medicine, University of Oxford, Oxford, UK
23.2: Clinical approach to the diagnosis of skin Jane Walker Psychological Medicine Research, 22.6.2: Anaemia: Pathophysiology, classification,
disease University of Oxford Department of Psychiatry, and clinical features; 22.6.3: Anaemia as a
Anilrudh A. Venugopal Los Angeles, CA, USA Warneford Hospital, Oxford, UK challenge to world health; 22.6.7: Disorders of the
8.6.11: Anaerobic bacteria 26.2: The psychiatric assessment of the medical patient; synthesis or function of haemoglobin
Kristien Verdonck Institute of Tropical Medicine, 26.3.4: Low mood G.J. Webb Centre for Liver and Gastrointestinal
Antwerp, Belgium Matthew C. Walker National Hospital of Neurology Research, Institute of Immunology and
8.5.25: HTLV-​1, HTLV-​2, and associated and Neurosurgery and UCL Institute of Immunotherapy, University of Birmingham,
diseases Neurology, Queen Square, London, UK Birmingham, UK
24.5.2: Narcolepsy 15.23.2: Autoimmune hepatitis
Christopher M. Verity Addenbrookes Hospital,
Cambridge, UK Elizabeth Wallin Transplant Research Immunology Lisa J. Webber St Mary’s Hospital, Imperial College
24.20: Developmental abnormalities of the central Group, Nuffield Department of Surgical Sciences, Healthcare NHS Trust, London, UK
nervous system University of Oxford, Oxford, UK 13.6.1: Ovarian disorders
Benjamin A. Vervaet Laboratory of 4.7: Principles of transplantation immunology George J. Webster Consultant Hepatologist and
Pathophysiology, University of Antwerp, Sarah Walsh King’s College Hospital, Gastroenterologist, University College Hospital
Antwerp, Belgium London, UK and Royal Free Hospital, London, UK
21.9.2: Chronic tubulointerstitial nephritis 23.16: Cutaneous reactions to drugs 15.3.2: Upper gastrointestinal endoscopy

†
It is with great regret that we report that Richard W.E. Watts died on 11 February, 2018 and David J. Weatherall died on 8 December, 2018.
lxvi Contributors

Anthony P. Weetman University of Sheffield, R.G. Will Professor of Clinical Neurology, Andrew F. Woodhouse Department of Infection
Sheffield, UK Department of Clinical Neurosciences, and Tropical Medicine, Birmingham Heartlands
13.3.1: The thyroid gland and disorders of thyroid University of Edinburgh, Edinburgh, UK Hospital, Birmingham, UK
function; 13.3.2: Thyroid cancer 24.11.5: Human prion diseases 8.6.32: Rat bite fevers (Streptobacillus moniliformis
Robert A. Weinstein Rush University, Chicago, Lisa Willcocks Consultant Physician and and Spirillum minus infection)
IL, USA Nephrologist, Cambridge University Hospitals, Jeremy Woodward Cambridge Intestinal Failure
8.6.4: Staphylococci Cambridge, UK and Transplant Unit, Addenbrooke’s Hospital,
Louis M. Weiss Department of Pathology, 21.8.3: Minimal change nephropathy and focal Cambridge, UK
Division of Parasitology and Tropical Medicine; segmental glomerulosclerosis 11.7: Artificial nutrition support; 15.2: Symptoms
Department of Medicine, Division of Infectious Bryan Williams University College London, of gastrointestinal disease
Diseases, Albert Einstein College of Medicine, London, UK Elaine M. Worcester Professor of Medicine,
Bronx, NY, USA 16.17.1: Essential hypertension: Definition, Nephrology Section, Department of Medicine,
8.7.7: Microsporidiosis; 8.8.7: Cystoisosporiasis epidemiology, and pathophysiology; University of Chicago, Chicago, USA
Robin A. Weiss University College London, London, UK 16.17.2: Essential hypertension: Diagnosis, 21.14: Disorders of renal calcium handling, urinary
8.5.26: Viruses and cancer assessment, and treatment stones, and nephrocalcinosis
Peter F. Weller William Bosworth Castle Professor David J. Williams Obstetric Physician, Institute for B. Paul Wordsworth Emeritus Professor of
of Medicine, Harvard Medical School, Boston; Women’s Health, University College London Clinical Rheumatology, Nuffield Department
Chief of the Infectious Diseases and the Allergy Hospital, London, UK of Orthopaedics, Rheumatology and
and Inflammation Divisions, Beth Israel 14.1: Physiological changes of normal pregnancy; Musculoskeletal Sciences, Botnar Research
Deaconess Medical Center, Boston, MD, USA 14.2: Nutrition in pregnancy; 14.3: Medical Centre, Nuffield Orthopaedic Centre,
22.3.8: Eosinophilia management of normal pregnancy Headington, Oxford, UK
Catherine Williamson Professor of Women’s 20.1: Skeletal disorders—​general approach and
A.U. Wells Interstitial Lung Disease Unit, Royal
Health, King’s College London and Honorary clinical conditions
Brompton Hospital, London, UK
18.11.1: Diffuse parenchymal lung disease: An Consultant in Obstetric Medicine, St Thomas’ Gary P. Wormser New York Medical College, NY, USA
introduction; 18.11.2: Idiopathic pulmonary and King’s College Hospitals, London, UK 8.6.33: Lyme borreliosis
fibrosis; 18.11.3: Bronchiolitis obliterans and 14.9: Liver and gastrointestinal diseases of Mark Wright Consultant Gastroenterologist, University
cryptogenic organizing pneumonia; 18.11.4: The pregnancy Hospital Southampton, Southampton, UK
lung in autoimmune rheumatic disorders; Bridget Wills Centre for Tropical Medicine 15.25: Diseases of the gallbladder and biliary tree
18.11.5: The lung in vasculitis and Global Health, Nuffield Department of Channa Jayasumana Faculty of Medicine, Rajatrata
Simon Wessely Department of Psychological Medicine, University of Oxford, Oxford, UK; University of Sri Lanka, Anuradhapura, Sri Lanka
Medicine, King’s College London, London, UK Oxford University Clinical Research Unit, 21.9.2: Chronic tubulointerstitial nephritis
26.4.2: Psychological treatments Hospital for Tropical Diseases, Ho Chi Minh Muhammad M. Yaqoob Barts Health NHS Trust,
City, Vietnam
Gilbert C. White, II Aster Chair for Medical Renal Unit, Royal London Hospital, London, UK
8.5.15: Dengue; 24.11.2: Viral infections
Research, Executive Vice President for Research, 21.17: Urinary tract obstruction
Director, Blood Research Institute, Versiti; R. Wilson Royal Brompton and Harefield NHS
Hasan Yazici Department of Medicine
Professor of Medicine, Biochemistry, and Trust, London, UK (Rheumatology), Academic Hospital,
Pharmacology, Associate Dean for Research, 18.9: Bronchiectasis Istanbul, Turkey
Medical College of Wisconsin, Milwaukee, Greg Winter MRC Laboratory of Molecular Biology, 19.11.10: Behçet’s syndrome
WI, USA Cambridge, UK Lam Minh Yen Oxford University Clinical Research
22.7.1: The biology of haemostasis and thrombosis 3.8: The evolution of therapeutic antibodies Unit, Hospital for Tropical Diseases, Ho Chi
Nicholas J. White Centre for Tropical Medicine and Miles Witham AGE Research Group, NIHR Minh City, Vietnam
Global Health, Nuffield Department of Medicine, Newcastle Biomedical Research Centre, 8.6.23: Tetanus
University of Oxford, Oxford, UK Newcastle University and Newcastle upon Tyne Duncan Young Nuffield Department of Clinical
8.8.2: Malaria Hospitals Trust, Newcastle upon Tyne, UK Neurosciences, University of Oxford,
Hilton C. Whittle Faculty of Infectious and Tropical 6.7: Drugs and prescribing in the older patient Oxford, UK
Diseases, London School of Hygiene and Tropical Fenella Wojnarowska Nuffield Department of 8.1.2: Clinical features and general management of
Medicine, London, UK Medicine, University of Oxford, Oxford, UK patients with severe infections
8.5.6: Measles 14.13: The skin in pregnancy; 23.4: Autoimmune Katherine Younger School of Biological and Health
Anthony S. Wierzbicki Department of Metabolic bullous diseases Sciences, Technological University Dublin,
Medicine/​Chemical Pathology, Guy’s and St Edwin K.S. Wong Institute of Genetic Medicine, Dublin, Ireland
Thomas’ Hospitals, London, UK Newcastle University, Newcastle upon 11.3: Minerals and trace elements
12.9: Disorders of peroxisomal metabolism Tyne, UK Sebahattin Yurdakul Division of Rheumatology,
in adults 21.10.6: Haemolytic uraemic syndrome Department of Medicine, Cerrahpasa Medical
Mark H. Wilcox Professor of Medical James L.N. Wood University of Cambridge, Faculty, University of Istanbul, Istanbul, Turkey
Microbiology, Microbiology, Old Medical Cambridge, UK 19.11.10: Behçet’s syndrome
School, Leeds General Infirmary, and University 8.1.1: Biology of pathogenic microorganisms Alberto Zanella Oncohematology Unit—​
of Leeds, Leeds, UK Jonathan Wood Substance Misuse Psychiatry, Pathophysiology of Anemias Unit, Foundation
8.6.24: Clostridium difficile Cambridgeshire and Peterborough NHS IRCCS Ca’ Granda Ospedale Maggiore, Milan, Italy
Kate Wiles Department of Women and Children’s Foundation Trust, Cambridge, UK 22.6.10: Erythrocyte enzymopathies
Health, King’s College London, London, UK 26.5.4: Alcohol misuse Adam Zeman Professor of Cognitive and
14.5: Renal disease in pregnancy Kathryn J. Wood Transplant Research Immunology Behavioural Neurology, University of Exeter
James S. Wiley Principal Research Fellow, Florey Group, Nuffield Department of Surgical Sciences, Medical School, Exeter, UK
Institute of Neuroscience, and Mental Health University of Oxford, Oxford, UK 24.2: Mind and brain: Building bridges between
Honorary Professor, University of Melbourne, 4.7: Principles of transplantation immunology neurology, psychiatry, and psychology
Melbourne, Vic, Australia Nicholas Wood University College London, Clive S. Zent University of Rochester Medical
22.6.8: Anaemias resulting from defective London, UK Center, Rochester, NY, USA
maturation of red cells 24.7.4: Ataxic disorders 22.4.5: Chronic lymphocytic leukaemia
SECTION 10
Environmental medicine,
occupational medicine, and
poisoning
Section editor: Jon G. Ayres

10.1 Environmental medicine, occupational 10.3.5 Lightning and electrical injuries 1696
medicine, and poisoning—Introduction 1637 Chris Andrews
Jon G. Ayres 10.3.6 Diseases of high terrestrial altitudes 1701
Tyler Albert, Erik R. Swenson, Andrew J. Pollard,
10.2 Occupational health 1638 Buddha Basnyat, and David R. Murdoch
10.2.1 Occupational and environmental health 1638 10.3.7 Radiation 1709
Raymond Agius and Debasish Sen Jill Meara
10.2.2 Occupational safety 1652 10.3.8 Disasters: Earthquakes, hurricanes, floods, and
Lawrence Waterman and Michelle Twigg volcanic eruptions 1713
10.2.3 Aviation medicine 1656 Peter J. Baxter
Michael Bagshaw 10.3.9 Bioterrorism 1718
10.2.4 Diving medicine 1664 Manfred S. Green
David M. Denison and Mark A. Glover
10.4 Poisoning 1725
10.2.5 Noise 1671
David Koh and Tar-Ching Aw 10.4.1 Poisoning by drugs and chemicals 1725
John A. Vale, Sally M. Bradberry, and D. Nicholas
10.2.6 Vibration 1673 Bateman
Tar-Ching Aw
10.4.2 Injuries, envenoming, poisoning, and
10.3 Environment and health 1677 allergic reactions caused by animals 1778
10.3.1 Air pollution and health 1677 David A. Warrell
Om P. Kurmi, Kin Bong Hubert Lam, 10.4.3 Poisonous fungi 1817
and Jon G. Ayres Hans Persson and David A. Warrell
10.3.2 Heat 1687 10.4.4 Poisonous plants 1828
Michael A. Stroud Michael Eddleston and Hans Persson
10.3.3 Cold 1689 10.5 Podoconiosis (nonfilarial elephantiasis) 1833
Michael A. Stroud
Gail Davey
10.3.4 Drowning 1691
Peter J. Fenner
10.1
Environmental medicine, occupational
medicine, and poisoning—Introduction
Jon G. Ayres

The environment, both the occupational and the wider environ- of climate change on health are based on forward projections from
ment, can affect health in many ways, both adversely and benefi- known existing causal links between environmental influences and
cially. While to date many of these effects have been well understood, health. These projections largely assume that these associations are
most specifically for the work environment, the importance of the linear, hence they are open to some uncertainty when considering
wider environment as a cause of ill health has been less well studied quantification of the health burden, but the likely impacts are at least
on the basis that there is not much one can do about general expos- broadly agreed, even if the quantification is uncertain. These are
ures, such as the weather, or specific events, such as volcanic erup- summarized in Box 10.1.1 and cover a wide area, ranging from the
tions, apart from deal with the direct effects. However, increasing impacts of temperature change itself through to changes in vector-​
awareness of the importance of the environment on health, such as based disease geography. Management of many of these situations
exposure to air pollution (both indoor and outdoor) and the short, are covered elsewhere in this textbook, if not in this section itself.
medium, and long-​term effects of climate change, has resulted in However, it needs to be understood that the physician has an ad-
better understanding of interventions that can improve health, or at visory and exemplary role with respect to climate change and health
least abrogate deleterious effects. by personal actions (e.g. walking or using a bike rather than a car
Many environmental exposures are complex, often involving a where possible), and by putting pressure on governments to sign
range of potential agents. This has proved a real problem when up to and implement recommendations of International Climate
trying to identify specific components that cause ill health, say Change agreements.
in polluted air. Knowledge of these components would help in
the design of interventions aimed at specific causal factors, ra-
ther than going for a blanket reduction in air pollution as a whole. Box 10.1.1 How this section is divided
This optimal approach has been helped by an improving ability
This section is divided into three broad areas:
to measure population exposure to particular environmental
1 Environment and health—​incorporating such major issues as air
agents, leading to the establishment of much more refined popu- pollution and climate change.
lation or individual dose response relationships that are crucial in 2 Work and health—​both the well-​recognized effects of work on health
understanding the efficacy of any interventions. In the future, im- (e.g. back pain, stress, and so on) and the less well-​recognized, but
proved technology will allow personal—​rather than population—​ equally important effects of health on work.
exposure measurement of a wide range of exposures, allowing 3 Poisoning—​there are many types of poison, natural and man-​made,
population-​based studies to determine exactly how important in- to which we can become exposed, either intentionally or accidentally.
dividual exposures are in conditions where multiple causal agents Included are the adverse effects of medications and treatments.
may be implicated. The subject matter discussed in this section of the textbook often
overlaps with that in other sections, hence several key areas are flagged
Climate change is another area where these sorts of problems
here but also covered elsewhere (e.g. occupational lung disease).
occur, but is compounded by the fact that estimates of the effects
10.2
Occupational health

CONTENTS key issues being the temporality, reversibility, exposure-​response,

10.2.1 Occupational and environmental health 1638 strength of association, and specificity of the illness with exposure
Raymond Agius and Debasish Sen to the factor in question, also biological plausibility, consistency
with other reports, and evidence of similar exposures producing
10.2.2 Occupational safety 1652
similar illness.
Lawrence Waterman
The prevention of occupational disease depends upon recogni-
10.2.3 Aviation medicine 1656 tion of the condition as occupational, assessment of ‘exposure’ and
Michael Bagshaw hence determination of risk, education of stakeholders, control of
10.2.4 Diving medicine 1664 the problem at source, audit of the risk management procedures,
David M. Denison and Mark A. Glover and perhaps health surveillance of those exposed using suitable
10.2.5 Noise 1671 techniques for the early detection of disease and a check on the ef-
David Koh and Tar-​Ching Aw fectiveness of the control measures. Extant health and safety legis-
lation is driven mainly by risk assessment, and those who generate
10.2.6 Vibration 1673
the risks are responsible for undertaking an assessment, the detail of
Tar-​Ching Aw
which must be commensurate with the complexity of the situation
and the ultimate risk.
Worker compensation, or the financial recompense for harm
done to an individual by work or workplace, can be for an injury or
a disease and might be difficult to secure even in the 21st century.
It is important that clinicians are aware of statutory compensation
schemes, and patients should be advised to claim for compensation
10.2.1 Occupational and if their disease and work exposure seem related. If the disease and/​or
environmental health work exposure are not scheduled, there may still be a case worthy of
pursuit under common law.
Raymond Agius and Debasish Sen Around the world, most people in work do not have access to an
occupational health service or an occupational physician, and this
is despite the International Labour Organization’s recommenda-
ESSENTIALS tions in 1985 for its members ‘to develop progressively occupa-
Occupational diseases are those for which work or, specific- tional health services for all workers’ and that ‘The provision made
ally, exposures in the workplace are necessary causes. The most should be adequate and appropriate to the specific needs of the
prevalent occupational diseases in developed countries today are undertaking’.
musculoskeletal and psychological disorders (usually stress-​
related conditions), but generally occupationally related malig-
nancies (e.g. mesothelioma related to asbestos exposure) have
the most serious outcomes. The proportion of all cancers attrib- Introduction
utable to occupational exposures is about 4%, with occupation-
ally related cancers almost exclusively concentrated in manual ‘Disease’ results from a combination of genetic, behavioural, and
workers aged 20 or over in sectors such as mining, agriculture, ‘environmental’ factors, generally cumulating with the passage of
and industry. time. However, proportionately, genetic factors explain very little
When presented with a patient whose illness might possibly have of the burden of ill health. Therefore, it behoves us as physicians to
been caused or aggravated by work or by other environmental fac- consider, as a first alternative or as a ‘default’, environmental fac-
tors, the physician can usefully adopt an approach similar to that tors, ranging from the ambient air we breathe to our occupation,
used for determining causation in epidemiological studies, with but including diet, micro-​organisms, and other exogenous factors
as the prime determinants of disease.
 10.2.1 Occupational and environmental health 1639

As physicians we should, first and foremost, aim to protect indi- addressing health-​related issues standing in the way of achieving a
viduals and society from such ill health through preventive meas- job in the first place.
ures. We need to be aware of the sources and nature of the physical,
ergonomic, chemical, microbial, and psychological hazards, how
people are exposed to them and the risk or likelihood of this hap- Definitions and scope: Occupational disease
pening, how they bring about adverse effects, and what structural,
organizational, or behavioural interventions we should advocate to What then is an occupational disease? Put simply, it is a disease for
protect health and prevent ill health. which work or, specifically, exposures in the workplace are neces-
When presented with a patient whose illness might possibly sary causes. The answer often has far-​reaching consequences, both
have been caused or aggravated by work or by other environ- in terms of suitability of employment, compensation costs, the in-
mental factors, the physician might need to broaden their usual clusion of controls against exposure, as well as legal or policy consid-
approach to history taking. Taking short cuts here can result in erations. For silicosis (caused by airborne quartz), or mesothelioma
missing the diagnosis altogether and in losing a vital opportunity (caused by asbestos), the disease is almost always caused by work
of making the patient better and of improving the fate of other and the key aetiological agent, silica, found in the workplace. But
coworkers. This additional information might be critical in at- what about bronchial cancer in a joiner exposed to asbestos? Is it
tributing the illness to work. Bradford Hill postulated guidelines an occupational disease even though it is impossible to assess the
for determining causation in epidemiological studies, which lend precise contribution of occupational versus non​occupational factors
themselves to be adapted for clinical purposes in an analogous (such as tobacco smoking) in any one individual? Epidemiologic
manner (see Table 10.2.1.1). Moreover, when taking an occupa- research on the excess of illness that is attributable to work can be
tional history, it is also important to determine exposure, and a job used to directly represent the impact of work on health at a popu-
title. For example, ‘engineer’, is not enough; a description of what lation level, as well as occupational exacerbations of symptoms and
the job entails and what agents or energies are involved are a bare disability in pre-​existing conditions, such as asthma brought on by
minimum. The full job description might need to go back several irritants in the workplace.
years—​pleural mesothelioma, for example, can occur half a cen- The most prevalent occupational diseases in developed coun-
tury after the first exposure to asbestos. tries today are musculoskeletal and psychological disorders (usually
The workplace is where many people spend a significant propor- stress-​related conditions) but generally occupationally related ma-
tion of their lives. Work is important for self-​esteem and well-​being lignancies have the most serious outcomes. However, when it comes
(physical and psychological) as well as for the economic well-​being to understanding the mechanism by which occupational diseases
of the individual and society. Work is good for us as long as it is occur, two basic concepts immediately arise: the fact that in the case
good work and, therefore, does not impose unacceptable risks to of two workers doing an identical job one will get the disease but the
our health. other may not; and the fact that with some workplace exposures,
Thus, in dealing with the individual, physicians, whatever their for example asbestos, the latency of the disease, in this case meso-
specialty or interest, need to explore occupational and other envir- thelioma, may mean many years before the disease appears. These
onmental causes of disease, to protect and better manage the pa- factors can make the diagnosis of occupational diseases difficult. On
tient concerned, and indirectly protect others from the same fate. the other hand, failures of safety aspects of work are usually very
Furthermore, the physician has a responsibility as part of managing obvious, especially if they lead to a workplace accident resulting
the patient’s health to do their best to help the patient achieve in an injury or even death. Fig. 10.2.1.1 guides the clinician to an
and maintain gainful and fulfilling employment, whether this in- outline of the hazards to health arising from the workplace or other
volves rehabilitation back to work, resolving presenteeism, or even environments.

Table 10.2.1.1 Analogies between determining causality in an epidemiologic context (the Bradford Hill criteria) in population studies, and
when dealing with an individual patient in a clinical context

Epidemiologic criteria for causality

Analogous clinical questions
Temporality When in relation to exposure do/​did the symptoms start?
Reversibility Do the symptoms improve when no longer exposed, e.g. after a weekend off, or by the end of a holiday?
Exposure-​response Are the symptoms especially worse when undertaking tasks or in areas with high exposures?
Strength of association Do other workers/​patients suffer from similar symptoms associated with the same exposures?
Specificity What other exposures/​causal factors could be responsible for the same symptoms? (Smoking perhaps?)
Other data, or information processing:
Consistency Are there other reports of the same symptoms associated with or caused by the same exposure?
Analogy Even if there is no evidence to hand of identical exposures or circumstances resulting in the same symptoms, have similar
agents/​chemicals of similar structure been implicated in the same symptoms of, for example ... dermatitis, ... or asthma.
Biological plausibility Do the symptoms ‘add up’ in terms of what is known about the mechanisms of disease?
1640 SECTION 10 Environmental medicine, occupational medicine, and poisoning

ERGONOMIC
Heavy lifting,
handling of loads
Abnormal PSYCHOLOGICAL
postures Work overload or
underload
High demand—poor
control
PHYSICAL Other stressors
High noise
exposure, or
vibration
Hot work
Radiation BIOLOGICAL
(ionizing and Work with infected
nonionizing) patients or
laboratory work:
blood–borne
CHEMICAL viruses,
Breathing in and/or tuberculosis,
handling chemicals or leptospirosis
other hazardous
substances; ingesting
chemicals: mineral
dusts, 'heavy metals',
organic solvents,
monomers,
hardeners, etc.

Fig. 10.2.1.1 Types of hazards, which may lead to occupational disease or other
environment-​related ill health.

When faced with a case of ill health, to exclude work or the envir- majority (2.02 million) dying from a range of work-​related diseases.
onment, which might include the patient’s workplace, in the differen- This equates to 5500 deaths each and every day caused by various
tial diagnosis, it is important to determine, through the occupational types of work-​related diseases. On top of this, the International Labour
history, the nature, duration, and intensity of any likely exposure, as Organization (ILO) also estimates 160 million cases of non​ fatal
illustrated in Fig. 10.2.1.1. The following are useful guides: work-​related diseases occurring annually worldwide. However, these
figures might well be serious underestimates. In the United Kingdom,
1. How was the task done? For example, was the adhesive applied
estimates for 2016/2017 indicate around 13 000 deaths each year are
with a brush while the patient leant over it?
thought to be linked to past exposures at work; primarily to chemicals
2. Was the airborne concentration of a dust or fume such that it
or dust. (Asbestos-related deaths, often with historic exposure, make
could be seen (although harmful particles are usually invisible
up the greatest number dying from work-related cancers).
to the naked eye), or the noise so loud that normal conversation
The types and trends of reported, non​fatal diseases worldwide
was difficult?
vary widely although some common features do exist: occupational
3. Is local exhaust ventilation/​extraction provided for the machine lung diseases from exposure to workplace dusts, gases, vapours, and
or area where work is taking place? fumes; musculoskeletal disorders particularly low back pain; psy-
4. Are the risks to health connected with work such that the em- chological disorders. In 2016/2017 an estimated 1.3 million people
ployer has (or should have) supplied workers with certain items in the United Kingdom were suffering from an illness (longstanding
of personal protective equipment such as gloves or a mask? as well as new) they believed was caused or made worse by their
Different categories of harmful agents require different and spe- current work; 516 000 were new cases among those working in the
cific forms of personal protection (e.g. rubber-​based gloves are previous 12 months, accounting for 25.7 million working days lost
not appropriate when handling solvents). due to work-related ill health in 2016/2017. Around 79% of new
The relationship between hazard, risk, and the eventual possible work-​related conditions were either musculoskeletal disorders or
onset of disease is a very important one, since it goes beyond stress, depression, or anxiety. Fig. 10.2.1.3 shows how the incident
‘clinching a diagnosis’ and extends to the crucial aspects of preven- cases distribute by major category from a general practice perspec-
tion of ill health, as illustrated in Fig. 10.2.1.2. tive. Most of the incident cases are musculoskeletal, but mental ill
health accounts for most of the sickness absence burden.
The ILO estimates that, worldwide, work-​related accidents and
The size of the problem diseases result in an annual 4% loss in gross domestic product, or
about US$2.8 trillion in direct and indirect costs. The cost of work-​
The International Labour Organization in 2013 estimated 2.34 million related diseases in the EU has been estimated to be at least €145 bil-
deaths each year from work-​related accidents and diseases, the vast lion per year, excluding compensation costs (for asbestos-​related
 10.2.1 Occupational and environmental health 1641

HAZARDS
Potential to cause harm
May arise from many sources

Intensity of
exposure
leading to dose

PRIMARY PREVENTION
Reduction through intervention
RISK or
likelihood of
effect/disease

PRECLINICAL/BIOLOGICAL
HEALTH EFFECTS

SECONDARY PREVENTION
Reduction in risk to others by
intervention

CLINICAL ILLNESS

TERTIARY PREVENTION
USUAL MEDICAL INTERVENTION Achieving improvement in
PLUS REHABILITATION capacity through occupational
rehabilitation

Fig. 10.2.1.2 From hazard, to risk, to disease, and the principles of prevention.

diseases, for example, of around €1.5 billion per year) and per-
History of occupational disease
sonal litigation/​compensation costs. In Great Britain, costs of new
cases of workplace illness are estimated at £8.6 billion (2012/​13
Some industries, such as mining, have always been considered haz-
data), shared between cost to the individual worker (pain, grief,
ardous. The ancient Egyptians recognized this by restricting such
and suffering), the employer (lost productivity), and government
work to slaves and criminals. Hippocrates emphasized the rela-
(healthcare).
tionship between environment (air and water) and health, but the

N = 6492 cases

1% 5% <1% 4% 2% <1% 5%
2% 3% 2%
3%
9%
43% 35%

51%
32% 48%
55%

% of cases % of cases sickness % days sickness

reported absence certified absence certified

Musculoskeletal Mental ill-health Skin

Respiratory Hearing loss Other

Fig. 10.2.1.3 Distribution of incident cases of work-​related ill health

reported by general practitioners to the THOR-​GP surveillance scheme
(University of Manchester) and associated certified sickness absence,
2006–​2015, by diagnostic criteria.
The THOR-GP Surveillance Scheme, COEH, The University of Manchester,
Manchester.
1642 SECTION 10 Environmental medicine, occupational medicine, and poisoning

earliest occupational physicians served military forces, Galen; for inhalation; ingestion; absorption through the skin; or a direct effect
example, being a physician to Roman gladiators. By the Middle on organs of sense, for example, the eyes and ears. Occupational
Ages, the plight of the free miner had been recognized by Georgius health risk management comprises recognition, evaluation, control,
Agricola (1494–​1555) and Paracelsus (1493–​1541). Agricola not monitoring, and review. Fig. 10.2.1.4 illustrates the overall manage-
only described the ‘galloping consumption’ of Carpathian silver ment of occupational health risks, and although a physician in a spe-
miners but also proposed ways of reducing the dust in mines by im- cialty other than occupational medicine will contend directly with
proved ventilation. only a small part of this algorithm, awareness of it is important for
The first authoritative treatise on occupational disease was written the better management of the index patient and for the prevention
by Ramazzini (1633–​1764). His book De Morbis Artificium describes of ill health in others.
many occupational diseases ranging from mercurialism in mirror Extant health and safety legislation is driven mainly by risk as-
workers to repetitive strain injury in clerical workers. The Industrial sessment, and those who generate the risks are responsible for
Revolution in the United Kingdom brought occupational diseases undertaking an assessment, the detail of which must be commen-
to the attention of Parliament, largely through the work of phil- surate with the complexity of the situation and the ultimate risk.
anthropists like Robert Owen, Robert Peel, and Lord Shaftesbury. Before embarking on any evaluation, especially where an occupa-
Early legislation to control the worst vicissitudes of factory labour tional cause is suspected, care must be exercised to determine what
was emasculated by Parliament but the process had begun. The First the known toxicological/​health effects are, previous evidence from
Act of 1802 (which introduced the concept of limiting the hours of similar circumstances and/​or environments, and any epidemio-
work and providing rest breaks in the working day) was followed logical evidence if available, as well as what the legislation requires.
by others leading to the 1833 Act which saw the start of His/​Her This is the ‘recognition’ aspect, and highlights the necessity not only
Majesty’s Factory Inspectorate—​the first enforcing, regulatory au- to be well informed but also competent to interpret the available in-
thority in this field anywhere in the world. formation and act appropriately
By the early 20th century, the toxic effects of arsenic, mercury, Table 10.2.1.2 shows how, after recognizing the possibility of a
phosphorus, and lead were common and understood in the West. hazard being present in the workplace, evaluating the likelihood of
Notification of these diseases became a requirement under health harm arising, through the assessment of risk(s), is undertaken in a
and safety law, and compensation for ill health was also granted. systematic manner. Similar approaches can be used in protecting the
But the world of work has changed since then, particularly community at large such as in establishing air quality standards.
in the developed world. Here we now have a move away from Clinically, the issue of ‘what’ to assess might be self-​evident; for
manufacturing industries (heavy engineering, coal mining, and so example, blood lead in a case of suspected lead poisoning. However,
on) to the provision of services, retail, and leisure. Consequently, the from the standpoint of preventive risk assessment, a systematic
heavy, often dirty, industries such as mining and shipbuilding are, in approach must be pursued to determine the specific purpose and
some countries, like the United Kingdom, few and far between. With value of the monitoring. For example, is biological monitoring or
the growth in the service sector, whole new ways of working have biological-​effect monitoring required? The former is the detection of
also been developed (flexible working, short-​term and ‘zero hours’ a chemical or its metabolite in a biological sample as a measure of ex-
contracts), and with this we now have a new set of occupational dis- posure (measurement of lead bound to red blood cells is a good ex-
eases (more biopsychosocial problems). While the working condi- ample). The latter is measurement of a change in some biochemical
tions in the developed world have improved steadily since the early or physiological variable to indicate the effect of the contaminant on
20th century, working conditions for many in developing countries the body (such as measurement of red cell or serum cholinesterase
remain hazardous, demonstrating an important tenet of occupa- activity in relation to organophosphorus pesticides). However, even
tional health practice: that is, while occupational disease can be these measurements do not necessarily indicate harm but require an
preventable, the continued—​often necessary—​use of hazardous ma- understanding of toxicology and epidemiology, as well as the pres-
terials and processes means that many such diseases are not elimin- ence of relevant clinical findings. Often it is not possible to measure
ated, but need to be controlled. uptake or a biological effect short of ‘harm’, and one can only detect
early manifestations of ill health, such as asthmatic symptoms from
exposure to colophony fume in soldering.
Prevention of occupational disease and other ‘Gold standard’ tests are rare in occupational health practice.
work-​related ill health Choice of an appropriate technique for making these measurements
should be based, where possible, on indices of sensitivity and speci-
The prevention of occupational disease depends upon recognition of ficity, as well as on the economics and acceptability of the technique.
the condition as occupational, assessment of ‘exposure’ and hence de- Remedial action: If the clinician suspects that work might be
termination of risk, education of stakeholders, control of the problem having an adverse impact or poses a significant risk to a patient’s
at source, audit of the risk management procedures, and perhaps health then they should advise the patient, and, with consent, the
health surveillance of those exposed using suitable techniques for the general practitioner and even the employer accordingly. If the clin-
early detection of disease and a check on the effectiveness of the con- ician does not feel confident enough to do this, then advice can be
trol measures. These procedures are outlined next. The legal duty on sought from occupational physician colleagues in the relevant in-
those who generate occupational and environmental health risks to dustry, or in the health service, or from regulatory bodies, which
manage them will vary from country to country. also have a professional advisory role (such as the Health and Safety
Occupational and environmental hazardous agents likely to Executive in the United Kingdom). Advice given to the patient
harm human health might attack the body in various ways: through should include information on precautions that might be needed
 10.2.1 Occupational and environmental health 1643

Prior
knowledge of
Hazards Q1. WHAT HAZARDS DO Occupational
WE HAVE? health referrals
Systematic
surveys

Employee/Union
concerns
Q2. HOW DO
WE ASSESS
THE RISKS? OCC hygiene measurements

Risk-based Hierarchy of
Q3. HOW CAN WE CONTROLS
HEALTH
surveillance etc MANAGE THE RISKS?
TRAINING &
retraining on OH
risks

Measurements/
Biomonitoring results

Q4. HOW CAN WE CHECK MONITOR all in

AUDIT against TO SEE IF OUR Q1. (Active and
standards & INTERVENTIONS HAVE Passive)
Occupational
Health Plan
WORKED?

Fig. 10.2.1.4 The overall strategy for managing Occupational Health Risks.

on returning to work, and whether any further investigations are pre-​employment ‘medicals’, only after a job offer is made. Fitness to
required. Information on occupational rehabilitation and fitness work within existing H&S legislation remains vitally important to fit
to work is available from other specialists and agencies including the job to the individual.
voluntary/​charitable bodies (such as the Royal National Institute of
Blind People—​RNIB, in the United Kingdom).
European health and safety (H&S) legislation is clear: the em- Occupational cancer
ployer must adapt the workplace to be a safe environment for the
employees. The employees should not have to adapt themselves Occupational cancer is the leading cause of work-​related deaths
to the stresses and strains of their work. Antidiscriminatory legis- worldwide. Very often, it is difficult to establish the association be-
lation, such as the Equality Act 2010 in the United Kingdom, now tween occupation and cancer due to the long latency and multifac-
requires preplacement medical assessment of workers and not torial causation of the disease. However, some of the associations

Table 10.2.1.2 Specific considerations in assessing health risks

Assessing Where exposure can occur? The whole workplace?

the Where specific hazards exist?
risks
Who is likely to be affected? Those working full or longer shifts?
Those working at increased metabolic/​breathing rate?
Those undertaking unusual/​unscheduled tasks, e.g. maintenance work?
Those already unwell?
Are environmental measurements needed? . . . ‘background’ and/​or ‘personal’?
How can the hazard enter the body? Route of entry and hence likely damage?
How likely is the exposure to cause a specific harmful Epidemiology and clinical toxicology, especially exposure-​response relationships
effect, and how severe?
When and what to measure/​evaluate? Before, during, after exposure?
Pre-​, postshift; end of working week? (Cumulative effect; different metabolic
half-​lives of hazards?)
1644 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Table 10.2.1.3 Some chemical and physical hazards causally associated with human cancer for which exposure has been mostly
occupational. Examples of the index processes are in square parentheses while suspected target organs are in round parentheses

Hazard Human target organ

Arsenic and arsenic compounds Skin, lung (liver, haematopoietic system, gastrointestinal tract, kidney)
Asbestos (most commonly in demolition nowadays) Lung, pleura, peritoneum, gastrointestinal tract, larynx
Benzene (manufacture, petroleum refining) Haemopoietic (lymphatic) system
Beryllium Lung
Chromium VI (i.e. hexavalent compounds) Lung (gastrointestinal tract)
Coal tars/​pitches (coke production and coal gasification) Skin, lung (bladder, gastrointestinal tract, haemopoietic/​lymphatic system)
Diesel exhaust particulates or other particles containing polycyclic aromatic Lung, bladder
hydrocarbons (vehicle exhaust, some foundry processes)
Formaldehyde (disinfection, preservation, manufacture of resins and binders) Nasopharynx
Inorganic acid mists (strong) containing sulphuric acid (isopropyl alcohol Larynx
manufacture)
Ionizing radiation (radiography, nuclear, and other industries) Haemopoietic/​lymphatic system, bone, skin, and other organs depending on
exposure and type of radiation
Mineral oils, untreated or mildly treated Skin (respiratory tract, bladder, gastrointestinal tract)
2-​Naphthylamine, and analogous aromatic amines (dye manufacture, rubber Bladder (liver)
industry)
Certain nickel compounds (nickel refining) Nasal sinuses, lung (larynx)
Radon and its decay products (uranium mining, but also domestic/​residential) Lung
Silica (crystalline, e.g. quartz) Lung
Vinyl chloride Liver, lung, brain, lymphatic and haematopoietic systems (gastrointestinal tract)
Wood dusts, especially hardwoods (furniture manufacturing) Nasal sinuses

are clear; for example, asbestos exposure and mesothelioma. Other process could, and hopefully should, subside. The physician seeking
associations are much more complex and less easily proven, such as to determine and thence prevent new circumstances with a risk of
the relationship between shift work and breast cancer. causing cancer must be aware that the causal agents, or analogues
There is a considerable body of evidence on what causes oc- of them, might be responsible for causing cancer in other processes
cupational cancer. The International Agency for Research on which are new and had not been recognized as risky. Therefore, in
Cancer (IARC) based in Lyon, France, is part of the World Health Table 10.2.1.3, the focus is on the chemical or physical hazard with
Organization and has an established programme for the systematic processes listed by way of illustration while bearing in mind that
evaluation of scientific evidence on the carcinogenicity of specific these or similar hazardous agents might nowadays be manifest else-
hazards and exposures. This it publishes in its extensive monograph where. The agents named are not necessarily word for word as in
series as an authoritative source of information on human carcino- the IARC documentation or as in legal schedules, partly for concise-
gens. To date, IARC has classified nearly two hundred hazards as ness and partly to consider more recent epidemiologic evidence. The
being established or probably carcinogenic to humans. IARC evaluation of carcinogenicity in humans sometimes applies to
Epidemiological evidence has been used to determine estimates the group of chemicals as a whole, and not necessarily all individual
of the proportion of all cancers attributable to occupational expos- chemicals within the group.
ures. In round numbers the proportion is to the order of 4%, with
a range of 2–​8% for a developed country like the United States or
the United Kingdom. Occupationally related cancers are almost ex- Musculoskeletal disorders
clusively concentrated in 20% or so of the population, comprising
manual workers aged 20 or over, in sectors such as mining, agricul- Statistical data from the European Union, including the United
ture, and industry. In this group, perhaps as many as one case of lung Kingdom, as well as the United States, indicate that musculoskeletal
or bladder cancer in every five might be attributable to workplace disorders have the highest reported incidence (Fig. 10.2.1.3) out of
exposure. the major categories of occupational or work-​related ill health—​in
A wide range of industrial processes have been causally associ- the United Kingdom there were an estimated 507 000 workers suf-
ated with human cancer. Attribution of carcinogenesis by industrial fering from work-related musculoskeletal disorders (new or long-
process is often the first evidential step, and many legally recognized standing) in 2016/2017. However, musculoskeletal symptoms are
causes for compensation (‘prescribed’ industrial diseases) still rely very common in the general population, a large proportion of which
on a definition by process. However, this approach has the short- are in employment so making a work connection is often difficult
coming of not necessarily being specific as to what chemical ex- to confirm. In some situations, a combination of occupational,
posure needs to be controlled. Moreover, with the passage of time, psychological, personal, social, and home factors can be involved.
once changes are implemented the risk associated with the original This makes the diagnosis of the more common disorders associated
 10.2.1 Occupational and environmental health 1645

with work, such as low back pain, non​specific upper limb pain, and exception of serious spinal diseases and nerve root problems, special
work-​related stress, particularly difficult because of the reliance on investigations are unnecessary, and rapid mobilization and return to
the subjective reporting of symptoms and the evidence of both cul- work should be advocated. Moreover, the rising incidence of back
tural and psychosocial influences, many of which are unrelated to pain reported to be work related, over a period of decades, cannot
work, on such symptoms being reported. The epidemic of so-​called be adequately explained by physical conditions at work or by work
‘repetitive strain injury’ in Australia during the 1980s highlighted practices. Cultural and psychological factors probably have to be in-
the complex interaction of illness beliefs and behaviour, as well as voked satisfactorily to account for the high frequency of back pain.
employment in determining the workers’ symptomatic complaints. In the upper limb, other musculoskeletal disorders such as carpal
Musculoskeletal disorders can occur in all types of industry with tunnel syndrome and De Quervain’s tenosynovitis might be related
high rates in post and courier services, agriculture, specialized con- to work, as well as to recreational activities, in tasks which involve
struction work, and aspects of healthcare. The occupational risk strenuous gripping.
factors implicated include: awkward posture; manual handling of Work can aggravate as well as cause musculoskeletal disorders
loads; keyboard and other repetitive work; and psychosocial factors. and the physician has a responsibility to rehabilitate people with
Musculoskeletal disorders cases are very variable in their clinical pro- musculoskeletal disorders back to work. Fortunately, the advent of
gress, though generally more predictable in this regard than mental new ‘biologics’ has made rehabilitation easier for patients with arth-
disorders. Thus, some affected workers might be unable to return to ritic disease, such as rheumatoid arthritis. They need to be assessed
work for a time, primarily because of pain, and/​or need adjustments for the effect that the condition might have on the performance of
to their work. However, in general, cases are not very serious and their work duties. The fluctuating nature of most forms of chronic
treatment might be limited to pain management and adjustments in arthritis makes precise predictions difficult. Physical disability can
the workplace to reduce the risk of recurrence. People tend to recover improve despite persistence of the disease. This is due to the bene-
and return to work, although conditions are often episodic. ficial effects of treatment, to the patient’s adaptation to the conse-
In the United Kingdom and elsewhere in the developed world, quences of the disease, and to successful rehabilitation at work.
low back pain is possibly the most common musculoskeletal condi-
tion experienced by people at work, making up 38% of musculoskel-
etal disorders by affected area in the UK in 2016/2017. Poor lifting Mental or psychological disorders related to work
and manual-​handling techniques and sitting for prolonged periods
in the course of work activities (e.g. professional drivers) are con- The reported incidence of work-​related stress and mental disorders
tributory factors. Nurses, porters, and bricklayers are groups with a in the United Kingdom, the wider EU, and also the United States
high prevalence of low back pain. The total cost of sickness absence, over recent years has increased dramatically (both in absolute rates
early retirement, and treatment for low back pain in many coun- as well as in comparison with other work-​related ill health), and in
tries is considerable. Historically this was exacerbated by the belief certain industry sectors such as health and social care, education,
by patients and their medical attendants that rest was needed for and finance, it is now the single biggest cause of sickness absence
recovery. However, there is now very good evidence that, with the from work. Several factors in the working environment have been

Sources of stress Individual Symptoms Disease

characteristics
Intrinsic to job
(DEMAND, CONTROL)

Org structure/climate
(CHANGE management)
PHYSICAL

Career PHYSICAL HEALTH

development Physical &
PSYCHOLOGICAL
PSYCHOLOGICAL Mental ill health
HEALTH

Relationships at work PERSONALITY

(SUPPORT)
BEHAVIOURAL

Role in org
(CONTROL)

Personal

Fig. 10.2.1.5 From stressors to disease.

After Cartwright S and Cooper CL (1997). Managing Workplace Stress. Sage Publications Inc.
1646 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Table 10.2.1.4 Occupational factors that can act as stressors (psychosocial hazards)

Work overload Quantitative: too much to do in the given time

Qualitative: demands beyond the skills or organizational capacity of the worker
Work underload Quantitative: not enough work to do
Qualitative: monotonous, boring tasks, or below the skills of the worker
Timing and control Shift work
Limitations on organizing one’s own work
Responsibility Role ambiguity, conflict
Unclear responsibility and accountability
Organizational culture, and relationships Lack of communication, participation
Bullying and other harassment
Financial and future prospects Inadequate reward or other recognition of ‘worth’
Job insecurity
Poor training, personal development, or other prospects for advancement
Hazards and comfort Physical, chemical, and biological hazards
Other environmental discomfort or concern at work

identified as potential psychosocial hazards. Fig. 10.2.1.5 illustrates • Tertiary intervention is concerned with rehabilitation of psycho-
the broad categories of stressors and the key stages in the patient’s logically distressed individuals. When anxiety or depression is
journey through symptoms of lack of well-​being to psychological or manifest, pharmacological intervention and behaviour therapy
physical ‘disease’, such as depression or coronary ischaemia. may be needed. Counselling might help, although its evidence
There are various models to account for the ‘stress’ that people base is weak. The source of stress can often be multifactorial, and
perceive when they are unable to cope. Karasek’s model is based on not, therefore, solely work related, but it has an impact upon work
‘demand’ versus ‘control’ wherein jobs with high demand and low performance and might be exacerbated by the demands of work.
control are the most stressful. In Siegrist’s model, the stress pro-
voking imbalance adversely affecting employee well-​being is the one
between ‘effort’ and ‘reward’.
Infections
Prolonged exposure to one or more of the ‘stressors’ categorized in
Table 10.2.1.4 can result in a range of symptoms of psychological dis-
Patients, notably those working in healthcare, are at an increased
tress such as feelings of anxiety, irritability, or aggressive behaviour,
risk of occupational infections. Blood-​borne infections such as
lack of concentration, lack of confidence, and an inability to make
hepatitis B and HIV pose practical problems for the safety of staff
decisions, sleep disturbance, and fatigue. There might also be asso-
during contact with infected patients, and the safety of patients
ciated physical symptoms, such as frequent headaches and nausea.
during contact with infected staff, especially during so-​called
Occupational stress is often identified as a result of the individual’s
‘exposure-​prone procedures’. Numerous cases of HIV infection
inappropriate (maladaptive) coping strategies, such as frequent
have occurred in healthcare workers following contact with in-
short-​term absences, alcohol and other substance abuse, and poor
fected blood or body fluids from patients. These have involved
time-​keeping, or by uncharacteristically poor work performance.
needlestick injuries, mainly from contaminated hollow-​bore nee-
Effective management of occupational stress usually requires an
dles, or substantial blood contamination of damaged skin. Cases of
integrated approach which includes attention to both the workplace
HIV transmission from healthcare workers to patients are extremely
and the individual and should include intervention at the three fol-
rare, but hepatitis B is far more easily transmissible, explaining
lowing levels:
the higher incidence of outbreaks from doctor to patient and vice
• Primary intervention focuses on the identification of particular versa. Healthcare staff should be protected from hepatitis B by
sources of stress in the working environment and the institution vaccination, but this does not cover other hepatitis viruses. Other
of measures such as policies and procedures to eliminate or reduce occupational infections affecting staff in microbiological labora-
these. These should not be viewed solely as ill health prevention, tories and other healthcare workers include tuberculosis, salmon-
but as generally good management practices. ellosis, brucellosis, syphilis, and malaria.
• Secondary intervention focuses on improving the coping skills Working in tropical environments also exposes workers to the
of employees, including managers, by the use of specific forms risk of tropical diseases. Occupational and environmental infections
of stress management training (e.g. relaxation/mindfulness, con- involve a range of organisms from viruses, rickettsiae, bacteria, and
flict management, assertiveness, time management) and health fungi to larger organisms such as parasites and insects. Occupations
promotional activities. These are particularly appropriate where involved, together with the diseases involved, are forestry and
workplace stressors are intrinsic to the particular occupation, and gamekeeping (Lyme disease), sewage work (leptospirosis and some
therefore not removable (e.g. the potential for aggressive confron- viruses), and farming (bovine tuberculosis, Q fever, and brucel-
tation with members of the public). losis). Although rare in the United Kingdom, anthrax still occurs
 10.2.1 Occupational and environmental health 1647

worldwide and can be responsible for fatalities typically following Many materials have been used to manufacture gloves, including
exposure to infected hides or bones, or indirectly during work such cotton, leather, nylon, glass fibre, acrylonitrile, rubber, neoprene,
as construction on contaminated soil containing spores, where tan- butyl rubber, polyurethane, PVC, PVA, and tetrafluoroethylene.
ning or leather factories had once existed. These confer specific protection for defined occupational exposures
but the ingredients that go into their manufacture, for example ac-
celerating agents such as thiurams, might also be a cause of derma-
Occupational dermatoses titis through skin contact.
When cleaning skin, agents should be chosen that clean ad-
Since the skin offers such a large area to physical and chemical ex- equately in a short period of time without having too strong a
posures in the workplace, it is not surprising that skin damage is degreasing effect. Detergents or solvents if used for cleaning will re-
a common occupational disease. An occupational dermatosis is a move fat from the skin, thus damaging its integrity and exposing it
pathological condition of the skin for which occupational exposure to further insults. Frequent handwashing, so-​called wet work, can
can be shown to be a major contributory factor. have the same effect.
The two most common skin conditions caused by/​made worse No so-​called barrier cream actually provides a barrier to pene-
by work are irritant and allergic contact dermatitis (eczema), the ir- tration of substances into the skin. In fact, in some situations they
ritant form accounting for 95% of all dermatoses. In Great Britain may actually enhance penetration and, occasionally, sensitization
it is estimated that there are tens of thousands of new cases of oc- may occur to some of the constituents of the cream. There are many
cupational dermatitis seen by general practitioners (GP) each year, ‘after-​work’ creams, essentially moisturizers, which have the benefit
while some 2000 of the more serious cases are reported by derma- of increasing the hydration of the skin following cleaning at the end
tologists. The diagnosis and management of skin conditions in gen- of the day. They are of particular benefit in occupations where exces-
eral is covered elsewhere (Section 23) but some key facts are worth sive drying of the skin may occur. Their use should be encouraged
reiterating: following ‘wet work’ and where hot air dryers are used, as these tend
to dry the skin unduly (towels are preferred for hand drying).
•​ a very detailed chronological occupational and non​occupational
Besides occupational dermatitis, and skin cancers or other
exposure history is essential;
skin damage caused by actinic (UV) radiation, other dermatoses
•​ about one-​third of cases are thought to be allergic in origin; might arise from work. The more important are briefly listed in
•​ in many cases, although it will be easy to decide whether the Table 10.2.1.5.
dermatitis (eczema) is allergic or irritant, this distinction between
allergic and irritant can sometimes be difficult to make;
•​ dermatitis that was allergic in origin may be aggravated and sus-
tained by exposure to irritants at work and at home; Cardiovascular system
•​ atopic subjects are at increased risk of irritant dermatitis.
Cardiovascular disease is a major cause of mortality and morbidity
The best form of prevention of dermatoses is to eliminate the con- in industrialized countries (see Section 16). The association between
tact and/​or control exposure at source by applying the principles personal risk factors and cardiovascular disease is well known, but
described earlier. In industrial situations, the hands and forearms now the evidence is also growing of occupational and environmental
are most at risk. The use of proper gloves (along with gauntlets or influences.
arm bands to prevent powders entering under the cuff), coupled There is good evidence from the classical studies of bus drivers
with a high standard of hygiene, can minimize contact, and provide and conductors that sedentary workers have a higher risk of is-
adequate protection. Where there is moving machinery, wearing chaemic heart disease than those who are more active. There is
gloves can pose a potential danger. Also when gloves are used, they some evidence linking job stress and heart disease. The Whitehall
might be taken off for tasks requiring manual dexterity, with the re- II cohort studies suggest that (lack of) control over one’s job is an
sult that contaminated hands are placed back inside the gloves. important factor in determining subsequent risk of myocardial

Table 10.2.1.5 Benign occupational dermatoses, other than dermatitis

Urticaria Type 1 hypersensitivity reaction and may be associated with rhinitis, Glass and ceramic fibres, fibreglass, latex
asthma, and most importantly anaphylaxis. Itching, dermographism
Psoriasis Identical to psoriasis from other causes. Can mimic dermatitis of the At sites of injury or friction in manual workers
hands but without vesicles
Infections Bacterial Streptococcus to anthrax
Viral Poxvirus (Orf), human papilloma virus
Fungal Tinea pedis, cattle ringworm, chronic candida (in wet work)
Acne Typical acne features if slightly worse with multiple comedones, for Oil, coal tar, chlorphenols, halogenated aromatics
example
Vitiligo Areas of depigmentation often covering large areas of skin Para substituted phenols, and hydroquinones
Scleroderma Skin changes may also include lesions Vinyl chloride, trichloroethene
Pigmentation Altered pigmentation of skin Mercury and silver (argyria)
1648 SECTION 10 Environmental medicine, occupational medicine, and poisoning

infarction. Overall, the risk is reported to be increasing by the ex-

Gastrointestinal tract
posure to various chemical substances, noise, stress, and working
long hours and shift work.
Though ingestion is a means of entry for occupational and envir-
Exposure to chemicals in the workplace or general air pollution
onmental hazardous substances, and important when skin con-
can contribute to cardiovascular ill health in several ways: provoking
tamination is transferred to food or cigarettes, there are defence
inflammation; damage to vascular endothelium; inducing dysrhyth-
mechanisms that limit the damage to the gastrointestinal tract from
mias; renal effects and effects secondary to anoxia.
such pollutants, and minimize their absorption. The mucous lining
Among physical agents, vibration is known to cause peripheral
of the gut and diarrhoea and vomiting form part of these defence
vascular disease and acute high exposure to noise is known to raise
mechanisms. Acute gastroenteritis might follow the ingestion of
blood pressure. Workers on rotating shifts have an increased risk of
chemicals such as soluble salts of heavy metals.
ischaemic heart disease.
The liver is frequently at risk from occupational and environ-
mental exposures, as it is the target organ for detoxification and me-
tabolism of absorbed compounds. A wide variety of infectious and
Genitourinary system chemical agents cause different types of hepatocellular injury, which
can eventually lead to cirrhosis and liver failure, although there has
The kidneys play a crucial role in detoxification and excretion been a decline in developed countries through improved working
and, therefore, bear the brunt of many exposures to toxic chem- conditions, and a shrinking manufacturing industry.
icals. Some toxic substances reach the kidney unchanged, but
most are metabolized to some extent or other. Some, such as
cadmium, become sequestered in the renal cortex while others, Haemopoietic system
such as the carcinogenic aromatic amines or their metabolites,
can be present in the bladder long enough and at a high enough Lead poisoning is one of the oldest recognized occupational diseases
concentration to induce malignant change in the transitional cell and is still common, especially in the developing world. Exposures
epithelium. to inorganic lead are widespread, ranging from non​ ferrous
Sudden, severe exposures to some chemicals can cause acute smelting to the burning off of old paint during refurbishment/​
nephropathy. Such compounds may damage the kidney directly due renovation work in construction. In the domestic environment a
to their intrinsic nephrotoxicity or may induce secondary damage particular hazard is the ingestion, usually by children, of lead com-
due to prerenal effects, such as the haemolysis following arsine ex- pounds from old (now banned) paints. Lead causes anaemia mainly
posure, or oxalate crystals in the distal nephron after ethylene glycol by inhibiting the enzymes involved in haem synthesis and also by
poisoning. haemolysis. The metal binds to erythrocytes and determination of
The metals most commonly implicated in renal disease are so-​ blood lead levels is used in the monitoring of lead-​exposed workers.
called heavy metals, such as mercury, cadmium, and lead (see A diagnosis of lead poisoning is supported by symptoms of malaise,
Section 21). Mercury exposure resulting in acute tubular necrosis colic, and constipation, signs of anaemia, and peripheral motor
or the nephrotic syndrome is most unusual these days at least in neuropathy (rare, usually only in severe cases), and microscopic
the Western world. Similarly, modern industrial exposures to cad- evidence in the erythrocytes of basophilic stippling (from abnormal
mium rarely result in the proximal or distal tubular dysfunction haemoglobin), elevated blood lead, low haemoglobin, raised free
or renal cortical damage that was more prevalent in the past. Lead erythrocyte protoporphyrin, and raised urinary δ-​aminolaevulinic
nephropathy is also a rarity nowadays, but was not uncommon in acid. Indications of excessive lead absorption should lead to re-
the early part of this century. Lead is capable of causing damage to moval of the affected worker from further occupational exposure,
all parts of the nephron. Subtle tests of renal enzymes are needed to with full investigation into, and control of, the circumstances of ex-
assess the effects of ‘heavy metal’ exposure on the kidney. posure to lead at work.
Chlorinated aliphatic solvents such as carbon tetrachloride Haemolysis and subsequent anaemia can follow occupational
and chloroform can cause a hepato-​renal syndrome. The renal exposure to ionizing radiation in the industrial use of radioactive
damage is largely an effect on the proximal tubular epithelium sources to test the integrity of welds, in the healthcare industry, and
which can lead to tubular necrosis and acute oliguric renal in nuclear power stations, as well as from chemical exposures (such
failure. The weight of evidence from case–​control studies of as to arsine).
workers exposed to solvents suggests an excess risk of chronic Benzene is encountered in the petroleum industry, and is used
proliferative glomerulonephritis. The mechanism is unclear, but as a starter chemical for the production of other aromatic organic
the demonstration of antiglomerular basement membrane anti- compounds. Its serious effects on the haemopoietic system include
body suggests possible autoimmune damage to the glomerular aplastic anaemia, leukaemia, and probably multiple myeloma.
basement membrane. Methaemoglobinaemia can result from exposure to occupational
Although the prostate possesses the curious ability to concen- and environmental agents such as nitrates, and nitro and amino
trate (and excrete) heavy metals, inconsistent evidence exists of oc- derivatives of aromatic compounds. Specific examples are aniline,
cupationally related prostatic disease. Cancers of the urinary tract aminobenzene, nitrobenzene, and nitrates in drinking water (from
associated with occupational exposure to aromatic amines and soil leachate). Babies are particularly susceptible to this. It is treated
polycyclic aromatic hydrocarbons were described earlier. by the intravenous administration of methylene blue.
 10.2.1 Occupational and environmental health 1649

Table 10.2.1.6 Some central nervous system health effects caused

Reproductive system by workplace or other environmental toxins

Children can be affected by parental exposure to physical and Disorders Manifestations Causal agent
chemical hazards. More recently, there has been much concern Acute intoxication Light-​headedness Carbon monoxide
that various organic environmental contaminants ranging from Loss of consciousness Organic solvents
pesticides to phthalates and other plasticizers, and compounds
Death (rare) Organophosphates
with oestrogenic properties might cause reproductive harm to the
community. In men there are indications that exposure to these Organic affective Fatigue Organic solvents
syndrome
‘endocrine disrupters’ has resulted in falling sperm counts, and an Irritability Lead
increased incidence of hypospadias and testicular cancer. Depression Mercury
Risk of adverse effects on human reproduction can include re- Chronic toxic Impaired neurobehavioural Organic solvents
duced fertility, spontaneous abortion, low birth weight, and child encephalopathy function (symptoms as
Lead (usually
­development disorders. In the United Kingdom, for example, new described)
organometallic)
and expectant parents make up a significant percentage of the work- Psychosis Marked emotional Carbon disulphide
force. It is estimated that there are some 350 000 pregnant, working instability
Manganese
women in any one year in the United Kingdom. Consistent evidence
Mercury
supports that work exposures to some chemical, biological, and
physical hazards, and certain working conditions and some occu- Toluene and related
solvents
pations have the potential to adversely affect reproductive health.
Several potential risk factors have been identified: exposure to Parkinsonian Tremor, rigidity, akinesia Manganese
syndrome
chemicals (heavy metals, solvents, pesticides), radiation, local heat Carbon disulphide
affecting sperm count and quality, having a heavy physical workload, Carbon monoxide
and working irregular work schedules. Rubella can be a problem Visual disturbance Impaired acuity or n-​Hexane
particularly for female healthcare workers and those working in peripheral field defect
Methanol
microbiological laboratories, especially if adequate procedures are
Organic mercury
not in place for occupational health screening and immunization of
this occupational group. Colour vision loss Organic solvents
Cerebellar or other Ataxic gait Acrylamide
damage
Organochlorine
insecticides
Neurological disorders
Methyl mercury
Damage to the central nervous system can be caused by a wide Seizures Lead (usually organic)
range of occupational or other environmental toxins, besides sub- Organic mercury
stances of abuse such as ethanol and other solvents. There is very Organochlorine
good evidence that exposure to lead (even at low level by occupa- insecticides
tional standards), usually through drinking water but possibly also Organotin compounds
through inhalation, contributes to cognitive deficiency in children.
Exposure to chemicals including lead, primarily encountered by
workers in manufacturing, construction, and agricultural jobs, can occasionally in the environment. This syndrome, chronic toxic
cause transient and persistent effects on the central nervous system encephalopathy, consisting primarily of memory impairment, im-
(Table 10.2.1.6). Transient central nervous system dysfunction is paired psychomotor function, and mood disorders, has been seen
most commonly caused by exposure to volatile organic solvents, to following chronic exposure to lead, styrene, carbon monoxide,
organophosphate insecticides, or to carbon monoxide. Many low and certain organic solvents. In more severe cases the deficits per-
molecular weight fat-​soluble organic solvents, especially if chlor- sist, but do not progress, following cessation of exposure. If be-
inated, are chemically very similar to the halogen-​substituted an- havioural symptoms are present without evidence of abnormal
aesthetic gases, and it is not surprising that they also have similar neurobehavioural test performances (i.e. organic affective syn-
biological effects. In each instance, these substances, acting through drome) reversal of these manifestations usually occurs following
different mechanisms, might cause central nervous system dys- cessation of exposure. Other rare central nervous system effects in-
function ranging from acute intoxication manifested by light-​ clude a Parkinsonian syndrome which might be a consequence of
headedness and dizziness to loss of consciousness and even death. toxic exposures to manganese.
Persistent central nervous system sequelae can occur following one Exposure to a range of toxic agents can cause damage to the per-
exposure episode if exposure levels are high and the duration of ex- ipheral nervous system causing either motor or sensorimotor poly-
posure is prolonged. neuropathy (Table 10.2.1.7). Less commonly nowadays, exposure
Persistent central nervous system dysfunction, manifesting as to lead at high levels for long periods can cause upper-​extremity
neurobehavioural performance deficits, has been reported, par- motor neuropathy, consisting of wrist extension weakness or wrist
ticularly in painters, following chronic exposure to moderate con- drop. Other specific substances (e.g. acrylamide, n-​hexacarbon ali-
centrations of various agents encountered in the workplace, and phatic solvents, and certain organophosphorus compounds) can
1650 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Table 10.2.1.7 Peripheral nervous system syndromes caused in many workplaces has been shown to be related to the presence of
by workplace or other environmental toxins psychosocial hazards. Important elements are health beliefs and atti-
tudes of the individual as well as the social and cultural environment.
Disorders Manifestation Causal agent
These influence their response to real or perceived exposure to haz-
Motor Wrist weakness, Lead
neuropathy foot drop
ards by determining their selection of which information to attend
to and their subsequent interpretation of that information. Specific
Mixed Symmetrical distal Acrylamide
sensorimotor sensory loss, mild examples of syndromes with these features which occur in both an
Arsenic occupational and wider community setting may be ‘multiple chem-
neuropathy motor dysfunction
Carbon disulphide ical sensitivity’ and ‘chronic fatigue syndrome’. Current approaches to
Carbon monoxide effective management of these and other similar conditions favour a
DDT ‘biopsychosocial’ approach, which rejects the artificial distinction be-
tween a physically and a psychologically based complaint and treats
n-​Hexane
both physical and psychological symptoms simultaneously.
Methyl n-​butyl ketone
Mercury
Organophosphorus compounds Compensation for occupational diseases
(various agents including
triorthocresyl phosphate)
Worker compensation, or the financial recompense for harm done
Thallium
to an individual by work or workplace, can be for an injury or a dis-
ease and might be difficult to secure even in the 21st century. In
the so-​called ‘first-​world’ nations (i.e. the industrialized society), a
act as axonal toxins causing a mixed sensorimotor polyneuropathy worker can receive compensation prescribed by the state, or through
manifesting the asymmetrical, distal sensory loss. litigation in the civil courts.
By the end of the 19th century, many nations in Europe and the
United States had passed workman’s compensation laws of one sort
Occupational disease caused by vibration or noise or another. Such schemes were usually restricted to specified diseases
or occupations. The United Kingdom, for example, has the Industrial
Certain jobs involving the use of vibrating hand tools or pneumatic Injuries Benefit Scheme by which, depending on the disease in ques-
drills may be responsible for the occurrence of peripheral neur- tion (from the list of Prescribed Disease) and the diagnosed degree
opathy, and loss of motor function if progressive, as part of ‘hand–​ of disability, compensation is paid by the state. There are over 70
arm vibration syndrome’ (HAVS). These disorders arise from a Prescribed Diseases known to be a risk to health from certain jobs,
combination of physical trauma to the nerve itself as well as damage and in 2011, figures from the Department of Work and pensions,
to blood vessels. Some workers with HAVS suffer adverse effects on United Kingdom, confirm 5920 cases of occupational diseases as
hand function and are no longer fit for work. being compensated, with pneumoconiosis, diffuse mesothelioma, and
Noise-​induced hearing loss is discussed in Chapter 10.3.4. osteoarthritis as the three most common diseases.
The principles underlying such statutory compensation schemes
are that they should be ‘no fault’, that the disease should be, with
Respiratory disorders reasonable certainty, caused by work, and that the benefit claimed
should offset job loss, wage-​earning deficit, and disability, or pro-
The respiratory tract is, in many occupations, the most important vide death benefit to the next of kin. Advice on proposed additions
route of exposure to hazardous substances. In many instances of oc- to the list of compensable diseases is made in the member states by
cupational diseases, it is the target organ. These conditions are dealt government-​appointed advisory groups. In the United Kingdom,
with in Section 18. this group is the Industrial Injuries Advisory Council, which reports
to the Secretary of State for the Department of Work and Pensions.
It is important that clinicians are aware of such schemes. If the
Medically unexplained symptoms disease and work exposure seem related, and are scheduled, patients
should be advised to claim for compensation. If the disease and/​or
A growing number of occupational health complaints are charac- work exposure are not scheduled, there may still be a case worthy of
terized by the lack of a firm diagnosis or a clear occupational causal pursuit under common law.
pathway. These include, in particular, complaints that consist of a
range of non​specific symptoms, typically headache, fatigue, nausea,
depressed mood, cognitive confusion, and sometimes eye and nasal Occupational health services
irritations. They are reported in diverse situations such as in air-​
conditioned offices with poor control (accounting for many cases of The notion that employers should provide healthcare for workers
‘sick building syndrome’), proximity to low-​frequency electromagnetic is hardly new and the role of the physician in caring for, as well as
fields, and perceived exposure to very low (often undetectable) levels advising on, diseases caused by work has been mentioned and goes
of chemicals. Moreover, the prevalence of musculoskeletal complaints back into the history of occupational medicine.
 10.2.1 Occupational and environmental health 1651

The first recognizable occupational health service in England in the form of ‘regulations’, requiring action from employers in par-
began in the mid-​18th century when the London (Quaker) Lead ticular occupational and environmental circumstances.
Company recognized the adverse effect of lead mining on workers In the developing world occupational and environmental health
and provided health and welfare services in north-​west England. often remains an almost unknown concept. National governments
Since then, occupational health provision has expanded along dif- in the developed world have approached the question of preventing
ferent lines in different countries. ill health at work in different ways, with the European Union’s dir-
Around the world, most people in work do not have access to an ectives increasingly dominating the scene in Europe. The EU dir-
occupational health service nor an occupational physician, and is ectives increasingly drive the occupational health and safety agenda
this despite the International Labour Organization’s recommenda- in member states, requiring them to adopt these principles and
tions, in 1985, under ILO Convention 161, for its members ‘to de- then modify or create national legislation in response. The EU phil-
velop progressively occupational health services for all workers’ and osophy has been to encourage the delivery of occupational health
that ‘The provision made should be adequate and appropriate to the to all by ‘competent’ persons, although the mode of delivery, even
specific needs of the undertaking’. the definition of competent, has been left to member states to inter-
In the United Kingdom, approximately one in 14 consultations pret. Most important, the level of service provided should be based
with a GP by those of working age are for conditions due to work on a thorough risk assessment of the work processes in that organ-
or that affects ability to work. GPs and secondary care specialists ization and a clear and logical procedure of risk management. To
in hospitals where these patients are sometimes referred therefore deliver even such a basic service requires multidisciplinary teams
need to think of work as a possible cause of ill health and ill health including trained physicians, hygienists, and nurses. Few com-
as a barrier to work. Both primary and secondary care physicians panies have such services, and many are too small even to contem-
need to communicate freely with occupational physicians and occu- plate such provision.
pational health services if these exist in their patients’ places of work Future development of occupational health services might de-
in order to keep their patients happy, healthy and in work for as long pend primarily on the economic climate, but also on perceptions of
as possible or to return them to work after an illness as quickly as the what constitutes occupationally mediated disease, as well as political
medical evidence justifies. will. Perversely, an exponential rise in legal action, insurance costs,
In practice, delivery of good occupational and environmental and compensation may also play a significant part in persuading
health practice is a multidisciplinary approach. It might include employers, and even nations, that competent occupational health
physicians, nurses, or hygienists who monitor and control exposure services are an absolute requirement of profitable organizations. If
to chemical, physical, and biological agents in the workplace; tox- this is to encompass small and medium-​sized enterprises, provi-
icologists; ergonomists; and psychologists able to assess psycho- sion must come either from larger employers (such as the National
social aspects of work. These specialists will promote occupational Health Service) or from private providers.
health, but for long-​term success that is sustained, it is crucial that
both managers and the workforce consider it an integral part of their
working practices and philosophy. Conclusion
Unfortunately, occupational health services are not available
universally and interpretation of the requirements varies greatly Clinicians can make important contributions in two ways to ‘occu-
between countries and employment sectors. Initially, most services pational health’ and hence to the health and economic well-​being
arose from a mixture of philanthropy and self-​interest; the theory of their patients and others. In the first instance they should have
being that the healthy worker was likely to be more productive, a high index of suspicion for occupational (and environmental)
a concept that holds sway today. Present-​day services range from causes of disease in their patients. These can manifest to physicians
total healthcare including primary care and hospital medicine (as in any specialty. Having reached a clinical diagnosis, especially in the
in some large multinationals operating in developing countries), case of work-​related ill health, they need to liaise with an occupa-
to outsourced independent occupational health services. Services tional physician or other occupational health professional, the rele-
in the United States of America and much of Europe might in- vant enforcing authority, or the employer directly so as to remove
clude general health promotion and education, but much inequity their patient from the harmful ‘exposure’ and to control exposure
in healthcare exists even between enterprises within the same to prevent similar occurrence in the patient and in other workers.
country. Secondly, whether or not the ill health is work related, the clinician
Recent increase in the provision of occupational health services has has an important role in giving advice about return to work and
followed the enactment of effective health and safety legislation (e.g. achieving occupational rehabilitation.
the Health and Safety at Work etc. Act (1974) in the United Kingdom). However, the delivery of ‘occupational health’ and of ‘environ-
Some countries, such as the Nordic countries, the Netherlands, and mental health’ is achieved through more than just a clinical ap-
Australia, require the provision of occupational health services by proach. Occupational health is concerned with managing the health
law. Statutory provision of such services in the United Kingdom of working people. While occupational physicians deal with the ef-
and the United States is limited to particular industrial sectors and fects of work on health, and the influence of health on work, other
specific occupational exposures, such as ionizing radiation, heavy professional groups, including nurses, hygienists, toxicologists,
metals, asbestos, and carcinogens. In general, primary legislation psychologists, and safety engineers, also have important roles to play
such as that produced in the United Kingdom then ‘enable’ a variety in keeping people healthy and at work. In common with other prob-
of government departments to create further secondary legislation lems in public health, the solutions mainly lie in a population based
1652 SECTION 10 Environmental medicine, occupational medicine, and poisoning

and societal approach to achieve health promotion and protection,

as well as ill health prevention. The strongest link to public health 10.2.2 Occupational safety
exist when work and the workplace (as well as the home, school, and
other environments) are used as a setting to promote good environ- Lawrence Waterman
mental standards, personal health, and healthy behaviours so as to
bring about the highest state of ‘well-​being’ for individuals, whether
in the working population or not. ESSENTIALS
Any approach to occupational health must acknowledge that acci-
dents in the workplace result in many injuries. Construction, agricul-
FURTHER READING ture, and primary extraction provide the main worksites for fatalities
Adisesh A, et al. (2013). Review: UK standard of care for occupa- and serious injuries, but many more minor injuries result from all
tional contact dermatitis and occupational contact urticaria. Br J types of work. Health and safety law has developed with an emphasis
Dermatol, 168, 1167–​75. on accident prevention that is based on designing and managing the
Agius R, Seaton A (2006). Practical occupational medicine, 2nd edition. working environment by:
Hodder Arnold, London.
Baroushi B (1993). Effects of the workplace on fertility and related (1) defining appropriate processes and work practices that are safe;
reproductive outcomes. Environ Health Perspect, 101 (Suppl. 2), (2) ensuring that the workplace and work equipment are suitable for
81–​90. the work to be undertaken;
Baxter PJ, et al. (2010). Hunter’s diseases of occupations, 10th edition. (3) developing and maintaining a health and safety culture, including
CRC Press, Boca Raton, FL. mechanisms to influence behaviour, so that everyone is focused
Burton AK, Bastys S, Wright IA, Main OJ (2005). Obstacles to recovery on the best and safest way to do their work.
from musculoskeletal disorders in industry, research report 323.
Establishing this approach to safety management begins with an
Health and Safety Executive (UK), London.
organization committing itself to a policy influenced by legal obli-
Cartwright S, Cooper CL (1997). Managing workplace stress. Sage
Publishing, Thousand Oaks, CA. gations and current good practice, such as the developing standards
Dick FD (2006). Solvent neurotoxicity. Occup Environ Med, 63, 221–​6. for corporate governance of risks and public reporting. Management
Grandjean P, Landrigan PJ (2006). Review: developmental neurotox- systems based on the formula ‘Plan–​Do–​Check–​Act’ are central to
icity of industrial chemicals. Lancet, 368, 2167–​78. accident prevention, with detailed decisions driven by risk assess-
Health and Safety Executive (UK) (2017/2018). Health and safety sta- ments. Risk assessments are formed when the hazards associated
tistics: annual report for Great Britain (2016/​17). http://​www.hse.gov. with the work are identified; that is, the potential for harm, and the
uk/​statistics likelihood, severity, and impact of that harm is assessed. This forms
International Labour Organization (ILO) (2013). The prevention of oc- the basis for defining precautions and mitigations to minimize likeli-
cupational diseases. http://​www.ilo.org/​wcmsp5/​groups/​public/​-​-​-​ hood and impact, in proportion to the degree of risk.
ed_​protect/​-​-​-​protrav/​-​-​-​safework/​documents/​publication/​wcms_​ A key ingredient to safety is genuine worker engagement, going
208226.pdf beyond the legal obligations for consultation. Organizations can im-
Langan-​Fox J, Cooper CL (eds) (2011). Handbook of stress in the occu-
prove their safety culture when they recognize that this is the product
pations. Edward Elgar, Cheltenham.
of individual and group values, attitudes, competence, and patterns of
Palmer KT, Brown I, Hobson J (2013). Fitness for work: the medical
behaviour that determine the commitment to, and the style and pro-
aspects, 5th edition. Oxford University Press, Oxford.
Rushton L, et al. (2012). Occupational cancer burden in Great Britain. ficiency of, their safety programmes. A positive culture requires appro-
Br J Cancer, 107, S3–​7. priate leadership, including genuine commitment of the most senior
Sithamparanadarajah R (2008). Controlling skin exposure to chemi- manager(s) in the organization, and an appropriate emphasis on com-
cals and wet-​work: a practical book. RMS Publishing, Stourbridge. petence, such that the right people, trained and skilled, are doing the
https://​www.personneltoday.com/​hr/​controlling-​skin-​exposure-​to-​ right job in the right way, with their supervisors and managers having
chemicals-​and-​wet-​work-​a-​practical-​book/​ ready access to competent health and safety advice when required.
Snashall D, Patel D (eds) (2013). ABC of occupational and envi- These basic concepts hold true in whichever country you are
ronmental medicine (ABC series), 3rd edition. Wiley-​ Blackwell, working. While this chapter draws heavily on the UK situation, where
Chichester. there has been considerable experience and development of ap-
Stellman JM (ed) (1998). Encyclopaedia of occupational health and proaches to health and safety, it is incumbent on any physician to
safety (vol.2—​Hazards), 4th edition. International Labour Office, consider the work environment and whether changes to the work-
Geneva.
place might improve not only the lot of their patients but others po-
Venables K (2013). Current topics in occupational epidemiology. Oxford
tentially at risk in the workplace.
University Press, Oxford.
Waddell G, Burton AK (2000). Occupational health guidelines for the
management of low back pain at work: evidence review. Occup Med
(Lond), 51, 124–​35.
Waddell G, Burton AK (2006). Is work good for your health and well-​ Introduction
being? TSO, London.
White RF, Proctor SP (1997). Review: solvents and neurotoxicity. Accidents, sometimes fatal, are an important cause of illness and harm
Lancet, 349, 1239–​43. to health at work. In 1995, the World Health Organization estimated
that every year, worldwide, there were approximately 120 million
 10.2.2 Occupational safety 1653

century onwards seemed to reflect Parliament’s desire to take action

only after a tragedy had happened. As industrial hazards were re-
1 Major vealed by research or major accidents, regulators conducted a form
of risk assessment and prescribed general control measures. As a re-
20 Minor
sult, many different and highly specific sets of regulations ended up
Property on the statute book, with overarching acts, such as the Factories Acts
30
damage imposing general duties applicable only to defined workplaces, such
600 Near miss as factories, workshops, offices, shops, and railway premises. The
1802 Health and Morals of Apprentices Act and subsequent legisla-
Fig. 10.2.2.1 Accident triangle developed by Frank Bird. tion were crucial in driving workplace controls. Many workers were
excluded but it was estimated that the 1974 Health and Safety at Work
accidents leading to 20 000 fatalities. In 2014, the International Labour Act brought up to 5 million workers within the ambit of the law.
Organization estimated that of 2.33 millions deaths from occupa- In the United Kingdom after the First World War, there were de-
tional accidents and work-related illness, 13.7% or 380 500 were due velopments outside legislation. The cooperative movement grew
to accidents (Reference: Global Estimates of Occupational Accidents into a major developer of social commerce, and other organizations,
and Work-Related Illnesses 2017, Paivi Hamalainen, Jukka Takala, such as the children’s organization Woodcraft Folk, were founded
Tan Boon Kiat, WSH Institute Singapore for the ILO, 2017). China, on ideas of social improvement. The public began to demand better
whose workforce is expanding quickly through rapid industrializa- management of industrial safety, both for moral and economic
tion, reported a rise in fatal accidents from 73 500 in 1998 to 80 000 reasons. The British Industrial Safety First Movement, later the
in 2010. According to official data the reported Chinese fatal accident Royal Society for the Prevention of Accidents (RoSPA), promoted
rate was 21 times that for the United Kingdom. In industries with a accident prevention through committees, workers’ participation,
poor safety record, such as mineral extraction and agriculture, the toll the employment of safety officers, joint accident investigations, and
of accidental injuries is matched or exceeded by the numbers made the promotion of positive attitudes.
ill by exposure to health risks. It is therefore appropriate to give ser- Enlightened industrial management that recognized the cost
ious consideration to the risks of both accidents and illnesses at work. of accidental losses, legal obligations, and voluntary efforts based
Accidents at work occur under varying circumstances. Globally, and on worker engagement and morality was summarized in the 1972
in the United Kingdom, the largest group of accidents and fatalities Robens Report, which formed the basis for the Health and Safety at
occur in the construction industry. Worldwide, one in six fatal work- Work Act 1974. Risk assessment, initially implicit, was later made
place accidents occurs on a construction site. However, in the United an explicit requirement. Worker engagement, through safety rep-
Kingdom in 2017/18, 24% of all such fatalities were associated with resentatives and worker/​management committees (at least in the
construction work with approximately 7% of the workforce, the higher minority of British workplaces with recognized trades unions),
proportion reflecting economic development away from traditionally was a new element. However, law always seemed to lag behind in-
hazardous industries such as heavy engineering and mining. But ser- dustrial developments. The 1974 Act established the Health and
ious accidents continue to occur: fires and explosions in chemical pro- Safety Commission and the Health and Safety Executive not only
cess plants, transportation disasters, and entanglement in machinery. to be custodians, developers, and enforcers of the law, but also to
Most accidents involve everyday events such as slips, trips, and hand-​ be responsible for identifying and disseminating good practice.
tool injuries that most commonly result in only minor injuries. Although many people accept the need for both enforcement and
Research since the 1950s has demonstrated that in any organiza- encouragement in dealing with enlightened and obstinate employers,
tion, many minor accidents occur for every serious one. This was some call for more prosecutions of companies and individual dir-
developed into a strategy for preventing accidental losses, both fi- ectors. Employers are no longer expected to adhere slavishly to sets
nancial and human, based on the concept of accident triangles of statutory rules, but to develop their own safety organization and
illustrating the relationship between minor events and serious ac- arrangements following good practice. It is now recognized that
cidents (Fig. 10.2.2.1). Despite the diversity of accidents and their safety is a key challenge to be addressed by management.
outcomes, their causes, and the underlying principles of safety man- Other events have influenced organizations’ approach to risk.
agement for their prevention are common to all accidents, and to the Financial scandals (Polly Peck, Mirror Group Newspapers) led
control of other health hazards at work. The three elements of safety to reports from committees chaired by Cadbury (on preventing
management are designed to address: malpractice), Greenbury (on the role of directors), and Hampel
• working environment—​ encompassing physical arrangements, (outlining good governance) that laid the foundations for Turnbull
equipment, materials, and the environment in which they are used and changes in the rules applying to publicly listed companies in the
• working processes and practices—​the way in which the work is United Kingdom. Management of risk and safety are essential com-
expected to be carried out, often embodied in written standard ponents of good corporate governance both in the public and vol-
operating procedures untary sectors. While these formal risk management requirements
were being developed, corporate social responsibility was maturing
• culture and behaviour—​the human element, that takes the work-
through the formulation of the Global Reporting Initiative and local
place and the procedures and brings them to life, summed up as
ventures such as corporate social responsibility indices, the launch
‘this is the way we do things around here’
of FTSE4Good, and ethical investment organizations. Their impact
In order to address these elements, employers have increasingly should not be underestimated. The history of companies such as
been encouraged to develop formal management systems. The key Railtrack, where major accidents led to loss of control, should re-
mechanism adopted for ‘encouragement’ has been the development mind directors that they are expected to govern in order to protect
of occupational health and safety law. British law from the mid-​19th the public, the organization, and its shareholders from such disasters.
1654 SECTION 10 Environmental medicine, occupational medicine, and poisoning

includes identifying accident risks inherent in the workplace and

The size of the problem
the work, assessing their significance and determining suitable pre-
cautions. There is a hierarchy of such controls, promulgated across
During the year 2014/​15, some 142 workers, employees, and self-​
the European Union in the Framework Directive, which targets
employed, were killed at work in the United Kingdom. This reflects both
protection of the whole group of exposed people rather than per-
effective accident reduction and a dramatic change in economic activity;
sonal protection:
there are now many more people working in call centres than in mining.
Numbers of non​ fatal accidents are less certain, because of • Elimination—​selection and design of facilities, equipment, and
underreporting. In the period 2014/​15 61 100 workers reported in- processes to prevent exposure to an identified risk. For example,
juries through the self-​reporting schemes that the Health and Safety fitting a long-​life plastic sign may avoid the need to repaint a
Executive uses to record injuries. According to figures recorded high board.
through Reporting of Injuries, Diseases and Dangerous Occurrences • Minimization—​ reducing risk. For example, selecting a less-​
Regulations 2013 (RIDDOR) 76 054 nonfatal injuries occurred in hazardous material, redesigning a tool, or replacing baskets
UK workplaces. Slipping and tripping are responsible for the largest and belts on a conveyor with softer, more resilient materials to
group of major injuries, almost three times the numbers of injuries reduce noise.
from moving machinery/​objects, from falls, or from direct handling. • Personal protection—​as a last resort, selecting methods of work
Statistics show that many employees suffer from mental ill health, and personal protective equipment so that the exposed workers
followed by musculoskeletal disorders. However, an individual’s per- are protected to some extent.
ception of what level of incapacity forces them to be absent from work
is clearly influenced by their mental state. The nature of the injuries Risk assessment is a critical activity. It requires a degree of know-
received and the process of rehabilitation and return to work are ledge and understanding of the work itself and of the principles
clearly important, but the safety practitioner is interested primarily of safety management. This means that in practice it is often best
in methods of prevention embodied in safety management systems conducted by a team made up of workers, managers, and safety
and the associated work to develop and maintain the safety culture. practitioners.

Safety management Monitoring performance

Accident prevention requires a safe working environment and suit- Residual risks that cannot be wholly eliminated require moni-
able equipment combined with safe behaviour by the workforce, toring. Key performance indicators may be used to explore
including the avoidance of error, by those doing hazardous work. training courses, supervisory inspections, and accident frequency
Most practical accident prevention involves physical safeguards or rates. Accident frequency rates are typically related to workers’
safety rules designed to prevent recurrence of unsafe conditions or hours (i.e. accidents per 100 000 h worked), allowing compari-
acts that have already led to accidents. Similarly, occupational hy- sons between different-​sized workplaces and workforces. Active
gienists anticipate, recognize, assess, and control hazards to health monitoring of key performance indicators is supplemented with
at work. Accidents usually result from a chain of connected events. reactive monitoring (accident investigations) to determine imme-
Effective safety management addresses the physical conditions, the diate and underlying causes of failure.
work processes, and the human behaviour that have combined to
cause harm and conversely could prevent harm.
Modern safety management is based on risk assessment and the Audit and review
definition and implementation of methods for preventing harm.
Good organizations learn from their experiences, and apply the
lessons. Regular audits check that safety policies are being imple-
Policy—​organizational commitment mented, that people are discharging their responsibilities, and pro-
cedures for safe working are documented and followed. Reviews are
Effective health and safety policies set out a clear direction for the more searching and make comparisons with other organizations.
organization, indicating what is expected of managers and workers. They ask the challenging question, ‘Are we doing the right or best
This may represent no more than a commitment to formal, min- things?’ These processes contribute to an organization’s ability to
imum legal compliance but most bodies express themselves more communicate to its stakeholders inside and outside the organiza-
in the manner of a mission statement. For example, Marks & tion, for example in the annual report. There are three types of cor-
Spencer is ‘committed to ensure the health, safety, and well-​being porate report on health and safety:
of all its employees, customers and others who visit or work on our
premises’. The policy is an opportunity clearly to state the responsi- • minimal reports on injuries and ill health, days lost, comparison
bilities and arrangements for delivering what is promised. with national or sector targets, and information on events such as
awards and/​or convictions
• comprehensive reports with statistics, trend analysis against per-
Planning formance indicators, director workplace visits, health and safety
training days, inspections and audits, emergency drills, and so on
The foundation of safety management is planning: to create the • verified reports (i.e. comprehensive reports that have been re-
right physical conditions and shape the activities undertaken. This viewed externally)
 10.2.2 Occupational safety 1655

Designer to ensure safety management is a fundamental approach

Safety management and safety culture
to construction projects. The Health and Safety Executive has re-
vised its guidance on safety management by updating the HSG
The effort to create and maintain a physically suitable workplace
65 Successful Health and Safety Management model. This revised
and equipment, and implement documented safe working prac-
model has a modernized approach that aligns more closely with
tices, will be effective only if it is matched by the engagement of
the principles of Plan–​Do–​Check–​Act which was laid out in the
the whole workforce from director to shop floor. A healthy and
management standard OHSAS 18001, now superseded by ISO
safe culture is one in which the members of the organization:
45001 management standard, published in 2018 and now used to
• understand and respect the hazards of their operations evaluate, certify, and accredit management systems worldwide.
• are alert to the many ways in which safe working systems may be The new standard is much more explicit and proscriptive about the
breached or bypassed leadership that organization are required to demonstrate and the
• are committed to maintaining safe working evidence auditors will seek to be satisfied. The standard is written
• honestly report problems and opportunities for improvement to align with recently updated management standards ISO 9001
Quality Management Systems and ISO 14001 Environmental
A key ingredient is real worker engagement, going beyond the Management. All of these new standards have stricter require-
legal obligations to consult. Organizations can progress when ments for organizations to demonstrate leadership to bring about
they recognize that their safety culture is the product of indi- changes and improvements in performance. Additionally, in the
vidual and group values, attitudes, competencies, and patterns of United Kingdom the Health and Safety Executive has published
behaviour that determine the commitment to, and the style and guidance aimed at small to medium-​sized enterprises, and cre-
proficiency of their safety programmes. Those with a positive ated a self-​assessment tool to establish what leadership activity is
culture communicate on a basis of mutual trust, share percep- in practice while identifying opportunities to improve leadership
tions of the importance of safety, and are confident in the efficacy performance.
of preventive measures. This becomes possible only when there
is appropriate leadership, including the commitment of the chief
executive. Cost recovery and sentencing guidelines
As an example, the strategy adopted by the Olympic Delivery In light of government reviews to reduce the administrative burden
Authority for the planning and construction of venues, test events, of health and safety on employers, many pieces of UK legislation
and infrastructure for the London 2012 Games, the 2–​4–​1 approach, have been repealed, amended, and updated to ease bureaucracy, re-
has allowed time to establish the right culture. The staff were com- move unnecessary red-​tape, and reduce costs. Changes to accident
mitted to weaving safe design and construction into all components reporting regulations (RIDDOR) brought in a change in threshold
of London 2012 and its legacy for east London and United Kingdom for when an employer must report injuries resulting in lost time
as a whole. This was made clear to all the contractors and other sup- from over 3 days to over 7 days. In addition, it was concluded that
pliers involved in this project. the cost burden for investigating and enforcing material breaches of
health and safety legislation should be borne by the employer at fault
and not the taxpayer. This has led to the Health and Safety (Fees)
Competence Regulations 2012 and the introduction of Fees for Intervention.
Under these arrangements, HSE can charge employers, based on an
Training is an essential part of any company’s safety arrangements. hourly rate of around £127 to recover costs associated with inves-
How well people have been trained to do what is required, from tigation, research, consultation with specialist advisors, and subse-
working safely to reporting problems, will influence the risks in the quent enforcement action where there has been a material breach of
working environment. legislation.
Competence is not purely defined by training and qualifications, Another major change to the enforcement process has been the
but by the additional skills, knowledge, and experience of individ- publication in 2016 of revised sentencing guidelines in for health and
uals in the workplace. The definition of competence has been up- safety offences, which has led to a significant increase in the financial
dated in the Construction (Design and Management) Regulations penalties levied on larger organisations—for example in 2017 Laing
2015 reflecting this approach. O’Rourke was fined £3.8m following a fatal accident, and Warburtons
the bakers £1.9m following an entrapment accident that resulted in
severe friction burns requiring skin grafts for the worker involved.
Current issues Prior to these changes, fines and custodial sentences were limited by
fairly low thresholds. Furthermore, sentences were more likely to be
Leadership based on the outcome of a breach in legislation. However, the Health
There has been an increasing drive to promote strong leadership and Safety at Work Act 1974 is based on risk of exposure and so the
within organizations, to continually improve safety and health risk new sentencing guidelines reflect this, as the sentence issued should
management performance. This is reflected in various activities. be based on the ‘harm risked’. The inflationary factors that can lead
The Institute of Directors published guidance on safety leadership to significantly increased fines and custodial sentences include culp-
aimed at those holding senior corporate positions. Furthermore, ability for an organization or individuals, harm risked, number of
there have been legal developments such as the Construction people exposed, and the financial turnover of the organization. This
(Design and Management) Regulations 2015 that have put a greater can lead to fines in the millions of pounds for large organizations
emphasis on the duties held by a client and new role of Principal and a shift from a typical six-​month custodial sentence to a possible
1656 SECTION 10 Environmental medicine, occupational medicine, and poisoning

18 months imprisonment. Although the Health and Safety at Work

Act 1974 has remained unchanged in this time, the new guidelines FURTHER READING
represent the most significant legal impact in the last 40 years. Bird FE, Germain GL (1966). Damage control (a new horizon in ac-
cident prevention and cost improvement). American Management
The changing world of work Associations, New York, NY.
An ageing working population, equality and diversity, and flex- British Safety Council and Robertson Cooper (2018). Future risk: The
ible working (sometimes referred to as the “gig economy” in which impact of work on health, safety and well-being. London.
Eves D, Gummer J (2005). Questioning performance: the director’s
work is undertaken without a formal contract of employment guar-
essential guide to health, safety and environment. UK Institution of
anteeing a “normal” working week—often resulting in employers
Occupational Safety and Health (IOSH), Wigston, Leicestershire.
treating the relevant workers as if they were self-employed and re-
Frick K, et al. (eds) (2000). Systematic occupational health and
sponsible for making all the choices about the work that they do) safety management—​perspectives on an international development.
are some features of the rapidly changing world of work. Over half Pergamon, Oxford.
of the British workforce is now employed in smaller organizations, Health and Safety Executive (2013). Managing for health and safety, 3rd
and over 90% of businesses employ fewer than 10 people. Part-​time edition. HSG65. http://​www.hse.gov.uk/​pubns/​books/​hsg65.htm
working has grown, and women now constitute half the workforce. Health and Safety Executive and Institute of Directors (2013). Leading
Globalization has intensified competitive pressures, particularly on health and safety at work, INDG417(rev1) 06/​13. http://​www.hse.
manufacturers. Public tolerance of accidents is very low and so there gov.uk/​pubns/​indg417.pdf
is pressure to make further improvements in occupational safety. In Reason J (1997). Managing the risk of organizational accidents. Ashgate,
the United Kingdom, there will soon be more people over 65 than Aldershot.
under 18 and many older people will continue to work past what was Sentencing Council (2015). Health and safety offences, corporate man-
regarded as normal retirement age. Above all, we may be entering a slaughter and food safety and hygiene offences: definitive guideline.
https://​w ww.sentencingcouncil.org.uk/​wp-​content/​uploads/​HS-​
new period of work shaped by Artifical Intelligence, robotics and
offences-​definitive-​guideline-​FINAL-​web.pdf
other technological aspects. A number of studies have recently been
Woolf AD (1973). Robens Report—​the wrong approach? Industrial
undertaken exploring the impact of these issues on health and safety
Law J, 2(1), 88.
at work.

Advice and assistance

Those likely to be affected deserve to be properly protected against
risks to their health and safety at work. Employers have a duty to
protect their employees by sensible risk management. Workers
also have a duty to protect their own and others’ health and safety.
10.2.3 Aviation medicine
Sensible risk management requires effective systems to control those Michael Bagshaw
risks that arise frequently and have serious consequences. Balancing
benefits and risks often requires expert help.
The Management of Health and Safety at Work Regulations re- ESSENTIALS
quire employers to appoint ‘ . . . one or more competent persons . . . ’
Travel by air is a safe means of transport, but puts people at various
to assist them in meeting their duty of controlling risks. Employers
physiological risks and is a potential means of spreading infectious
and managers are in the best position to understand the health
disease.
and safety issues in their business. Coupled with the knowledge
Physiological risks associated with flying include hypoxia—​
of employees, this is often enough to ensure that risks are properly
atmospheric pressure falls with altitude. The minimum cabin pres-
controlled, especially where the hazards are those commonly en-
sure in commercial passenger aircraft (565 mm Hg, 75.1 kPa) brings
countered at work and methods for their control are already estab-
a healthy individual’s arterial P along the plateau of the oxyhaemo-
lished practice. However, if the risks are complex or large numbers of
globin dissociation curve until just at the top of the steep part, but
employees are involved, expert help may be needed.
does not cause desaturation. By contrast, people with respiratory dis-
Employers can rely on one or more of their employees to give them
ease and a low arterial oxygen pressure may desaturate, which can
competent help, provided the employees have been given enough
be overcome by administering 30% oxygen, this being equivalent to
time, training, and access to information. The employer could:
breathing air at ground level. Guidance for assessing a passenger’s
• train or develop the necessary skills in an existing employee fitness to fly is provided by the websites of the Aerospace Medical
• recruit someone with the necessary skills Association and the British Thoracic Society. A second physiological
• make use of consultancy support staff risk is increased exposure to cosmic radiation, although there is no
evidence that this leads to abnormality or disease.
Formally qualified health and safety practitioners can work with a Other medical problems associated with flying include (1) venous
team of risk managers, including occupational health advisers. In thromboembolism—​the relative risk is significant, but the absolute
the United Kingdom, the Institution of Occupational Safety and risk is very low. Medical practitioners need to be circumspect in
Health sets standards and awards qualifications. advising preventative measures, taking account of the efficacy and
Preventing accidents at work makes an important contribution risk profile of any intervention, but compression stockings and/​or a
to the health and well-​being of all who may be affected by an en- single prophylactic dose of low molecular weight heparin may be re-
terprise, but achieving this aim requires a systematic approach and commended in high-​risk cases. (2) Jet lag—​there is no simple solution
leadership.
 10.2.3 Aviation medicine 1657

for combating the effects of jet lag: the individual must evolve strat- Physics of the flight environment
egies to suit their particular needs.
There is no evidence of a causative association between the use of The Earth’s atmosphere is an oxygen-​rich gas shielding the ground
engine bleed air for pressurization and ill health of aircraft occupants. below from solar radiation above. Subjected to gravity, compressed
Transmission of disease—​there is no evidence that the pressurized under its own weight, the atmosphere is denser close to the ground
aircraft cabin itself encourages transmission of disease, and recircu- than further away. Long waves of infrared light penetrate it easily
lation of cabin air is not a risk factor for contracting symptoms of but heat the ground below. Heated ground reradiates some of this
upper respiratory tract infection. It is important that individuals with heat at shorter wavelengths which are absorbed by carbon dioxide
a febrile illness should not travel on commercial aircraft. Restricting and water vapour, making the air close to the surface much warmer
air travel will not prevent global spread of pandemic influenza, but than that higher up. Short waves of ultraviolet sunlight, absorbed
might delay the spread sufficiently to allow countries time to prepare. by oxygen molecules early in their journey, create a belt of ozone at
high altitudes. Some rays intercepted in the same region generate
secondary rays that extend lower down. Very few reach the ground.
At sea level, the atmosphere exerts a pressure of about 760 mm Hg
Introduction (101 kPa); it is variably moist, has a temperature that ranges from –​
60°C to +60 °C, and moves at wind speeds from 0 to 160 km/​h. With
To answer practical questions about the effects of flight on the body, increasing altitude, the temperature, pressure, and water content of
it is necessary to understand the physics and physiology of flight, the the atmosphere fall and wind speeds increase (Fig. 10.2.3.1).
discipline of aviation medicine.
Aerospace medicine is very much a specialized discipline, with a Atmospheric pressure
history traced back to the descriptions of altered physiology during Total gas pressure falls with altitude in a regular manner, halving
balloon ascent by Glaisher and Coxwell in 1862. every 18 000 ft (5500 m) (Fig. 10.2.3.2). The oxygen content of the
Aviation medicine concerns the well-​being of humans in flight atmosphere (20.93%) is constant to very high altitudes, so the same
within the Earth’s atmosphere, whereas space medicine concerns curve can be used to obtain the ambient oxygen pressure by rescaling
the welfare of humans flying beyond the atmosphere and the Earth’s the ordinate (Fig. 10.2.3.2). The oxygen pressure of physiological
gravitational pull. Space medicine addresses the problems asso- importance is that which exists in ambient air when it is warmed and
ciated with very prolonged flight times and life support within a wetted on entering the bronchial tree. This raises water vapour pres-
self-​contained environment, as well as weightlessness, exposure to sure to about 47 mm Hg (6.3 kPa) regardless of the total gas pressure
high doses of cosmic radiation, and the psychological aspects of pro- outside. The oxygen pressure in moist inspired gas (PiO2) fully satur-
longed spaceflight. Those seeking information on the specific effects ated with water vapour at 37 °C is given by the relationship:
of space flight are referred to the specialized texts in the ‘Further
reading’ section at the end of this chapter. PiO2 = FiO2 ( Patm − 47 )

Heat lets molecules escape

150
Some rays are absorbed

Infrared UV
Cosmic
100
Altitude (ft × 103)

50

0
0 1 −60 0 40 0 10
Gravity pulls atmosphere down Pressure (atm) Temperature (°C) O3 concentration
(p.p.m.)

Fig. 10.2.3.1 Some physical features of the Earth’s atmosphere, showing the variations in barometric pressure, air temperature, and ozone
concentration with altitude. (NB: There is an international aviation safety convention that all altitudes are given in feet.) The shaded diagram on the
left illustrates how the Earth’s atmosphere is compressed under its own weight. The atmosphere absorbs much solar radiation.
1658 SECTION 10 Environmental medicine, occupational medicine, and poisoning

1.0 0.20 Protection against effects of cosmic radiation

PB PO2 The International Commission on Radiological Protection (ICRP)
0.8
0.15 recommended in 1991 that exposure of flight crew members to
Pressure (atm)

0.6 cosmic radiation in jet aircraft should be considered part of occupa-

0.10 tional exposure to ionizing radiation.
0.4 The ICRP limits for occupational exposure are a 5-​year average
0.05 effective dose of 20 millisieverts (mSv) per year, with no more than
0.2
50 mSv in a single year. The annual limit for the general public is 1 mSv.
0.0 0.0
0 20 40 60 80 0 20 40 60 80
Cosmic radiation doses
Altitude (ft ×10 3 )
The effect of ionizing radiation depends not only on the dose ab-
Fig. 10.2.3.2 The variations of barometric pressure (PB) and ambient
sorbed, but also on the type and energy of the radiation and the tis-
oxygen pressure (PO2) with altitude.
sues involved. These factors are taken into account in deriving the
dose equivalent measured in Sieverts (Sv). However, doses of cosmic
radiation are so low that figures are usually quoted in microsieverts
where FiO2, the fractional concentration of oxygen in the inspirate, (µSv) or millisieverts (mSv). Calculated and measured doses are well
is 0.2093 and Patm = atmospheric pressure. within the ICRP recommended limits.
Atmospheric temperature Health risks of cosmic radiation
The atmospheric temperature reduces at 1.98 °C/​1000 ft (300 m) While it is known that there is no level of ionizing radiation ex-
from the standard sea level temperature of 15°C, to the tropo- posure below which effects do not occur, current epidemiological
pause (40 000 ft (12 200 m)). It remains stable at –​56 °C up to about evidence indicates that the probability of airline crew members or
80 000 ft (24 400 m) and then rises to almost body temperature at passengers suffering any abnormality or disease as a result of ex-
about 150 000 ft (46 000 m), but by then air density is so low that its posure to cosmic radiation is very low.
temperature is unimportant.

Atmospheric ozone
Physiology of flight
Atmospheric ozone is formed by ultraviolet irradiation of diatomic
oxygen molecules which dissociate into atoms. At very high alti- The physiological effects of flight are distinguished from those of
tudes, all oxygen exists in the monatomic form. Lower down, some terrestrial high altitude because exposures are relatively rapid, brief,
of this monatomic oxygen combines with oxygen molecules to form and not cumulative. Flyers do not adapt to the hypoxic environment,
the triatomic gas ozone, with concentrations up to 10 parts per mil- unlike inhabitants of terrestrial high altitudes. However, the aircraft
lion (ppm). The ozonosphere normally exists between 40 000 and can be a means of transporting an individual to a high-​altitude
140 000 ft (12 200 and 42 700 m). Below 40 000 ft (12 200 m), the destination.
irradiation is normally too weak for significant amounts of ozone to
form. Concentrations of 1 ppm at sea level can cause lung irritation. Hypoxia
Modern passenger jet aircraft are fitted with catalytic converters Oxygen has a dual role in most animal cells, being simultaneously
in the environmental control system, which break down the ozone life-​giving and extremely poisonous. In air, or dissolved in simple
before it enters the pressurized cabin. solution, it is benign and only ionized with difficulty. However, once
an electron is successfully attached to an oxygen molecule it becomes
Cosmic radiation a highly corrosive superoxide ion, forming a cascade of other very
Aircraft occupants are exposed to elevated levels of cosmic radiation destructive oxygen radicals. This is an essential feature of oxygen
of galactic and solar origin. toxicity, which is discussed in Chapter 10.2.4. Superoxide dismutase
The sun has a varying magnetic field, which reverses direction and various peroxidases have evolved to protect most cells from the
approximately every 11 years. Near the reversal, at ‘solar min- effects of spontaneous formation of oxygen radicals by quenching
imum’, there are few sunspots and the sun’s magnetic field extending the ions as rapidly as they appear.
throughout the solar system is relatively weak. At solar maximum, Other enzymes have evolved which harness this property in a
there are many sunspots and other manifestations of magnetic controlled way. There are three types: oxidases, oxygenases, and
turbulence. hydroxylases. Quantitatively, cytochrome a3 oxidase is the most
The Earth’s magnetic field has a larger effect than the sun’s mag- important because, using oxygen as the ultimate electron sink, it
netic field on cosmic radiation approaching the atmosphere. The allows many metabolic processes to proceed at the same time un-
protective effect is greatest at the equator and least at the magnetic locking and trapping most of the energy the body needs (oxidative
poles. At jet aircraft operating altitudes, galactic cosmic radiation phosphorylation).
is 2.5–​5 times more intense in polar regions than near the equator. Oxygenases introduce an oxygen molecule into organic molecules
The Earth’s surface is shielded from cosmic radiation by the at- creating new compounds. Although these enzymes consume only a
mosphere, the ambient radiation decreasing with altitude by ap- small fraction of the body’s total oxygen requirement, they are par-
proximately 15% for each increase of around 2000 ft (dependent on ticularly important for production and dismemberment of many
latitude). critical compounds such as the amine transmitters of the brain.
 10.2.3 Aviation medicine 1659

Hydroxylases insert one atom of oxygen and another of hydrogen The Alveolar ventilation equation The Alveolar air equation pictures VA
ignores dead-space, and supposes trapped in a bag, and notes there must
into organic molecules. They too are responsible for many critical there is a stream of oxygen-rich CO 2 be a link between the rise in PCO2 and
metabolic processes and for the denaturation of many drugs in the free gas, VA and says, for practical the fall in PO2, so that, for most practical
purposes: purposes:
liver, kidney, and elsewhere.
These enzymes differ in their affinity for oxygen, described by the PACO2 ∝ MCO2 /VA PAO2 = PIO2 – PaCO2 /R
VA
Michaelis constant (for oxygen). This constant (KmO2) is that partial
pressure of oxygen which, when all other factors are equal, allows Rise ∝ MCO2

Partial pressure
Minus the almost
an oxygen-​consuming reaction to proceed at half its maximum vel- equal O 2
ocity. The major oxidase (cytochrome a3), which is the cocatalyst uptake, MO2 VA
of oxidative phosphorylation, has a very high oxygen affinity and Plus the CO2
output, MCO2 Fall ∝ MO2
thus a very low KmO2, of 1 mm Hg or less. Thus, this particular type
of oxygen consumption, representing 80–​90% of the whole, can Time
MCO2 MO2
proceed at high rate down to very low levels of oxygen supply. By
contrast (Fig. 10.2.3.3), the other enzymes, which are quantitatively Fig. 10.2.3.4 Graphical representations of the alveolar ventilation and
less important but qualitatively critical, have Michaelis constants alveolar air equations.
for oxygen that vary from 5 to 250 mm Hg (0.7–​33.3 kPa). A fall in
oxygen supply will influence these processes long before oxidative
Although Fig. 10.2.3.2 describes how ambient oxygen pressure
phosphorylation is affected and at times when overall oxygen con-
is related to altitude, it does not convey the pressure of oxygen to be
sumption is diminished little if at all.
found in the lungs. That pressure is determined by two equations
When humans are exposed to hypoxia, systemic and intracel-
(Fig. 10.2.3.4). The alveolar ventilation equation states that alveolar
lular changes operate together to minimize hypoxic injury and re-
CO2 pressure (PaCO2) depends only on CO2 excretion (CO2) and
store adequate oxygenation. Emerging evidence indicates that the
alveolar ventilation (Va), so:
hypoxia-​inducible factor (HIF) family of transcription factors plays
a central regulatory role in these homeostatic changes at both the
PaCO2 = k (CO2 /Va ).
systemic and cellular levels. HIF was discovered through its action
as the transcriptional activator of erythropoietin, and has sub- The alveolar air equation states that since at any one time there
sequently been found to control intracellular hypoxic responses is a fixed trading ratio between oxygen uptake and CO2 excre-
throughout the body. HIF is primarily regulated by specific prolyl tion (R = CO2/​O2), alveolar oxygen pressure (PaO2) can be calcu-
hydroxylase-​domain enzymes (PHDs) that initiate its degradation lated from the moist inspired oxygen pressure (PiO2*) and alveolar
via the von Hippel-​Lindau tumour suppressor protein (VHL). The PCO2, so:
oxygen and iron dependency of PHD activity accounts for regula-
tion of the pathway by both cellular oxygen and iron status. Recent PaO2 = PiO2 * − ( PaCO2/R )
studies conducted in patients with rare genetic diseases have begun
to uncover the wider importance of the PHD-​VHL-​HIF axis in Progressive hypoxia leads to a mild hyperventilation (i.e. a rise
systems-​level human biology. These studies indicate that, in addition in Va and fall in PaCO2). Thus, it is possible to plot alveolar oxygen
to regulating erythropoiesis, the system plays an important role in pressure against altitude (Fig. 10.2.3.5a).
cardiopulmonary regulation. When arterialized blood leaves a healthy lung the oxygen pres-
sure is some 10 mm Hg less than that in the alveoli, due to uneven

The Michaelis–Menten equation when the substrate is oxygen:

MO2 /MO2 max = PO2 /(PO2 + KmO2) (a) (b)
1.2 150 150 Whole-blood O2-Hb
Cytochrome a3 oxidase dissociation
Blood PO2 (mmHg)

1.0 Inspired air

PO2 (mmHg)

1 100 100
a-v∆ MO2/Q
MO 2/M O2 max

0.8 5
s 50 Arterial 50
0.6 25
xyg enase blood
.
a
and o Alveolar v
r oxidases gas
0.4 Othe 0 0
100 0 10 20 30 0 100
250 Altitude (ft × 103) Oxygen saturation (%)
0.2
KmO2
0.0 Fig. 10.2.3.5 (a) Variations in moist inspired, alveolar, and arterial
0 40 80 120 160
PO2 (mmHg) oxygen pressure (PO2) with altitude in normal men. (b) The conventional
oxygen–​haemoglobin dissociation curve of whole blood plotted to the
Fig. 10.2.3.3 Curves of oxygen uptake (O2) as a fraction of the same pressure scale as the left-​hand graph, so that arterial O2 content
theoretical maximum (O2max) against the partial pressure of oxygen can be read directly (at the same horizontal level as the PO2 curve). It also
(PO2) for a family of oxygen-​handling enzymes with Michaelis constants emphasizes that the arteriovenous oxygen content difference (a–​vΔ) is
for oxygen (KmO2) from 1 to 250 mm Hg. proportional to the ratio of oxygen uptake (MO2) to local blood flow (Q).
1660 SECTION 10 Environmental medicine, occupational medicine, and poisoning

0.20 (a) (b)

Detectable losses in learning and 8 80
night vision
0.15 Time of useful Consciousness is lost
Degeneration in already-learnt tasks consciousness once this area exceeds

Alveolar PO2 (mmHg)

6 60
PO2 (atm)

Physical weakness about 150 mm Hg/s

0.10

Time (min)
Coma on exertion
Coma within minutes at rest 4 Normal range 40
0.05 Death
Average
Must breathe pure oxygen at
positive pressure to survive 2 20
0.00 beyond here
0 20 40 60 80
Altitude (ft × 103)
0 0
Fig. 10.2.3.6 A summary of the functional consequences of altitude 24 26 28 30 0 120
hypoxia. Altitude (ft × 103 ) Time (s)

Fig. 10.2.3.7 (a) Variations in the time of useful consciousness with

matching of ventilation to perfusion, some anatomical shunting, altitude. (b) One way of expressing the dose of hypoxia needed to bring
and an almost nominal obstacle to diffusion. In resting people, the about loss of consciousness.
alveolar–​arterial oxygen gradient does not change much with alti-
tude, although the relative importance of the factors contributing In trained and healthy individuals breathing normally (i.e.
to it alter considerably; so subtracting a further 10–​15 mm Hg de- with an alveolar PCO2 of 35–​40 mm Hg (4.7–​5.3 kPa)), the
scribes the relation between arterial oxygen pressure and altitude dose of hypoxia acceptable before loss of useful consciousness
(Fig. 10.2.3.5). is equivalent on a curve of alveolar PO2 against time, to an area
The most important change is the loss of pressure driving oxygen of 150 mm Hg/s, where PO2 is less than 38 mm Hg (5.1 kPa)
from the alveoli to blood, as the fall in alveolar PO2 is much greater (Fig. 10.2.3.7b). However, this is sensitive to many other factors,
than that in mixed venous PO2 (because of the shape of the oxygen such as the degree of hyperventilation and the acceleration to
dissociation curve). As a result, the alveolar–​ venous gradient which the individual is exposed at the time. Hyperventilation
for oxygen diffusion is smaller and equilibration slower than at causes cerebral vasoconstriction, and positive headwards accel-
ground level. eration (+Gz) opposes the upward flow of blood to the brain.
People ascend to altitude in a matter of minutes, rather than over Exertion quickens loss of consciousness, because blood transits
several days, and adapt to hypoxia by an increase in blood flow and a quickly through the lungs leaving insufficient time for oxygen
modest hyperventilation, limiting the effects of hypoxia. The effects equilibration.
are shown in Fig. 10.2.3.6. The minimum cabin pressure of 565 mm Hg (75.1 kPA) (8000 ft
Individuals abruptly exposed to altitudes of 10 000 ft (3000 m) (2440 m)) in commercial passenger aircraft, will bring a healthy
and above suffer mental and physical effects, and is the ceiling individual’s arterial PO2 along the plateau of the oxyhaemoglobin
above which aviators are provided with oxygen. To allow a margin dissociation curve until just at the top of the steep part (Fig.
of safety, the maximum certified cabin altitude in civilian pas- 10.2.3.5), still saturated. At ground level, people with respiratory
senger aircraft is 8000 ft (2440 m), at which barometric pressure disease may have arterial oxygen pressures as low as 55–​60 mm Hg
is 565 mm Hg and arterial oxygen pressure is around 55 mm Hg (7.3–​8 kPa). As they ascend to 8000 ft (2440 m) their arterial PO2
(see Fig 10.2.3.5b, the oxyhaemoglobin dissociation curve), and will fall further. If their hypoxaemia at ground level is due to a
venous oxygen pressures have only fallen by 1–​2 mm Hg. Even at mismatch of ventilation to perfusion, as is usually the case, the
this altitude, there is a decrease in performance. The latest gener- drop in arterial PO2 will not be as extensive as in healthy people
ation of passenger aircraft are manufactured from newer materials (about 40 mm Hg or 5.3 kPa), but if it is due to diffusion defect
which provide greater strength from a given mass, thus allowing a associated with desaturation on exertion, as in some fibrotic con-
higher differential cabin pressure with a lower cabin altitude. ditions, it may be greater. However, in either event, it can be re-
Two physiological features of altitude hypoxia are important in versed completely by the administration of oxygen, 30% oxygen at
aviation. The first is the total lack of awareness of cerebral impair- 8000 ft (2440 m) being equivalent to breathing air at ground level.
ment. The second is the time of useful consciousness, describing Given prior notice, most airlines can provide a personal oxygen
how rapidly consciousness is lost thus dictating how quickly the supply for any passenger, although there may be a charge. (The
condition must be recognized and corrective action taken. altitudes of the patient’s destination and transit points en route
The time of useful consciousness is the interval after the onset of should also be considered.)
hypoxia during which an individual can carry out some purposeful
activity. The general relation between this time interval and the alti- Oxygen equipment and pressure cabins
tude of sudden exposure is shown in Fig. 10.2.3.7a. It diminishes Aircraft operating below 10 000 ft (3000 m) do not require oxygen
from about 4 min at 25 000 ft (7620 m) to a minimum of roughly equipment. Many sophisticated light aircraft which can cruise above
15 s, which is reached at 35 000 (10 700 m) to 40 000 ft (12 200 m). 10 000 ft do not have pressurized cabins, so oxygen equipment must
This asymptote represents the sum of the 7 s or so required for be provided.
blood to travel from the lungs to the brain and the time needed for Other aircraft that fly higher usually have reinforced cabins
the brain to utilize the oxygen already dissolved in its substance. capable of holding a high-​differential pressure between inside and
 10.2.3 Aviation medicine 1661

out. These are the high-​differential type, seen in passenger and Cabin air flow
transport aircraft generally, and the low-​differential variety found
in military high-​performance aircraft. The former, holding a high
transmural pressure, maintain cabin pressure above 565 mm Hg
(8000 ft (2440 m)). They provide an environment in which the
occupants breathe cabin air. However, it is possible that the pres-
surization system can fail, allowing the cabin pressure to fall to
the external ambient value. This can be limited by descent below
10 000 ft (3000 m), subject to air traffic control and terrain con-
straints. An emergency oxygen supply is available for passengers
and crew.
The aircraft’s environmental control system automatically man-
ages the internal cabin environment, providing healthy and com-
fortable surroundings for all occupants. There are regulatory
requirements for minimum cabin air pressure, maximum levels of
carbon monoxide, carbon dioxide and ozone, and minimum ven-
tilation flow rates. The cabin air must also be free from harmful or
hazardous concentrations of gases or vapours. Fig. 10.2.3.8 Cabin air circulation and distribution.
The cabin air supply is bled from the outside air entering the air-
craft engine, or may be supplied from the outside air via electrically Mechanical effects of pressure change
driven compressors. It is then passed through the air-​conditioning
packs and mixed with filtered recirculated air before distribution In civilian passenger and transport aircraft the climb to cruise alti-
to the cabin. The system provides approximately 20 cubic feet (566 tude takes about 30 min and involves a maximum fall of about
litres) of air per minute per passenger, of which about 50% is re- 200 mm Hg (26.6 kPA) in cabin pressure (to the equivalent of
circulated air (compared with up to 80% recirculated in buildings 8000 ft (2440 m)). Descent to land takes much the same time. Body
and other forms of public transport), giving a complete cabin air fluids and tissues generally are virtually incompressible and do not
exchange every 2–​3 minutes. alter shape to any important extent when such pressures changes
These high ventilatory flow rates maintain normal pressurization, are applied. The same is true of cavities such as the lungs, gut,
as well as temperature control and the removal of odours and carbon middle ear, and facial sinuses that contain air, provided that they
dioxide. The high flow rates also ensure that the volume of oxygen can vent easily. Gas-​containing spaces that cannot vent easily be-
far exceeds the requirements of the aircraft occupants (0.34 litre/​min have differently.
at rest and 0.85 litre/​min when walking). The thoraco-​abdominal wall can develop transmural pressures of
The air is distributed to the cabin via overhead ducts and grills +100 mm Hg or so briefly, but is normally flaccid and has a trans-
running the length of the cabin. The airflow circulates around the mural pressure of a few millimetres of mercury. Gas within will
cabin rather than along the cabin and is continuously extracted usually be at a pressure very close to that outside, and must follow
through vents at floor level as shown in Fig. 10.2.3.8. Boyle’s law. Ascent from ground level (760 mm Hg) to 8000 ft (2440
The recirculated air is passed through high efficiency particu- m) (565 mm Hg or 75.3 kPa) will expand a given volume of trapped
late air filters of the same specification used in hospital operating gas in a completely pliable container by about 35%. This may cause
theatres, giving 99.99% efficiency in the removal of physical contam- slightly uncomfortable gut distension in healthy people, but it is not
inants such as microbial particles. Aircraft cabin air has been dem- an important problem.
onstrated to be bacteriologically cleaner than the air in buildings, Even very diseased lungs can vent themselves over a minute or so.
trains, or buses. In consequence, the risk of lung rupture in normal flight is extremely
Although clean, the aircraft cabin air remains dry. During the rare (Fig. 10.2.3.9).
flight, moisture is derived from the metabolism and activities of the
cabin occupants as well as from the galleys and washrooms, giving
Each
a maximum relative humidity in the order of 10–​20%. These levels Each tube has
balloon has Approximate range
an expiratory
are associated with surface drying of skin, mucous membranes, resistance,R a capacity, C of bursting pressures
and cornea which may cause discomfort. Normal homeostatic Maximum
The chest balloon
mechanisms prevent dehydration and no harm to health has been wall is volume
demonstrated. very
Normal
floppy
A high-​differential cabin limits the aircraft’s range and manoeuv- breathing
C
rability and increases the risk of catastrophic damage if the fuselage
is punctured. So, military high-​performance aircraft are fitted with
low-​differential cabins, which prevent cabin pressure falling below Zero
The time-constant of emptying of
280 mm Hg (37.2 kPA) (equivalent to a pressure altitude of 25 000 ft any balloon is proportional to the
0 100
Transmural pressure (mm Hg)
(7620 m)). At this level decompression illness becomes a poten- product, RC.
tial hazard (see next). In such aircraft, oxygen equipment is used Fig. 10.2.3.9 A graphical summary of the factors determining lung
routinely. rupture.
1662 SECTION 10 Environmental medicine, occupational medicine, and poisoning

100 during flight or the spread of infectious disease, because the passen-
Frequency of decompression gers disperse after the flight before clinical symptoms or signs have
sickness at the end of
2 h exposure
become manifest. However, organizations such as the Aerospace
Medical Association, the European Civil Aviation Conference and
the World Health Organization have supported or undertaken
Incidence (%)

50
Exertion epidemiological studies to establish the prevalence of conditions
such as flight-​related deep venous thrombosis (DVT) and venous
thromboembolism (VTE), spread of tuberculosis (TB), and spread
Probable
threshold Rest
of newly emerging infectious diseases such as severe acute respira-
tory syndrome (SARS) and avian flu.

0 20 30 40 Jet lag
Altitude (ft × 103) Besides sleep, the major influence on waking performance and alert-
Fig. 10.2.3.10 The incidence of decompression sickness (percentage) ness is the internal circadian clock. Circadian rhythms fluctuate on
at the end of 2 hours of exposure to various altitudes in men at rest, or a regular cycle, which lasts something over 24 hours. The circadian
exerting themselves. rhythms are controlled by the suprachiasmatic nucleus of the hypo-
thalamus. Many body functions have their own circadian rhythm
and they are synchronized to a 24-​hour pattern by ‘zeitgebers’ (time
The cavity of the middle ear vents easily, but sometimes fails to
givers), light being among the most powerful.
fill because the lower part of the Eustachian tube behaves as a non-​
Moving to a new light/​dark schedule (as in time zone changes)
return valve, especially when it is inflamed. As a result, the cavity
leads to a discrepancy between internal suprachiasmatic nucleus
equilibrates quite easily on ascent but does not refill on descent, and
timing and external environmental cues. The internal clock can take
the eardrum bows inwards, causing pain that can be severe (otic
days or weeks to readjust, depending on the number of time zones
barotrauma).
crossed (desynchronosis).
Altitude-​induced decompression illness Fatigue is defined as the likelihood of falling asleep. Therefore, in
practical terms, there is little difference between chronic fatigue and
If ambient pressure falls quickly to less than half its original value,
acute tiredness. Fatigue can be caused by sleep loss and circadian
the gas dissolved in blood and tissue fluids may come out of solu-
desynchronosis, but it can also result from low motivation and low
tion precipitously, forming bubbles and obstructing flow in small
levels of external stimulation.
blood vessels. The time symptoms take to develop varies widely be-
tween individuals and shortens markedly as the altitude of exposure Preventative measures
rises. A guide to these times and variability is given in Fig. 10.2.3.10.
Sleep scheduling:
Symptoms usually resolve quickly after a descent of a few thou-
sand feet and rarely persist after descent to ground level, breathing • At home the best possible sleep should be obtained before a trip;
oxygen. Should they persist, treatment should be along the lines de- • On a trip, as much sleep per 24 hours should be obtained as would
tailed in Chapter 10.2.4. be at home;
Atmospheric pressure halves at 18 000 ft and decompression • Feelings should be trusted—​if the individual feels sleepy and cir-
illness occurs rarely, if at all, below this altitude. It is very rare below cumstances permit, then they should sleep.
25 000 ft (7600 m) and therefore is normally of no concern at normal
passenger aircraft cabin altitudes, although the risk continues to be Good sleep habits:
significant in some military flights. However, it does occasionally • A regular presleep routine should be developed;
occur in those passengers who have been exposed to a hyperbaric • Sleep time should not be reduced;
environment prior to flight, such as divers and tunnel workers. Sub-​ • The individual should avoid going to bed hungry, but should not
aqua divers (q.v.) are advised to allow a minimum of 12 hours to eat or drink heavily before going to bed;
elapse between diving and flight, or 24 hours if the dive required
• Alcohol or caffeine should be avoided before bedtime.
decompression stops.
Caffeine consumption may be used to increase alertness. A cup of
coffee usually takes between about 15 and 30 minutes to become ef-
Clinical aspects of aviation medicine fective, and the effect lasts for between 3 and 4 hours. However this
is less effective for individuals who regularly drink large amounts of
Travel by air is a safe means of transport. However, from the physio- caffeine-​containing beverages.
logical point of view, flying is a means of putting people at risk as well Bright light (more than 2500 lux), used at the appropriate time in
as being a potential means of spreading infectious disease. Modern the circadian cycle, can help to reset the circadian clock.
technology, coupled with stringent training requirements for flight After flying east, the traveller should be exposed to evening
crew, minimizes these risks but clinicians need to be aware of the ap- light, but morning light avoided. Conversely, when travelling
plications of physics and physiology to the flight environment. west, morning light should be sought, and evening light avoided.
It can be difficult to apply epidemiological principles when con- This makes the best use of the natural zeitgebers in resetting the
sidering incidence and outcomes of medical conditions acquired body clock.
 10.2.3 Aviation medicine 1663

Temazepam is a short-​acting benzodiazepine with a short half-​ lower the risk of asymptomatic DVT, but it remains unclear as to
life. Many people find this drug helpful in promoting sleep and if whether this reduction is clinically significant.
used for two or three days after travel, can assist in resetting the One study has shown that for 20–​40% of travellers, the com-
sleep cycle. mercially available stockings do not fit adequately. It is essential for
Melatonin is secreted by the pineal gland with a rhythm linked stockings to be correctly fitted so as to provide adequate compres-
to the light/​dark cycle through the suprachiasmatic nucleus. It is ef- sion to stimulate venous return.
fective in inducing sleep when taken at the appropriate stage in the Although the use of low molecular weight heparin for the preven-
circadian cycle. However, if taken at the wrong stage, it can disrupt tion of DVT in the aviation setting is not supported by direct evi-
the sleep/​wake cycle and destabilize sleep patterns. This limits its dence, in a high-​risk traveller consideration may be given to a single
usefulness in treating jet lag. prophylactic dose prior to flying.
There is no simple or single solution for combating the effects of While the relative risk of developing venous thrombosis when
jet lag. The individual has to evolve the strategies to suit his or her flying is significant, the absolute risk of developing symptomatic
particular needs. DVT is very low. The absolute risk of developing a pulmonary em-
bolus during or after a flight between the United Kingdom and the
Traveller’s thrombosis (DVT/​VTE) east coast of the United States has been calculated as less than one
Long haul travel is associated with prolonged periods of immobility, in a million.
a recognized risk factor for DVT first described by Virchow in 1856. Medical practitioners need to be circumspect in advising any pre-
However, there have been concerns as to whether there are other ventative measures, taking careful account of efficacy and risk pro-
factors specific to air travel which further increase the risk. file of the preventative method.
In the general population DVT occurs in 1–​3 per 1000 people per
year, of which 20% give rise to pulmonary embolism. Increasing age Passenger fitness to fly
is known to be a strong risk factor, possibly due to decreased mo- Medical clearance is required when:
bility and reduced muscular tone.
• fitness to travel is in doubt as a result of recent illness, hospitaliza-
The pathogenesis of thrombosis still relies on the basic premise
tion, injury, surgery or instability of an acute or chronic medical
of Virchow who identified circulatory stasis, hypocoagulability, and
condition;
endothelial injury as the risk factors.
• special services are required (e.g. oxygen, stretcher, or authority
Several clinical studies have shown an association between
to carry or use accompanying medical equipment, such as a venti-
air travel and the risk of DVT, with the risk of VTE in travellers
lator or a nebulizer).
increasing with the distance travelled. A recent case–​control study
showed that all modes of travel increased the risk of venous throm- Medical clearance is not required for carriage of an invalid passenger
bosis about twofold, with an absolute risk of one thrombosis per outside these categories, although special needs (such as a wheel-
6000 journeys. chair) must be reported to the airline at the time of booking.
It has been found that combinations of risk factors synergistically It is vital that passengers remember to carry with them any essen-
increase the risk of thrombosis. In people with factor V Leiden, the tial medication, and not pack it in their checked baggage.
risk of thrombosis after flying was about 14 times increased and in Deterioration on holiday or on a business trip of a previously
women using oral contraceptives, it was around 20-​fold increased. stable condition, or an accident, can often give rise to the need for
It has also been shown that the risk rises with the number of flights medical clearance for the return journey. A stretcher may be re-
taken in a short time-​frame, as well as with the duration of the flight. quired, together with medical support, and this can incur consid-
Most of these clots are asymptomatic and disperse naturally. erable cost. It is important for all travellers to have adequate travel
Thus, even though the overall risk of venous thrombosis after air insurance.
travel is only moderately increased, clear subgroups can be identi-
fied in whom the risk is higher. Assessment criteria
The low humidity of the aircraft cabin does not in itself lead to de- The passenger’s exercise tolerance can provide a useful guide on
hydration. Excessive alcohol consumption may cause dehydration, fitness to fly; if unable to walk a distance greater than about 50 m
but there is no evidence that this is a significant risk factor leading without developing dyspnoea, there is a risk that the passenger will
to DVT. be unable to tolerate the relative hypoxia of the pressurized cabin.
Two studies of reduced oxygen partial pressure with non​hypoxic A good source of guidance is provided by the web sites of the
control groups found no evidence of coagulation. There is no evi- Aerospace Medical Association and the British Thoracic Society.
dence that hypoxia or the hypobaric environment of an aircraft
cabin is a significant risk factor for the development of DVT. Spread of infectious disease
Although there is good evidence for the value of aspirin in There is no evidence that the pressurized cabin itself makes trans-
preventing arterial thromboembolic disease, its role in the preven- mission of disease any more likely, and it has been shown that re-
tion of venous thromboembolic disease is much less clear. The side circulation of cabin air is not a risk factor for contracting symptoms
effect profile is significant. of upper respiratory tract infection. Data suggest that risk of dis-
There is no evidence to support the use of aspirin in preventing ease transmission to susceptible passengers, by person-​to-​person
the development of DVT during flight. droplet spread within the aircraft cabin, is associated with sitting
For those travellers at medium to high risk of DVT, there is evi- within two rows of a contagious passenger for a flight time of more
dence that the use of compression stockings appears to substantially than 8 hours.
1664 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Newly emerging infectious disease House of Lords Inquiry (2007). Air travel and health: an update. The
SARS is an atypical pneumonia caused by a novel coronavirus which Stationery Office Ltd, London.
first appeared in the Far East in 2003. Thousands of flights took place Kuipers S, et al. (2007). The absolute risk of venous thrombosis after
to and from what the World Health Organization (WHO) defined air travel: a cohort study. PLoS Med, 4, 1508–​14.
as ‘affected areas’ during the outbreak, but transmission occurred Gradwell DP, Rainford DJ (eds) (2016). Ernsting’s aviation medicine,
only on five flights involving 29 secondary cases (24 cases on one 5th edition. CRC Press, London.
Rosenberg CA, Pak F (1997). Emergencies in the air: problems, man-
flight). In addition, a further 40 flights were identified, on which
agement and prevention. J Emerg Med, 15, 159–​64.
one or more probable cases (i.e. symptomatic at the time of travel)
Thibeault C (1997). Special committee report: cabin air quality.
travelled, but where no secondary cases developed. Thus, the risk of
Aviation, Space and Environmental Medicine, 68, 80–​2.
transmission on board an aircraft is thought to be low. Zuckerman JN (ed) (2013). Principles and practice of travel medicine,
Avian influenza (‘bird flu’) is a highly pathogenic strain A/​H5N1 2nd edition. Wiley-Blackwell, Oxford.
causing an epidemic among birds in Asia, Europe, and Africa. Human
infection is very rare, but serious when it occurs. During 2006, WHO
reported a total of 109 cases, of which 79 died. None of the reported cases
occurred within Europe, and air travel is not thought to be a risk factor.
On the other hand, pandemic influenza causes major morbidity
and mortality in humans, with serious economic and social conse-
quences. It usually affects a large proportion of the global population 10.2.4 Diving medicine
due to the absence of immunity, and spreads very rapidly throughout David M. Denison and Mark A. Glover
the world. Influenza pandemics occurred in 1918 (‘Spanish flu’), 1957
(‘Asian flu’), and in 1968 (‘Hong Kong flu’), all with high mortality.
The WHO strategy for rapid containment of an emerging influ- ESSENTIALS
enza pandemic aims to interrupt disease transmission by isolating
and treating infectious individuals, treating and quarantining ex- Diving remains the principal means of exploring and exploiting shal-
posed people, and minimizing the exposure of uninfected persons. lower underwater zones. Immersion and rapid change in pressure
Modelling suggests that restricting air travel will not prevent the with depth cause most problems unique to diving.
global spread of pandemic influenza, but might delay the spread suf- Effects of pressure on gases and ventilation
ficiently to allow countries time to prepare. Guidelines can be ac- Gas density, partial pressures, and solubility vary proportionately
cessed from http://​www.who.org or http://​www.cdc.gov. with ambient pressure. At elevated partial pressure, nitrogen be-
It is important that individuals should not travel on commercial comes narcotic, as can other inert gases, and contaminants barely
aircraft with a febrile illness. detectable at the surface can become toxic. Hyperoxia irritates the
lungs and the central nervous system, sometimes causing gener-
alized seizures. A safe gas mixture at depth can become hypoxic
Future issues
as the partial pressure of oxygen decreases during the return to
surface.
Aerospace medicine is a subject that is largely understood. There is con-
Ventilation is compromised at depth and failure of CO2 elimin-
cern among some flight crew about health effects due to oil pyrolysis
ation increasingly limits activity. Some divers are not distressed by
products in the cabin air. Evidence is conflicting and research is ongoing.
elevated CO2, but this does not protect them from its toxic effects.
The major peer-​ reviewed journal in the field is Aerospace
Medicine and Human Performance (formerly Aviation, Space and Clinical problems associated with diving and fitness to dive
Environmental Medicine), published by the Aerospace Medical Immersion hazards include aquatic flora and fauna, water move-
Association, which is worth reading to keep up to date with aviation ment, impaired visibility and thermal control, and enhanced sound
medicine’s evolution and innovation. and blast propagation. Immersion predisposes susceptible individ-
uals to pulmonary oedema. Aspiration of seawater can cause pul-
monary inflammation and systemic manifestations. Water entering
FURTHER READING the external auditory meati can induce disabling caloric vertigo.
Bagshaw M (2014). Air contamination health effects. Aerospace The final common pathway in many diving-​related fatalities is
Medical Association, Alexandria VA, USA. http://www.asma.org/ drowning.
asma/media/asma/Travel-Publications/Air-contamination-health- Decompression illness—is caused by ascent from a dive which re-
effects-report-v2-7-Apr2014.pdf duces ambient pressure. This releases excess dissolved inert gas from
Campbell RD, Bagshaw M (2002). Human performance and limita-
tissues, often in the form of bubbles. Alternatively, gas in the airways
tions in aviation, 3rd edition. Blackwell Science, Oxford.
can expand, rupture the lung, and force its way into the systemic cir-
Coker RK (ed) (2004). Managing passengers with respiratory disease
planning air travel: British Thoracic Society recommendations. British
culation via the pulmonary veins. Typical symptoms caused by these
Thoracic Society Standards of Care Committee, London. bubbles include rash, limb pain and neurological deficit (often motor
DeHart RL, Millet KC, Murphy J (eds) (1996). Fundamentals of aero- weakness, numbness and paraesthesiae, also disturbance of higher
space medicine. Williams and Wilkins, Philadelphia, PA. cerebral function which can impair the diver’s insight). Symptoms de-
House of Lords Inquiry (2000). Air travel and health. Her Majesty’s velop within a few minutes to 24 h of surfacing in most cases and can
Stationery Office, London. manifest before reaching the surface in arterial gas embolism arising
 10.2.4 Diving medicine 1665

(a) (b)
from pulmonary rupture and in decompression from deep, very long Percentage of ocean area Percentage of ocean area
duration dives. Management requires exclusion of other diagnoses 0 100 0 10
0 0
without delaying first aid treatment of decompression illness with Continental shelves Limit for breathing
oxygen
oxygen (as close to 100% as possible) and rehydration, followed by Continental slopes
definitive recompression. Intracardiac right–​left shunts, such as pa- Abyssal plains Limit for air

Depth (km)
tent foramen ovale, predispose to the condition. Extracardiac (pul- Chasms

Depth (m)
monary) shunts can also permit a similar paradoxical embolization
of bubbles.
Barotrauma—​gas-​filled spaces within, or surrounding, the body Salvage from
HMS Edinburgh 1981
will be damaged unless they are flexible enough to accommodate
pressure-​mediated changes in volume, or they are ventilated to pre- Probable limit to
practical diving at
vent distortion. Divers’ ears, sinuses, lungs, carious teeth, or their ambient pressure
12 600
masks and suits are vulnerable.
Long-​term consequences of diving—​these include aseptic bone in- Fig. 10.2.4.1 (a) A cumulative depth versus area plot of the oceans.
farcts, impaired higher cerebral function, and hearing loss. (b) A similar plot of the top 600 m, including the continental shelves.
Fitness to dive—​unrestricted diving demands a high level of phys-
ical and medical fitness. Potential disqualifying factors include con- A typical shore (Fig. 10.2.4.1) slopes down to between 200 and
ditions that might incapacitate, impair, injure, or distract a diver; 300 m at a gradient of about 1 in 50. Diving is largely confined to this
predispose to decompression illness or barotraumas; or mimic de- continental shelf. Thereafter, the continental slope descends to be-
compression illness. tween 3 and 6 km at a gradient of roughly 1 in 15 to vast flat expanses
of soft mud, the abyssal plains, interrupted by occasional mountains
and chasms. The deepest point is just over 11 km below the surface.
Currents, arising from differences in water temperature and sal-
Introduction inity, course across the abyssal plains and well up the continental
slopes as mineral-​rich streams supplying plant life in sunlit upper
Divers are exposed to many hazards while remote from medical zones. Animals concentrate here to feed on these plants or on each
care. As a result, diving medicine is largely concerned with preven- other. Eighty per cent (80%) of the ocean biomass lies in the top
tion. It requires a thorough understanding of the diver’s environ- 200 m, mainly close to the shore. Together, these sites form an area
ment and work. equal to Africa, infinitely more fertile and, as yet, virtually unfarmed.
Some dives are conducted in dry pressurized chambers, but most
involve immersion in fluids such as seawater. Immersion and rapid
change in pressure with depth are responsible for most diving prob- Limitations to diving
lems. Ambient pressure in seawater rises by approximately 100 kPa
for every 10-​m descent. Gas densities and partial pressures are pro- Currents often exceed swimming speed (Fig. 10.2.4.2a) and may re-
portional to ambient pressure. The amount of a chemically inert gas, strict diving to an hour or two each day during slack water. High
such as nitrogen or helium that can dissolve in a diver’s body is pro- waves frequently prevent divers from being launched or recovered
portional to its partial pressure. safely (Fig. 10.2.4.2b). Tidal currents tunnelled along marine

(a) Tidal currents (b) Wave heights above 2 m

Comfortable swim Arabian

Sea
Maximal swim 50

Borneo Texas
Cook Inlet
Texas
Incidence (%)

Louisiana
North Sea
Persian Gulf North
Sea
California Usual
Arabian Sea Some

0 5 J F M A M J J A S O N D
Tidal current (knots) Month of the year

Fig. 10.2.4.2 (a) A plot of the usual and the not uncommonly seen tidal currents in eight diving sites
around the world. (b) A plot of the percentage incidence of waves exceeding a height of 2 m at different
times of the year in three of the diving sites.
1666 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Temperature (°C) (a) (b)

Constant speed Constant load
−5 0 5 10 15 20 25 30 3 3
0
Water

Polar Polar Temperate

winter summer Water
100 2 2
Tropical
Depth (m)

M O2 (l/min)
M O2 (l/min)
200 1 1
Air
Air

300
0 0
Fig. 10.2.4.3 Variations in sea temperature with site and depth. Note 0 300 600 0 40 80 120
that water temperatures of less than 20°C are too cold for unclothed Ergometer load (kpm/min) Pedal rate (r.p.m.)
individuals to stay in for very long. Fig. 10.2.4.4 A comparison of oxygen consumption (ṀO2) when
pedalling a cycle ergometer in air and under water, (a) at a constant
canyons, and springs of fresh water or falls of cold ocean water, can speed (60 rev/​min) and (b) at a constant light load. Note the high cost of
moving the limbs through water. Most people’s aerobic capacity is about
carry divers in unexpected directions without them being aware. 2.5 litres O2/​min.
Dawn arrives late and dusk comes early to the sea. Light halves in
intensity with every 1 or 2 m of descent, and it is effectively ‘night’
below 80 m. Most recreational diving takes place in clear, shallow, the chest, distending large veins, and right atrium. A larger volume
and placid waters. Professional diving occurs throughout the year, of blood is displaced if immersion is in cold water, due to the per-
alongside or beneath large obstructions, and in turbid waters where ipheral vasoconstriction that results. Local stretch receptors in-
finding the task, let alone completing it, can be very demanding. terpret this central fluid shift as excess circulating volume and
Backscattering often makes artificial illumination ineffective. promote diuresis, resulting in hypovolaemia on emersion. Since
Underwater, binaural localization of sound is poor. Pressure gas is usually delivered to the mouth at ambient pressure, the pres-
waves travel almost five times as fast and many times more efficiently sure gradient across mouth, thorax, and upper abdomen can in-
through water than air. This increases susceptibility to blast injury. crease inspiratory or expiratory effort, depending on the diver’s
Loss of air conduction raises auditory thresholds by 30–​60 dB. attitude in the water.
Neoprene foam hoods raise thresholds by a further 30 dB or so. The displaced blood increases cardiac preload. This predisposes
Only the surface waters of tropical seas are warm enough for indi- susceptible individuals to ‘immersion pulmonary oedema’ which
viduals to remain effective without insulation for any length of time can occur despite normal cardiac function, and usually after a dive
(Fig. 10.2.4.3). Body temperature can be maintained at 37°C with in cold water or involving strenuous exercise. Prevalence is esti-
minimal effort in air at 18–​24°C, the zone of thermal neutrality. In mated at approximately 1% of the recreational diving population
water, this zone is high and narrow (35–​35.5°C). Loss of tactile dis- and it can recur. In one study, a history of pulmonary oedema after
crimination and manual dexterity are major problems when working diving in cold water was associated with elevated peripheral vas-
in cold water. Exercise or excessive insulation in warm water rapidly cular resistance, especially after a cold challenge, and an increased
leads to hyperthermia. risk of developing hypertension. An acute increase in preload and
afterload is presumed to cause the oedema. Treatment of persistent
mild symptoms is with supplemental inspired oxygen. Diuretics and
Effects of simple immersion vasodilators have been used to treat more severe cases. It typically
resolves within hours although some fatalities have been reported.
Water resists movement, making most tasks more tiring and less Physiological studies and case reports suggest that sildenafil has po-
efficient than on land (Fig. 10.2.4.4). A swimmer can sustain tential for prevention of immersion pulmonary oedema. Divers and
about 5 kgf thrust (c. 50 N), enough for propulsion at 1 to 2 knots swimmers with cardiac compromise are also at increased risk of
(1.85–​3.7 km/​h). Full inspiration makes an adult swimmer about pulmonary oedema.
2.5 kgf (c.25 N) positively buoyant, requiring half of maximum Aspiration of small amounts of seawater can cause ‘saltwater as-
thrust to descend. Breathing out to residual volume results in piration syndrome’, characterized by productive cough, retrosternal
about 2.5 kgf (25 N) negative buoyancy, requiring half of max- discomfort, and haemoptysis during, or within 2 h of, a dive. Fever,
imum thrust to ascend. The neutrally buoyant diver can be poised aches, malaise, and even impaired consciousness can develop. The
at will but body weight can no longer be used to apply leverage or casualty is usually normocapnic, often hypoxic, and sometimes has
torque, or to stay in place against a current. a leucocytosis. Treatment is rest and supplemental inspired oxygen.
Immersion opposes the effect of gravity and displaces blood Warming often helps extrapulmonary symptoms. Most cases resolve
from distensible vessels in dependent limbs. About 500 ml enters spontaneously within 6 to 24 h.
 10.2.4 Diving medicine 1667

If cool water enters one ear canal before the other, then a transient is easily engineered but is wasteful of gas. Most divers now use
‘caloric vertigo’ can result. Recurrent immersion can cause problems valves that provide gas only on demand. Self-​contained underwater
such as otitis externa. breathing apparatus (scuba) allows the diver to carry an on-​demand
supply of gas independent from the surface. Basic configurations of
this equipment rarely last for more than 1 h. Rebreather equipment
Problems of descent achieves greater endurance by replacing oxygen and removing CO2
from exhaled gas so that it can be recirculated.
The chest wall can maintain a pressure difference equivalent to 1 or 2 m
of water, so gas within the body is virtually at the same pressure as the Inert gas narcosis
surrounding sea. The lung of a breath-​hold diver is compressed from At raised partial pressure, nitrogen and several other inert gases with
total lung capacity to residual volume at 30 m (400 kPa), so they will high solubility in lipids act like anaesthetics. Effects develop within
need half of their aerobic capacity to ascend. Variation in gas volume minutes and reverse rapidly because they depend on passive solu-
in clothing and equipment further complicates buoyancy control. tion. Air is often breathed down to depths of 50 m, although sophis-
ticated tests of cerebral function show impairment starting at 20 m.
Barotrauma of descent When deeper than 50 m, effects become more obvious. Narcosis
Barotrauma is the term used to describe mechanical damage caused is completely reversed on ascent. Using a less narcotic gas such as
by changes in gas volume as pressure varies. helium allows divers to reach the lowermost parts of the contin-
Compression will force a diver’s face into an unvented mask. The ental shelves without narcosis. Divers can complete routine tasks
resulting facial oedema and subconjunctival haemorrhages usually while narcosed if they have repeatedly rehearsed them at increasing
resolve spontaneously. If gas is not added to a dry suit on descent, depths. Cognition and problem-​solving, however, remain impaired.
particularly if it is poorly tailored, it can pinch the skin resulting in
linear wheals, commonly distributed around the neck, axillae, and Hypercapnia
groins. These require no active intervention but should not be con- Work of breathing and physiological dead space increase as gas be-
fused with cutaneous signs of decompression illness (DCI). Severe comes denser at pressure. Hyperventilation is difficult at depth but
suit squeeze can limit a diver’s movements. can still occur. Breathing a dense gas mixture such as air at great depth
Blood is drawn into the chest vessels to compensate for reduced will cause hypercapnia. Some divers hypoventilate involuntarily and
lung volume, so lung injury occurs only at very great depths in become hypercapnic even in favourable conditions at depths as
breath-​hold dives. When gas in obstructed sinuses is compressed, shallow as 30–​40 m. Although these divers enjoy good gas economy,
sinus walls become oedematous and may bleed. Epistaxis often oc- hypercapnia increases risk of inert gas narcosis, cerebral oxygen tox-
curs on ascent, as blood or clot is expelled by re-​expanding gas. icity, and DCI. Use of a less dense mixture, such as oxygen-​in-​helium,
Middle-​ear barotrauma is the most common problem in diving. reduces this effect. Hypercapnia can also result from equipment mal-
Eustachian tube dysfunction or poor ‘ear-​clearing’ technique pre- function, contaminated gas, or voluntary hypoventilation.
vents ventilation of the middle ear. Compression of the trapped gas
draws the round and oval windows of the inner ear and the eardrum Oxygen toxicity
towards the middle ear space. Eardrum perforations can occur. They Oxygen toxicity is due to complex biochemical interactions and
normally heal spontaneously, but persistent ruptures require sur- takes time to develop and to reverse. There is a wide range of inter-​
gery. Diving should be avoided until the drums have healed. and intraindividual sensitivity.
Strenuous Valsalva-​like efforts to ventilate the middle ear raise Inspired oxygen partial pressure exceeding 50 kPa is toxic to
thoracic pressure. This transmits to the perilymph and can be suf- the lungs. Irritation of lung endothelium and epithelium causes a
ficient to rupture the oval or, more typically, the round window. spreading tracheobronchitis and reduction in lung volumes, flows,
This is known as inner-​ear barotrauma. Immediate or delayed ver- and gas transfer. Symptoms appear after about 6 h at partial pres-
tigo, tinnitus, and hearing loss (usually at high frequencies) ensue. sures around 79–​89 kPa and after 3 h at around 200 kPa. Advanced
Management is bed rest with the head elevated, avoidance of raised pulmonary changes can be irreversible, but symptoms typically di-
intrathoracic pressure, and consultation with an ear, nose, and throat minish rapidly in 2–​4 h with complete recovery in 1–​3 days. Lung
(ENT) surgeon who might elect to explore the middle ear and to re- function similarly recovers rapidly, although small decrements can
pair the rupture surgically. If the symptoms appear after a dive, they persist for more than a week.
can mimic vestibular DCI. If there is any doubt, a diving medicine Although pulmonary damage continues central nervous system
specialist should be consulted. toxicity becomes the primary limit to diving (Fig. 10.2.4.5) as in-
Barotrauma of descent can also affect a blocked external auditory spired partial pressure of oxygen rises further. This is unlikely to
meatus, gas spaces in carious teeth and under fillings or, in the event occur if the inspired partial pressure of oxygen does not exceed
of loss of breathing gas pressure, the whole body. 200 kPa when at rest in a dry, comfortable environment but exercise,
shivering, hypercapnia, anxiety, immersion, and pyrexia potentiate
cerebral oxygen toxicity. As a result, inspired oxygen is usually
Problems while at increased pressure maintained between maxima of 130 and 160 kPa when in water,
depending on work levels. Manifestations of oxygen toxicity include
For prolonged dives, compressed gas is delivered to the diver at the visual disturbances, tinnitus, irritability, and dizziness. A general-
same pressure as the surrounding water. This can be via a hose from ized seizure will usually follow if the oxygen partial pressure is not
the surface. A continuous flow through the helmet or face mask reduced promptly. Toxicity while immersed can be very dangerous
1668 SECTION 10 Environmental medicine, occupational medicine, and poisoning

5 ventilates via its Eustachian Tube before the other, uneven vestibular
stimulation can cause a transient ‘alternobaric vertigo’. If gas in
sinuses cannot escape, it might eventually burst them. Rupture of
4
the ethmoid sinus is rare but feared because of the risk of deep infec-
tion. The gut is quite resilient, but in some cases, especially on rapid
3 Convulsions ascent, ruptures have occurred. Dental barotrauma is also reported
PIO2 (atm)

and rapid ascents can fracture teeth.

2 In a minority of individuals, the facial nerve or maxillary branch
of the trigeminal nerve are exposed to pressure changes in the
middle ear and maxillary sinus, respectively. If gas is not vented
1 from the space on ascent, overpressure can impair the nerve’s blood
Reduction in vital capacity
supply, and hence cause a cranial nerve deficit a few minutes after as-
0
0 10 20 30 cent. This could be misdiagnosed as DCI. Release of pressure brings
Time (h) about resolution, which is usually within minutes and unlikely to
Fig. 10.2.4.5 Commonly observed pulmonary and central nervous O2
exceed 2 h.
toxicity versus time curves related to inspired Po2 (PIo2) (constructed from Compressed gas diving allows the diver to fill the lungs at depth
the data of many workers). and, therefore, to burst them on ascent unless they are adequately
vented. About 9.3 kPa of sustained overpressure (barely 1 m of sea-
water) bursts a lung. Ascent at a controlled rate, breathing nor-
but, in the safety of a hyperbaric chamber, partial pressures up to mally or exhaling, allows the lungs, which have a time constant of
300 kPa are used for maximum therapeutic effect. emptying close to 0.3 s, to empty and minimizes the risk of rupture.
Multiple therapeutic hyperbaric exposures can cause myopic lens Ascent at too rapid a rate, or while breath-​holding, risks lung
changes. They have also been reported in divers breathing oxygen rupture. Central tears lead to mediastinal emphysema. Peripheral
for many hours. Most are reversible within 12 weeks of last exposure. tears cause pneumothorax. Gas can embolize into the systemic cir-
culation, the most significant targets being central nervous system
High-​pressure nervous syndrome and myocardium. Escaped gas expands as the ascent continues,
Breathing oxygen-​in-​helium at depths in excess of 100 m causes making matters worse. The victim might lose consciousness or de-
tremor. Impaired higher function and level of consciousness and, velop neurological deficit almost immediately. Otherwise dyspnoea,
in more severe cases, convulsions, occur at greater depths. It is pre- cough, haemoptysis, voice change, or discomfort in the throat or
sumed that extreme pressures directly compress nerve components retrosternal region develop a few minutes later. There might be sur-
and affect their function. Depth and rate of pressurization influence gical emphysema of the neck and upper chest, increased cardiac
the nature and incidence of symptoms. Slower compressions reduce dullness or crepitus, and/​or evidence of a pneumothorax.
both incidence and severity. Some habituation occurs during pro- Patients with neurological signs should be recompressed as soon
longed exposure. Adding a small amount of narcotic gas such as ni- as possible. In the meantime, first aid management is oxygen (as close
trogen to the breathing mixture reduces some of the manifestations to 100% as possible) and careful rehydration. Recompression will
but individual variation in side effects and optimum dose makes this also reduce the volume of escaped gas if severe pneumomediastinum
technique unsuitable for commercial diving. or subcutaneous emphysema threatens the airway.

Decompression illness (DCI)

Problems of ascent More inert gas dissolves in tissues as dive depth or duration increases.
On a safe ascent, this gas comes out of solution, often forming bub-
On ascent, partial pressures of gases fall as they expand, and less gas bles in the venous circulation, slowly enough for it to diffuse out
can remain in solution. harmlessly via the lungs. Tissues are said to be ‘supersaturated’ until
all of the excess gas is eliminated. If bubbles are too large or too nu-
Hypoxia of ascent merous, they can block blood vessels, damage vascular endothelium,
Hypoxia will occur if breath is held for long enough in any circum- and induce ‘foreign body’ reactions. More severe decompression can
stance. Ordinarily, the rise in CO2 stimulates the breath-​hold diver generate extravascular bubbles within solid tissues, causing distor-
to take a breath but predive hyperventilation will delay this, some- tion and even rupturing cells. The term decompression sickness de-
times to a dangerous extent. A frankly hypoxic mixture can be sup- scribes disease caused by gas coming out of solution. DCI includes
plied by mistake during a compressed gas dive. In some rebreathers, both decompression sickness and disease caused by bubbles escaped
a hard-​working diver can consume oxygen faster than the design from a ruptured lung.
delivers it to the mixture (dilution hypoxia). Although the oxygen The lungs can filter out moderate numbers of venous gas emboli
partial pressure might be sufficient to sustain consciousness at depth before they reach the systemic circulation. It is possible that this
in any of these situations, ascent will cause it to fall further. ‘filter’ might be circumvented by right–​left shunts such as patent for-
amen ovale or pulmonary arteriovenous anastomosis. One in four
Barotrauma of ascent healthy people has a patent foramen ovale, but many are only ‘probe-​
Middle-​ear barotrauma can occur on ascent as well as descent. The patent’ with little chance of shunting. Foramina exceeding 10 mm
mechanism of injury is due to expansion of trapped gas. If one ear in maximum dimension are found in less than 1%. Over half of the
 10.2.4 Diving medicine 1669

victims of neurological DCI in one study had medium or large patent a few minutes or as much as 24 h after a dive, often as a dull and
foramina. Some have questioned whether a patent foramen ovale is a poorly localized ache of gradual onset. It is not usually made worse
primary cause of decompression illness and have proposed that, for by moving the joint, although weight bearing might make knee
instance, a significant pulmonary bubble load could trigger vasocon- pain worse. Signs of inflammation are uncommon. Left untreated,
striction, raise right heart pressures, and open a previously ‘closed’ the pain will regress and disappear over 2 or 3 days. Recompression
foramen. Increasing intrathoracic pressure by heavy lifting and commonly improves the pain quickly.
Valsalva-​like manoeuvres to clear ears, could have a similar effect. Although recreational divers also experience limb pain, neuro-
It has been estimated that the odds ratio of serious decompres- logical symptoms are more likely. Sensory disturbance is common,
sion sickness in divers with a patent foramen ovale is around 2:5. with numbness and paraesthesiae being frequent manifestations.
This estimate did not consider foramen ovale size and larger defects One fulminant form starts with pain distributed along a thoracol-
are likely to be associated with higher risk. Absolute risk of decom- umbar dermatome (girdle pain) followed by loss of sensation and
pression sickness for the whole diving population is low, however, at power in the lower limbs.
a little over 2 per 10 000 dives, and primary screening for foramen Involvement of the brain is common and can be subtle. This can
ovale is not advocated. ‘Undeserved’ DCI justifies screening with impair insight and delay a diver’s decision to seek assistance. Denial
bubble-​contrast echocardiography. If a large foramen ovale is found, is also a frequent feature. Any of the higher functions can be in-
the usual approach is to advise less provocative diving or percutan- volved, including loss of short-​term memory, altered affect, visual
eous closure of the defect. Migraine with aura is associated with an disturbance, and loss of consciousness. Inner-​ear DCI can be con-
increased risk of patent foramen ovale and is accepted as an indica- fused with inner-​ear barotrauma. Bubbles do not necessarily respect
tion for screening. The discovery of a large shunt in a diving candi- normal anatomical boundaries, and patchy or multisystem presen-
date who has not suffered from a diving-​related illness would usually tations are common.
be considered to be a significant risk factor for DCI. Cardiopulmonary symptoms and signs are unusual but, if present,
After breathing an unchanging gas mixture for 24–​48 h at a constant usually indicate a severe case. Cutaneous manifestations range from
pressure, no more gas accumulates in tissues. Decompression from this itching, sometimes with a papular rash, through to patches of skin
‘saturated’ state takes as long as several days, but it does not lengthen if ‘marbling’ characterized by a reticular cyanosis on a pallid back-
dive duration is extended. This is the basis of saturation diving. A vast ground with an erythematous periphery. Blockage of the lymphatic
amount of experimental work has been done to determine the safe system by bubbles can cause tender nodes and oedema which typic-
limits to ‘no-​stop’ diving (Fig. 10.2.4.6) and the depth–​time profiles ally affects face, neck, or breast.
that must be followed on returning to the surface after longer dives. It is not unusual to exhibit several manifestations, or for them to
DCI occurs in about 1% of dives conducted within ‘safe’ schedules, appear at different times and to evolve in different ways. Less specific
in some 2–​3% of dives at the limits of these schedules, and in many constitutional symptoms, such as fatigue, malaise, headache, and
badly conducted dives. Signs of arterial gas embolism following pul- anorexia can be difficult to distinguish from transient self-​limiting
monary rupture will usually present within the first 10 min after sur- illnesses, but they are usually of no concern unless other manifest-
facing; 50% of all DCI cases will develop symptoms within 1 h of ations are present or they are severe enough to affect function.
surfacing and 90% within 6 h. Divers developing any manifestation of DCI within 24 h of a dive
The most common presentation in military and commercial should be managed as if they have the condition unless an alternative
diving is limb pain, commonly of the shoulders or elbows in divers, diagnosis is more likely. First aid management is supplemental in-
and of the knees and hips in tunnel workers. Pain might present spired oxygen (as close to 100% as possible) and rehydration. All but
trivial cases of DCI should be recompressed as soon as possible; it is
Time (h) an effective treatment and reduces the size and promotes resorption
0 1 2 3 4 5 6
of existing bubbles before irreversible infarction and oedema occur
0 while preventing formation of new bubbles. High inspired partial
Above the line:
pressures of oxygen facilitate removal of excess inert gas, relieve is-
OK to make an ascent without
10 decompression stops chaemia, and reduce oedema, inflammation, and reperfusion injury.
The goal is as complete a resolution of symptoms as possible at depth
and to avoid recurrence on surfacing. Relapse or residual symptoms
20
require retreatment, so detailed postrecompression examination is
Depth (m)

necessary. DCI may fail to resolve completely.

30
Miscellaneous related problems
Below the line:
40
must make an ascent with A diver who ascends more rapidly than the planned decompres-
decompression stops sion schedule has ‘omitted decompression’. Risk of DCI is increased.
Treatment is oxygen and, in more extreme cases, recompression.
50
New exposure to an inert gas when saturated with another can
increase overall gas burden if there is a mismatch in the rate at
60 which the gases diffuse into and out of a tissue. This can cause a
Fig. 10.2.4.6 The ‘no-​stop’ diving curve that determines whether a bubble-​related disease, for which decompression is not the imme-
dive has been shallow and brief enough for the diver to make an ascent diate provocation and is known as ‘isobaric counterdiffusion’. The
to the surface without decompression stops. site affected depends on the location of the interface between the
1670 SECTION 10 Environmental medicine, occupational medicine, and poisoning

two gases. It can cause inner-​ear or skin symptoms in saturation

Fitness to dive
divers. Progression can be halted by altering the gas mixture. It can
be treated by recompression and prevented by increasing environ-
Fitness assessment balances real and theoretical hazards against em-
mental pressure slightly in order to reduce super-​saturation of the
ployer and physician liability and duty of care, legislation, and the
tissue before changing gas mixtures.
candidate’s livelihood or desire to dive. Some organizations adopt
Several hours after breathing high fractions of oxygen, a diver can
didactic standards. Others use guidelines, which leave room for
develop an exudate in the middle ear, yet remain able to ventilate
judgement by the physician and, sometimes, for informed risk to be
the ears. This might be due to consumption of oxygen causing an
carried by the candidate.
insidious volume reduction, or due to a direct toxic effect of oxygen
Military and commercial diving is physically demanding and
upon the middle-​ear epithelium. The problem resolves spontan-
often remote from medical aid. These divers undergo periodic med-
eously within hours.
ical examinations. Periodicity and extent of examination depend on
Differential pressure across a restricted aperture can generate
local regulations. Many recreational divers simply complete regular
large forces with serious, and often fatal, consequences. Examples
health declarations, undergoing examination only if a question is
include the inflow to a culvert or a sudden breach in a pipe con-
answered ‘positively’.
taining gas at lower pressure than ambient. Potential mechanisms
Assessments aim to determine whether candidates:
of injury include entrapment, compromised inspiratory effort, pri-
mary trauma, and critical damage to equipment. • are sufficiently physically fit to rescue a fellow diver, to swim in
swift currents and rough waters, and to undertake any related
non​diving tasks
Problems after the dive • are medically fit and have no problems that might incapacitate,
impair, distract, predispose to decompression illness or baro-
Autopsies on some asymptomatic divers with no history of DCI trauma, or otherwise make them a liability to themselves or others
have revealed that their brains and spinal cords contain consid- • have an acceptable risk of long-​term health consequences from
erably more micro-​ infarcts than those of non​ diving controls. diving
Although the consequences of such damage are considered slight
• require any restrictions or adjustments
or subclinical, subjective reports of forgetfulness and poor concen-
tration have been correlated with diving experience. Subjectively We must avoid understatement of the dangers of diving, especially
forgetful divers, as a group, performed worse than controls in tests at its most extreme, but must also assess hazard and risk realistically,
of cognitive function, especially memory. They also had struc- enabling imaginative solutions for, and greater acceptability of, dis-
tural differences on brain MRI. A history of welding increases the abled divers who can often dive usefully without jeopardizing health
probability of a diver reporting these problems and the respirable or safety of those involved.
heavy metal particles arising from preparation of surfaces and An individual who is bodily fit, mentally stable, free of conditions
the welding fumes might be responsible for at least some of these such as epilepsy, obstructive lung disease, ill-​controlled diabetes or
findings. asthma, alcohol or drug addiction, and has no history of ruptured
Imaging of long bones of divers and caisson workers show eardrums or aural surgery is likely to be medically fit to dive. An
aseptic infarcts (dysbaric osteonecrosis) in a sizeable minority (up acute chest, upper airway, or ear infection would be grounds for
to 11%). The incidence is higher in those with a history of overt temporary unfitness. Diving should be avoided while taking medi-
DCI. Lesions can occur after a single decompression, but their in- cation that could impair exercise capacity, ability to think clearly,
cidence rises with age, depth, and diving intensity. Those in the or ability to orientate in space. Medical conditions that can mimic
head, neck, or shaft are asymptomatic, but those at juxta-​articular DCI deserve careful assessment. Women are advised not to dive
surfaces can be disabling. They are more common in caisson during pregnancy as evidence is suggestive, though not yet con-
workers than divers, but are even seen in professional breath-​hold clusive, that the unborn child is at increased risk of developmental
divers, such as the Ama of Japan, in whom the dissolved gas burden defect.
must be light. The aetiology is unknown, but gas embolism is the Compromised gas flow or gas exchange could predispose to
favoured explanation. injury or an inability to cope with the respiratory demands of
Commercial diving, especially saturation diving, enlarges total diving. Risk factors for spontaneous lung rupture such as dis-
lung capacity and forced vital capacity (FVC). This is attributed to tortion of lung tissue must be carefully assessed. Cross-​sectional
training effects of prolonged breathing of compressed gases. The imaging can identify many more bullae than are visible on plain
FEV1/​FVC ratio falls, due partly to the rise in FVC, but there are films but, in the absence of a validated quantification of risk of
also hints of additional small-​airway damage. Pulmonary capillary barotraumatic rupture, interpretation in terms of fitness to dive
blood volume, as judged by carbon monoxide transfer, also falls. remains subjective.
This appears to be due to transient episodes of hyperoxia during If a candidate runs several kilometres a day, is a good swimmer,
saturation-​diving procedures, but might also be associated with was always good at games at school, and has no history of recent
venous gas emboli released during decompression. The effects are respiratory disease, they are very likely to be fit to dive. FEV1 multi-
slight but definite and can be cumulative. There are no obvious clin- plied by 35 measures the maximal voluntary ventilation, an indi-
ical consequences. cator of respiratory fitness. FEV1 should, therefore, be more than
Mild high-​tone deafness is found in commercial divers and is at- 75% predicted. FVC should also be more than 75% predicted be-
tributed to the noise of gas flows within their helmets. cause there is good evidence that subjects with a low FVC and, by
 10.2.5 Noise 1671

inference, lungs that are too small for their bodies, are more liable to world. The Divers’ Alert Network, for instance, has international
lung rupture on rapid ascents. coverage, and contact details can be obtained from http://​www.
Possible pre-​existing blebs, bullae, or air-​trapping on postincident diversalertnetwork.org/​contact/​international.asp
CT of chest in a small case series of pulmonary barotrauma after free
ascents in candidates with unusually large lungs (volumes greater
than 120% of predicted) has raised concerns for some diving clin- FURTHER READING
icians. Until more is known, it would be prudent to consider care-
Bennett M, Mitchell S, Dominguez A (2003). Adjunctive treatment of
fully all candidates with ‘outlier’ spirometry values, whether too decompression illness with a non-​steroidal anti-​inflammatory drug
large or small. (tenoxicam) reduces compression requirements. Undersea Hyperb
The FEV1/​FVC ratio has not been found to be especially helpful. Med, 30, 195–​204.
What matters most in diving is the time constant of emptying of the Bove AA (2004). Bove and Davis’ diving medicine, 4th edition. W.B.
full lungs. The peak expiratory flow (PEF)/​FVC ratio is a reasonable Saunders, Philadelphia, PA.
measure of this, and PEF should be at least 1.5 times predicted FVC British Thoracic Society Fitness to Dive Group (2003). British Thoracic
per second. Society guidelines on respiratory aspects of fitness for diving.
Past or current asthma used to be an absolute contraindication Thorax, 58, 3–​13.
to diving on theoretical grounds of increased risk of lung rupture Brubakk A, Neuman T (eds) (2003). Bennett and Elliott’s physiology
on fast ascents. Childhood asthma often disappears, however, and and medicine of diving, 5th edition. W.B. Saunders, London.
very many people with current mild asthma are known to dive fre- Edmonds C, et al. (eds) (2015). Diving and subaquatic medicine, 5th
edition. CRC Press, Boca Raton, FL.
quently without ill effect. The British Thoracic Society’s guidelines
Lundgren CEG, Miller JN (eds) (1999). The lung at depth. Dekker,
permit diving in asymptomatic asthma with normal spirometry,
New York, NY.
negative exercise test, PEF no more than 10% below best values, Macdiarmid JI, et al. (2004). Co-​ordinated investigation into the
and requiring no more than regular inhaled anti-​inflammatory possible long-​term health effects of diving at work. In: Examination
agents. of the long-​term health impact of diving: the ELTHI diving study. HSE
Alternative causes of osteonecrotic lesions must be excluded be- Books, HMSO, Norwich.
fore a dysbaric aetiology is accepted. If lesions are asymptomatic, Naval Sea Systems Command, U.S. Department of the Navy (2018).
the medical examiner might consider restriction from experimental U.S. Navy Diving Manual (Revision 7, Change A, April 2018).
or provocative deep diving. Symptomatic lesions will be more re- https://www.navsea.navy.mil/Portals/103/Documents/SUPSALV/
strictive and, if the articular surface collapses, a joint replacement Diving/US%20DIVING%20MANUAL_REV7_ChangeA-6.6.18.
might be required. MRI has been shown to be more sensitive than pdf?ver=2018-06-15-102549-030
traditional plain X-​ray screening. MRI can detect potential lesions Slade JB, et al. (2001). Pulmonary edema associated with scuba
within days of a dsybaric insult, whereas X-​ray evidence may take diving: case reports and review. Chest, 120, 1686–​94.
several months to appear. Some lesions visible on MRI, including Smart D, et al. (2015). Joint position statement on persistent for-
amen ovale (PFO) and diving. South Pacific Underwater Medicine
those in juxta-​articular locations, have remained asymptomatic and
Society (SPUMS) and the United Kingdom Sports Diving Medical
have resolved spontaneously. As a result, such lesions require careful
Committee (UKSDMC). Diving Hyperb Med, 45, 129–​31.
serial monitoring before any decision is made that will limit a diver’s UK Health and Safety Executive (2009). Research report RR761—​
employability in the long-​term. Differential pressure hazards in diving. http://​www.hse.gov.uk/​re-
search/​rrpdf/​rr761.pdf
Wilmshurst P, Bryson P (2000). Relationship between the clinical fea-
tures of neurological decompression illness and its causes. Clin Sci,
Conclusion
99, 65–​75.
Wilmshurst PT, et al. (1989). Cold-​induced pulmonary oedema in
More effective therapies for DCI are sought, either instead of, or scuba divers and swimmers and subsequent development of hyper-
to supplement recompression. Surface oxygen is used as a first tension. Lancet, i, 62–​5.
aid measure but might have a role as a definitive treatment in
selected groups. Intravenous perfluorocarbons and lidocaine
have both attracted interest, but more evidence is required. An
intervention as simple as an oral non​steroidal anti-​inflammatory
drug showed promise in reducing compression requirements in
a recent randomized controlled study. Further meticulous data 10.2.5 Noise
collection will help to identify subgroups who need minimal or
more aggressive treatment from the outset. It will also help to David Koh and Tar-​Ching Aw†
clarify issues of safety of drugs, and of medical conditions, while
diving.
A local hyperbaric facility can advise on management of diving ESSENTIALS
disorders. In Britain, if the nearest suitable facility is not known, Noise can affect hearing in the occupational setting but can have
the British Hyperbaric Association provides a 24-​h advice line other effects where exposures are non​occupational. For clinical
(07831 151523) for England, Wales, and Northern Ireland and
Aberdeen Royal Infirmary (0345 408 6008) provides the service
for Scotland. There are many helpful organizations around the †
It is with great regret that we report that Tar-Ching Aw died on 18 July, 2017.
1672 SECTION 10 Environmental medicine, occupational medicine, and poisoning

purposes, noise is measured in decibels weighted according to the Clinical effects

sensitivity of the human ear (dB(A)). Regardless of source, the effects
of overexposure to noise are similar. Initially there is a temporary Exposure to loud noise can cause auditory and non​auditory effects.
threshold shift, where reversibility of hearing loss is possible with re- There is wide variation in individual susceptibility. Massive impulse
moval away from further noise. Noise-​induced hearing loss occurs pressures (e.g. from bomb blasts), can cause acute acoustic trauma.
following prolonged or intense exposure, with poor prospects for There can be a perforation of the tympanic membrane or disruption
improvement of hearing. The classical audiogram for noise-​induced of the ossicular chain with associated pain and hearing loss, or occa-
hearing loss shows a 4 kHz dip. Non​auditory effects of prolonged sionally hyperacusis.
noise exposure include annoyance, sleep disturbance, hypertension, An early response to loud noise exposure (e.g. among those
and cardiovascular disease, stress, and impaired cognitive perform- who work in noisy environments or those attending loud mu-
ance. Prevention of noise-​induced hearing loss is by reducing ex- sical events) is temporarily increased hearing threshold. This
posure to noise at source, minimizing exposure time, using hearing temporary threshold shift might be accompanied by tinnitus. The
protection, and participating in surveillance. transient dullness of hearing typically lasts up to 24 h, after which
hearing thresholds return to normal. With continuing exposure,
the magnitude of this temporary sensorineural hearing loss and
the recovery time increase until, after months or years, there is a
Introduction permanent shift in threshold, which might be accompanied by tin-
nitus. Hearing damage due to chronic or variable noise exposure
Noise is any unwanted sound. Excessive noise damages the coch- might not become apparent until early or middle age, depending
lear hair cells, breaking and disrupting the cilia, which act as on when exposure commenced, and on duration and intensity
local electromechanical amplifiers. This can result in physical and of the noise.
psychological harm. On audiograms, noise-​induced hearing loss is detected as a dip
at 4 kHz (Fig. 10.2.5.1). Affected people find it difficult to distin-
guish between similar sounds, particularly consonants, in the pres-
Exposure ence of moderate background noise. With severe hearing loss, the
listener may experience ‘loudness recruitment’, a rapid, uncomfort-
The two important characteristics of sound are its intensity and fre- able increase in sound perceived when intensity increases beyond
quency. The human audible sound intensity range is 0–​120 decibels. the already abnormal hearing thresholds. With continued noise
The decibel (dB) scale is logarithmic rather than linear, therefore exposure, the 4-​kHz dip on audiograms extends to lower frequen-
every increase in sound intensity of 3 dB is equivalent to a doubling cies and hearing thresholds worsen. This might be combined with
of sound intensity. In young adults, the ear sound frequency ranges presbyacusis (age-​related hearing loss) in later years.
from 20 Hz to 20 kHz, but its sensitivity is not equal across this Worldwide, about 16% of hearing loss is estimated to be associ-
range. To mimic the response of the human ear and to allow for ated with occupational noise exposure.
the variation in ear sensitivity to different frequencies, sound level In addition to hearing loss, noise exposure can lead to non-​
meters apply a weighting to the sound intensities, and express the auditory effects such as sleep disturbance, hypertension, and car-
readings as dB(A), that is, decibels weighted by the A scale (as de- diovascular disease, stress, and impaired cognitive performance.
fined by international standards). Typical sound levels are 65 dB(A)
for normal conversation at a distance of 1 m; 140 dB(A) for a jet
aircraft taking off 25 m away; and 160 dB(A) for a rivet gun near 0
the ear.
10
Noisy industries include manufacturing, construction, engineer­
ing, metalworking, motor sports, the military, and entertainment 20
industries. Instantaneous noise levels can be assessed using a noise 30
Hearing level (dB)

meter. For cumulative noise exposure, a personal noise dosimeter 40

provides an ‘equivalent noise dose’ by averaging the frequencies and
50
intensities over an 8-​h shift. In the United Kingdom, the Control
of Noise at Work Regulations 2005 stipulate an exposure limit of 60
87 dB(A) averaged over 8 h/​day or 140 dB(A) for any instantaneous 70
impulse noise. 80
Besides occupational exposure, lower intensity community noise
90
(e.g. from airports or urban traffic) is recognized to be associated
with adverse health effects. Several studies have shown increased 100
mortality from cardiovascular diseases among people living near 110
125 250 500 1000 2000 4000 8000
noisy airports. The use of personal music players at excessive vol-
umes for prolonged periods can also result in significant and haz- Right Frequency (Hz) Left
ardous noise exposure. There is also evidence that background noise Fig. 10.2.5.1 Audiogram typical of noise-​induced hearing loss with a
can impair learning in schools. dip at 4 kHz frequency. Red circles, right ear; blue crosses, left ear.
 10.2.6 Vibration 1673

There might be symptoms of annoyance, distraction, fatigue, sleep

disturbance, and feelings of isolation. These can combine to re- FURTHER READING
duce work output and efficiency. Accidents in noisy workplaces Basner M, et al. (2014). Auditory and non-​auditory effects of noise on
have been attributed partly to inability to hear verbal warnings health. Lancet, 383, 1325–​32.
or instructions clearly. Prolonged exposure to community noise Hammer MS, Swinburn TK, Neitzel RL (2014). Environmental noise
might be associated with increased mortality from cardiovascular pollution in the United States: developing an effective public health
disease. response. Environ Health Perspect, 122, 115.

Diagnosis

A diagnosis of noise-​ induced hearing loss is established by

noise exposure assessment, a history of hearing difficulty that
might be accompanied by tinnitus, and an audiogram showing
10.2.6 Vibration
the classical sensorineural 4-​kHz dip. Where abnormalities are Tar-​Ching Aw†
detected, it is important to establish the history of occupational,
leisure, and community noise exposure, exposure to ototoxic
drugs and chemicals, previous ear pathology or surgery, other ESSENTIALS
relevant medical history, and the compliance with use of hearing
Various occupations can lead to exposure to vibration, which can be
protection.
transmitted to the whole body or localized to the hands. The main
clinical effect of whole-​body vibration exposure is low back pain.
Effects from hand-​transmitted vibration can be (1) vascular, with
Management and prevention manifestations of secondary Raynaud’s phenomenon; (2) neuro-
logical, often presenting as paraesthesia and reduced sensory percep-
Otoscopic examination, tuning fork tests, and bone-​conduction
tion; and (3) musculoskeletal, including reduced grip strength and loss
audiometry should be carried out to exclude conductive hearing
of manual dexterity. In tropical countries, as opposed to temperate
loss. Unusual asymmetrical audiograms with vertigo or unilat-
climates, the clinical manifestations are predominantly neurological
eral tinnitus require otorhinolaryngologist referral to exclude
and musculoskeletal, instead of vascular. Management requires ex-
cerebellopontine angle pathology (e.g. acoustic neuroma).
clusion of differential diagnoses, and the identification and reduction
People with hearing loss and tinnitus might benefit from using
of exposure to vibration at source. Diagnosis of an index case should
hearing aids, counselling, and a tinnitus-​masking device.
prompt further investigation and where possible, modification of the
The emphasis in dealing with noise-​induced hearing loss must be
system of work to prevent other cases from occurring.
on prevention. Employers whose workplaces are noisy should es-
tablish a hearing conservation programme, with commitment to a
robust ‘noise policy’, at the highest level of management. To control
noise at source, engineering controls can be used to make equip-
Introduction
ment less noisy, or processes can be redesigned to reduce noise
output. Exposure to noise can be limited by separating its source
Vibration is ‘the mechanical oscillation of a surface around its refer-
from the workers using soundproof enclosures or shelters. In the
ence point’. Workplace exposure to vibration results in local effects,
United Kingdom a limit for noise exposure has been set at 87 dB(A)
mainly on the hands when the vibration is transmitted to the upper
averaged over an 8-​h day or 140 dB(A) for any instantaneous im-
limbs. The clinical syndrome used to be termed ‘vibration white
pulse noise. Hearing protection using ear plugs or ear muffs can
finger’, highlighting the vascular features. The current term is ‘hand–​
reduce noise exposure at the ear by 3 dB(A) to 15 dB(A), but it must
arm vibration syndrome’, reflecting a combination of vascular, sen-
be fitted and used correctly to be effective.
sorineural, and musculoskeletal components. When vibration is
The diagnosis of workplace noise-​ induced hearing loss in a
transmitted to the whole body, systemic effects, mainly low back
worker should be treated as a sentinel event indicating that other
pain, result.† It is with great regret that we report that Tar-Ching Aw
workers were at similar risk and that prompt preventive measures
died on 18 July, 2017.
should be implemented. After reduction of noise at source, any re-
sidual noise exposure of workers (exceeding 85 dB(A) as defined by
the United Kingdom Control of Noise at Work Regulations 2005)
warrants health surveillance. This involves symptom review and
Exposure
annual audiometry. In some cases, it may be necessary to consider
It has been estimated that 5–​25% of the workforce in Europe is
changing jobs. Clinicians should also advise affected people about
exposed to whole-​body vibration, while up to 11% are exposed
benefits available from state compensation schemes.
to hand-​transmitted vibration. Occupational exposure to whole-​
For control of community noise and exposure to personal music
body vibration occurs in helicopter pilots, and in drivers of heavy
players, other preventive measures are required. These include
vehicles (e.g. tractors, forklift trucks, mobile cranes, and buses).
urban planning, restriction of flight paths, and flight timings for air-
ports, and innovative health education to reduce listening time and
volume of personal music players. †
It is with great regret that we report that Tar-Ching Aw died on 18 July, 2017.
1674 SECTION 10 Environmental medicine, occupational medicine, and poisoning

visual disturbances, and urinary and abdominal complaints. However,

low back pain is the only effect reliably associated with whole-​body vi-
bration. In vocational drivers, low back pain can occur as a result of
vibration, poor posture within the vehicle cab, and from additional
tasks, such as frequent handling or lifting of heavy loads.

Hand–​arm transmitted vibration

This causes secondary Raynaud’s phenomenon presenting as prom-
inent episodic digital pallor, usually on exposure to cold or following
contact with cold objects (Fig. 10.2.6.3). These symptoms often
occur in the morning, or following outdoor activity such as fishing
or gardening, especially in cold weather. The vascular changes might
be accompanied by neurological and musculoskeletal effects that con-
tribute to disability. Vascular and sensorineural effects might appear
Fig. 10.2.6.1 Exposure to vibration from grinding a metal component and progress independently. The latent period between initial exposure
against a rotating wheel with an abrasive surface.
and development of symptoms is usually 5–​10 years, but can range
from between 6 months and 20 years depending on intensity and dur-
The nature of the surface over which land vehicles are driven, as well ation of exposure. The sequence of colour changes in the affected digits
as the characteristics of the vehicle cabs, contribute to the vibration. starts with pallor, followed by a bluish hue due to cyanosis, and then
Hand–​arm vibration exposure occurs in factory workers involved redness on reversal of the vascular spasm. Reversal can be spontaneous
in fettling, chipping, grinding (Fig. 10.2.6.1), riveting, swaging, and or can follow warming of the hands. Each episode usually lasts several
using handheld pneumatic hammers, drills, chisels, and rotary tools. minutes, and there can be several episodes per day or week.
Forestry, agricultural, and wood workers using chain saws, miners Neurological effects include paraesthesia, reduced temperature
drilling rock surfaces, and construction and road workers using perception, loss of manual dexterity, and pain. Severe tingling and
drills (Fig. 10.2.6.2), and compactors are also at risk. discomfort often follow rapid warming of the hands. Loss of the ability
to distinguish and hold small objects, such as coins, or to button up
clothing causes physical and social disability. Musculoskeletal effects
Clinical effects are not as well established, although effects such as muscle weakness,
bony exostoses, carpal tunnel syndrome, and Dupuytren’s contrac-
Whole-​body vibration ture have been associated with exposure to vibration.
Exposure to whole-​body vibration has been linked to physiological
changes to the cardiovascular, respiratory, and musculoskeletal sys-
Diagnosis
tems. Clinical effects include headache, motion sickness, sleep and
The criteria for a diagnosis of hand–​arm vibration syndrome are:
• evidence of sufficient exposure to vibration; guides to the amount
of exposure to vibration from various tools are available (e.g. on the
National Institute of Working Life website, http://​umetech.niwl.se)

Fig. 10.2.6.2 Exposure to vibration in a road worker from use of a Fig. 10.2.6.3 Patient with hand–​arm vibration syndrome showing
handheld drill. prominent digital pallor.
 10.2.6 Vibration 1675

• confirmed episodic pallor of the digits and/​or sensorineural deciding on a change of job duties. An alternative scoring system
effects (the Griffin scale) summarizes severity of effect by giving a higher
• documented latent period between initial exposure to vibration score for affected terminal phalanges and the thumbs. Such scoring
and onset of symptoms 5–​10 years systems provide a more objective basis for following up patients with
• assessing the likelihood of other causes of Raynaud’s phenomenon hand–​arm vibration syndrome.
or sensory abnormalities Engineering controls can minimize the transmission of vibra-
tion from machinery to the body or hands. The Health and Safety
The presence of associated musculoskeletal features supports the Executive in the United Kingdom has defined action values and
diagnosis. Physical examination might show callosities on the limit values for exposure to vibration. Action values refer to steps
hands, loss of light touch sensation or two-​point discrimination in that have to be put in place at these exposure levels, and limit
the affected digits, and poor grip strength, although there might values are legally binding standards that should not be exceeded.
be no obvious abnormalities, especially in the early stages of the Patients with hand–​arm vibration syndrome might be able to con-
disease. tinue in the same job following reduction of exposure to vibration.
Various clinical and special tests have been used in the evalu- Workers with continuing exposure to hand-​transmitted vibration
ation of patients with hand–​arm vibration syndrome. These in- should be under regular health surveillance. Where the condi-
clude digital blood pressure measurements, vibrotactile thresholds, tion is severe and the source of vibration cannot be eliminated,
sensory aesthesiometry, and cold provocation tests. However, the redeployment should be considered. In early cases, redeployment
clinical and occupational history is of greater importance than the might arrest or reverse the progression of symptoms. In severe
results of any of these tests in the diagnosis of hand–​arm vibration cases, the disease might progress regardless of removal from fur-
syndrome. ther exposure to vibration.
The differential diagnosis should consider other causes of Advice to the patient includes avoidance or reduction of fur-
Raynaud’s phenomenon. The cause might be constitutional or ther exposure to vibration, use of appropriate gloves, keeping the
it might be secondary to rheumatoid arthritis, systemic lupus body and hands warm especially in cold weather, and cessation of
erythematosus, scleroderma, and other autoimmune disorders, cigarette smoking. Vasodilatory drugs such as tolazoline, inositol,
cryoglobulinaemia, frostbite, or thoracic outlet syndrome. Use of and cyclandelate, and calcium channel antagonists such as verapamil
ergot, clonidine, and β-​blockers, occupational exposure to vinyl and nifedipine, angiotensin-​converting enzyme inhibitors, prosta-
chloride monomer, and heavy cigarette smoking are other recog- glandins, and stanazolol have been tried with varying success. In the
nized causal factors. United Kingdom, the patient should also be advised about entitle-
ment to prescribed diseases benefits, which are awarded depending
on severity. This UK scheme is administered by the Department for
Management, treatment, and prevention Work and Pensions through local social security offices. Other coun-
tries have their own workmen’s compensation schemes for diseases
The severity of hand–​arm vibration syndrome can be staged using of occupational origin.
the Stockholm Workshop Scale (Table 10.2.6.1). This scale provides A diagnosis of Raynaud’s phenomenon should always include de-
separate staging for the vascular and the sensorineural effects. For tailed inquiry into occupational exposure to vibration. Diagnosis
example, stage ‘2L(3)/​1R(3)’ for the vascular component refers to of hand–​arm vibration syndrome should be viewed as a sentinel
three digits at stage 2 in the left hand; and three digits at stage 1 in the event warranting further investigation of the workplace to assess
right hand (i.e. stage/​hand/​number of digits). Further subdivision whether improvements in work practices can be implemented to
of stage 2 into early and late effects has been suggested as a basis for prevent the occurrence of other cases.

Table 10.2.6.1 The Stockholm Workshop Scale for hand–​arm vibration syndrome

A. Vascular component
Stage Grade Description
0 No attacks
1 Mild Occasional attacks affecting only tips of one or more fingers
2 Moderate Occasional attacks affecting distal and middle (rarely proximal) phalanges of one or more fingers
3 Severe Frequent attacks affecting all phalanges of most fingers
4 Very severe As in stage 3, with trophic changes in the fingertips
B. Sensorineural component
Stage Description
0SN Vibration-​exposed but no symptoms
1SN Intermittent numbness with or without tingling
2SN Intermittent or persistent numbness, reduced sensory perception
3SN Intermittent or persistent numbness, reduced tactile discrimination, and/​or manipulative dexterity
1676 SECTION 10 Environmental medicine, occupational medicine, and poisoning

FURTHER READING Health and Safety Executive (2016). Hand-​arm vibration exposure
­calculator.   http://​w ww.hse.gov.uk/​v ibration/​hav/​v ibrationcalc.
European Agency for Safety and Health at Work (2008). Workplace
htm
exposure to vibration in Europe: an expert review. Office of Official
Mason H, Poole K (2004). Clinical testing and management of indi-
Publications of the European Communities, Luxembourg.
viduals exposed to hand-​transmitted vibration: an evidence review.
Health and Safety Executive (2005). Hand-​arm vibration: the control
Faculty of Occupational Medicine, London.
of vibration at work regulations 2005 & guidance on regulation. HSE
Books, Sudbury.
10.3
Environment and health

CONTENTS contribute to atmospheric air pollution, although their relative im-

10.3.1 Air pollution and health 1677 portance has declined since the Industrial Revolution and the advent
Om P. Kurmi, Kin Bong Hubert Lam, and Jon G. Ayres of modern fossil fuel-​based economies.
Pollutants may be classified as (1) primary (emitted directly into
10.3.2 Heat 1687
the atmosphere) or secondary (formed in the air through chemical
Michael A. Stroud
reactions with other pollutants and gases); (2) indoor or outdoor;
10.3.3 Cold 1689 (3) gaseous or particulate.
Michael A. Stroud The main problem in determining health effects of individual air
10.3.4 Drowning 1691 pollutants is that in real life they are never experienced in isolation, but
Peter J. Fenner many large studies have shown a link between air pollution and ad-
10.3.5 Lightning and electrical injuries 1696 verse cardiovascular and respiratory outcomes. Long-​term exposure
Chris Andrews to air pollution, especially fine particulate, could also adversely af-
fect other outcomes such as diabetes, impaired cognitive function,
10.3.6 Diseases of high terrestrial altitudes 1701
preterm birth, and lower birthweight. Air pollution—​even at low
Tyler Albert, Eric R. Swenson, Andrew J. Pollard, Buddha Basnyat,
levels—​possesses significant health risk, particularly among sensitive
and David R. Murdoch
individuals. The latest Global Burden of Disease Study 2013 estimated
10.3.7 Radiation 1709 2.9 million premature deaths could be attributed to ambient air pol-
Jill Meara lution, of which 88% occurred in low and middle-​income countries.
10.3.8 Disasters: Earthquakes, hurricanes, floods, Although by definition all air pollutants are hazardous, only the
and volcanic eruptions 1713 major ones (e.g. particulate matter, sulphur dioxide, nitrogen dioxide
Peter J. Baxter
and ozone) in the atmosphere are monitored and regulated by legis-
10.3.9 Bioterrorism 1718 lation in most countries. Ambient air pollution in high-​income coun-
Manfred S. Green tries has reduced significantly in the last few decades, but further
reduction in pollutant levels will inevitably require very high cost. As
low-​and middle-​income countries are experiencing fast economic
growth, air pollution is likely to continue to be a significant con-
tributor of global morbidity and mortality in the future.

10.3.1 Air pollution and health Introduction

Om P. Kurmi, Kin Bong Hubert Lam, Concerns about air quality and its effects on health have been ex-
and Jon G. Ayres pressed for many hundreds of years. The lime burners of the 1300s
were blamed for polluting the air and John Evelyn in his famous
diary railed against the polluted air of the City of London. The do-
ESSENTIALS mestic pollution of those years was later compounded by the ad-
The term ‘occupational and environmental health’ includes any act vent of the Industrial Revolution in the 18th century, when the
of emission of any substance, likely to be hazardous in nature, which sulphurous emissions from factories were regarded as a necessary
is either not originally present or is present in a higher concentration evil meaning, as it did, jobs and payment for the working popula-
than normal in the natural atmosphere. Most air pollutants are gen- tion. This grudging acceptance remained until the London smog of
erated from human activities (e.g. energy, transportation, industry, 4–​9 December 1952 when an increase in coal being burnt in do-
agriculture), but natural events in the living (e.g. methane emissions mestic grates in a cold week together with a temperature inversion
in wetlands) and non​living environment (e.g. volcanic eruptions) also with a ‘blocking’ zone of high pressure accumulated pollutants at
street level. Within a week, 4000 excess deaths occurred during
1678 SECTION 10 Environmental medicine, occupational medicine, and poisoning

that six-​day period. In fact, a re-​assessment of the data suggested a as more studies of health effects of long-​term exposure are under-
­further 13 500 deaths in the weeks and months that followed. As a taken, the true picture of the burden due to air pollution is begin-
direct consequence, the Clean Air Act of 1956 was passed, which re- ning to unravel.
sulted in a marked reduction in particulate pollution and to a lesser
reduction in sulphur dioxide levels, such that in the late 1970s there
was a general belief that air pollution and its potential health prob- Sources and types of air pollutants
lems had been conquered. However, in the 1980s a different type
of air pollution—​nitrogen dioxide, fine particulates, and hydrocar- Very often the term ‘air pollution’ is understood to be an act of emis-
bons arising from vehicle emissions—​was realized. These pollutants sion of any substance, likely to be hazardous in nature, which is either
are not only harmful in their own right but also act as a substrate not originally present or is present in a higher concentration than
for the formation of ozone, the combination of all these pollutants normal in the natural atmosphere. While it is true that most air pol-
comprising the photochemical pollution so characteristic of Los lutants are generated from human activities (e.g. energy, transporta-
Angeles, Athens, and Mexico City, and increasingly commonly in tion, industry, agriculture), natural events in the living (e.g. methane
East and South Asia. As a result, urban dwellers worldwide are now emissions in wetlands), and non​living environment (e.g. volcanic
facing long-​term exposures to air pollution. eruptions, lightning strikes, natural radioactive decay) also con-
As we spend most of our lives indoors, indoor air quality is clearly tribute to atmospheric air pollution, but their relative importance has
equally important. In high-​income countries as well as in urban declined since the Industrial Revolution and the advent of modern
areas of low-​and middle-​income countries (LMICs) most indoor fossil fuel-​based economy, at least in high-​income countries.
levels of pollutants are driven by outdoor levels. In such settings Given the loose definition, it is not surprising that a long list of
tobacco smoke becomes the most important source of indoor pol- substances could be defined as air pollutants. They can be classified
lutant, exposure to which has been shown extensively to impart ad- by number of ways, and Table 10.3.1.1 presents three commonly
verse health effects. However, in the rural and less developed parts used criteria with further subclassifications.
of the LMICs combustion products of solid fuels, derived from bio- In the urban environment, the concentration of airborne pollu-
mass (e.g. wood, animal dung, agricultural residues) and coal for tants is usually higher outdoors compared to indoors because of the
heating and cooking purposes, dominate the scene. It has been esti- high volume of vehicular emissions. However, improved thermal
mated that nearly one-​third of the world’s population are relying on insulation and the use of air conditioning systems in modern dwell-
solid fuels, most of whom use traditional unventilated stoves of low ings may also facilitate the accumulation of indoor pollutants, par-
efficiency, producing large quantities of pollutants, particularly par- ticularly when people smoke in their homes. On the other hand, in
ticulate matter and carbon monoxide. While there has been ample LMICs, especially in the rural areas, indoor pollutant level can be
evidence to suggest the global burden of mortality and morbidity many times higher than the outdoor environment because of the use
associated with household air pollution is substantial and compar- of solid fuels for cooking and heating, a common phenomenon in
able to ambient air pollution, it has not received adequate attention unventilated dwellings.
until recently. Pollutants can also be grouped by their physical properties, often
At present the extent of the health effect(s) of these pollutants, by their state and size. Under such a classification scheme particu-
alone or in combination, are a continuing matter for research and late matter (PM), sometimes known as total suspended particulate,
debate. Although acute effects have often been deemed to be small, is a mixture of solid particles and aerosols suspended in the air with

Table 10.3.1.1 Major classifications of air pollutants

A. Primary–​secondary pollutants
a. Primary: Pollutants emitted directly into the atmosphere (e.g. SO2, some NOx species, CO, PM)
b. Secondary: Pollutants that form in the air as a result of chemical reactions with other pollutants and gases (e.g. O3, NOx, and some PM)
B. Indoor–​outdoor pollutants
a. Indoor pollutants
i. Sources: Combustion, cooking, heating, smoking, particle resuspension, building materials, air conditioning, consumer products, biological agents
ii. P
 roducts: Combustion products (e.g. tobacco and solid fuel), CO, CO2, sVOC (e.g. aldehydes, alcohols, alkanes, and ketones), microbial agents and
organic dusts, radon, manmade vitreous fibres
b. Outdoor pollutants
i. Sources: Industrial, commercial, transportation, agricultural, natural, transboundary
ii. Products: SO2, O3, NOx, CO, PM, VOC, sVOC
C. Gaseous–​particulate pollutants
a. Gaseous: SO2, NOx, ozone, CO, VOC, sVOC (e.g. PAHs, dioxins, benzene, aldehydes, 1,3-​butadiene)
b. Particulate: Coarse or thoracic particles (aerodynamic diameter 2.5–​10 µm; regulatory standard = PM10), fine PM, or respirable (0.1–​2.5 µm; regulatory
standard = PM2.5); ultrafine PM (<0.1 µm; not regulated)

SO2, sulphur dioxide; NOx, oxides of nitrogen; CO, carbon monoxide; CO2, carbon dioxide; sVOC, semi-​volatile organic compounds; PM, particulate matter; PAHs, polycyclic aromatic
hydrocarbons.
Pollutants such as particulate matter (PM), sulphur dioxide (SO2), and carbon monoxide (CO) are examples of primary pollutants which, as combustion product of fossil fuels, are
released into the atmosphere directly from sources. Secondary pollutants are formed by primary pollutants in the atmosphere. One such example is ground (tropospheric) level ozone
(as opposed to stratospheric ozone, which is naturally occurring), formed by chemical reactions of oxides of nitrogen and hydrocarbons in the presence of sunlight. Ozone is one of
the main constituents of the photochemical smog, which is typical in cities with many motor vehicles on warm sunny days.
From Bernstein JA, et al. (2004). Health effects of air pollution. Journal of Allergy and Clinical Immunology, 115(5), 1116–​23, with permission from Elsevier.
 10.3.1 Air pollution and health 1679

variations in size, composition, and origin. The major components Mortality Air Pollution Study), APHENA (Air pollution and
of PM are inorganic compounds such as sulphates, nitrates, am- health: a European and North American approach), PAPA (Public
monia, black carbon, sea salt, and mineral dust, and organic sub- health and Air Pollution in Asia), and ESCAPE (European Study of
stances including pollen and mould. Coarse or ‘inhalable particles’ Cohorts for Air Pollution Effects) studies have provided evidence
have an aerodynamic diameter of ≤10 µm (known as PM10), are showing the link between air pollution and adverse cardiovascular
chiefly derived from attrition of larger particles particularly from and respiratory outcomes (including ischaemic heart disease, stroke,
abraded soil, road dust (from brake and tyre), construction debris, heart failure, asthma, and chronic bronchitis), particularly in terms
or also from aggregation of smaller combustion particles which can of excess mortality associated with short-​and long-​term exposures.
be inhaled to the lower respiratory system. Fine or ‘respirable par- Recent evidence suggests long-​term exposure to air pollution, es-
ticles’ (aerodynamic diameter of ≤2.5 µm; PM2.5) are a subset of the pecially fine particulate, could also adversely affect other outcomes
PM10 fraction, which can penetrate deep into the lungs through the such as diabetes, impaired cognitive function, preterm birth, and
bronchioles to the alveoli where gas-​exchange takes place. Ultrafine lower birthweight.
particles are less than 100 nm in size, and may even penetrate into Indeed, the latest Global Burden of Disease Study 2017 estimated
the systemic circulation. 4.2 million premature deaths could be attributed to ambient air pol-
lution in 2015, of which more than 80% occurred in LMICs; the ma-
jority of them in the World Health Organization (WHO) Western
Measurement of a health effect Pacific and Southeast Asia regions. However, as most of the studies
investigating health effects to date have been done in high-​income
The main problem in determining health effects of individual air countries where the current air pollutant level is 15–​20-​fold lower than
pollutants is that in real life they are never experienced in isolation. that in LMICs, it raises the question whether concentration-​response
There are multiple potential interactions, not only with other air functions, primarily derived from high-​income countries, could be
pollutants, but with other factors such as weather conditions (as in extrapolated to estimate the burden in LMICs. More importantly, it
the 1952 London smog), levels of airborne allergen, the presence of is extremely difficult to ascertain and quantify the level and duration
a respiratory tract infection, exercise, diet, socioeconomic status, of exposure to airborne pollutant at both population and individual
and actively or passively inhaled cigarette smoke. Some health ef- levels with high accuracy and precision. Coexposure at the same time
fects may also be attributed to multiple risk factors at a time and to another pollutant will likely affect any physiological response as will
hence making determination of specific, pollutant-​induced health the presence of cofactors such as age, individual susceptibility (pres-
effects difficult. ence of comorbidities, concurrent respiratory tract infection, degree
There are three main ways whereby a health effect can be assessed: of bronchial responsiveness), smoking, physical activity (which in-
animal studies, challenge studies in humans, and by epidemiological creases effective lung dose due to enhanced ventilation) or diet. Such
studies (including cross-​sectional, time series, case-​crossover, and variations within and between individuals have added the complexity
cohort studies). Each has their problems but when determining na- in interpreting the findings from previous literature.
tional ambient air quality standards all available types of data may Although health effects of air pollution could be at times difficult
be taken into consideration. When determining national ambient to assess and to ascertain from observational studies, interventions
air quality standards, the aim is to try and define a no observable (often associated with pollution abatement legislations) have pro-
effect level (NOEL), that is, the level of a specific pollutant where no vided indirect evidence to support the link between air pollution and
health effect can be demonstrated. The rough rule of thumb that has adverse health outcomes. A ban on ‘smoky’ coal sale and burning
been used is to take as the standard a level one-​tenth of the NOEL in Ireland, first introduced in Dublin in 1990 and subsequently ex-
obtained from human chamber/​challenge studies or one-​hundredth tended to cities and towns nationwide, has resulted in substantial
of the NOEL determined by animal studies. Risk assessment is reductions in cardiorespiratory hospital admissions and respiratory
difficult and very largely arbitrary. Although individual risks are mortality. Associations between improved air quality and reduc-
relatively easily measurable in the workplace, when considering am- tion in mortality have also been reported following the reduction of
bient airborne pollution individual risk and public health load has sulphur content of fuel in Hong Kong in 1990. On the other hand,
not been very well characterized to date. This is partly because the conflicting findings have been reported in studies investigating the
health effects of outdoor air pollution are considerably less than the effect of low emission/​congestion charging zones on pollutant levels.
risks of active cigarette smoking or the risks of other well-​recognized Nevertheless, a study in Rome estimated that residents living near
aetiological factors (e.g. high blood pressure). Moreover, potential main roads have gained 3.4 days per person following the intro-
sources of confounding, primarily in terms of socioeconomic status duction of low emission zones in 2006. Transient changes in air
and cigarette smoking might have affected the interpretation of the quality have also been demonstrated to have measurable population
health effects of air pollution. health benefits. During the 2008 Olympic and Paralympic Games
(July–​September) the Chinese government implemented a series of
aggressive pollution control measures in Beijing and surrounding
Ambient (outdoor) air pollution and health effects areas, including restriction or complete shutdown of industrial and
construction operations and an alternative-​day driving scheme. As
Large-​scale multicity and indeed multinational studies, such as a result, large reductions in gaseous and particulate pollutant levels
the early Harvard Six Cities, American Cancer Society cohort, were achieved during this period (-​13% to -​60%) compared with the
and Adventist Health Air Pollution (AHSMOG) studies in the pre-​Olympic period. During this time, there was a significant reduc-
United States, and the more recent NMMAPS (National Morbidity tion in levels of inflammatory and thrombotic biomarkers in healthy
1680 SECTION 10 Environmental medicine, occupational medicine, and poisoning

young adults living in Beijing, but reverting to pre-​Olympic period Human challenge and animal model studies have suggested that
levels as the control measures were relaxed after the Paralympic exposure to diesel exhaust has potent inflammatory effects involving
Games. A reduction in cardiovascular mortality was also observed lung epithelial cells and alveolar macrophages. Healthy volunteers ex-
in the same period. However, it is important to note that such major posed to 300 µg/​m3 diesel exhaust or particulates for one hour in a
athletic events inevitably introduce disturbances to the normal city controlled chamber have been shown to have increased neutrophil
life, such that changes in health events might not have been entirely counts in sputum and bronchial biopsy specimens and increases in IL-​
explained by changes in air quality. 6, IL-​8, and growth-​related oncogene α-​levels, with minimal change
In the following paragraphs health effects of the major air pollu- in lung function. In patients with mild asthma, exposure to diesel can
tants will be described in some detail. increase airway hyperresponsiveness to methacholine and airway re-
sistance. Longer-​term (3 months) of higher dose of diesel exhaust in
Sulphur dioxide (SO2) animals increased airway hyperresponsiveness significantly but the ef-
SO2 comes from the combustion of sulphur-​containing fossil fuel, fect disappeared when the animals were relocated to cleaner environ-
usually in power stations and ocean-​going vessels. Emissions in ment for further 3 months. On the other hand, the mechanism leading
high-​income countries have been reduced drastically thanks to the to adverse cardiovascular health outcome is relatively unclear. It has
availability of low-​sulphur fuel and improvement in flue-​gas desul- been reported that PM exposure is associated with up-​regulation of
phurization. However, in countries with high reliance on coal, SO2 fibrinogen and platelet levels, while sequestration of red blood cells in
continues to be a major pollutant and precursor to acid rain. the lung could increase the risk of cardiac arrhythmia.
Controlled human challenge studies in both asthmatic and Epidemiological studies, particularly multicity studies, have
healthy individuals have reported that around 5 minutes’ exposure provided substantial evidence to suggest short-​and long-​term ex-
to inhaled SO2 induces rapid onset bronchoconstriction resulting posure to PM10 and PM2.5 results in increase in cardiorespiratory
in decrease in FEV1 or increase in airway resistance within 2 min- emergency room visits, hospital admissions and mortality (mainly
utes of exposure. SO2 causes tracheitis and reduces ciliary func- ischaemic heart disease and stroke). Pooled analysis from 110 time
tion in vitro, while in vivo it can cause bronchoconstriction in series studies reported for a 10 µg/​m3 increase in PM2.5 concentra-
exercising asthmatics at levels experienced in urban areas today. tion there is an 1.5% increase in daily respiratory and 0.8% increase
Non​asthmatic individuals, particularly those who are atopic, will in cardiovascular mortality, respectively. With regard to the effects
also develop bronchoconstriction with SO2 on exercise but only of long-​term exposure, the multicentre ESCAPE used data from 22
at significantly with higher exposures (≥1300 µg/​m3). This sen- European cohorts and found 7% increase in all natural cause mor-
sitivity to the effects of SO2 could have a genetic component as a tality per 5 µg/​m3 increase in PM2.5. There is also support for links
recent study among asthmatic patients spirometrically responsive between long-​term PM2.5 exposure and other endpoints, including
(>12% decrease in forced expiratory volume in 1 s (FEV1)) to ex- adverse birth outcomes (low birth weight, preterm birth, and small
posure to SO2 reported significant association between the TNF​α for gestational age), childhood respiratory disease, and impaired
promotor polymorphism and asthma. It has been estimated that neurodevelopment and cognitive function.
25% of asthmatics are sensitive to less than 0.5 ppm of SO2 while
exercising. Oxides of nitrogen (NOx)
Although among healthy adults the effect is usually short lived The major oxides of nitrogen, nitric oxide (NO), nitrous oxide
and there is a spontaneous recovery within 30 minutes of initial ex- (N2O), and nitrogen dioxide (NO2) are regarded together as NOx,
posure, in asthmatic patients, recovery could take up to 4 hours. On but it is NO2 that receives most attention as the other two have no
the other hand, a meta-​analysis of time series studies (focusing on known deleterious health effects. While one-​third of ambient NO2
short-​term effect) has found positive association in terms of hospital comes from diesel engines, the highest exposures to ambient NO2
admission as well as mortality for both cardiovascular and respira- for most individuals, however, are seen indoors in gas-​fired kitchens,
tory health outcomes. Many studies worldwide have shown chronic where levels may reach 900 µg/​m3 for short periods. A more usual
effects of sulphur dioxide on absenteeism, respiratory symptoms, indoor level is 190 µg/​m3 (100 ppb) compared to an outdoor urban
and on prevalence and mortality of chronic obstructive pulmonary level of around 60 µg/​m3.
disease (COPD). The effects of ambient levels of NO2 is a matter of much debate as
some question whether NO2 is merely an indicator of other pollu-
Particulate matter (PM10 and PM2.5) tants (particularly PM). Oxides of nitrogen can react with ammonia,
As described previously, PM comprises a wide range of particles moisture, and other compounds to form small particles and is also
or aerosols of different sizes and composition. Recent studies have a precursor to photochemical smog. An early study showed that
shown PM to have specific health effects independent of SO2, which 190 µg/​m3 NO2 increased airway responsiveness in exercising asth-
is often emitted simultaneously and the individual effects of which matics, but subsequent studies, even up to exposures of 700 µg/​m3,
were previously thought to be difficult to disentangle. In high-​ showed no effect. In a controlled chamber study, healthy smokers
income countries traffic emission, particularly diesel exhaust, is the exposed to high levels of NO2 had induced inflammatory response
main source of PM. It has been demonstrated that particle size is in the airway that was characterized by neutrophil influx and re-
negatively related to the extent of adverse health effect, probably ex- duced lymphocytes count. NO2 at very high levels are often only
plained by the high surface area to volume ratio in smaller particles, present in occupational settings, and can cause acute pulmonary
which encourages adsorption of more toxic compounds at a given oedema. Cross-​sectional and short-​term longitudinal epidemio-
mass. The small size also enables the particles to enter the systemic logical studies have shown NO2 to be associated with airway in-
circulation and into tissues and organs. flammation in healthy subjects and increase in respiratory symptoms
 10.3.1 Air pollution and health 1681

in asthma patients. Susceptible individuals living close to main roads The main sources of airborne PAHs in the outdoor environment are
are likely to have worsened respiratory symptoms leading to in- from evaporation of solvents and fuels and from combustion of car-
creased hospital admissions and premature mortality. Similar to bonaceous materials at high temperature, predominantly in emissions
PM, there is also evidence that long-​term exposure to NO2 is linked from motor vehicles. Of the different PAH species, benzene and, to
to increased cardiovascular emergency admissions and mortality, a lesser extent, benzo [a]‌anthracene, benzo[a]pyrene and dibenz[ah]
mainly due to stroke and myocardial infarction. A pooled ana- anthracene are known to be carcinogenic. With introduction of
lysis from 110 time series studies showed per unit µg/​m3 increase stricter guidelines, current ambient B[a]P concentration has reduced
in NOx would increase the risk of all-​cause, cardiovascular and from around 100 ng/​m3 in 1945 down to 0.3 ng/​m3 in high-​income
respiratory mortality by 0.17% (0.12–​0.23%), 0.11% (–​0.12–​0.35%), countries. However, the major exposure to PAHs in human is tobacco
and 0.15% (–​0.29–​0.59), respectively. smoking and burning of fuels, particularly in an indoor environment.
Benzene is present in significant quantities in cigarette smoke and, on
Ozone (O3) average, cigarette smokers take in about 2 mg/​day compared with less
Ozone is a highly reactive molecule which is formed by the action of than 0.2 mg/​day for most non​smokers, although passively exposed
ultraviolet light on NOx and hydrocarbon fragments emitted by ve- non​smokers will be exposed to approximately 60% more benzene
hicles. It is formed mostly during the summer months and tends to than non​passive non​smokers. Short-​term exposure to PAHs causes
build up over a prolonged warm spell. Levels are often higher in rural impaired lung function in asthmatics and thrombotic effects in people
areas downwind from cities as urban nitric oxide neutralizes ozone with major coronary heart diseases. Individuals in occupational set-
while the formation of ozone takes a little time as polluted air is taken tings exposed to air pollutants with a mixture of PAHs for long dur-
downwind. It is also probable that ozone enhances the formation of ations have reported increases in incidence of skin, lung, bladder, and
aerosol strong acid, thus significantly affecting the ambient pollutant gastrointestinal cancers, as well as a raised risk of cell damage via gene
mix. There is a diurnal variation with peak levels being achieved in mutation and cardiopulmonary mortality.
late afternoon. In winter, ozone levels are almost unmeasurably low
but in summer can exceed hourly values of 200 µg/​m3. Carbon monoxide (CO)
Ozone causes inflammatory changes (mainly neutrophilic) in the The major source of CO for cigarette smokers is, and will remain, cig-
bronchial mucosa at levels as low as 160 µg/​m3, at which level changes arette smoke. For non​smokers, including children, vehicle emissions
in forced vital capacity and FEV1 can be detected after an exposure of passively inhaled cigarette smoke, and indoor cooking are the main
1 hour and can persist for up to 24 hours. Individual responses to chal- contributors. Exposures are far greater in tunnels, car parks, garages,
lenge with ozone vary widely between normal and asthmatic individ- and in dense, slow moving traffic. Kerbside levels in towns are of the
uals, but asthma patients appear not to be more sensitive to the effects order of 20 µg/​m3 which, with chronic exposure, would produce a
than normal subjects. It is possible that women are more susceptible. carboxyhaemoglobin level of around 3%. WHO guidelines aim to
Repetitive exposures seem to produce a lesser response suggesting a keep blood levels of carboxyhaemoglobin to less than 2% in non-​
latency effect which is difficult to understand in view of the known smokers. In non​smokers levels of carboxyhaemoglobin rarely exceed
inflammatory effect of this gas. Summer peaks of ozone have been 3%. CO exerts its toxic effect not just by the formation of carboxy-
associated with peaks in hospital admissions for asthma in several haemoglobin but also because it shifts the oxygen dissociation curve
areas of North America. Ozone at levels which do not cause an effect to the left. As a result, blood levels of around 3.6% will reduce the time
on airway function can cause bronchoconstriction when patients are to onset of angina on exercise. The fetuses of smoking mothers might
pre-​exposed to usual ambient SO2 which suggests a potentiating effect have carboxyhaemoglobin levels up to 2.5 times that of the mother.
of air pollutants, which has great logical appeal. Ozone at 240 µg/​m3 How the fetus is able to concentrate CO and what the health effects
has also been shown to enhance the bronchoconstrictor response to might be to the fetus are unknown. Recent studies have reported that
inhaled allergen which again reinforces the very likely possibility that exposure to CO is likely to reduce the maximal exercise capacity in
current air pollutants exert their effect in a permissive way. healthy young individuals and hence reduces the time to angina and,
The large multicentre APHENA study has provided data on short-​ in some cases, the time to ST-​segment depression in people with car-
term effects of ozone. It found statistically significant associations for diovascular disease, albeit at a concentration that is lower than that
1-​hour ozone and all-​cause mortality and cardiovascular mortality. needed to reduce exercise capacity in healthy individuals.
Recent cohort analyses suggest an effect of long-​term exposure to
ozone on mortality, at least for respiratory or cardiorespiratory mor-
tality, especially in people with potential predisposing conditions. Indoor air pollution and health effects
Polycyclic aromatic hydrocarbons (PAHs) While common air pollutants are often released to the atmosphere
These form part of the total hydrocarbons, a wide range of com- from traffic, power stations, and factories, this is not to say air pollu-
pounds most of which have no known human health effect. When tion exists only outdoors. It could easily be forgotten that even in in-
considering total hydrocarbons methane is usually excluded, the re- door setting, where people could spend up to 90% of their time, there
maining hydrocarbons largely comprising alkanes. Because of their are outdoor–​indoor transfers, as well as indoor emission sources, and
association with PM, total hydrocarbons are usually expressed as because they are confined environments concentration of pollutants
parts per billion of carbon. PAHs are partitioned between the par- could be much higher indoors than outdoors. Indoor air quality can
ticulate and gas phase, the lower molecular weight molecules being be considered with respect to the domestic and occupational set-
in the gas phase. The carcinogenicity of PAHs increases with the in- tings. In high-​income countries, domestic exposures are predomin-
crease of their molecular weight, but reduction in acute toxicity. antly PM, CO, NO2, PAHs, and volatile organic compounds due to
1682 SECTION 10 Environmental medicine, occupational medicine, and poisoning

combustion (tobacco smoke and fuel for cooking/​heating), domestic stroke), and respiratory diseases (COPD, onset and exacerbations
activities (cleaning and cooking), and building and furnishing ma- of asthma, and respiratory tract infections) are the main causes of
terials (adhesives and radon) and biological pollutants (allergens mortality and morbidity. Associations with other conditions such
and moulds). From the occupational point of view, specific expos- as cognitive impairment, degenerative eye disease, and mental ill
ures which lead to occupational asthma are dealt with elsewhere but health have been reported. Its irritant effect should not be ignored as
non​specific problems, such as the ‘sick building syndrome’ will be this is likely to be the reason most people object to passive smoking.
covered next in brief. In LMICs, however, poor indoor air quality is The effect of the irritation per se has no known long-​term physical
related to the burning of solid fuels using inefficient stoves, which effects, but the effect on quality of life at home (or work) can be con-
produce very high concentrations of PM, CO, and other combustion siderable. In neonates and children, environmental tobacco smoke
products, often many folds higher than what is measured in the am- could have developmental effects (low birth weight, preterm birth,
bient atmosphere. This household air pollution affects one-​third of and sudden infant death syndrome) and respiratory effects (retarded
the world’s population and is therefore a major cause of morbidity lung function growth, lower respiratory tract infection, respiratory
and mortality globally. It is estimated that in 2013, 2.9 million pre- symptoms, and asthma onset and exacerbations).
mature deaths and 81.1 million disability adjusted life years (DALYs) Recently a new concept of ‘third-​hand smoke’ has been postulated,
can be attributed to household air pollution. India and China alone which refers to tobacco smoke residue that settles onto surfaces and
accounted for 60% of the total premature deaths. dust and re-​emitted and re-​suspended into the air. While currently
Control of indoor pollution is contentious. Most attempts are there is no direct evidence of the harmful effect of this third-​hand
aimed at increasing room ventilation rates, which have shown sig- smoke, tobacco-​specific lung carcinogen 4-​(methylnitroasmino)-​1-​
nificant improvements in odour levels and occupant satisfaction (3-​pyridyl)-​1-​butanone (NNK) has been found to be present on sur-
while air filtration, although attractive, has yet to be shown to be as faces in most homes occupied by smokers, providing rationale for
effective. In LMICs where household air pollution dominates, a wide further research in this field.
range of interventions, including use of cleaner alternative fuels (e.g. An updated Cochrane review published in 2016 examined the ef-
biogas), replacement of traditional cook stoves with more efficient fects of implementing smoking bans and found consistent evidence
ones, improving ventilation (e.g. retrofitting chimneys), and change of improving cardiovascular health outcomes and reducing mortality
in use behaviour (e.g. keeping children away from smoke), have for associated smoking-​related illnesses. Several countries have ex-
been implemented with varying levels of success. tended the smoking ban to private vehicles in the presence of chil-
Ascertainment and quantification of exposure indoors is more dren. The impact of such legislation is still too early to be assessed.
difficult than outdoors because there exist very large variations in Electronic cigarettes (e-​cigarettes) have gained popularity in re-
pollutant levels across different microenvironments (e.g. rooms cent years, either as a substitute of cigarettes or as an aid for smoking
within the same dwelling) and exposure between and within indi- cessation. While these battery-​powered nicotine vaporizers do not
viduals, determined by several factors including proximity to emis- emit combustion products of tobacco, the aerosols produced by
sion source, permeability and ventilation of the microenvironment, e-​cigarettes not only significantly increase indoor PM2.5 concen-
and time-​activity pattern of individuals. Consequently, personal ex- trations (up to 300 times), but can also contain toxicants including
posures estimated from detailed diary of indoor and outdoor time-​ glycols, aldehydes, metals, volatile organic compounds, and PAHs,
activity patterns will give a better idea of time exposure to specific some of which do not appear in cigarette smoke. Data on the health
pollutant(s) when trying to estimate a health risk. effects of exposure to e-​cigarette aerosols have been sparse. In vitro
studies have shown increases in oxidative stress and decreases in epi-
thelial cell viability 24 h after e-​cigarette aerosol exposure compared
to clean air controls. Results from small-​scale preclinical studies
Selected indoor exposures in
have been conflicting.
high-​income countries
Cooking emissions
Tobacco smoke Natural gas cooking appliances are a source of indoor NO2 and CO
The most important indoor pollutant is tobacco smoke from the and contribute to deteriorated air quality when not adequately venti-
smouldering tobacco and exhaled by smokers. Known as environ- lated. The health effects of ambient NO2 and CO have been described
mental tobacco smoke or second-​hand smoke, it is a mixture of toxic earlier, and the use of gas for cooking have also been shown to be
and carcinogenic chemicals and particulates. A smoker of 20 cigar- associated with respiratory symptoms among females. But cooking
ettes a day contributes about 20 µg/​m3 to 24-​h indoor particulate itself, which is the treatment of food with heat, would promote de-
concentrations, and in a house containing several heavy smokers the composition and volatilization of lipids and amino acids in food,
24-​h ambient air quality standard of 50 µg/​m3 for PM10 can easily be leading to emissions. The types and levels of pollutants in cooking
exceeded. Those smokers are exposed not only to mainstream smoke emissions are highly heterogeneous and depend on food ingredi-
(inhaled through the mouthpiece) but also to the environmental ents and methods of cooking (e.g. frying, grilling, and baking), but
tobacco smoke they generate (also known as sidestream smoke), generally include PM, volatile organic compounds, PAHs, and het-
which is more toxic on a weight for weight basis compared to main- erocyclic amines. Some of these compounds are known mutagens
stream smoke. As a consequence, the adverse health effects of ex- and carcinogens. A link between exposure to cooking emissions and
posure to environmental tobacco smoke are similar to those caused lung cancer has been proposed, although causality has not been to-
or exacerbated by direct smoking. In adults, cancers (particularly tally confirmed. It should be noted that all of the currently available
lung cancer), cardiovascular diseases (ischaemic heart disease and data were derived exclusively from the Chinese population.
 10.3.1 Air pollution and health 1683

Radon of the condition are substantial. The acceptance of sick building syn-
Radon-​222 is a noble gas, a natural decay product of radium-​226, drome as an entity has led to the condition playing an important role
with a half-​life of 3.8 days. It decays through four short-​lived ‘radon in new building design. In buildings already affected, modification
daughters’ to lead-​210. Two of the radon daughters, polonium-​218 of the ventilation very often produces significant improvements in
and polonium-​214, are α-​emitters. These cause bronchial mucosal symptom severity and frequency.
damage when they decay within the lung and inhalation can thus
lead to lung cancer. It has been estimated that 3–​14% of all lung Household air pollution in LMICs
cancer cases could be attributable to radon.
In the 1970s it became clear that radon is invariably present in in- In LMICs, particularly sub-​Saharan Africa and South Asia, indoor
door air. Indoor levels vary considerably and in some dwellings levels air quality is dominated by emissions from solid fuel (coal and bio-
are unacceptably high. The worldwide average indoor radon level has mass) for cooking and heating. Although the proportion of the
been estimated at 39 Bq/​m3, compared to 5–​15 Bq/​m3 outdoors. The household relying on solid fuel has decreased substantially from
main sources of indoor radon are the rock or soil on which the house 62% in 1980, 53% in 1990, 46% in 2005 to 41% in 2010, the total
is built, building materials used in the construction of the dwelling, number of people using solid fuel has remained approximately at
natural gas, and water usage. The pooling of studies from Europe, 2.8 billion in the last three decades. The types of fuel used depend
North America, and China has suggested an increase in risk of lung upon local availability and seasonality, for example, coal is predom-
cancer of 8–​13% per 100 Bq/​m3 increase in indoor radon level. inantly used in China, whereas biomass such as wood, rice husk,
twigs, charcoal, and dried animal dungs is used in India.
Biological pollutants Solid fuels are often burnt in traditional cookstoves of low energy
Allergens and moulds are the most important biological pollutants conversion efficiency without chimneys such that combustion is
found in indoor air. Excrements of pests (house dust mites, cock- usually incomplete and releases large amounts of carbon (as par-
roaches, rodents) and dander of pets (particularly cats) are powerful ticulates) and CO. Women, due to their traditional role in domestic
allergens that may lead to the development of asthma and other al- purposes in LMICs and young children, who often stay with their
lergic diseases. Several dust mite control measures (e.g. washing of mothers, are exposed to very high concentrations of air pollutants.
bed linens) have been shown to be highly effective in reducing mite The 24-​hour concentrations of PM2.5 measured in kitchen environ-
allergen, but the efficacy of these measures in preventing asthma is ment from different settings ranges from 100 to 5000 µg/​m3 which
still under debate. Removal or relocation of pets has been recom- is many folds higher compared to the WHO recommended guide-
mended as the best measure but the reluctance of owners to give up lines of 25 µg/​m3. Similarly, concentration of CO in enclosed kit-
their pets makes this difficult to implement. Air filtration as an alter- chen with little ventilation can be many folds higher than the WHO
native has been proposed but the results have not been encouraging. recommended level of 7 mg/​m3 for 24-​hour measurement. In rural
Dampness is common in dwellings around the world, especially communities where solid fuels are predominantly used for domestic
in overcrowded and poorly ventilated environments. Mould is only purposes, the air pollution from kitchen exfiltrates to outdoor
but one group of microbes that thrives in damp conditions. Its spores creating higher ambient air pollutant concentrations. In a cross-​
and fragments are potent allergens that are largely responsible for sectional study of 250 Nepalese rural homes the mean 24-​hour in-
the health effects. There is sufficient evidence to support a causal door PM2.5 concentration in the kitchen where cooking is carried out
link between dampness (and mould) and asthma development and was 455 µg/​m3, the concentration in veranda where the other family
exacerbations. However, a systematic review of trials and controlled members spend most of their time was 129 µg/​m3 and nearly 100 m
before–​after studies of the effects of repairing mould-​damaged away from house was 7.4 µg/​m3 (Fig. 10.3.1.1). This suggests indi-
buildings did not find convincing beneficial effect (reduction) in viduals using cleaner fuels but living in a community where solid
asthma-​related symptoms and respiratory infections. fuels are used are also likely to be exposed higher air pollution.
Like cigarette smoke, biomass smoke is a concentrated cocktail
Sick building syndrome of chemicals, the toxicity of which is dependent on the type of fuel.
In the early 1970s, illness or symptom complexes were recognized as Animal studies suggest short-​term wood smoke exposure could af-
being related to occupancy of certain buildings. Sick building syn- fect the physiology of the larynx, airway, and alveoli. Biomass smoke
drome is characterized by an increased prevalence in a particular also contains high levels of reactive oxygen species, causing inflam-
building of a range of non​specific symptoms typical of mucosal ir- matory response and DNA damage in vitro. Emissions arising from
ritation (e.g. sore/​dry eyes, sore nose, dry mouth, sore throat) often coal burning have been classified as definite carcinogens and those
with lethargy and headaches. Symptoms usually disappear as soon from biomass fuels as probable carcinogens. There have been very
as an affected individual leaves the building, but a 12-​year follow-​ few controlled biomass smoke-​exposure studies in humans, but acti-
up on 239 diagnosed Swedish patients found that symptoms could vation of circulating platelets, neutrophils, and monocytes has been
be long-​lasting with significant impact on their social life. Indoor reported with high levels of leukocyte-​platelet aggregates in chron-
environmental parameters such as ventilation, temperature, relative ically biomass smoke-​exposed individuals.
humidity, and indoor chemical (e.g. formaldehyde, volatile organic Long-​term exposure to coal smoke has been associated with over
compounds) levels have been proposed as risk factors but there does 130% increased risk of lung cancer and over threefold increase in
not appear to be a consistent relationship of presence of severity of nasopharyngeal cancer compared to unexposed individuals. PAHs,
symptoms. Symptoms are usually reported more often by women particularly benzo[a]pyrene, appear to be directly involved in car-
than men. It was initially believed that the problem of sick building cinogenesis, as they are readily absorbed through the respiratory
syndrome was minor, but it is now recognized that the financial costs tract, gastrointestinal tract, and skin and circulated systemically.
1684 SECTION 10 Environmental medicine, occupational medicine, and poisoning

(a) childhood and ultimately in adulthood, but this needs to be con-

firmed in long-​term prospective cohorts.
Although the association between cardiovascular diseases and
ambient air pollution has been well established, there is no direct
evidence to conclude the same with household air pollution. Few
short-​term observational studies have reported increased sys-
tolic and diastolic blood pressure, elevated oxidized low-​density
lipoprotein, significant increase in platelet aggregation, platelet
P-​selectin expression, raised anticardiolipin IgG and IgM anti-
bodies, increased mean carotid intima-​media thickness and in-
creased prevalence of atherosclerotic plaques among those exposed
to biomass smoke. A randomized controlled trial reported reduced
ST-​segment depression among those who received improved cook
stoves, hinting exposure to wood smoke could affect ventricular
repolarization.
Other endpoints such as adverse pregnancy outcomes and peri-
(b) natal risks (birth defects, low birthweight, and sepsis), and impaired
physical and cognitive development in children have been reported.
Biomass users, especially in rural communities, often spend con-
siderable amount of time collecting firewood and are likely to have
injuries from falls and muscloskeletal problems. A significant in-
creased risk of cataract and teary eyes among biomass smoke-​ex-
posed individuals have also been reported.
Switching to cleaner fuels, such as electricity, is the most effective
intervention but this option is not always feasible. Adoption of im-
proved cookstoves that are more efficient is a viable alternative. At
present, 27% of the total population using solid fuels have access
to improved cookstoves, most being in China (70%). Major pro-
jects have been launched to produce and disseminate improved
cookstoves on a global scale. A recent systematic review examined
the effect of stove interventions and concluded while most studies
reported a reduction of household air pollution particularly PM and
Fig. 10.3.1.1 Household air pollution in kitchen. (a) A man cooking CO levels, they were not enough to meet WHO air quality recom-
food on traditional stove without chimney using wood; (b) a cot hanging mendations. Nevertheless, reductions in self-​reported respiratory
from the kitchen ceiling where an infant is usually kept when the mother and non​respiratory symptoms among those who received im-
is performing the cooking activities. proved cookstoves have been found. On the other hand, there was
Photos taken by Om P Kurmi.
no conclusive evidence of improvement in objective measures of
lung function and birth weight. The results from these intervention
There is good evidence to suggest that exposure to wood smoke studies highlighted importance of user behaviour and compliance
is associated with an increased risk of COPD even among never (e.g. exclusive use of improved cookstoves above traditional op-
smokers. A meta-​analysis reported 80% of excess risk of COPD tions) and the long-​term proper maintenance of the stoves.
and 132% of excess risk for chronic bronchitis among those ex-
posed to household air pollution compared to those who used
clean fuel for cooking. It has been suggested that the mechanism Air quality guidelines and standards
of how biomass smoke develop COPD might be similar to that
of cigarette smoking. Both are generated from the combustion Although by definition all air pollutants are hazardous, only the
of plant materials, which generates complex carbon-​based par- major ones (e.g. PM, SO2, NO2, and ozone) in the atmosphere are
ticles coated with PAHs and irritant gases such as formaldehyde monitored and regulated by legislation in most countries. While no
and acrolein and this could increase the expression of some of threshold concentration has been identified below which air pollu-
the matrix metalloproteinases as in the case of tobacco smoke. tion has no effect on population health, different limits and target
In children, exposure to biomass smoke (average PM10 level up values have been proposed by various international organizations
to 1000–​2000 µg/​m3) increases acute lower respiratory infections. and national governments, driven by a basket of factors including
The underlying mechanism by which biomass smoke predisposes scientific evidence of adverse health effect, cost, feasibility, and pol-
individuals to respiratory infections is unknown, although evi- itical will. In most cases, the national guidelines in LMICs tend to
dence from controlled chamber study suggested biomass com- be more relaxed compared to those in the high-​income coun-
bustion may enhance susceptibility to bacterial pneumonia. Early tries. Table 10.3.1.2 shows three most widely used contemporary
life exposure to household air pollution might be associated with guidelines and standards from the WHO, the US Environmental
reduced lung function and increased respiratory symptoms in Protection Agency (US EPA), and the European Union (EU).
 10.3.1 Air pollution and health 1685

Table 10.3.1.2 Various major national and international guidelines on major air pollutants

Pollutants Mean concentration allowed when averaged over timea

10-​min 1-​hr 8-​hr 24-​hr Annual
PM10 (µg/​m3)
WHO –​ –​ –​ 50 20
US EPA –​ –​ –​ 150a
EU –​ –​ –​ 50 40
PM2.5 (µg/​m3)
WHO –​ –​ –​ 25 10
US EPA –​ –​ –​ 35 Ϯ 12† or 15‡
EU –​ –​ –​ –​ 25
3
Nitrogen dioxide (µg/​m )
WHO –​ 200 –​ –​ 40
#
US EPA 190 –​ –​ –​ 99.7
EU –​ 200 –​ –​ 40
3
Ozone (µg/​m )
WHO –​ –​ 100 –​ –​
US EPA –​ –​ 140## –​ –​
EU 120
Sulphur dioxide (µg/​m3)
WHO 500 –​ –​ –​ 20
US EPA –​ 200 b –​ –​ –​
EU –​ 350 –​ 125 –​
Ϯ
a
Not to be exceeded more than once per year over three years; 98th percentile averaged over 3 years; Primary pollutant: Annual mean averaged over 3 years; ‡ Secondary
†

pollutant: Annual mean averaged over 3 years; # 98th percentile of 1-​hour daily maximum concentration, averaged over 3 years; ## Annual fourth-​highest daily maximum 8-​hour
concentration, averaged over 3 years; b Primary pollutant: 99th percentile of 1-​hr daily maximum concentration, averaged over 3 years. The latest guidelines used in tables can be
obtained from WHO (http://​apps.who.int/​iris/​bitstream/​10665/​69477/​1/​WHO_​SDE_​PHE_​OEH_​06.02_​eng.pdf); US EPA (http://​www3.epa.gov/​ttn/​naaqs/​criteria.html) and EU
(http://​ec.europa.eu/​environment/​air/​quality/​standards.htm) webpages.

In contrast, indoor air quality is not normally regulated, except issued non​legal binding guidelines based on health risk of damp-
for airborne pollutants generated in the workplace, the standards ness and mould (WHO 2009) and common chemicals found in
of which are enforced separately by occupational safety and health indoor environment (WHO 2010), but the adoption of such guide-
regulations beyond the scope of this Section. Certain countries lines has not been widespread in its member states. WHO has also
have set up emission standards of volatile compounds (e.g. formal- developed air quality guidelines on household air pollution, par-
dehyde) from building and interior furnishing materials, primarily ticularly to those using solid fuel for cooking. The guideline is sum-
aiming to control the associated sick building syndrome. WHO has marized in Table 10.3.1.3.

Table 10.3.1.3 Summary of published WHO air quality guideline values for household air pollution

Pollutant Mean concentration over averaging time Unit risk Comments

(unit for guidelines)
15 min 30 min 1 hour 8 hours 24 hours 1 year
PM2.5 (µg/​m3) –​ –​ –​ –​ 25a 10 –​ 24–​hour guideline not to
exceed max. 3 days/​year
PM10 (µg/​m3) –​ –​ –​ –​ 50a 20 –​ 24–​hour guideline not to
exceed max. 3 days/​year
Benzene (risk of leukaemia per 1 µg/​m3) –​ –​ –​ –​ –​ –​ 6.0 × 10–​6 No safe level
3
Carbon monoxide (mg/​m ) 100 –​ 35 10 7 –​ –​ –​
Formaldehyde (mg/​m3) –​ 0.1 –​ –​ –​ –​ –​ –​
3
Naphthalene (mg/​m ) –​ –​ –​ –​ –​ 0.01 –​ –​
Nitrogen dioxide (µg/​m3) –​ –​ 200 –​ –​ 40 –​ –​
b 3
PAHs (risk of lung cancer per 1 ng/​m ) B[a]‌P –​ –​ –​ –​ –​ –​ 8.7 × 10 –​5
No safe level
a
The 24-​hour average values for PM10 and PM2.5 refer to the 99th percentile of the distribution of daily values (i.e. the fourth next highest value of the year).
b
PAHs, polycyclic aromatic hydrocarbons, B[a]‌P, benzo[a]pyrene: In view of the difficulties in developing guideline for PAH mixtures, B[a]P was considered to represent the best single
indicator compound.
 1686

Table 10.3.1.4 The Daily Air Quality Index, showing exposure concentration and accompanied health messages (accessed from http://​uk-​air.defra.gov.uk/​)

Air pollution index bands Low Low Low Moderate Moderate Moderate High High High Very high
(value) → (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)
Pollutants Sampling time Concentration of specific pollutants at different air pollution index bands
(µg/​m3)
PM10 24-​hr mean 0–​16 17–​33 34–​50 51–​58 59–​66 67–​75 76–​83 84–​91 92–​100 ≥101
PM2.5 24-​hr mean 0–​11 12–​23 24–​35 >36–​41 >42–​47 >47–​53 54–​58 59–​64 65–​70 ≥71
SO2 15-​min mean 0–​88 89–​177 178–​266 267–​354 355–​443 444–​532 533–​710 711–​887 888–​1064 ≥1065
NO2 1-​hr mean 0–​67 68–​134 135–​200 201–​267 268–​334 335–​400 401–​467 468–​534 535–​600 ≥601
O3 8-​hr mean 0–​33 34–​66 67–​100 101–​120 121–​140 141–​160 161–​187 188–​213 214–​240 ≥241
Accompanying health Enjoy your usual outdoor activities. Adults and children with lung problems, and Adults and children with lung problems, and Adults and children with lung
messages for individuals adults with heart problems, who experience adults with heart problems, should reduce problems, adults with heart
at risk symptoms, should consider reducing strenuous physical exertion, particularly problems, and older people,
strenuous physical activity, particularly outdoors. outdoors, and particularly if they experience should avoid strenuous
symptoms. People with asthma may find they physical activity. People with
need to use their reliever inhaler more often. asthma may find they need
Older people should also reduce physical to use their reliever inhaler
SECTION 10 Environmental medicine, occupational medicine, and poisoning

exertion. more often.

Accompanying health Enjoy your usual outdoor activities. Enjoy your usual outdoor activities. Anyone experiencing discomfort such as sore Anyone experiencing
messages for the general eyes, cough, or sore throat should consider discomfort such as sore eyes,
population reducing activity, particularly outdoors. cough, or sore throat should
consider reducing activity,
particularly outdoors.

PM10, particulate matter less than 10 µm aerodynamic diameter; PM2.5, particulate matter less than 2.5 µm aerodynamic diameter; SO2, sulphur dioxide; NO2, nitrogen dioxide; O3, ozone.
 10.3.2 Heat 1687

Air quality index

10.3.2 Heat
Based on the air quality guidelines, government agencies around Michael A. Stroud
the world have drawn up variations of air quality index to commu-
nicate information about real-​time and short-​term forecast levels
of air pollution and its possible associated health effects to the
ESSENTIALS
public. In the United Kingdom, on the advice of the Committee
on Medical Effects of Air Pollutants (COMEAP), the Department Rising body temperature triggers behavioural and physiological
for Environment Food and Rural Affairs (Defra) uses pollutant responses including reduction in physical activity, alterations of
(PM10, PM2.5, SO2, NO2, and ozone) concentration data obtained clothing, skin vasodilatation, and sweating. Heat-​related illness is
from its national monitoring network and computer based models relatively common, especially with high humidity or prolonged
to derive a health-​based Daily Air Quality Index, which provides physical activity. Risk can be reduced by acclimatization with re-
recommendations on the actions to be taken by the public based peated heat exposure, but some individuals seem to be particularly
on the current and forecasted (next day) air pollution levels. susceptible.
The Daily Air Quality Index is a 10-​point scale divided into four Clinical presentations of heat-​related illness include (1) ‘heat ex-
colour-​coded bands: low (1–​3), moderate (4–​6), high (7–​9), and haustion’—​the commonest manifestation, with symptoms including
very high (10) (Table 10.3.1.4). Members of the public will first de- nausea, weakness, headache, and thirst. Patients appear dehydrated,
termine whether they are at risk from air pollution (from the add- complain of being hot, and are flushed and sweaty. Treatment re-
itional information accompanying the Daily Air Quality Index), quires rest and fluids, given orally or (in severe cases) intravenously.
and read the health messages corresponding to the pollution band (2) ‘Heat stroke’ victims often complain of headache, may be drowsy
for recommended actions (e.g. reducing physical exertion). The or irritable, and may claim to feel cold. Core temperature is usually
main objective behind this is the prevention of adverse health ef- 38–​41°C, but the patient is shivering with dry, vasoconstricted skin.
fects from short-​term elevations in air pollution. It is anticipated Treatment requires (a) aggressive rapid cooling—​tepid water and fan-​
that such a forewarning system could help sensitive individuals to assisted evaporation in the first instance, with more invasive meas-
modify their behaviour to reduce their individual exposure to the ures (e.g. intraperitoneal fluids, if required); (b) close biochemical
pollution, or reduce the severity of their symptoms. monitoring; (c) supportive care for organ failure. There is significant
mortality.

FURTHER READING
Atkinson RW, et al. (2015). Fine particle components and health—​ Thermoregulation in the heat
a systematic review and meta-​ analysis of epidemiological time
series studies of daily mortality and hospital admissions. J Expo Sci Most of human evolution took place in Africa and hence all hu-
Environ Epidemiol, 25, 208–​14. mans are heat tolerant. We try to maintain a near-​tropical micro-
Brunekreef B, Holgate ST (2002). Air pollution and health. Lancet, climate against our skin, by using clothing to reduce heat loss to our
360, 1233–​41. surroundings. Thermal balance is regulated by the hypothalamus,
Cohen AJ, et al. (2017). Estimates and 25-year trends of the global burden which integrates information from skin temperature sensors with
of disease attributable to ambient air pollution: an analysis of data from core temperature data from receptors within walls of large blood
the Global Burden of Diseases study 2015. Lancet, 389, 1907–18.
vessels and the brain. Rising temperatures trigger both behavioural
Gauderman WJ, et al. (2015). Association of improved air quality with
and physiological responses.
lung development in children. N Engl J Med, 372, 905–​13.
Behavioural changes include reducing physical activity, altering
GBD Risk Factors Collaborators (2015). Global, regional, and national
comparative risk assessment of 79 behavioural, environmental and clothing, and seeking shade or cool shelter. Cold drinks are also
occupational, and metabolic risks or clusters of risks in 188 coun- helpful. Although these responses seem simplistic, decisions may
tries, 1990–​2013: a systematic analysis for the Global Burden of not be straightforward. If physical activity is low and water is in
Disease Study 2013. Lancet, 386, 2287–​323. short supply, it is better to increase clothing cover and protect your-
Gordon SB, et al. (2014). Respiratory risks from household air pollution self from high radiant heat inputs. If activity must be continued
in low and middle income countries. Lancet Resp Med, 2, 823–​60. and water is freely available, minimal clothing to permit maximal
Kurmi OP, Lam KBH, Ayres JG (2012). Indoor air pollution and sweat evaporation is preferable. Immediate physiological responses
the lung in low-​and medium-​income countries. Eur Resp J, 40, involve vasodilatation of skin and subcutaneous blood vessels to
239–​54. enhance surface heat loss from radiation, conduction, and convec-
Pope CAI, Ezzati M, Dockery DW (2009). Fine-​particulate air pollution tion. The vasodilatation is triggered by a sympathetic cholinergic
and life expectancy in the United States. N Engl J Med, 360, 376–​86. reflex in response to skin warming, with additional direct effects
Soule EK, et al. (2017). Electronic cigarette use and indoor air quality
of heat on arteriolar tone. In a resting person, skin vasodilatation
in a natural setting. Tob Control, 26, 109–​12.
can maintain thermal equilibrium in environmental temperatures
Thomas E, et al. (2015). Improved stove interventions to reduce
up to 32°C, but with higher temperatures or heat production from
household air pollution in low and middle income countries: a de-
scriptive systematic review. BMC Public Health, 15, 1–​15. activity, core temperatures will rise. This will trigger sweating to
promote evaporative cooling.
1688 SECTION 10 Environmental medicine, occupational medicine, and poisoning

dehydrated with a tachycardia and low blood pressure. If hyper-

Heat acclimatization
thermic, the casualty should be complaining of feeling hot and will
appear flushed and sweaty. The absence of these symptoms and signs,
Repeated heat exposure can increase our capacity to lose heat by
especially with a very high core temperature, suggests heat stroke.
about 20-​fold. This is partly due to greater skin blood flow from in-
Heat exhaustion is ascribable to sodium and/​or water depletion, but
creases in circulating volume and improved vasodilatory responses,
discriminating between these can be difficult. Sodium depletion tends
but changes in sweating responses are more important. In the
to be greater if the casualty was poorly acclimatized and hence sweated
non​acclimatized, sweating is triggered by a rise in core tempera-
relatively more sodium than water. Conversely, water depletion is more
ture of about 1°C and maximum rates are limited to about 0.5 litre/​
common in acclimatized individuals. Muscle cramps or whole-​body
h. Following acclimatization, a 0.5°C core rise will trigger the re-
dehydration without marked changes in haematocrit or serum proteins
sponse and sweat rates may exceed 2.0 litre/​h. Acclimatization also
are suggestive of excessive sodium loss, but serum sodium tends to be
leads to aldosterone-​mediated reductions in sodium loss in both
normal in such cases unless enthusiastic fluid replacement without
sweat and urine. The acclimatized individual therefore requires no
salt has led to hyponatraemia. This sometimes occurs in runners after
sodium supplementation and giving supplements can delay the ac-
completing marathons in hot environments. In predominantly water-​
climatization process. Avoiding them altogether, however, risks salt
depleted heat exhaustion, haematocrit, serum proteins, and serum so-
depletion in non​acclimatized persons during prolonged heat stress.
dium tend to be high. Renal impairment occurs in either form of heat
Acclimatization develops swiftly and around 90% of maximum heat
exhaustion and the treatment of both types often requires 5–​10 litres of
tolerance is present after 7–​10 days, on which core temperature has
oral or intravenous fluids in the first 24 h. Sodium supplementation is
risen by more than 1°C for more than 1 h. Physical exertion com-
given as appropriate, but if sodium status is uncertain, it is usually safer
bined with heat makes the changes even more rapid. After returning
to provide some than to precipitate acute hyponatraemia.
to cool environments, adaptation is lost in 20–​40 days.

Heat stroke
Susceptibility to heat-​related illness
Mild heat stroke has occurred when a hot environment or high ac-
Although we are generally heat tolerant, heat-​related illness is rela- tivity levels have led to pyrexia with cerebral disturbance. Core tem-
tively common, and several factors increase vulnerability. Above perature is usually 38–​41°C. The condition frequently follows heat
an environmental temperature of about 35°C, we tend to gain exhaustion but temperature may have risen rapidly allowing no time
heat from our surroundings, and this, along with metabolic heat for salt or water depletion. Sufferers have headaches and may be ei-
production, can only be lost via evaporation of sweat. Hot envir- ther drowsy or irritable. They often hyperventilate. The great danger
onments with high humidity are therefore the greatest threat. is progression to more severe heat stroke, in which core tempera-
Acclimatization status has a marked influence on heat-​related risks, ture reaches levels that cause irreversible denaturing of proteins.
the unacclimatized being prone to hyperthermia and salt depletion, This usually occurs at above 41.5°C. Damage is widespread and par-
while the fully acclimatized are vulnerable to dehydration from high ticularly affects brain, liver, kidney, and muscle. Furthermore, the
sweat rates. Dehydration in itself limits sweating capacity and skin hypothalamic thermoregulatory centre may fail, switching off vaso-
blood flow and hence increases risks. It can occur easily since thirst dilatation and sweating, and switching on cold defences inappropri-
is a poor trigger for adequate drinking. Sweat rates in the acclima- ately. Patients may therefore claim to feel cold and on examination
tized can also exceed gut capacity for water absorption. may be shivering with a dry, vasoconstricted skin. A disastrous vi-
Prolonged physical activity can cause heat illness under quite cious cycle of increasing temperatures can then ensue.
modest environmental conditions. This is particularly common Treatment for all heat stroke requires early recognition and rapid
when individuals are obliged to wear clothing that is insulative or cooling. Tepid water and fan-​assisted evaporation may be more ef-
vapour-​impermeable. Military heat casualties are sometimes due fective than immersion in cold water, which can limit heat loss by
to these factors, but there have also been fatalities in soldiers who stimulating intense peripheral vasoconstriction. Intraperitoneal
have been susceptible to heat for no obvious cause. Such genetic or fluids, paralysis, and ventilation may be needed and, in extreme
constitutional vulnerability should be suspected whenever a heat-​ circiumstances, cooling by cardiac bypass should be considered.
related problem occurs following relatively modest heat stress. These Hyperkalaemia, hypocalcaemia, acidosis, rhabdomyolysis, dissem-
people should be strongly advised to avoid similar circumstances inated intravascular coagulation, and hepatic or renal failure are
in future. Obesity and poor physical fitness are further risk factors common complications. Ventricular fibrillation is a frequent ter-
in the heat, as is diabetic autonomic dysfunction. Older people are minal event. Even if apparently resuscitated and cooled success-
generally heat sensitive and, in addition, are prone to problems from fully, a 12-​to 24-​h ‘lucid interval’ may precede major deterioration.
the increased circulatory demands of vasodilatation. Drugs can also Permanent neurological damage is common.
induce heat illness (see following paragraphs).

Drug-​induced heat illness

Heat exhaustion
Many drugs can cause mild degrees of pyrexia by inducing local or
Most casualties in hot environments suffer from heat exhaustion. systemic inflammation or hypersensitivity. Some also increase sus-
There is usually a history of prolonged heat stress followed by nausea, ceptibility to environmental heat by inhibiting central thermoregu-
weakness, headache, thirst, and sometimes collapse. Patients appear lation (e.g. barbiturates and phenothiazines) or reducing sweating
 10.3.3 Cold 1689

capacity (e.g. anticholinergics). Salicylate overdose can generate

Hypothermia
heat stroke by increasing metabolic heat production while impairing
hypothalamic regulation. There are two types of heat-​related drug This occurs especially with wind and wetting, and is seen indoors
reactions, however, which are particularly dangerous. in older people and those who are thin. At a core temperature of
35°C, victims complain of cold, act appropriately, shiver, and are
Malignant hyperpyrexia peripherally vasoconstricted, but with further cooling they may be-
This is usually a dominantly inherited condition, although dif- come confused or drowsy and appropriate physiological responses
ferent gene defects may affect families. Administration of a disappear. Coma occurs at 26–​32°C, and death typically at 17–​26°C.
variety of anaesthetic agents, including halothane and suxameth- General investigation and management is as for any comatose pa-
onium, leads to rapid, massive heat production from generalized tient, but specific issues include (1) accurate measurement of core
increases in skeletal muscle tone. Contraction is triggered at the temperature requires a low-​reading rectal thermometer; (2) meas-
muscle cell membrane and hence neuromuscular blocking agents urement of serum amylase (risk of pancreatitis) and creatine kinase
are ineffective. Intravenous dantrolene, an inhibitor of muscle (risk of rhabdomyolysis); (3) rewarming—​if onset of cooling was pro-
calcium flux, is helpful and can be used along with ventilation longed, rewarming should generally be slow; (4) diagnosis of death—​
and cooling/​supportive measures. Fatalities are common, and it is apparently dead victims should be rewarmed whenever possible
therefore important to avoid risks whenever possible. In patients before resuscitation is abandoned.
with a relevant personal or family history, in whom an anaesthetic Non​freezing cold injury
is unavoidable, oral dantrolene should be given prior to the use of
This occurs when skin temperatures below 12°C are maintained for
low-​risk agents.
prolonged periods, particularly in water (e.g. trench foot). This causes
Neuroleptic malignant syndrome local tissue damage, particularly to nerves, which can be permanent.
This condition has similarities to malignant hyperpyrexia but is in- Frostbite
duced by idiosyncratic reactions to normal doses of antidopaminergic Frozen tissues initially appear hard, white, and anaesthetic, but with
drugs, including phenothiazines and butyrophenones. The onset is rewarming become swollen, painful, and blistered. There may be ir-
less rapid than malignant hyperpyrexia, occurring over a few days. reversible necrosis, but initial appearances can be misleading and
The increased muscle tone is also induced presynaptically and hence hence early amputation should be avoided. Once thawed, frostbite
neuromuscular blocking agents help. Some recreational drugs, such treatment is similar to that for burns.
as ecstasy, can induce this type of response, although most cases
of ecstasy-​induced hyperthermia are probably cases of heat stroke
induced by enthusiastic dancing with limited fluid intake in hot,
humid environments. Thermoregulation in the cold

It has only been 10 000 to 15 000 years since ancestral humans dwelt
FURTHER READING exclusively in warm or hot climates. Humans are therefore poorly
Bouchama A, Knochel JP (2002). Heat stroke. N Engl J Med, 346, adapted to cold, and hypothermia occurs quite frequently even in
1978–​88. temperate regions. With water immersion it may occur even in the
Hodgson P (1991). Malignant hyperthermia and the neuroleptic ma- tropics. In truly cold areas, there is also the risk of non​freezing cold
lignant syndrome. In: Swash M, Oxbury J (eds) Clinical neurology, injury and frostbite. Nevertheless, behavioural changes allow us to
pp. 1344–​5. Churchill Livingstone, Edinburgh. operate safely even in the coldest environments.
Hubbard RW, Armstrong LE (1988). The heat illnesses: biochemical, Core temperatures in the cold are usually maintained by ad-
ultrastructural, and fluid-​electrolyte considerations. In: Pandolf justments in clothing and physical activity. The latter can increase
KB, Sawka MN, Gonzalez R (eds) Human performance physiology heat production from a resting 100 W to 1–​2 kW. This is very ef-
and environmental medicine at terrestrial extremes, pp. 305–​59.
fective. Although it takes highly specialized, multilayered clothing
Benchmark, Indianapolis, IN.
to keep warm while inactive in an environment of +5°C, clothing
insulation equivalent to normal office dress (1 clo) will maintain
core temperature even in an environment of –​20°C when working
moderately hard.
Our limited physiological cold protection is under hypothalamic
control. Falling surface and, to a lesser extent, core temperatures lead
10.3.3 Cold to decreased blood flow in the skin due to increased sympathetic ad-
renergic tone and direct cooling effects of cold on skin arterioles.
Michael A. Stroud This minimizes surface heat loss. Unfortunately, vasoconstriction
also leads to severe cooling of the hands and feet with problems of
temporary skin numbness, muscle weakness, and risks of more per-
ESSENTIALS manent peripheral cold injury. It is often this peripheral cooling that
Humans are poorly adapted to cold, which can cause hypothermia, limits our capacity to work in the cold.
non​freezing cold injury, and frostbite. Falling skin temperatures will also lead to higher resting muscle
tone and shivering, especially when declining core temperature
1690 SECTION 10 Environmental medicine, occupational medicine, and poisoning

releases hypothalamic inhibition of shivering. These mechanisms in a cool environment). Drugs that impair consciousness or induce
can only increase resting heat production to around 500 W and, vasodilatation are risk factors, and alcohol is particularly hazardous.
unlike newborn infants and some other mammals, adult humans Alcoholics with no fixed abode and a tendency to hypoglycaemia are
cannot add significant non​shivering heat production to this figure. frequent urban cold casualties.

Effects of falling core temperature Hypothermic illness

Falling core temperature leads to progressive decline in function. At General management of the hypothermic casualty is similar to that
34–​36°C, hypothermic individuals are conscious of feeling cold and for any comatose or semicomatose person. Abnormalities in blood
try to move around, add clothing, or seek shelter. Simultaneously, gases, pH, electrolytes, and glucose are common, and pancreatitis
physiological defences are activated. With further falls of tempera- or rhabdomyolysis are recognized complications. Accurate meas-
ture, mental and physical problems increase. Some people become urement of core temperature is surprisingly difficult. Axillary, tym-
withdrawn while others exhibit aggression or disinhibition. Once panic, and oral temperatures can all be misleading. A low-​reading
core temperatures reach 33–​34°C, victims often stagger and be- rectal thermometer is best. Hypothermia has one very specific risk.
come confused or drowsy. It is also around this point that ‘paradox- Pronouncement of death is fraught with difficulty since profound
ical undressing’ may occur. This phenomenon is well described and bradycardia, minimal stroke volume, and marked respiratory de-
appears to be due to hypothalamic dysfunction with alteration of pression occur. The old adage that you are ‘never dead unless warm
set-​point temperature. Victims therefore feel warm or even hot and and dead’ must be taken seriously.
appropriate behavioural and physiological responses disappear. At A variety of rewarming methods are available. Warm blankets and
core temperatures varying between 26 and 32°C coma will ensue, hot drinks will suffice in many cases but, although they are widely
and between 17 and 26°C cardiac output becomes inadequate to used, metallized ‘space blankets’ are of no proven benefit. Warmed
sustain life for prolonged periods. The risk of ventricular fibrilla- intravenous fluids are helpful and, in extreme cases, peritoneal
tion is also high. Nevertheless, successful resuscitations of victims warmed fluids or cardiac bypass can be used. Specialized equipment
with core temperatures below 15°C have been reported (see also providing heated, humidified air also permits core rewarming. Hot
Chapter 9.5.3). baths are effective but difficult to use safely since a paradoxical fall
in core temperature can occur as blood flow is rapidly restored to
cold limbs. In general, if cooling was prolonged in onset or duration,
Causes of hypothermia rewarming must be undertaken with extreme caution. In critical
cases, where rapid rewarming is needed, full resuscitation facilities
Several factors increase hypothermic risk. Wetting of skin or must be available, although safe defibrillation in the presence of
clothing extracts enormous amounts of heat and reduces insulation water is impossible.
of garments. Complete immersion is particularly hazardous and Careful monitoring during rewarming is vital. Blood volumes
worldwide more than 100 000 people per year die of cold shock or are often low due to early cold-​induced diuresis, followed by the in-
inexorable hypothermia in the water. This far exceeds deaths from ability of hypothermic kidneys to retain salt and water. In immer-
drowning without cold. Winds also increase environmental cooling sion casualties, hydrostatic effects on the limbs may have promoted
and a still air temperature of +5 °C equates to –​50 °C if wind speed is additional fluid loss and, if possible, these people must be kept re-
40 km/​h. Coupled with rain, these effects often contribute to hypo- cumbent throughout rescue and rewarming to minimize risks from
thermic accidents among hill walkers and mountaineers, although extreme postural hypotension. Warming cell membranes are ex-
in these cases fatigue may contribute. Prolonged exertion depletes tremely unstable, and uncontrollable fluxes in potassium and other
muscle glycogen which reduces heat production capacity from both electrolytes may occur, although care must be taken in interpreting
exercise and shivering. Low blood glucose also impairs hypothal- biochemical results from cold peripheral blood sampling.
amic temperature control.
Small, thin people cool easily because of their increased
surface-​to-​volume ratios. They also have reduced subcutaneous Non​freezing cold injury
insulation and low heat-​producing mass. A fat person can main-
tain core temperature at rest, even if mean skin temperature is Local temperatures of less than 12°C prevent normal membrane
12°C, whereas a thin person struggles to maintain thermal equi- pumping and paralyse nerve and muscle conduction. If such
librium with a skin temperature of 25°C. However, rapid cooling cooling is prolonged, permanent damage may ensue. Immersion in
can sometimes have benefits. A small child in cold water may cool cold water is particularly likely to cause this type of damage and
so rapidly that vagally triggered bradycardia and lowered brain soldiers in military campaigns are frequent victims of ‘trench foot’.
metabolic demands may permit successful resuscitation after very Long-​term damage is likely whenever an anaesthetic, paralysed,
prolonged immersion. cold region becomes hot, red, painful, and swollen after rewarming,
Older people may also be small and thin and are at risk of so-​ although this change may take several days. Degeneration of nerve
called ‘urban hypothermia’. Poverty, illness, immobility, malnutri- and muscle can then follow, leading to prolonged anaesthesia,
tion, and a less sensitive regulatory system may contribute, but in muscle contractures, or inappropriate peripheral vascular control
many cases hypothermia on admission to hospital is secondary to with intolerance to local heat or cold. There may be slow improve-
other pathology (e.g. a stroke may have led to prolonged immobility ment over months or years.
 10.3.4 Drowning 1691

Frostbite young children and epileptics in baths. Personal flotation devices

(life jackets) are the best preventive strategy in boating activities.
Human tissues freeze at around –​2 °C. Ice forms outside cells but Prevention and rescue efforts of life-​savers are effective in swimming
the remaining extracellular fluid becomes hyperosmolar and hence pools and on patrolled beaches.
severe intracellular dehydration occurs. This denatures proteins.
Clinical features
Vascular endothelial cells are particularly vulnerable, and following
rewarming, small blood vessels may leak plasma and then become Prognosis cannot reliably be predicted, but cardiovascular status is a
blocked by red cell sludge and clot. Additional ischaemic necrosis is better prognostic indicator than neurological presentation. Patients
then superimposed on the frost damage. who are neurologically responsive at the scene of immersion, in sinus
Frozen tissues appear hard and white and are anaesthetic. rhythm and with reactive pupils, have good outcomes. Those who
Rewarming leads to pain and swelling, often accompanied by blis- are asystolic on arrival at hospital and remain comatose for more
tering. Deep-​freezing results in irreversible necrosis but appear- than 3 h have a poor prognosis unless they are hypothermic. Patients
ances can be misleading, and early amputation of digits should be with a normal chest radiograph on admission usually survive.
avoided. If still frozen, rewarming is best achieved rapidly by using Management
immersion in water at 40–​42°C, although any thawing should be
The factors that influence outcome are (1) immediate management—​
avoided if refreezing is likely. Once thawed, treatment is similar
including rapid rescue; laying the victim on their side for assessment of
to that used for burns with prevention of infection paramount.
the airway and breathing to assist drainage of any excess water from the
Generous analgesia is required.
airways and lungs; prompt and effective bystander cardiopulmonary
resuscitation, using supplemental oxygen if available, preferably with
oxygen of highest concentration possible (e.g. bag–​valve–​mask) and an
FURTHER READING oropharyngeal airway, endotracheal tube, or laryngeal mask airway in
Dexter WW (1990). Hypothermia. Safe and efficient methods of comatose victims (if suitably skilled personnel are present). (2) Hospital
rewarming the patient. Postgrad Med, 88, 55–​8, 61–​4. management—​important elements are (a) ventilatory support to main-
Giesbrecht GG (2000). Cold stress, near drowning and accidental tain adequate arterial oxygenation, which may involve the use of extra-
hypothermia: a review. Aviat Space Environ Med, 71, 733–​52. corporeal membrane oxygenation and/​or cardiopulmonary bypass in
Granberg PO (1997). Cold injury. In: Chant ADB, Barros D’Sa AAB refractory cases; (b) colloid resuscitation, (c) recognition and treatment
(eds) Emergency vascular practice, pp. 119–​34. Hodder Arnold,
of complications (e.g. secondary pneumonia).
London.
Hamlet MP (1988). Human cold injuries. In: Pandolf KB, Sawka MN,
Gonzalez R (eds) Human performance physiology and environ-
mental medicine at terrestrial extremes, pp. 435–​66. Benchmark, Definition
Indianapolis, IN.
Stroud MA (1993). Environmental temperature and physiological Drowning has most recently been defined as ‘the process of experi-
function. In: Ulijaszek SJ, Strickland SS (eds) Seasonality and human encing respiratory impairment from submersion/​ immersion in
ecology, pp. 38–​53. Cambridge University Press, Cambridge.
liquid’. Outcomes of drowning should be classified as death, mor-
bidity, and no morbidity. Recent guidelines suggest that the term
‘submersion injury’ or non​fatal drowning should replace ‘near-​
drowning’, although the latter is still commonly used. The lack of a
universally agreed standard definition makes it difficult to evaluate
the results of studies of drowning and submersion, particularly as
10.3.4 Drowning drowning remains difficult to diagnose at autopsy.

Peter J. Fenner
Mortality and morbidity

ESSENTIALS Acute prolonged hypoxia causes haemodynamic effects, cerebral

damage, and death. Neurological morbidity in survivors of near-​
Drowning is a major preventable cause of death, most frequently
drowning includes difficulties with learning, memory, attention and
in children and in developing countries. Aspiration (whether of salt
planning, and cerebral palsy. A large study of childhood immersions
or fresh water) is usual in drowning and near-​drowning (known as
has shown that approximately 70% of survivors have no neuro-
non​fatal, or submersion injury) and leads to cardiac arrest within a
logical deficit, 30% have some deficit; 3% will live in a permanent
few minutes. Death or severe neurological impairment occurs after
vegetative state.
submersion for more than 5–​10 min, but much longer durations may
be tolerated in hypothermic conditions.
Prevention Epidemiology
Precautions include proper supervision of children in recreation
areas such as swimming pools, beaches, and river banks, and of The estimated incidence of drowning is 0.5 million per year,
making it the fourth most common fatal injury worldwide in the
1692 SECTION 10 Environmental medicine, occupational medicine, and poisoning

global burden of disease. It is the seventh leading cause of death Alcohol

from unintentional injury in all ages and the second leading cause Alcohol affects vision, balance, movement, and reasoning and is a
in children aged 1–​14 years. Incidences of drowning are highest in major risk factor for drowning in adolescent and adult swimmers,
children up to 4 years old. In infants and toddlers under 12 months, water craft operators, and passengers, who fall overboard while in-
bathtub and bucket immersions are the highest cause of drowning. toxicated. At the time of rescue, resuscitation, or death, 25–​50% of
Ten per cent (10%) of fatal bucket or tub immersions are attrib- adult and adolescent victims of drowning had some exposure to
utable to child abuse. Smooth and slippery bathtubs are particu- alcohol.
larly dangerous and bathtub seats are unsafe, particularly if infants
are left unattended. Worldwide, drowning rates in young children,
many of whom are unsupervised, have decreased little, despite po- Pathophysiology
tentially effective preventive strategies such as fencing of swimming
pools, providing education appropriate to the particular circum- Aspiration is usual in drowning. Earlier figures had suggested that
stances, or increased surveillance. Although there are few such pre- approximately 10–​15% of victims of drowning had not aspirated
ventive strategies for older children, drowning rates have declined water but recent figures show an incidence of only 2%. In these
dramatically in the last decade. cases, death may result from laryngeal spasm and asphyxia during
Developing countries have the highest rates of drowning. Thirty-​ submersion. Early animal studies in anaesthetized dogs showed that
eight per cent (38%) of the world’s drownings occur in the Western spontaneous respiratory efforts continued for around 60 s after im-
Pacific region and Africa, where the drowning mortality rate is 13.1 mersion. Complete cardiac arrest supervenes after 4.5 min (mean
per 100 000 population per year. Children aged 5–​14 years suffer 262 s). Recent Chinese bronchoscopic studies in anaesthetized
the highest mortality rate. Children under the age of 5 years have dogs whose lungs were filled with seawater showed that the bronchi
the highest drowning mortality rate for both sexes. The mother’s fill with bronchoalveolar fluid, causing increasing blood lactate
age and literacy and family income are identified as risk factors. In dehydrogenase-​L and alkaline phosphatase levels. Electron micros-
Bangladesh, drowning has been shown to be a major cause of child- copy shows injuries to type II alveolar epithelial cells, thickened re-
hood mortality: among 1-​to 4-​year-​olds; there are 156 fatal drown- spiratory mucosa, and platelet adherence.
ings/​100 000 population per year. Younger males were at greatest Haemodynamic effects following inspiration of liquid are similar.
risk of drowning in rural areas, mainly in ditches and ponds. In There is a rapid fall in cardiac output, while pulmonary capil-
China, estimated drowning mortality rates for all age groups were lary wedge pressure, central venous pressure, and pulmonary vas-
29.8/​100 000/​year for boys and 29.6 for girls. cular resistance increase. Reduction in the dynamic compliance of
In the United States of America in 2000, more than 1400 children the lungs is similar, following inspiration of all types of solutions.
younger than 20 years drowned. It is the seventh leading cause of However, aspiration of large volumes of hypertonic seawater draws
unintentional injury deaths for all ages, the second leading cause fluid into the lung from the circulation by osmosis, resulting in fluid-​
of all deaths from injury in children aged 1–​14 years and the third filled, non​ventilated, but perfused alveoli incapable of normal gas
most common cause of fatality in people under 15 years (after car exchange while aspiration. Conversely, aspiration of large amounts
accidents and asphyxia). Many drownings occur during recre- of hypotonic freshwater may cause sufficient absorption of fluid into
ation in swimming pools, spas, hot tubs, lakes, rivers, or oceans. the circulation from the alveoli to cause both acute hypervolaemia
Approximately 53% of victims needed hospitalization or transfer for and haemolysis. Within 1 h, pulmonary oedema develops, resulting
more specialized care. Drowning rates were highest among children in a decrease in circulating blood volume. Early studies suggested
up to 4 years old. that 85% of human drowning victims aspirated 22 ml/​kg of water
Worldwide, ocean drownings are less common than freshwater or less, but it has been estimated that about 10% of body weight of
drownings, probably because fewer children swim unsupervised water may be absorbed from the lungs during freshwater drowning.
in the ocean, and increasing numbers now swim on patrolled Since the brain has a limited ability to maintain adenosine tri-
beaches in more-​developed countries, where prevention and the phosphate levels anaerobically when cerebral blood flow is reduced,
rescue efforts of life-​saving associations have proved effective. Rate it suffers irreparable damage within 4–​6 min. Death or severe neuro-
of drowning varies with climate, availability of beaches, lakes, and logical impairment occurs after submersion of more than 5–​10 min.
other natural and artificial water sources, provision of life-​saving However, in hypothermic conditions, brain activity may be restored
services, improvements in designs and rules for water craft, and the after up to 60 min of submersion apnoea. Bystanders’ estimates of
use of life jackets. Rock fishing carries a high risk of drowning and submersion time are usually inaccurate.
near-​drowning. A genetic basis has been suggested for unexplained
drowning or near-​drowning. Hypothermia
(See Chapter 10.3.3.)
Ethnicity A low body temperature generally indicates the severity of the
White American children aged 1–​4 years drown twice as often as drowning incident. Sudden immersion in ice water causes a reflex
African-​American children of the same age. These accidents usu- cardiorespiratory response, called ‘cold shock’, causing an initial
ally happen in residential swimming pools. Conversely, in the age gasp and hyperventilation despite hypocapnia and also hyper-
group 5–​19 years, African-​Americans drown more often than white tension. Continuous aspiration of cold water results in rapid core
Americans. Australian aboriginal children drown more often than cooling, while the circulation is intact. Such victims may survive
non​indigenous children. Worldwide, fatal drowning is generally with little or no neurological deficit after long submersion with
more prevalent in indigenous races than in others. extreme hypoxia. After submersion for a maximum of 10 min in
 10.3.4 Drowning 1693

water at 16°C, a good outcome can be predicted in 96.6% of victims. (including epilepsy), as a result of alcohol and drugs, metabolic
New evidence supports the use of mild hypothermia for periods disease (including hypoglycaemia), and even child abuse and
of 12–​24 h in comatose drowned victims. A 6-​year-​old boy, who murder. In countries with long coastlines and many bathing
presented with a rectal temperature of 16.4°C after a 65-​min sub- beaches, drowning is common and is often caused by swimmers
mersion, survived, apparently neurologically intact when his blood being caught in ‘rip currents’ (also known as ‘rips’) (large vol-
was rewarmed in increments of 3°C over 96 min. However, later umes of water returning back out to sea after onshore wave action)
neuropsychological testing revealed cognitive difficulties, espe- (Fig. 10.3.4.1); there is no such entity as the frequently suggested
cially global memory impairment, despite the fact that MRI and ‘undertow’. Swimmers in difficulty may be able to shout for help
magnetoencephalography were normal. In adults, success is less but, contrary to public opinion, those who are drowning do not.
common. A notable exception was a 31-​year-​old man with a core Most drowning victims adopt a characteristic vertical position in
temperature of 23°C who had been asystolic for 80 min, but was the water—​legs hanging vertically, head tilted back for quick ex-
warmed by cardiopulmonary bypass and recovered. halation and inhalation before bobbing underwater, with no time
Despite discouraging data from animal studies, recent reports or sufficient breath to call for help. After only 20–​60 s, victims may
suggest that in hypothermic submersion-​ associated cardiac ar- submerge permanently.
rest, adrenaline and vasopressin may help to achieve the vaso-
pressor response needed to restore spontaneous circulation prior
to rewarming. This treatment could obviate prolonged mechanical Clinical features
cardiopulmonary resuscitation, or the use of extracorporeal circula-
tion. It has proved effective in restoring spontaneous circulation, but Prognostic indicators
one patient died of multiorgan failure 15 h later. None of the recent developments in assessment, treatment, or
In warm-​water drowning there appears to be no statistically equipment has improved survival rates among submersion victims.
significant correlation between duration of submersion and Prevention and rapid rescue remain the most effective means of re-
survival. ducing the toll. The key to a successful outcome and return to pro-
ductive, full life is early bystander cardiopulmonary resuscitation,
early and aggressive advanced life support methods (Fig. 10.3.4.2),
Causes of drowning induced hypothermia when appropriate, careful rewarming,
including extracorporal membrane oxygenation, and extracorporal
Drowning occurs in many different situations: after accidental im- warming where needed. However, up to 25% of drowning victims
mersion in people with little or no swimming ability, with head presenting to the hospital emergency department will die and a
and neck injury, following cardiac and neurological emergencies further 6% suffer neurological sequelae. The prognosis cannot

Fig. 10.3.4.1 Australians swimming in the sea at Petrel Cove near Victor Harbour despite
notice warning of rip currents.
Courtesy of D A Warrell.
1694 SECTION 10 Environmental medicine, occupational medicine, and poisoning

(a) Rapid hypothermia from sudden submersion in cold water (see

Chapter 10.3.3) carries a relatively good prognosis, compared to in-
sidious hypothermia developed during prolonged submersion that
results in cardiac arrest.

Neurological status
Victims who are alert when medical help arrives have a survival rate
approaching 100%, whereas the prognosis in those who are coma-
tose with fixed, dilated pupils is poor. Among victims with impaired
consciousness, 87% will survive without neurological defects and
2% with minor defects, while 11% will die. Approximately 40–​50%
of victims who are comatose on arrival have incapacitating brain
damage. Those with no spontaneous limb movements and abnormal
brain stem function 24 h after the accident have a poor neurological
outcome.
A modified Glasgow Coma Score is helpful in evaluating neuro-
logical injury. A score of 5 or less predicts a mortality risk of over
80%. Pupil reactivity at the time of arrival differentiates survivors
from fatalities but could not differentiate between those with minor
or incapacitating neurological deficits. Fixed, dilated pupils or
total flaccidity are associated with a high mortality. Victims with
any motor activity, even posturing or seizures, in the immediate
postresuscitation period had a higher incidence of intact survival,
but abnormal posturing that persisted or recurred after 12–​24 h in-
(b)
dicated a high probability of severe brain damage.
An abnormal CT scan in the initial 36 h following an immersion
incident is associated with a dismal prognosis. MRI with qualitative
and quantitative MR spectroscopy data may allow a more accurate
prognosis.
The gravity of the early clinical state, the estimated duration of
cardiorespiratory arrest, and the severity of the hypothermia, seiz-
ures, and paroxysmal electroencephalogram (EEG) activity do not
determine the severity of submersion injury encephalopathy. Early
EEG patterns with moderate background activity, sleep patterns,
response to auditory and painful stimulations, and numerous β-
rhythms suggest a good outcome, whereas bad outcomes are sug-
gested by high voltage, rhythmic δ-waves; biphasic sharp waves;
monotonous EEG, ‘burst-​suppression’ pattern, and absence of β-
Fig. 10.3.4.2 (a, b) Cardiopulmonary resuscitation including rhythms. Children who show no spontaneous movements and have
defibrillation being carried out on the beach by Australian surf abnormal brainstem function 24 h after submersion injury are likely
life-​savers, in a man who suffered a cardiac arrest while swimming. to suffer severe neurological deficits or death.
Courtesy of P J Fenner.

be predicted from the initial clinical presentation, laboratory, or Treatment

electrophysiological examinations, but those with a normal chest
radiograph on admission usually survive; Pao2 may not relate to Victims of submersion injury must be treated immediately for venti-
radiographic appearances. Although the cause and pathophysio- latory insufficiency, hypoxia, and the resulting acidosis. A successful
logical changes of pulmonary insufficiency vary depending on the outcome depends on early effective resuscitation at the scene and on
type and volume of fluid aspirated, serum electrolyte and haemo- competent intensive life support. In-​water resuscitation is effective
globin concentrations (or haematocrit) do not predict survival. within 5 mins of the shore, or longer, if the victim shows signs of in-
creased activity after the initial breaths of the shore.
Cardiovascular status
This is a better guide to outcome than neurological status. Mortality Immediate
is high in victims with circulatory arrest on admission, but those Laying victims on their side for assessment of the airway and
in sinus rhythm with reactive pupils, who are neurologically re- breathing will assist drainage of any excess water from the airways
sponsive at the scene of immersion, have good outcomes. Those and lungs (Fig. 10.3.4.2). If necessary, on-​site cardiopulmonary re-
who are asystolic on arrival at hospital and remain comatose for suscitation should be started as soon as possible using supplemental
more than 3 h have a poor prognosis unless they are hypothermic. oxygen if available, preferably in the highest concentration (e.g.
 10.3.4 Drowning 1695

bag–​ valve–​mask). An oropharyngeal airway, endotracheal tube,

or laryngeal mask airway should be inserted in comatose victims,
if suitably skilled personnel are present. Pulse oximetry is helpful.
Vomiting and regurgitation are significant risks during early resus-
citation. Respiratory and cardiopulmonary arrest may occur after
an apparently successful rescue, mandating close, uninterrupted
monitoring, and the early administration of oxygen to all immer-
sion victims.

At the hospital
On arrival at the hospital, after a clear airway and cardio-​circulatory
support have been established, arterial blood gas tensions and pH
should be measured. The pH of the blood will indicate whether there
is a residual metabolic acidosis after a substantial period of hypoxia.
Mechanical ventilation may be necessary with positive end-​
expiratory pressure, or continuous positive airway pressure to main-
tain arterial oxygen pressure above 10 kPa with an inspired oxygen
fraction below 0.6.
After both freshwater and seawater aspiration, large volumes
of intravenous colloid are usually needed while circulating blood
volume and cardiac output are estimated. Freshwater aspiration is
more likely to cause pulmonary oedema. A central venous catheter
or pulmonary artery catheter helps to assess the effective circulating Fig. 10.3.4.3 Multilingual talking sign warning of dangers on an
blood volume to guide fluid therapy. Failure of response to intra- Australian beach.
vascular replacement with 20 ml/​kg of colloid is an indication for Courtesy of P J Fenner.
starting inotropes. Steroid and prophylactic antibiotic therapy do
not appear to increase the chance of survival.
pool-​fencing compulsory. Strategies for the prevention of drowning
Inpatient treatment should also consider hazards in rural areas. Multilingual notices on
Extracorporeal membrane oxygenation has been proved to be ef- public beaches are important (Fig. 10.3.4.3) but are often ignored
fective after drowning. Patients with severe hypoxaemia may have (Fig. 10.3.4.1).
irreversible cerebral ischaemia. A 3-​year-​old drowned girl in re- Swimming ability and safety skills of young children can be im-
fractory cardiorespiratory arrest was successfully resuscitated using proved by training. Education of the public is essential. In Australian
cardiopulmonary bypass, and then extracorporeal membrane oxy- surf, only 17% of rescues and resuscitations, up to 95% of them suc-
genation for 4 days. Despite a prolonged period in a vegetative state, cessful, occurred within patrolled areas, while 55% (62% of them
she later made an almost complete neurological recovery. successfully) occurred outside patrolled areas. Resuscitation success
If adult respiratory distress syndrome occurs, it is usually within rates fell with increasing distance from patrolled areas. Among non-​
6 h of admission. There is evidence that alveolar epithelial barrier boating drownings in Australia, 4.7% are among overseas tourists,
function is well preserved even after aspiration of large quantities 89% of whom drown in the ocean.
of hypertonic salt water. Surfactant has been used with some suc- An adult should supervise all epileptic children and infants aged
cess in refractory respiratory failure in near-​drowning, but it is under 3 while they are in the bath. Currently, up to 89% of children
expensive. aged 35 to 59 months and 6% of those younger than 3 years of age are
The risk of secondary pneumonia is high, especially when mech- bathed without adult supervision.
anical ventilation has been used. Although prophylactic antibiotics Drownings associated with boating and personalized water craft
are not recommended, broad-​spectrum antibiotics may be required. can be prevented by using life jackets (personal flotation devices),
Mild reversible renal impairment is rare. Initial serum creatinine, but as many as 50% of boaters do not use them. Efforts to increase
marked metabolic acidosis, abnormal urinalysis, or significant their use should target adolescents, adults, and boating enthusiasts,
blood lymphocytosis are markers of impending acute renal failure. especially those using motor boats. In Alaska’s commercial fishing
industry, specific measures designed to prevent drowning after ves-
sels have capsized and sunk have proved successful.
Prevention of drowning In most age groups, more men drown than women. This probably
reflects men’s overestimation of their abilities, and perhaps greater
Swimming pools and natural bodies of water are the greatest risk to alcohol consumption. Middle-​aged men dominate the group who
young children. Preventive measures include public media educa- die of cardiac events (mostly on the surface) (Fig. 10.3.4.2). Fatalities
tion and campaigns, parental education and supervision, training in from breath-​holding hypoxia during diving tend to occur in young
cardiopulmonary resuscitation, better safety standards, and safety males. Hyperventilation to increase breath-​hold time is a dangerous
devices such as the fencing of swimming pools. The number of pool practice that should be discouraged. Drownings are rare at super-
drownings in Brisbane, Australia, decreased after legislation made vised water parks, thanks to the large number of lifeguards on duty.
1696 SECTION 10 Environmental medicine, occupational medicine, and poisoning

FURTHER READING Victims of electric shock might suffer prolonged attachment to the
source of electric current and must be disconnected from the source
Bierens J, et al. (eds) (2006). The handbook on drowning. Springer, before resuscitation. A victim still attached to a source of current is
Berlin.
dangerous to touch. The most expedient method of disconnection is
Hasibeder WR (2003). Drowning. Curr Opin Anaesthesiol, 16, 139–​45.
to turn the offending power off.
Idris AH, et al. (2003). Recommended guidelines for uniform re-
porting of data from drowning: the ‘Utstein style’. Resuscitation, Consequences of the shock include:
59, 45–​57. (1) Immediate scale—​ventricular fibrillation, which is the mechanism
Papa L, Hoelle R, Idris A (2005). Systematic review of definitions for of fatality, sometimes leading to persistent cardiac dysfunction in
drowning incidents. Resuscitation, 65, 255–​64. survivors;
Piette MH, De Letter EA (2006). Drowning: still a difficult autopsy (2) Neurological and muscular manifestations, both early and late,
diagnosis. Forensic Sci Int, 163, 1–​9.
including paraesthesiae, and pareses. In the early stages, gener-
Salomez F, Vincent JL (2004). Drowning: a review of epidemi-
alized convulsions, respiratory embarrassment, due to tetanic
ology, pathophysiology, treatment and prevention. Resuscitation,
spasm, and rhabdomyolysis may occur;
63, 261–​8.
van Beeck EF, et al. (2005). A new definition of drowning: towards (3) Burns, which might be severe and require expert surgical atten-
documentation and prevention of a global public health problem. tion. Electroporation (a special form of cell membrane disrup-
Bull World Health Organ, 83, 853–​6. tion by electric fields) contributes to cell death; delineation using
polaxamers can direct the extent of surgical debridement.
(4) In the longer term, persistent paraesthesiae and pareses occur,
with a particular fatiguability of the musculature, evidenced
as loss of stamina. Visual and auditory dysfunction may occur.
The most disabling consequence is the psychological syn-
drome, which has its own unique character.
10.3.5 Lightning and
electrical injuries
Chris Andrews Introduction

Lightning is a powerful force; it provides spectacular displays and

has evoked an extensive mythology. It is poorly understood in med-
ESSENTIALS
ical terms and it is only recently that its characterization, physically
Lightning and psychologically, has been made more plain.
Lightning strikes are rare accidents but carry a 10% case fatality, killing The comparatively recent discovery and distribution of electricity
0.1–​0.3 per million population each year. During thunderstorms, the have had an equally profound effect, and provide truth to the adage
risk is increased by sheltering under trees or by being on open water, that ‘electricity is a good servant and a bad master’.
on tractors, or in open fields or in outdoor activity. Generation of electricity occurs in several ways, but in the final
Lightning is considered to cause instant asystole. It is suspected analysis electrons are imbued with energy by a generator of electric
clinically if someone is found collapsed in the open with linear or current. From any given generator notionally one conductor em-
feathered burns (see next), exploded clothing, and ruptured ear- anates to be a source of current in the form of electrons, and this
drums. Victims are safe to handle, with most victims showing current is delivered by the conductor to a location where electrical
keraunoparalysis (cold, pulseless, mottled extremities, not unlike work can be done. This conductor is generally termed the ‘active’
compartment syndromes). Immediate cardiopulmonary resuscita- conductor. A second conductor is required to return the electrons
tion is mandatory. Survivors might develop complications including in a less energetic state to the generator for re-​energization. This
pain syndromes and psychological sequelae. Burns are generally of is the return path, or the neutral conductor. The electrical system
minor consequence, unlike electrical injury. The most disabling con- is referenced to earth, and the second conductor might indeed be
sequences of the injury are generally the psychological sequelae. earth. Alternatively, a common method of injury occurs when an
Electric shock individual contacts the active conductor and earth simultaneously.
While it could be argued that earth reference creates danger on the
The term electrocution implies death from electric shock. Survivors one hand, on the other technical considerations show that system
are said to have been exposed to or received an electric shock. stability and predictability is enhanced by earth reference.
Electrocution is the fifth most common cause of workplace
death, mainly affecting utilities, mining, and construction labourers.
Domestic electrical accidents are common, where contact with over- Epidemiology
head power lines, faulty power tools, and particularly using extension
cords, are the most common causes, with metal ladders and an-
Lightning injury
tennae being particularly dangerous. Prevention is by implementing
codes of safe practice. It is not appreciated that only a small fraction of lightning strike
to individuals lead to fatality. The latest accepted case fatality of
 10.3.5 Lightning and electrical injuries 1697

lightning shock is 10% and is around 0.3 per million population in 4. As current disperses away from the base of a strike to ground, an
the United States of America each year, but fewer than 0.1 per mil- individual might divert current flowing in the ground through
lion in the United Kingdom. themselves. This is termed ‘shock due to increase in earth poten-
In the early part of the 20th century, most people struck by light- tial’, or simply ‘earth potential rise’.
ning were outdoor workers (67%) and outdoor recreationalists 5. A recently documented mechanism is the transient flow of cur-
(28%). Nowadays, the breakdown is 45% and 50%, respectively, rent due to corona and streamer formation around the upper
explained by changes in social and work habits. Indoor strikes parts of an individual. The current to provide these streamers
(e.g. by current conducted through communication or power ap- flows from ground through the individual to project upwards to
paratus) continue to account for about 5% of these accidents, but reach a descending stroke from a cloud.
few fatalities.
It has been found that both cardiac and respiratory function cease
Men are more often injured than women (1.67 males to 0.33
instantaneously under lightning strike, the cardiac arrest being asys-
females); the age group most at risk is 20–​29 years. Risky situ-
tolic. Cardiac function restarts under local pacemaker control, but
ations include sheltering under trees (particularly), on open water,
respiratory function does not recommence, and secondary hypoxic
on tractors, in open fields, and playing outdoor sports, like golf.
cardiac arrest supervenes.
Regional differences correlate well with storm activity and popula-
The major cranial orifices are portals of entry for lightning cur-
tion density in that area.
rent, and from there the pathways to the brainstem are short.
Electrical injury Respiratory function is thought to be affected in the brainstem. Fluid
channels (cerebrospinal fluid and blood) might be channels to the
Electrocution ranks fifth in the causes of workplace death, ac-
myocardium.
counting for the death of 10 000 workers each year in the United
The QT prolongation resulting from lightning injury can predis-
States, with a further 10 million being injured. Most of the victims
pose to episodic arrhythmias.
work for utility companies, followed by mining and construction
There is no evidence at all for one dictum, viz., that lightning in-
workers. Contact with power lines causes 53% of fatal shocks, and
hibits body metabolism. Resuscitation is as urgent as with any other
contact with power tools accounts for a further 22%. The most dan-
injury. There is no evidence for the notion sometimes quoted that
gerous times of day seem to be between 10.00 a.m. and 3.00 p.m. on
resuscitation can be delayed in a lightning victim. There is similarly
Mondays, Tuesdays, and Thursdays. Most of the victims are trade
no evidence that metal on the head, or the presence of a mobile tele-
and labouring staff; sales, clerical, and professional categories are
phone (cellphone), predisposes to being struck.
at least risk. Metal ladders and antennae are particularly dangerous
and can easily be hoisted into overhead power lines. Codes of safe
Electrical injury
practice are written accordingly.
In domestic situations, contact with overhead lines by ladders With electric shock, it is important to assess the points of entry and
and poles is again important. Faulty, including amateur, repair exit and the pathway of current through the body. Once the pathway
of equipment, and faulty apparatus, wiring, and especially power has been determined, a locus for expected injury can be established,
and extension cords account for large numbers of deaths and in- and the flow of current can be estimated from the applied voltage
juries. Children are at particular risk. Death from domestic electric divided by the impedance of the proposed pathway. Most imped-
shock has shown a marked decrease with the introduction of re- ance is in the skin barriers, and is non​linear. There is initial (contact)
sidual current devices. These are items of good practice, and sense impedance, which decreases as current flow continues. Impedance
if current is diverted from the active supply to earth rather than also varies with time since application, contact surface area, and
neutral, and then interrupt the supply in a matter of milliseconds. frequency.
These will not ameliorate every accident, but are considered to act Contacts can be with the active and neutral (return) conductor, or
in 80% of cases, notably active conductor to earth shocks. While with the active conductor and earth, with earth providing the return
they ameliorate the fatal effects in these cases, victims still can have path to the generator. Indeed, these considerations become blurred
several of the stated consequences. as most countries operate an MEN distribution system (Multiple
Earthed Neutral). In this system, the earth referencing comes about
as the neutral conductor is connected to earth regularly along its
Mechanisms of injury route back to the generator. Return paths are then shared between
earth and neutral.
Lightning injury For currents with a frequency of 15–​100 Hz, externally ap-
Lightning injury may be sustained in five separate ways: plied from hand to hand, or hand to foot, relevant variables char-
acterizing the current are the threshold of perception (0.5 mA)
1. A person might be struck directly. This might represent the most and ‘let go’ current (10 mA). The threshold of fibrillation (where
common cause of fatality. threat to life can occur) is a higher threshold again. For example,
2. A nearby object, such as a tree or a building, might be struck, there is a 50% chance of fibrillation when 2000 mA is conducted
and someone in direct contact with it might receive a shock. for 10 ms, or at the other extreme 100 mA conducted for 10 s,
3. Without direct contact an arc might ‘jump’ to a nearby person in a hand to foot path. Direct internal application of less than
from the struck object, thereby generating a ‘side flash’. This is 200 µA to the heart muscle can induce fibrillation. Dangerous cur-
particularly dangerous in the unwise event of sheltering under rent levels as well as impedance parameters are documented in
a tree. standards.
1698 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Joule heating might account for tissue damage in the path of

the current. It can be calculated from the power dissipation in the
tissue—​the square of the tissue current (often hard to estimate)
times its impedance. The complex phenomenon of electroporation,
where cell membranes are breached by the electrical induction of
unstable pores in the membrane, can also lead to cell death. The
complex nature of internal electric fields leads to internal field
damage which is difficult to quantify and predict.

Presentation of the injured person

The presentations and physical consequences of electrical and

lightning injury are different, and hence the application of prin-
ciples from one to the other is invalid, physically.
On the other hand, the psychological consequences are similar,
and they may be considered together.

Lightning injury
A witnessed strike offers the best chance of resuscitation. The victim
is not dangerous to touch, and does not constitute a risk to the res- Fig. 10.3.5.1 Example of keraunographic marking.
cuer. Immediate cardiopulmonary resuscitation is paramount. It has Courtesy Dr Ajay Mahajan (Mahajan AL, Rajan R, et al. (2007). Lichtenberg
figures: cutaneous manifestation of phone electrocution from lightning. J Plast
been stated that: Reconstr Aesthet Surg, 61(1),111–​13). Reprinted with permission from Elsevier.
Any person found with linear burns and clothing exploded off should
be treated as the victim of a lightning strike. Feathering burns are The syndrome resembles a compartment syndrome and occurs
pathognomic of lightning injury and occur in no other type of in- in the line of passage of the strike current. It resolves spontan-
jury. . . . Another complex diagnostic of lightning injury includes linear eously within 24 h with no sequelae, and requires no surgical
or punctate burns, tympanic membrane rupture, confusion, and out-
intervention.
door location . . . .
Burns are of minor consequence in lightning injury, and again
In assessing a lightning victim, the following features must be sought. require little intervention. Entry and exit burns might be full
thickness, though small. Arborescent (feathering) burns re-
Cardiovascular and pulmonary consequences semble fern-​like patterns on the skin (Fig. 10.3.5.1). Their aeti-
Asystolic arrest is the main cardiac event in lightning injury. ology has been convincingly shown to be due to an inflammatory
Electrocardiographic (ECG) findings can take many forms, with response following field arcing across the skin. They fade within
ischaemic and infarct forms. They almost invariably resolve com- 24 h. Linear burns are due to the passage of hot plasma tongues
pletely over time. Alterations in QT interval and arrhythmias of over the skin. Eschar is simply allowed to separate without fur-
many kinds are seen. ECG changes might not occur until late in ther treatment. Flash might be seen, like sunburn or welder’s
the course, and so are poor diagnostic tools. Respiratory arrest is flash, from the profound radiation of the strike. Sheet burns
common. A person not suffering cardiopulmonary arrest is highly resulting from efflux of hot plasma can be a variant of linear
unlikely to die from lightning strike. burning, since both seem to follow moisture and sweat lines.
There might be contact burns from metal such as buckles and
Neurological consequences coins. It is said that these are thermal, but doubt has been cast
Direct neural injury can occur both centrally and peripherally. All on this.
forms of intracranial bleeding have been reported. Direct cerebral
damage particularly affects the basal ganglia, cerebellum, and brain- Eye, ear, and explosive injuries
stem. Dural tears, scalp haematomata, and fractures are also seen. The explosive force of the lightning insult blasts clothing apart
Seizures occur as a result of anoxia and injury. (Fig. 10.3.5.2), and may cause percussive injury to the lungs and
Peripheral nerve injury, including autonomic injury, can give pro- abdominal viscera. Tympanic membranes are usually ruptured,
longed and long-​lasting disability, which often develops late. Other perhaps from the explosive force of the strike. Percussive eye in-
late features include spinal cord atrophic paralysis, cerebellar ataxia, jury, particularly retinal, has been reported. Cataracts can develop
incoordination, paraesthesiae, and aphasia. Continuing complex re- much later.
gional pain syndromes may be seen.
Other injuries
Keraunoparalysis and burns Renal and haematological damage have occasionally been re-
More than 70% of victims demonstrate keraunoparalysis. This is ported. Several writers examining lightning strike during preg-
a syndrome of cold, pulseless, mottled, and asensory extremities. nancy suggest that outcome for a fetus is poor, independent of
 10.3.5 Lightning and electrical injuries 1699

(a) (b) Neurological and muscular consequences

Neural injury can be categorized into early and late syndromes, at
cerebral, cord, and peripheral levels.
Early tetanic muscular contraction locks the victim on to the
electrical conductors. This tetany can compromise respiratory
function. Neurological injury might be hard to distinguish from
hypoxic and vasospastic injury. Similarly, neural injury is often
hard to separate from ischaemic injury due to vessel spasm. Early
and late generalized convulsions can occur. Pareses and paraes-
thesiae might develop, both early and late. There is a characteristic
easy fatiguing of the musculature, which resembles a profound loss
of stamina.
In the long term, complex regional pain syndromes and other
chronic pain syndromes must be considered.

Burns
Burns are often severe in electrical injury and merit much treatment
effort. Arc and flame burns and contact burns from current entry
and exit are seen. For example, tetanic gripping of the electrical con-
ductor causes grasp burns to the hand.
Severe internal thermal or electroporation damage can occur.
The management is largely surgical. Joints, ligaments, and tendons
might be severely damaged by the heat generated, and osteonecrosis
Fig. 10.3.5.2 Reconstruction of external result of a lightning strike. might be seen. Amputations are relatively common.
Courtesy Professor Mary Ann Cooper, University of Illinois, Chicago.
Other aspects
that for the mother. Menstrual and sexual difficulties have been Widespread muscle damage generates myoglobin that must be
reported, though the latter could be more of a psychological cleared by the kidney with a severe risk of renal damage. Other
nature. metabolic and biochemical disturbances secondary to hypoxia
might develop. Massive hyperkalaemia has implications for the use
Electrical injury of depolarizing muscle relaxants.
In contrast with lightning injury, victims might suffer prolonged Eye damage includes retinal damage, with punctation and detach-
attachment to the source of electrical current, making them ment, and thermal damage to other media. During follow-​up the
dangerous to touch. Before resuscitation, they must be separated possibility of ocular pareses and cataracts must be recognized.
from the current source, and this usually means interrupting the After shock during pregnancy, the prognosis for the fetus is poor.
current flow at the supply point. Non​focal injury is more likely in survivors.
Burns are far more serious, and might merit intense surgical
treatment. The likelihood of internal burning (remembering the Psychological consequences of electrical
possibility of electroporation) might require further surgical inter- and lightning injuries
vention. Cardiac and respiratory burns can also occur. Although electrical and lightning injuries are fundamentally dif-
ferent in nature and management, their psychological sequelae
Cardiovascular consequences are similar. Sequelae (‘remote symptoms’, so-​called as they occur
Ventricular fibrillation is the most common fatal cardiac ar- with no evidence of current passage through the brain) can be
rhythmia following electrical injury. Cardiopulmonary resus- profoundly disabling. They most often come to attention via
citation is urgently required. Electricity suppliers have standard Worker’s Compensation and litigation, and if ignored, do a great
first aid/​resuscitation procedures. Cardiac dysfunction can persist disservice to a victim. They can persist for many years and might
for long periods, and ECG changes may not resolve. never resolve. The changes have the features of organic psycho-
Recent studies indicate the importance of vascular chan- logical consequences.
nels for the passage of current. Alterations in vascular function This is the overall picture, though it might be suggested that a
have been documented, and further, similar alterations in ves- psychological reaction to the loss of function and continuing
sels remote from the current passage have been demonstrated pain might be functionally generated, although many believe
at the same time. These findings point to humoral factors in that findings from neuropsychological testing strongly suggest an
mediating electrical injury. The findings also cause us to ques- organic basis.
tion whether most of the damage is mediated by current passage Indeed, recent research in depression indicates that the
through fluid channels, rather than previously claimed nerve hippocampus is found to diminish in volume, implicating that
conduction. such volume changes, together with changes in cortisol and
1700 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Table 10.3.5.1 Proportions and enumeration of remote injuries

Treatment of the injuries
Proportions
Memory disturbance 71% First, urgent and life-​
saving treatment must be administered.
Secondly, there must be surveillance for delayed sequelae, and
Concentration disturbance 63%
thirdly, long-​term monitoring for morbidity, including cataract
Aggression and irritation 67% formation and psychological problems.
Wariness and phobia 58%
Loss of mental powers 50%
Lightning injury
Social isolation 38% First, the casualty is resuscitated and evacuated. Cardiopulmonary
Sleep disorder 38%
resuscitation is continued until medical emergency help is obtained.
Ventilation and cardiac support might be required.
and others including confusion, word finding disability, anxiety, depression,
and learning disorders. ECG monitoring must be used to detect subtle effects like QT
prolongation. Associated trauma is treated.
Subdivisions of remote injuries
In the long term, patients are observed for development of
Memory and learning deficits
pain syndromes. Ocular and auditory functions are monitored.
Globally 19% Sensitivity to the psychological sequelae is required, and preventive
more specifically
Visual 35% interviewing might be useful.
Visuospatial 38% Carbamazepine, gabapentin, clonazepam, flecainide, and
Auditory 62% mexilitine are useful to control neurally derived pain and resulting
Verbal learning deficit 54% weakness. An antidepressant is a useful adjunct to this.
Verbal fluency deficit 46%
Electrical injury
Concentration and attention deficit 46%/​42%
Urgent life support is indicated. Ventilatory and inotropic sup-
Executive function deficit 38%
port and correction of arrhythmias may be required together with
Reduced executive speed 62% correction of biochemical abnormalities, and attention to any
and others including general and verbal IQ decrease, dynamic coordination myoglobinuria. For burns, progressive debridement and/​or ampu-
decrease, slowed information processing, deficit in fine motor skills, phobia,
tation might be needed.
and anxiety and depression.
Specialized rehabilitation may be required. Associated trauma is
treated. Ocular and auditory functions are monitored, and psycho-
logical disturbances are reviewed. In the long term, surveillance is
brain-​derived neurotrophic factor, are important in causing de- similar to lightning injury.
pressive syndromes. Research in the sequelae of electric shock
also shows reduction in hippocampal volume as a direct conse- Psychological elements
quence of peripheral shock. In all cases, the management of the psychological syndrome is
Several of these symptoms develop over time postinjury, and paramount and might be the greatest determinant of long-​term
might not be present for some weeks after the initial examin- functional capability. Awareness of the impact of the injury on em-
ation where the emphasis is more on the physical symptoms. The ployment and relationships and social networks is fundamental.
state of the victim, in totality, deteriorates for 12–​18 months fol- Cognitive and computer aids are being developed, and cognitive
lowing the injury, then improves to achieve stability 18 months to support is important.
3 years from the injury though falling short of original premorbid Personality change, social withdrawal, sexual dysfunction, with
function. loss of earning capacity, places a large strain on marital partnerships,
The remote symptoms follow two major categories—​emotional, and this requires special support.
personality, and behavioural consequences on the one hand, An antidepressant such as an SSRI/​SNRI (selective serotonin re-
versus cognitive and higher function consequences on the other, uptake inhibitor/​serotonin and norepinephrine reuptake inhibitor),
with effects on cognitive agility and speed. or a tricyclic such as clomipramine, may be useful. Agomelatine is
Table 10.3.5.1 is a summary of psychological findings. showing some promise in this application.
An important part of evaluating a victim is to submit them to Early and continuing neuropsychological assessment and support
neuropsychological testing. The aim of such testing, in part, is to is desirable.
objectify the dysfunctions that are seen, and if possible, subdivide
them more specifically.
It is unfortunate that in evaluating an electric shock victim Controversy
or a lightning victim, too many examiners regard the psycho-
logical syndrome as either representing malingering, or of no The place of polaxamers in discovering the extent of electropor-
consequence, to the victim’s severe detriment. It has been docu- ation and in delineating debridement levels is of great interest.
mented that assessment by those unfamiliar with the injury over- A polaxamer is a polymer with a central hydrophobic chain
looks or wrongly diagnoses over 90% of the resulting syndrome flanked by two hydrophilic chains. There are multiple vari-
features. ants of each of these elements. In this structure, however, they
 10.3.6 Diseases of high terrestrial altitudes 1701

resemble the structure of cell membranes, and they can be

patched into cell membrane defects including those caused by 10.3.6 Diseases of high
electroporation. On the one hand they might offer a therapeutic
restorative for damaged membranes, and on the other a radio-​ terrestrial altitudes
labelled polaxamer might be used for imaging the extent of
damage.
Tyler Albert, Erik R. Swenson, Andrew J. Pollard,
The mechanisms of the psychological disability and remote in- Buddha Basnyat, and David R. Murdoch
jury are beginning to be elucidated. Victims are frequently written
off as malingering or simply depressed, when a more extensive
syndrome exists. Expert evaluation is highly desirable, especially ESSENTIALS
if litigation or compensation is involved. The useful duration Ascent to altitudes above 2500 m leads to exposure to hypobaric hypoxia.
of monitoring of otherwise asymptomatic people has not been This affects performance on first arrival at high altitude and disturbs sleep,
determined. but physiological changes occur over time to defend arterial and tissue
A pressing need is the formulation of the psychological oxygenation and allow the individual to adjust. This process of acclima-
syndrome into a Diagnostic and Statistical Manual (DSM) tization includes (1) an increase in the rate and depth of breathing; and
formulation. (2) an increase in red cell mass, and in red cell 2,3-​diphosphoglycerate.
Acclimatization is no longer fully possible at extreme altitude (>5800 m)
and the exposed individual will gradually deteriorate.
Altitude illness results from a failure to adjust to hypobaric hypoxia
FURTHER READING at altitude. Risk is increased by ascent to higher altitudes, by more
Andrews CJ (2006). Further documentation of remote effects of elec- rapid gain in altitude, and (in some people) genetic predisposition;
trical injury, with comments on the place of neuropsychological the condition may be avoided in most cases by slow, graded ascent.
testing and functional scanning. IEEE Trans Biomed Eng, 53, Clinical presentation occurs soon after arriving at a new altitude,
2102–​13. most often manifest as one of three conditions:
Andrews CJ, et al. (1992). Lightning injuries: electrical, medical and
legal aspects. CRC Press, Boca Raton, FL. Acute mountain sickness
Andrews CJ, Reisner AD (2017). The neuropsychological conse- A common condition that presents with non​specific symptoms,
quences of lightning and electrical injury: review and hypotheses for including headache and anorexia. The victim is likely to be apathetic,
causation. Neural Regen Res, 12, 677–​86. but clinical examination is generally unremarkable. Mild cases usu-
Cherington M, Cooper MA (eds) (1995). Seminars in Neurology, ally resolve with rest and avoidance of further ascent. Those whose
15 (3, 4). symptoms fail to resolve (or worsen) should descend immediately.
Cooper MA (1980). Lightning injuries: prognostic signs for death. Ann Treatment with acetazolamide (which can also be used as prophy-
Emerg Med, 9, 134.
laxis) or dexamethasone is often given in severe cases.
Cooper MA, Andrews C, Holle R (2005). Lightning injuries.
In: Auerbach P (ed) Wilderness medicine, 4th edition, pp. 73–​111. High-​altitude cerebral oedema
Mosby, St Louis, MO. An uncommon condition that typically presents with worsening
Cooper MA, Andrews CJ (2005). Disability, not death, is the issue symptoms of acute mountain sickness and ataxia, with progressive
in lightning injury. Proc Int Conf On Lightn Stat Elec, Boeing, neurological symptoms including behavioural changes, confusion,
Seattle, WA.
and impairment of consciousness. Papilloedema and focal neuro-
Hendler N (2005). Overlooked diagnoses in chronic pain: analysis of
logical signs may be present. Treatment is urgent, with the most im-
survivors of electric shock and lightning strike. J Occup Env Med,
portant measure being descent. Oxygen or simulated descent using
47, 796–​805.
Kurtulus, A., Acar, K., Adiguzel, E., Boz, B. (2008). Hippocampal a portable hyperbaric chamber can be helpful. Dexamethasone is
neuron loss due to electric injury in rats: a stereological study. Legal widely recommended (and can be used as prophylaxis).
Medicine (Tokyo), 22, 2671–​5. High-​altitude pulmonary oedema
Lee RC, Capelli-​Schellpfeffer M, Kelley K (eds) (1994). Electrical
A relatively uncommon condition with significant mortality that typ-
injury: a multidisciplinary approach to prevention, therapy & re-
ically presents with dyspnoea and cough. Signs include low-​grade
habilitation. Ann N Y Acad Sci, 720.
Lee RC, Cravalho EG, Burke JF (1992). Electric trauma. Cambridge fever, tachycardia, tachypnoea, basal crepitations, and (in late dis-
University Press, Cambridge. ease) cyanosis. Treatment is urgent, with the most important measure
Morse MS, Berg JS, TenWolde RL (2004). Diffuse electrical injury: a being descent. Oxygen should be given if available. Simulated des-
study of 89 subjects reporting long-​term symptomatology that is re- cent using a portable hyperbaric chamber can be helpful. Nifedipine
mote to the theoretical current Pathway. IEEE Trans Biomed Eng, reduces pulmonary artery pressure, relieves symptoms, and is usually
51, 1449–​59. given (and can be used as prophylaxis).
Park K, et al. (2012). Alterations in arterial function after high-​voltage
Chronic mountain sickness and other medical problems
electrical injury. Critical Care, 16, R25.
Reisner A (2013). Possible mechanisms for delayed neurological Chronic mountain sickness (Monge’s disease) is a disease of adults
damage in lightning and electrical injury. Brain Injury, 27, who reside for prolonged periods at high altitude and develop
565–​9. polycythaemia and eventually cor pulmonale. Symptoms appear to
1702 SECTION 10 Environmental medicine, occupational medicine, and poisoning

resolve with descent, but treatment with venesection has been at- Box 10.3.6.1 Altitude—​definitions
tempted in those who remain at altitude. High-​altitude pulmonary Intermediate altitude (1500–​2500 m)
hypertension has been described in both infants and adults, pre- Physiological changes due to hypobaric hypoxia (such as reduced exer-
dominantly native lowlanders who ascend to and reside at high alti- cise performance, increased ventilation, increased haematopoiesis) are
tude: this also appears to resolve on descent. detectable, but arterial oxygen saturation remains above 90%. Acute
Pre-​existing medical conditions are mostly little affected by as- altitude illness is unlikely.
cent to altitude, but people particularly likely to be affected by High altitude (2500–​3500 m)
hypoxia/​altitude include those with (1) coronary ischaemia and a Acute altitude illness is common following rapid ascent to this altitude.
strongly positive exercise treadmill test; (2) sickle cell disease or trait; Very high altitude (3500–​5800 m)
(3) chronic pulmonary disease, especially pre-​existing pulmonary Arterial oxygen saturation falls below 90%. Acute altitude illness is
common and marked hypoxaemia can occur during exercise and sleep.
hypertension from any cause.
Extreme altitude (>5800 m)
Further acclimatization cannot be achieved, progressive physiological
deterioration occurs, and survival cannot be maintained permanently.
Introduction Marked hypoxaemia occurs at rest.

High-​altitude regions of the world, once considered remote and ac-

cessible to only a few individuals, are in fact home to over 200 million In addition to hypoxia, several other characteristics of the high-​
people living permanently above 2500 m in Asia, South America, altitude environment are important to understand. Temperature
and North America. In South America, miners and astronomers decreases approximately 1°C for every 150 m rise in altitude,
work for long durations at altitudes over 4500 m, while an equal irrespective of latitude, so that high-​altitude areas are considerably
number of tourists spend time at these altitudes in such activities as colder. Ultraviolet penetration increases by approximately 12% for each
trekking, skiing, and pilgrimages. Anyone at these altitudes is sus- 1000 m altitude gain, increasing the risk of sunburn, ultraviolet kera-
ceptible to high-​altitude illnesses which, if not recognized and ap- titis, and other sun-​related problems. The low humidity at high altitude
propriately treated, can spoil the experience of alpine environments, contributes greatly to fluid loss and dehydration, as does the increased
impair work ability, and in the worst scenarios cause death. solar radiation, which might be very much exaggerated by reflection
from snow. While air quality is generally superior in mountainous areas,
heavily populated areas in valleys that are prone to inversions can be
The high-​altitude environment associated with unhealthy concentrations of irritating gases and
particulates.
Although the percentage of oxygen in ambient air remains con-
stant at 21%, barometric pressure decreases with increasing altitude,
leading to a corresponding fall in partial pressure of oxygen (Po2) Effects of hypobaric hypoxia
(Fig. 10.3.6.1). At 2500 m the barometric pressure and inspired Po2
are about 75% those of sea level values. At 5000 m, which is close to A reduction in exercise capacity is a major effect of ascent to high
the maximum for permanent human habitation, Po2 is about half altitudes. Maximal oxygen consumption decreases by approxi-
of the sea-​level value. On the summit of Mount Everest (8848 m), mately 10% for each 1000-​m gain in altitude above 1500 m, and this
Po2 is about one-​third of the sea-​level value. In human physiology, does not recover appreciably with acclimatization. Reduced max-
the definitions of high altitude in Box 10.3.6.1 are commonly used. imal oxygen consumption occurs by a reduction in mitochondrial
Po2, interfering with the function of the electron transport chain
and adenosine triphosphate synthesis, or through central inhibition
in the brain to prevent injurious tissue hypoxia. Genetic factors are
800 partly responsible for individual variations in exercise performance
at high altitudes. For example, Tibetans, a population having resided
Barometric pressure (mmHg)

700
Mont Blanc 4807 m at high altitude for more than 25 000 years, have a variant of the gene
600 encoding a transcription factor (hypoxia inducible factor -​2, HIF-​2),
Mount Everest and mountaineers who perform well at high altitudes have a higher
500
8848 m expression of an angiotensin-​converting enzyme gene variant.
400 Sleep can also be disturbed at high altitude. There is difficulty
getting to sleep, frequent arousals, less rapid eye movement (REM)
300
time, and a decrease in slow-​wave sleep. Periodic breathing, char-
200 acterized by episodes of hyperpnoea followed by apnoea, is rela-
0 2000 4000 6000 8000 10000
Altitude (m)
tively common among travellers over 2500 m. It is thought to
Barometric pressure falls as altitude increases result from instability of the respiratory control system through
enhanced hypoxic drive or response to CO2, and can be minimized
Fig. 10.3.6.1 Change in barometric pressure with altitude. by the use of acetazolamide. Hypoxaemia during apnoeic episodes
© Pollard, Andrew J. and Murdoch, David R., The High Altitude Medicine Handbook
(3e). Oxford: Radcliffe Medical Press Ltd; 2003. Reproduced with the permission of during periodic breathing likely accounts for many of the arousals
the copyright holder. from sleep that are experienced at high altitude.
 10.3.6 Diseases of high terrestrial altitudes 1703

Neuropsychological changes at high altitude are often quite subtle, redistribution of blood flow: coronary and cutaneous flow both fall,
although various changes in mental performance have been docu- cerebral and retinal flow increase, and renal flow decreases initially
mented. Attention span, short-​term memory, arithmetic ability, and although returns to normal with acclimatization.
decision-​making can all be impaired at altitudes over 4000 m.
Fluid balance
Acclimatization Central blood volume increases with ascent to high altitude due
Acclimatization is the process of gradual adjustment to high alti- to peripheral venous constriction. This, in turn, can suppress anti-
tude hypoxia. In general, it is a physiological process involving a diuretic hormone and aldosterone to induce a diuresis along with
series of adjustments that occur in both the short term (minutes an independent action of peripheral chemoreceptors stimulated by
to hours) and long term (days to weeks). These changes enhance hypoxia to reduce renal sodium and water reabsorption.
oxygen delivery to cells and efficiency of oxygen use. In contrast,
‘altitude adaptation’ refers to physiological changes that occur over Extreme altitudes
longer time periods (decades and generations) and confer advan- Acclimatization in adults seems to be possible up to about 5500 m.
tages for life at high altitude. Acclimatization reduces the impact of Above this height, there is a fine balance between adjustment to
high-​altitude hypoxia, but is insufficient to fully return the body to high altitude and deterioration as a result of chronic hypoxia. The
its sea-​level normoxic capacities. term ‘high-​altitude deterioration’ refers to the general deterior-
The principal steps involved in high altitude acclimatization can ation in physical condition that occurs after lengthy stays at extreme
be summarized as follows: altitudes. Typical features include progressive weight loss (fat and
muscle), worsening appetite, poor sleep, and increased lethargy.
Ventilation The most extreme altitudes, such as the summit of Mount Everest,
Hyperventilation is the most important feature of acclimatiza- are very close to the limit of human tolerance to hypoxia. Indeed,
tion and serves to defend alveolar Po2 and thus arterial and tissue early estimates indicated that all available oxygen on the summit
Po2. Increases in the rate and depth of breathing, termed the hyp- of Mount Everest would be required for basal oxygen uptake, with
oxic ventilatory response, are mediated by hypoxic stimulation of none left for physical exertion. Alveolar gas samples taken near the
peripheral chemoreceptors located mainly in the carotid bodies. summit of Everest (8400 m; barometric pressure, 36.3 kPa) show an
Hyperventilation increases alveolar Po2 in the face of decreased in- inspired Po2 = 6.27 kPa, and alveolar Po2 = 4.00 kPa. Mean arterial
spired Po2, while also reducing alveolar Pco2 leading to a respira- gas values at this altitude were: Po2 3.3 kPa; Pco2 1.8 kPa; pH 7.5;
tory alkalosis. Although initially the alkalosis limits the full hypoxic oxygen saturation 54%. Consequently, it is extraordinary that some
ventilatory response, eventually it is somewhat compensated for by humans are able to climb to this height without using supplemen-
increased urinary bicarbonate excretion over several days and subse- tary oxygen. Missing in our efforts to fully describe acclimatization
quently followed by a further increase in ventilation over the course and the profound altitudes that some individuals can attain are pro-
of several weeks, reflecting an increase in intrinsic hypoxic sensitivity found changes at the levels of the microcirculation and cellular me-
of the peripheral chemoreceptors. The degree of hyperventilation in tabolism. Many of these might involve the hundreds of genes that are
response to high-​altitude hypoxia can be profound and, with exercise, up-​and down-regulated by gene transcription factors called hypoxia
it may be what subjectively causes a person to have to stop. Alveolar inducible factors 1 and 2 (HIF). Several reports have suggested mild,
ventilation increases approximately fivefold on the summit of Mount possibly permanent, defects in cognition in climbers who have as-
Everest, where inspired Po2 is less than one-​third of its sea-​level value cended to extreme high altitudes.
and arterial Pco2 values as low as 10 mmHg at rest have been recorded.
Illnesses due to altitude
Blood Until high-​altitude acclimatization has occurred, lack of physio-
Although erythropoietin secretion is increased within 2 h of ascent logical compensation for hypobaric hypoxia can manifest as altitude
to high altitude, it takes many days to weeks for an increase in red illness. Acute mountain sickness, high-​altitude pulmonary oedema,
cell mass to occur. This ultimately increases the oxygen-​carrying and high-​altitude cerebral oedema are recognized distinct clinical
capacity of the blood and permits greater oxygen transport to tis- syndromes of altitude illness. Acute mountain sickness is both the
sues. The shift in the oxyhaemoglobin dissociation curve to the most common and the quickest to develop, and while it often pre-
right, which occurs on ascent and is due to an increase in red cell cedes high-​altitude pulmonary oedema or high-​altitude cerebral oe-
2,3-​diphosphoglycerate, which favours unloading of oxygen in the dema, either can occur in its absence.
tissues. However, this particular adjustment is offset by the shift to Development of altitude illness usually occurs after a rapid ascent,
the left caused by the respiratory alkalosis mentioned previously, although there is considerable variation in susceptibility between in-
leaving the P50 essentially unchanged. dividuals. Genetic factors are likely to be important in determining
susceptibility, but several other factors are contributory and are dis-
Circulation cussed in the following paragraphs.
Although there is an abrupt increase in cardiac output on ascent to
high altitude, there follows a progressive decrease in stroke volume Acute mountain sickness
and maximal cardiac output is reduced at all levels of exercise, Incidence rates of acute mountain sickness vary with the absolute
including maximal exercise. Although there is no evidence for insuf- altitude gained and the speed of ascent. Some 30–​50% of those who
ficient myocardial oxygenation, there is disagreement about whether ascend to 4500 m on a standard trek in the Himalayas develop acute
the myocardium is depressed by hypoxia. There is an immediate mountain sickness. Its incidence is greater at higher altitudes and
1704 SECTION 10 Environmental medicine, occupational medicine, and poisoning

with greater gains in altitude, and might be precipitated by physical that these techniques lack sufficient sensitivity, particularly if the
exertion, although this remains controversial. Some people have a oedema is not global. However, brain volume does increase after
history of recurrent acute mountain sickness, suggesting individual longer exposure to hypoxia. Some recent evidence suggests that oxi-
susceptibility. dative stress might be involved in the development of acute moun-
Typically, symptoms of acute mountain sickness begin 6–​12 h after tain sickness. Other theories include hypoxia-​mediated irritation of
ascent to altitudes over 2500 m. The familiar features are non​specific the trigeminal system from hypoxia-​mediated increase in radical
symptoms that are readily confused with many other illnesses and oxygen species or nitrosative radicals.
include: Mild acute mountain sickness usually resolves if the victim
avoids further ascent and rests. Paracetamol (acetaminophen),
• headache non​ steroidal anti-​inflammatory agents, and other analgesics
• nausea might bring relief from headache. Those whose symptoms fail to
• vomiting resolve or worsen should descend immediately. More severe symp-
• fatigue toms will also resolve with descent, but some people will require
• anorexia treatment to facilitate descent. Supplementary oxygen might be
• dizziness beneficial if available. Treatment with acetazolamide (250 mg or-
• sleep disturbance ally, three times daily), or dexamethasone (4 mg orally, four times
daily) can be useful in severe cases. Acetazolamide is a carbonic
For practical purposes, people ascending to altitude with unex- anhydrase inhibitor, which increases renal excretion of bicar-
plained symptoms that include the above mentioned should be as- bonate to induce a metabolic acidosis. The hyperventilation in-
sumed to have acute mountain sickness. The headache is typically duced by the respiratory compensation improves oxygenation and
worse at night, upon lying down, and with a Valsalva manoeuvre. helps relieve symptoms.
Anorexia is often pronounced. Clinical examination is typically un- Portable hyperbaric chambers are widely used on trekking routes
remarkable, although it might reveal some peripheral oedema. There and can be pressurized to simulate a 500–​700 m descent, tempor-
might be tachycardia and elevated core temperature. Typically, the arily relieving symptoms in order to facilitate a true descent. These
person with acute mountain sickness is apathetic and withdrawn, chambers are inflated with a hand or foot pump to achieve the baro-
often seeking solitude (see Fig. 10.3.6.2). metric pressure of a lower elevation. CO2 is removed by the airflow
The aetiology of acute mountain sickness is unknown. It has generated by the pumping action, and a CO2 scrubber is included in
been argued that it is a mild form of cerebral oedema since it often some models.
precedes development of high-​altitude cerebral oedema, and the Acute mountain sickness can be avoided or prevented in most
symptoms of acute mountain sickness include symptoms of head- cases by carefully graded ascent. Above 3000 m, a rate of ascent of
ache and nausea consistent with a mild increase in intracranial 300–​600 m per day with a rest day every 1000 m will avoid symp-
pressure. Brain imaging studies have not found increases in global toms for most people. However, there is considerable individual
brain volume or oedema in the first 6–​10 h after exposure to hyp- variation. For some destinations, itineraries are rapid enough to in-
oxia despite symptoms of acute mountain sickness, but it might be duce symptoms of acute mountain sickness in a large proportion

Fig. 10.3.6.2 A trekker in Kunde Clinic at 3840 m with symptoms of acute mountain sickness
(headache, anorexia, lethargy, and malaise) en route to Everest Base Camp.
Courtesy of T Albert.
 10.3.6 Diseases of high terrestrial altitudes 1705

of travellers. For this reason, prophylaxis with acetazolamide, release of mediators in the central nervous system in response to
started on the day before ascent over 3000 m (125–​250 mg twice hypoxia might also contribute.
daily or 250–​500 mg daily of the slow-​release preparation) is fre- In view of the seriousness of high-​altitude cerebral oedema, treat-
quently recommended for prevention and can be quite effective. ment is urgently required, and the most important measure is imme-
Since the side effects induced by this drug may be serious (allergic diate descent. Oxygen therapy or simulated descent using a portable
reactions), mimic acute mountain sickness in some respects (head- hyperbaric chamber can improve oxygenation and symptoms and
ache, nausea, anorexia), or be intolerable (paresthesiae), several test thus facilitate descent. Intravenous dexamethasone (8 mg followed
doses should be tried before it is used for prophylaxis during ascent. by 4 mg, orally four times per day) might improve symptoms and
There is evidence that acetazolamide doses of 125 mg twice daily is widely recommended. high-​altitude cerebral oedema tends to re-
can be effective in some people. Dexamethasone can also be useful cover more slowly than other forms of altitude illness and ataxia is
for prophylaxis, although its mechanism of action is unknown. One often the last sign to disappear.
study found that the inhaled corticosteroid budesonide, in doses High-​altitude cerebral oedema is probably prevented by slow,
unable to generate significant blood levels to act at the brain, was as graded ascent (as with acute mountain sickness described previ-
effective as oral dexamethasone. However, two subsequent studies ously) and prophylaxis with dexamethasone might be beneficial for
could not confirm this efficacy. In recent trials, ginkgo biloba has those with a risk of the condition.
been found to be ineffective and thus is not advised, particularly
since it is not a regulated pharmaceutical and preparations can vary High-​altitude pulmonary oedema
in content and contamination with other substances. Theophylline High-​altitude pulmonary oedema typically occurs within 4 days
reduces periodic breathing during sleep, but not oxygenation, and of ascent to altitudes over 2500 m and might be accompanied by
probably has little utility in prophylaxis. symptoms of acute mountain sickness or high-​altitude cerebral oe-
dema. It presents more frequently with increasing altitude: 1–​2%
High-​altitude cerebral oedema of people may be affected at 4500 m, but rates as high as 10% have
Unlike acute mountain sickness, which is quite common among been reported after rapid ascent at this altitude. Previous episodes
travellers to high altitude, high-​ altitude cerebral oedema and of high-​altitude pulmonary oedema for an individual repeating the
high-​altitude pulmonary oedema are relatively uncommon. High-​ same ascent rate and altitude gain confer a 60–​70% likelihood of re-
altitude cerebral oedema is more typical after ascent to altitudes currence. It can also occur in those who have become acclimatized at
over 4000 m, but cases have been described even at the modest ele- one altitude and then make a further ascent. A form of high-​altitude
vation of 2100 m. As with acute mountain sickness, higher rates pulmonary oedema, known as re-​entry high-​altitude pulmonary oe-
are found at the highest altitudes and after more rapid ascent. At dema, can occur in adults and often more in children living at high
4000 to 5500 m, rates of 1% have been described amongst trek- altitude after returning home from a lowland vacation. It is a serious
kers. High-​altitude cerebral oedema is usually preceded by acute form of altitude illness and is associated with fatality when not man-
mountain sickness and is frequently associated with high-​altitude aged urgently and appropriately.
pulmonary oedema since the greater hypoxemia occurring with High-​altitude pulmonary oedema is slightly more common in
high-​altitude pulmonary oedema is the equivalent to suddenly men than women. The risk of it developing is increased by cold,
being at an even higher altitude (see following paragraphs). rapid ascent, exertion, coexistent viral infection, and possibly by
Symptoms of acute mountain sickness have usually been present drugs or ingestions that cause respiratory depression, such as al-
for 1 to 2 days before the onset of high-​altitude cerebral oedema. cohol. Individual susceptibility is well recognized and those who
Risk factors for the development of high-​altitude cerebral oedema have previously suffered from it appear to be more susceptible in the
are probably similar to those recognized for other forms of altitude future. There are various genetic associations described including
illness. high-​altitude cerebral oedema might be more common in pulmonary surfactant protein A, HLA DR6, HLA DQ4, epithe-
the presence of intracranial space-​occupying lesions such as cysts lial sodium channel protein, and endothelial nitric oxide synthase.
or tumours. People with raised pulmonary blood flow or an exaggerated hypoxic
Worsening symptoms of acute mountain sickness and ataxia are pulmonary vascular response might also be more susceptible (i.e.
typical early signs of development of high-​altitude cerebral oedema. those with atrial septal defect, unilateral absence of a pulmonary ar-
Behavioural changes (being irrational, withdrawn, or exuberant), tery or a chronic respiratory condition).
confusion, and a change in conscious level leading to coma might People with high-​altitude pulmonary oedema typically present
ensue. Papilloedema might be present. Both focal neurological signs with dyspnoea out of proportion to others in the group and cough.
and cranial nerve lesions can occur. Brain imaging studies show The breathlessness is made worse with exertion and can present with
typical signs of cerebral oedema, particularly in the splenium of the blood-​tinged frothy sputum and frank haemoptysis. Other symp-
corpus callosum, with changes in white matter signal, compression toms include chest pain, orthopnoea, nausea, insomnia, headache,
of sulci, and blunting of gyri. Lumbar puncture, if undertaken, re- dizziness, and confusion. Low-​grade fever is a common finding to-
veals elevated pressures but is otherwise normal. High-​altitude cere- gether with tachycardia, tachypnoea, crackles on auscultation of the
bral oedema is indistinguishable clinically from many other causes chest, and cyanosis in late disease.
of compromised cerebral function. There is a very high mortality Signs of right ventricular enlargement can be present with an
among those who develop coma. accentuated pulmonary second heart sound and right ventricular
It is likely that high-​altitude cerebral oedema is a vasogenic oe- heave. Oxygen saturations are decreased from the prevailing levels of
dema resulting from injury to the blood–​brain barrier, following those acclimatizing well, the electrocardiogram shows right axis de-
disturbances in cerebral autoregulation. Cytotoxic oedema from viation, tachycardia, and peaked P-​waves, and the chest radiograph
1706 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Fig. 10.3.6.3 Chest X-​ray and CT scan of a patient with high altitude pulmonary oedema.
Courtesy of E. Swenson.

shows pulmonary oedema (Fig 10.3.6.3), often more prominently and sildenafil have been used and might be beneficial, but nifedi-
on the right. pine is most widely used. Portable hyperbaric chambers are often
In patients who have been studied with cardiac catheterization available on commercial trekking routes (see Fig. 10.3.6.4). They
during high-​altitude pulmonary oedema, pulmonary arterial pres- can simulate descent, improve oxygenation, and relieve symptoms.
sure is often quite elevated, but pulmonary wedge pressures are Devices that help provide positive expiratory airway pressure
normal, ruling out heart failure. Most people who are susceptible might also improve oxygenation.
to high-​altitude pulmonary oedema show an abnormal rise in their The risk of high-​altitude pulmonary oedema is reduced by slow,
pulmonary arterial pressure at sea level during exposure to hyp- graded ascent. Above 3000 m, a rate of ascent of 300–​600 m per day
oxia or on normoxic exercise. Hypoxic pulmonary vasoconstriction with a rest day every 1000 m is recommended. Nifedipine (20-​mg
varies almost fivefold among healthy persons, and at sea level or low slow release preparation, three times daily) and other calcium channel
altitudes poses no problems. blockers, dexamethasone (8 mg twice daily), inhaled salmeterol, a
The clinical syndrome is not unique, and similar findings occur in β2-​
andrenoceptor agonist, and phosphodiesterase-​ 5 inhibitors
other respiratory diseases, including acute bacterial or viral pneu- are effective for prophylaxis in those known to be susceptible.
monia and pulmonary embolism. High-​altitude cough (see fol- Acetazolamide, which inhibits hypoxic pulmonary vasoconstriction
lowing paragraph) might also cause diagnostic confusion. by a mechanism unrelated to its action as a carbonic anhydrase in-
As described earlier, high-​altitude pulmonary oedema appears hibitor, might also be effective in its prevention, although it has not
to result from an exaggerated hypoxic pulmonary vasoconstrictor been formally tested for this indication. Dexamethasone, while ef-
response. Because there is regional unevenness in the response, fective in prevention for high-​altitude pulmonary oedema-​susceptible
this leads to downstream pressure increase in over-​perfused areas persons, does not appear to be efficacious in treatment. This might
that lead to capillary leak, either from pressure induced changes stem from the fact that its action largely is dependent on changes in
in permeability or at the extreme capillary stress failure and frank gene transcription that require many hours to become effective.
bleeding into the alveolar space. Once high-​altitude pulmonary
oedema is recognized, the victim must descend. Even descent of High-​altitude retinal haemorrhage
several hundred metres can be enough to raise the barometric Retinal haemorrhages occur frequently at altitudes of 5000 m or
pressure sufficiently to increase inspired oxygen tensions and re- higher, even in those without acute mountain sickness or high-​
duce pulmonary artery pressure. Without appropriate manage- altitude cerebral oedema. Although usually asymptomatic, they
ment, it can be fatal, and further ascent should not be undertaken. can cause visual problems if the macula is involved (Fig. 10.3.6.5).
In a mountain environment, immediate descent might be im- The causes of high-​altitude retinal haemorrhage can include in-
possible because of weather or other circumstances. The patient creased cerebral blood flow, Valsalva manoeuvres (during exer-
might be so breathless that they cannot move and, as mentioned tion or coughing), polycythaemia, and hypoxia-​mediated capillary
earlier, at a very high risk to develop high-​altitude cerebral oe- endothelial permeability. In most instances of high-​altitude retinal
dema. Adjunctive therapies might improve symptoms and allow haemorrhage without altitude illness, descent might not be neces-
descent. The patient should be encouraged to sit up to prevent sary. The haemorrhages usually resolve within days to weeks. If vi-
orthopnoea. Oxygen should be given if available. As a strong sion is compromised or there is concomitant altitude illness, descent
inhibitor of hypoxic pulmonary vasoconstriction, nifedipine is mandatory.
(20 mg slow release preparation, four times daily) reduces pul-
monary artery pressure and relieves symptoms. Side effects of ni- Peripheral oedema
fedipine include headache, dizziness, and postural hypotension, Swelling of the hands, face, and ankles commonly occurs at
but the drug is generally well tolerated. Other pulmonary vaso- high altitude and might not be related to acute mountain sick­
dilators such as hydralazine, phentolamine, inhaled nitric oxide, ness, high-​altitude cerebral oedema, or high-​altitude pulmonary
 10.3.6 Diseases of high terrestrial altitudes 1707

Fig. 10.3.6.4 An example of a portable hyperbaric chamber being set up in the Alps.
Courtesy of E Swenson.

oedema. Anasarca is seldom seen. Descent or diuretics will treat also demonstrated down-​regulation of the β-​receptors of the heart.
the oedema. However, travel to high altitude can precipitate new-​ onset an-
gina, although it is unclear whether this is related to exertion or to
High-​altitude cough hypobaric hypoxia as such. People with cardiac risk factors or with
Dry hacking cough is a common, bothersome problem at high previous myocardial ischaemia, coronary artery bypass surgery, or
altitude, and has caused rib fractures in some severe cases. High-​ angioplasty are considered to be at high risk if they have a strongly
altitude cough is probably multifactorial in origin: water loss from positive exercise treadmill test.
the airways due to hyperventilation of cold-​dry air, post nasal drip, Although cold air and exercise are triggers for asthma, many asth-
acute mountain sickness, high-​altitude pulmonary oedema, and matics remain well at high altitude. This might be due to decreased
bronchoconstriction have all been invoked as possible causes of alti- density of the air, a lack of allergens, or the increase in steroid hor-
tude related cough. Breathing through a silk scarf, throat lozenges, mones produced under hypoxic stress. However, it is important
and steam inhalation might be helpful. If there is nasal congestion, a for asthmatics going up to high altitude to carry their medicines
decongestant nasal spray is useful. (including an oral corticosteroid) with them and have a well-​defined
action plan to deal with any exacerbation.
Many people with well-​controlled epilepsy can venture safely
Effects of high altitude on pre-​existing to high altitudes, but there remain some causes for concern.
medical conditions Hyperventilation leading to hypocapnia and hypoxia are themselves
triggers for seizure activity.
Hypertensive patients should continue their medications at high People with sickle cell disease or trait are at high risk of sickle
altitude, and the vast majority of hypertensive skiers and trekkers crises above 2000 m, and should avoid staying at altitude.
do very well despite a transient rise in the blood pressure. Some pa- Diabetics might find that increased energy expenditure at high
tients with labile hypertension might have a sudden, dangerous rise altitude alters carbohydrate and insulin requirements. Consequently,
in their blood pressure at high altitude and, for them, blood pres- rapidly acting insulin, close monitoring, availability of oral and
sure monitoring might be necessary. The exaggerated blood pres- intravenous glucose, and knowledgeable companions are im-
sure response to high altitude is apparently mediated by increased portant. Loss of diabetic control due to intercurrent infections, like
α-​adrenergic activity. Hence an α-​blocker might be useful or, as diarrhoea, is also possible. It is especially important that insulin pre-
shown recently in a well-​conducted randomized study, angiotensin parations never freeze, and one option for prevention is by keeping
receptor blockade with valsartan up to 3500 m is effective. them close to the body.
People with stable coronary artery disease tolerate intermediate Pre-​existing pulmonary hypertension from any cause can be
and high altitudes relatively well, even while exercising. This might a problem at high altitude and comes close to being an absolute
be partly attributable to the marked reduction in maximal exer- contraindication to travel above very modest altitudes (<2500 m).
cise at high altitude, which reduces myocardial oxygen demand Mitral stenosis, kyphoscoliosis, and congenital cardiac defects with
and maximal heart rate. Animal experiments at high altitude have pulmonary hypertension can predispose to high-​altitude pulmonary
1708 SECTION 10 Environmental medicine, occupational medicine, and poisoning

(a) previously asymptomatic people with heterozygous protein C and

S deficiency and antiphospholipid syndrome. Risk of thrombosis
might have been increased by dehydration and polycythaemia.
Immobility during inclement weather, coupled with dehydration
and polycythaemia, might also predispose to deep vein thrombosis
leading to pulmonary embolism. Unanswered questions about the
effects of high altitude on blood coagulation include the use of oral
contraceptives and whether prophylactic aspirin prevents throm-
bosis. Subjects taking warfarin might experience changes in the
drug’s metabolism and monitoring may be needed, thus restricting
high altitude destinations to those places where international
normalized ratio measurements are possible, such as large ski re-
sorts with medical centres.

Chronic mountain sickness (Monge’s disease) and

high-​altitude pulmonary hypertension
(b)
Excessive erythrocytosis, severe hypoxaemia, and, in some cases,
moderate to severe pulmonary hypertension leading to cor
pulmonale are the features of chronic mountain sickness. This dis-
ease, also known as Monge’s disease, is a disease of long-​term resi-
dents of altitudes above 2500 m. Besides South America, where
this condition was originally described, chronic mountain sickness
has also been documented in Colorado and in the Han Chinese
population in Tibet. Migration to low altitude cures the problem.
Venesection, acetazolamide and, possibly, angiotensin converting
enzyme inhibitors have been shown to be helpful. It is important
to distinguish chronic mountain sickness from chronic obstructive
pulmonary disease.
High-​altitude pulmonary hypertension is now the accepted term
for diseases that include adult subacute mountain sickness and
infantile subacute mountain sickness. Unlike chronic mountain
Fig. 10.3.6.5 Contrasting retinal appearances on Mount Everest. sickness, which is characterized by erythrocytosis, the primary fea-
(a) Normal retina of a well-​acclimatized and well-​oxygenated climber ture of this condition is pulmonary hypertension leading to heart
shortly after reaching the summit (8848 m). (b) Retinal haemorrhages in a failure. The adult form has been described exclusively in Indian sol-
poorly acclimatized climber at the North Col (7100 m).
diers living at extreme altitudes for prolonged periods. The infantile
Copyright Daniel Morris, Newcastle.
form has been seen mainly in Han Chinese immigrants in Tibet.
These conditions bear a striking pathophysiological resemblance to
oedema and are therefore hazardous at high altitude. Those with brisket disease in cattle. Descent from high altitude completely cures
chronic obstructive pulmonary disease frequently report increased the problem. High-​altitude pulmonary hypertension of chronic
dyspnoea and reduced exercise tolerance when they ascend to high onset is also well described.
altitude.

FURTHER READING
Other illnesses at altitude Bärtsch P, et al. (2004). Acute mountain sickness: controversies and
advances. High Alt Med Biol, 5, 110–​24.
Focal neurological problems are occasionally encountered at high Bärtsch P, et al. (2005). Physiological aspects of high-​altitude pul-
altitude. Transient ischaemic attacks and strokes, cerebral venous monary edema. J Appl Physiol, 98, 1101–​10.
thrombosis, subarachnoid haemorrhage, high-​ altitude syncope, Bärtsch P, Swenson ER (2013). Acute high-​altitude illnesses. NEJM,
delirium, transient global amnesia, cranial nerve palsies, cortical 368, 2294–​302.
blindness, and amaurosis fugax have all been reported. However, it is Basnyat B, Murdoch DR (2003). High-​altitude illness. Lancet, 361,
unclear whether these deficits are related to hypoxia of high altitude 1967–​74.
Baumgartner RW, Siegel AM, Hackett PH (2007). Going high with
and most need to be distinguished from acute mountain sickness
preexisting neurological conditions. High Alt Med Biol, 8, 108–​16.
and high-​altitude cerebral oedema.
Dehnert C, et al. (2005). Identification of individuals susceptible to
Venous thrombosis has been reported at high altitude, although
high-altitude pulmonary oedema at low altitude. Eur Respir J, 25,
its association with high-​altitude exposure is uncertain. Cases of 545–51.
cerebral venous thrombosis at high altitude have been reported in
 10.3.7 Radiation 1709

Imray C, et al. (2011). Acute altitude illness. BMJ, 343, d4943. Information on the health effects of other types of non​ionizing
Lipman GS, et al. (2012). Ibuprofen prevents altitude illness: a radiation (e.g. radiofrequency microwaves, and power-​frequency
randomized controlled trial for prevention of altitude illness electric and magnetic fields) is less robust, but controls are recom-
with nonsteroidal anti-​inflammatories. Ann Emerg Med, 59, mended to prevent those health effects that are established.
484–​90.
Luks AM (2012). Clinician’s corner: what do we know about safe
ascent rates at high altitude? High Alt Med Biol, 13, 147–​52.
Luks AM, Swenson ER (2007). Travel to high altitude with pre-​ Introduction
existing lung disease. Eur Respir J, 29, 770–​792.
Maggiorini M, et al. (2006). Both tadalafil and dexamethasone may The term radiation applies to emissions in the electromagnetic
reduce the incidence of high-​altitude pulmonary edema: a random- spectrum. Only ionizing radiation is energetic enough to cause
ized trial. Ann Intern Med, 145, 497–​506. ionization of matter. There are natural sources of ionizing radi-
Rimoldi SF, et al. (2010). High-​altitude exposure in patients with car- ation, such as radon gas or cosmic rays, and manufactured sources,
diovascular disease: risk assessment and practical recommenda-
such as X-​rays and radioactive isotopes produced in nuclear re-
tions. Prog Cardiovasc Dis, 52, 512–​24.
actors. Excluding medical exposures, natural radiation accounts
Roach RC, Hackett PH (2001). Association of polymorphisms in
for most human exposure. Some types of non​ionizing radiation
pulmonary surfactant protein A1 and A2 genes with high-​altitude
pulmonary edema. Chest 128, 1611–​20. are also health hazards. These include radiant heat, ultraviolet ra-
Schoene RB (2004). Unraveling the mechanism of high altitude pul- diation, radio waves, microwaves, and power-​frequency electro-
monary edema. High Alt Med Biol, 5, 125–​35. magnetic fields.
Swenson ER, Schoene RB (2014). High altitude pulmonary edema.
In: Swenson ER, Bartsch P (eds) High altitude: human adaptation
to hypoxia, pp. 405–28. Springer Publications, New York, NY. Historical perspective

The dangers of ionizing radiation became apparent almost as

soon as experiments with radioactive materials began. In the early
20th century, radiologists often calibrated their machines by the
dose causing erythema on their hands. Many, including Marie
Skłodowska-​Curie and her daughter Irène Joliot-​Curie, died of
10.3.7 Radiation radiation-​induced cancers. Despite universal exposure to natural
Jill Meara background radiation, there is a general fear of ionizing radiation,
especially that associated with nuclear power and nuclear weapons.
The hazards of certain types of non​ionizing radiation, such
as sunburn and electrical discharge in thunderstorms, are well
ESSENTIALS
known, but the health of pioneers in non​ionizing radiation re-
Ionizing radiation search was not affected. Recently, the safety of power-​frequency
Ionizing radiation has sufficient energy to break chemical bonds and and radiofrequency fields—​ at the levels to which the public
produce charged ions in living tissue. These changes might cause cell are exposed—​has been questioned. However, hypotheses about
death, but breaks of both strands of a DNA molecule that do not kill possible long-​term health effects, such as induction of cancer, lack
a cell can be a precursor of cancer. biologically plausible mechanisms or confirmation by high-​quality
Excluding medical exposures, natural radiation accounts for epidemiological studies.
most human exposure, which produces health effects that might
be (1) stochastic, where the probability of manifesting the effect
depends on the radiation dose, including carcinogenesis and in- Ionizing radiation: Mechanism of harm
duction of heritable defects; (2) psychological, especially following
accidental exposures; and (3) tissue reactions, occurring when suf- Atoms, radioactivity, and radiation
ficient cells are killed after exposure to radiation doses above a cer-
Isotopes of some elements are unstable and undergo radioactive
tain threshold, including the acute radiation syndrome (radiation
decay. The time taken for half of a given quantity to decay is called
sickness) and radiation burns.
the half-​life, which ranges from fractions of a second to thousands
Prevention—​legislative dose-​limits prevent tissue reactions and re-
of years, depending on the particular isotope. The unit of radio-
duce the risk of stochastic effects, although all doses should be kept
activity is the becquerel (Bq). 1 Bq equals 1 atomic disintegration
as low as reasonably achievable.
per second. The natural radionuclide potassium-​40 (40K), with
Non​ionizing radiation a half-​life of 1.250 × 109 years, makes up 120 parts per million of
Ultraviolet radiation affects primarily (1) the skin, causing sunburn all potassium on Earth. Since there is about 4000 Bq of 40K in an
in the short term and skin cancer in the long term; and (2) the eye, average person, there are about 14 million radioactive disintegra-
causing photokeratitis and photoconjunctivitis (arc eye, snow blind- tions per hour from 40K inside the average human body.
ness) in the short term, and conjunctival and corneal disorders and Unstable isotopes (radionuclides) decay and release energy as
cataracts in the long term. subatomic particles (α-​or β-​particles) or γ-​rays. X-​rays are pro-
duced by bombarding a metal target with electrons in a vacuum.
1710 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Neutrons are produced during nuclear fission reactions. These

vary in the extent to which they can penetrate the body and can
interact with tissues and cells. α-​Particles are densely ionizing and
are stopped by the dead layer of the skin, but constitute a hazard
if taken into the body. β-​Particles can penetrate the body to the
depth of a few centimetres; X-​and γ-​rays penetrate the body and,
if not absorbed, pass through it. Lead shielding is needed to pro-
tect against X-​rays and γ-​rays. These properties of radiation affect
the location and extent of cellular damage following exposure and
dictate the protective methods required.
Ionizing radiation has sufficient energy to break chemical bonds
and produce charged ions in living tissue. Most of these changes are
inconsequential, others can be repaired, but there is a finite prob-
ability that damage might cause cell death. Breaks of both strands
of a DNA molecule might not kill a cell, but they are known to be a
precursor of cancer.

Measuring radiation risk

Acute cell damage depends on the energy imparted by the radiation.

The mean energy absorbed per unit mass of tissue (absorbed dose) is
Fig. 10.3.7.1 Mature radiation burn showing central necrosis and
measured in gray (Gy). 1 Gy is equal to 1 joule (J) deposited per kilo- annular epilation.
gram of tissue. Radiation and tissue-​weighting factors are used to Reproduced with permission from The Radiological Accident in Lilo, International
convert the absorbed dose in Gy to an effective dose in sieverts (Sv). Atomic Energy Agency, Vienna (2000). © IAEA, 2000.
This allows external and internal exposures from all types of ion-
izing radiation to be integrated into one dose, on the basis of equality
accidents are rare and the initial symptoms of radiation sickness
of stochastic risk. The United Kingdom average annual individual
are non​specific, resembling influenza or food poisoning, so phys-
natural background radiation dose is 2.3 mSv. The typical dose from
icians might be involved in diagnosis and treatment before the
an anteroposterior chest radiograph is 0.02 mSv and that from an
true cause is appreciated. Patients might present to a range of dif-
abdominal CT scan is 10 mSv.
ferent medical settings. For example, the theft of a caesium-​137
(137Cs) radiotherapy source in Goiânia, Brazil, led to 50 people
being overexposed, and resulted in four deaths. Many people and
Health effects of exposure to ionizing radiation
large areas of land and property were contaminated before the
true cause of the incident was appreciated.
There are three types of health effects associated with exposure to
ionizing radiation: stochastic effects, psychological effects, and
tissue reactions.
Clinical features of radiation-​induced
• In stochastic effects, the probability of manifesting the effect tissue reactions
depends on the radiation dose and include carcinogenesis and
induction of heritable defects. Radiation-​ induced cancer is External exposures, either whole body or partial, do not render
clinically and pathologically indistinguishable from idiopathic patients radioactive and thus pose no radiation risk to medical at-
cases. Risks at low-​radiation doses are extrapolated from animal, tendants. If the patient has ingested or inhaled radioactive mater-
experimental, and epidemiological studies at higher doses as- ials, or has wounds containing them (internal exposure), they and
suming a linear no-​threshold model. This implies that there is no their waste products can pose a persisting radiation or contamin-
‘safe’ radiation dose, but very small exposures convey very small ation hazard to other people. Decontamination of radioactive ma-
risks. The absolute cancer risk per unit of radiation dose (risk terial on skin or clothing is often straightforward, but should not
coefficient) is estimated to be 5.5%/​Sv. Recent data suggest that take precedence over life-​saving procedures. If contamination is
cardiovascular system damage might also be a stochastic effect of suspected, contact a radiation-​protection expert for monitoring and
radiation, with a similar risk coefficient as for cancer induction. avoid spread of material. Stable iodine can be used to block uptake
• Psychological effects are found especially following acci- of radioactive isotopes of iodine. Chelating agents, such as ethylene-
dental exposures. Readers are referred to the literature on risk diamine tetraacetic acid, and ion-​exchange resins, such as Prussian
communication. blue, can be used to enhance excretion of certain internal radio-
• Tissue reactions (also called deterministic effects) occur after ex- nuclides, such as 137Cs and actinides.
posure to radiation doses above a certain threshold, when suffi- Partial-​
body exposures, especially of the extremities, might
cient cells are killed. These include the acute radiation syndrome not be accompanied by systemic disease if the equivalent whole-​
(radiation sickness) and radiation burns (Fig. 10.3.7.1). Radiation body dose does not reach the symptom threshold. Symptoms of
 10.3.7 Radiation 1711

radiation burns include erythema, oedema, dry and wet desquam- dose (between 0.1 and 10 Gy), follows first-​order kinetics and can
ation, blistering, pain, necrosis, and gangrene. There are no path- be estimated by multiplying the lymphocyte depletion rate con-
ognomonic features, but margins of ulcers might show epilation. stant by 8.6.
Radiation burns can extend deep into the soft tissue, increasing Chromosome aberration assays, mainly dicentrics (chromosomes
fluid loss and risk of infection. Skin injuries evolve slowly, usually with two centromeres) in lymphocytes or other chromosomal ab-
over weeks to months, can become very painful, and are resistant normalities detected by fluorescence in situ hybridization, can be
to treatment. used to give a more precise estimate of whole-​body dose. These as-
says can be used for several years after exposure.
Acute radiation syndrome
The acute radiation syndrome is a rare (handfuls of cases per year
worldwide), multiphasic illness. The prodrome of high exposure to Treatment of acute radiation syndrome
external ionizing radiation is sudden anorexia, nausea, and vomiting,
headache, fatigue, fever, and diarrhoea, sometimes with erythema Good clinical care ensures the best chance of recovery, provided
and itching, usually lasting 24–​48 h. The timing of onset, severity, that some stem cells have survived the radiation exposure. Early
and duration of prodromal symptoms depend on the radiation dose. treatment of associated conventional injuries is important. Routine
After a latent period of apparent recovery, effects of the killing of monitoring should include daily full blood counts, and blood cul-
cells—​especially stem cells—​appear. Severity depends on the radi- tures and other infection screens, especially in febrile patients.
ation dose. The main clinical features are: As a rule of thumb, patients with an estimated dose of 2 Gy or
more should be observed in hospital and monitored for onset of
• haematopoietic syndrome, at whole-​body radiation doses ex-
acute radiation syndrome, but not all will require intensive treat-
ceeding 1 Gy—​significant reductions in blood cell counts, infec-
ment. Patients with doses of more than 4 Gy should be presumed to
tion, haemorrhage, and anaemia
be developing acute radiation syndrome. Early arrangements should
• gastrointestinal syndrome at whole-​body radiation doses around
be made for specialist treatment.
6 Gy—​breakdown of the integrity of the gut wall leading to mas-
The mainstays of treatment are:
sive fluid and electrolyte loss and ingression of pathogens
• radiation pneumonitis and the cerebrovascular syndrome (at doses • symptomatic treatment (e.g. early wound closure, antiemetics,
exceeding 20 Gy)—​respiratory failure, hypotension, and major im- analgesics, and fluid replacement)
pairments of cognitive function • early cytokine (colony stimulating factor) therapy
• radiation burns if the skin dose exceeds 20 Gy • avoiding infection by barrier isolation (or reverse isolation) with
strict environmental control, oral feeding with cooked food only
If the patient survives this phase, recovery is likely. High radiation
and meticulous hand and nail hygiene, skin, and hair disinfection
doses can also lead to permanent sterility.
and minimization of invasive procedures
Several triage categories have been published, relating the severity
• supporting affected organs until surviving stem cells multiply and
and time-​course of symptoms and signs to prognosis. Although
repopulate the relevant organ/​tissue (e.g. consider gastrointestinal
the threshold radiation dose for symptoms is approximately 1 Gy,
decontamination, antibiotics, blood, and platelet transfusions).
lymphocyte dosimetry can detect acute doses down to about 100 mGy.
Avoid antacids, proton pump inhibitors, and H2 blockers to
Patients who also have conventional injuries have a worse prognosis.
maintain gastric acidity; use sucralfate to avoid stress ulcers
Without medical treatment, an acute dose of approximately 4 Gy is
likely to be fatal within 60 days in 50% of those exposed. Doses over Bone marrow transplants have not been proven to be beneficial.
10 Gy are likely to be fatal sooner, despite treatment. Similar doses There is weak evidence for erythropoiesis stimulating agents and
over longer periods (days, weeks, and so on) might cause less severe haematopoietic stem cells having benefit.
symptoms as the body has time to repair the damage and the main
concern in such patients may be the stochastic risks. Haematopoietic syndrome
Reverse barrier nursing and topical treatments to decrease bacterial/​
fungal colonization should be used. Intravenous lines should be kept
Clinical investigation to a minimum and sited to decrease infection risk. Febrile neutro-
penic patients should be given broad-​ spectrum antimicrobials.
This includes full history, examination, cytogenetic and regular Established infections should be treated as for other patients with
blood tests. The estimated radiation dose is needed to predict the neutropenic sepsis. Early use of antifungal agents or antiviral drugs
clinical course of the patient and plan treatment. This dose should might be required to prevent late mortality.
be revised as treatment progresses because the heterogeneous na-
ture of accidental exposures makes the scale of radiation damage Gastrointestinal syndrome
difficult to estimate. Use supportive therapy to prevent infection and dehydration.
Vomiting less than 2 h after acute exposure indicates a dose of at 5-​hydroxytryptamine-​3 (5HT3) receptor antagonists should be
least 3 Gy. However, there is considerable individual variation and used prophylactically if whole-​body dose exceeds 2 Gy. Diarrhoea
vomiting is not invariable, even at high doses. Prodromal symp- should be treated with antidiarrhoeals, fluids, and electrolytes.
toms last for more than 24 h with doses exceeding 6 Gy. The pattern Prophylactic antibiotics should be considered. Food with a low
of fall in blood levels of lymphocytes, granulocytes, platelets, and microbial content might minimize infection risks. Enteral feeding
red cells depends on radiation dose. For pure γ-​field exposures, the should be used if possible.
1712 SECTION 10 Environmental medicine, occupational medicine, and poisoning

and, probably, pinguecula. Cumulative exposure to ultraviolet radi-

Treatment of radiation burns
ation is a major cause of cortical cataracts, but its importance in the
general population remains uncertain.
Wound contamination is treated by gentle wound cleansing and de-
bridement. Wastes arising should be treated as contaminated. Care Immune responses
should be taken not to break intact skin and introduce internal con-
Exposure to ultraviolet radiation can suppress immune responses
tamination. Systemic corticosteroids are now not recommended
by complex mechanisms, but the significance for human health and
without a specific indication.
response to vaccinations is uncertain.
Radiation burn treatments include: topical steroids, hyperbaric
oxygen, pentoxifylline with oral vitamin E, wet dressings, alginates, Radiofrequency electromagnetic waves
hydrocolloids, and anti-​inflammatory agents. Growth factors have The widespread adoption of radiofrequency microwaves in wireless
been used to foster granulation and epithelialization. Wide exci- technology, including mobile phones and wi-​fi, has led to concerns
sion, surgical repair, and skin grafting might be necessary by sur- about adverse health effects. High exposure to radio frequencies
geons experienced in the management of chronic vascular injury. can cause thermal burns. There is no evidence that there is signifi-
Systemic mesenchymal stem cells have been used, but need further cant risk to the general public from exposure to radiofrequency
evaluation. radiation or from use of micro/​radiowave appliances. However,
Combined injury these are new technologies and a cautious approach is appropriate
because of the lack of scientific evidence. Public Health England
Surgical correction of life-​threatening and other major injuries (PHE) recommends that children should use mobile phones only
should be carried out as soon as possible (within 36–​48 h); elective for important calls.
procedures should be postponed until late in the convalescent
period (45–​60 days), following haematopoietic recovery. Surgical Power-​frequency electric and magnetic fields
wounds and traumatic lacerations tend to heal more slowly in ir- There are concerns that power-​frequency electric and magnetic
radiated tissues. fields might have adverse effects on health even at levels below
those required to interfere with nerves through induced fields and
currents. The evidence is controversial. However, epidemiological
Health effects of exposures to studies had shown a consistent statistical association—​not neces-
non​ionizing radiation sarily indicating causation—​between unusually high background
magnetic fields in homes and/​or residential proximity to power
Ultraviolet radiation lines and increased risk of childhood leukaemia (possibly 2–​5 at-
Ultraviolet radiation primarily affects the skin and the eye. The tributable cases per year in the United Kingdom). This prompted
short-​term skin effect is sunburn, with erythema and oedema. In the International Agency for Research on Cancer to classify power-​
some people, sunburn is followed by increased production of mel- frequency electric and magnetic fields as ‘possibly carcinogenic’. In
anin (suntan) but this offers only minimal protection against further March 2004, the United Kingdom Health Protection Agency (now
exposure. Acute ocular exposure to ultraviolet radiation can lead to PHE) recommended that the government should consider precau-
photokeratitis and photoconjunctivitis (arc eye, snow blindness, and tionary protection from power-​frequency electric and magnetic
so on). fields. More recent studies have failed to confirm this association.
The most serious long-​term effect of ultraviolet radiation is induc- Static magnetic fields
tion of skin cancer. Non​melanoma skin cancers, mainly basal cell
Head movements in static magnetic fields stronger than 2 T can cause
carcinomas and squamous cell carcinomas, are common in white
symptoms such as vertigo, nausea, a metallic taste, and phosphenes
populations but are rarely fatal. The overall incidence is difficult
(seeing light without light entering the eye). Humans undergoing
to assess because of underreporting, but is likely to exceed 100 000
MRI (magnetic resonance imaging) are exposed to static magnetic
cases per year in the United Kingdom. The incidence of malignant
fields exceeding 2 T. There are insufficient data to indicate long-​term
melanoma, which is much more likely to be fatal, has increased
health effects of exposures to static electric and magnetic fields.
substantially in white populations for several decades causing about
Stronger fields should be used with care in controlled or experi-
2150 deaths/​year in the United Kingdom. Chronic exposure to
mental situations with more rigorous patient monitoring. Limits
solar radiation causes photo-​ageing of the skin, characterized by a
have also been advised for switched gradient and radiofrequency
leathery, wrinkled appearance and loss of elasticity. Suberythemal
exposures from MRI.
quantities of ultraviolet radiation are beneficial in stimulating
vitamin D synthesis in the skin. Vitamin D has been associated with
several musculoskeletal and non​musculoskeletal health outcomes,
FURTHER READING
including hypotheses about protection from cancer. Overall, there is
insufficient evidence on vitamin D and non​musculoskeletal health Bennett P, et al. (eds) (2010). Risk communication and public health,
2nd edition. Oxford University Press, Oxford.
outcomes to set adequate vitamin D intakes from dietary or UV
Dainiak N, et al. (2011). First global consensus for evidence-​based
sources over and above those established to prevent musculoskeletal
management of the hematopoetic syndrome resulting from ex-
disease.
posure to ionising radiation. Disaster Med Publ Hlth Preparedness,
Repeated ocular exposure is a major factor in corneal and con- 5, 202–​12.
junctival diseases, such as climatic droplet keratopathy, pterygium,
 10.3.8 Disasters 1713

Dainiak N, et al. (2011). Literature review and global consensus on man-

agement of acute radiation syndrome affecting non-​hematopoetic 10.3.8 Disasters: Earthquakes,
organ systems. Disaster Med Publ Hlth Preparedness, 5, 183–​201.
Gourmelon P, et al. (2010). European consensus on the medical man- hurricanes, floods, and
agement of acute radiation syndrome and analysis of the radiation
accidents in Belgium and Senegal. Health Physics, 98, 825–​32.
volcanic eruptions
Mettler F, Upton A (2008). Medical effects of ionizing radiation, 3rd Peter J. Baxter
edition. Saunders Elsevier, Philadelphia, PA.
Radiation Emergency Assistance Center/​Training Site (2013). The
medical aspects of radiation incidents. Oak Ridge USA, Publications
ESSENTIALS
& Radiation Resources. https://​orise.orau.gov/​reacts/​documents/​
medical-​aspects-​of-​radiation-​incidents.pdf Natural disasters (including earthquakes, volcanic eruptions, hur-
Rojas-​Palma C, et al. (2009). TMT Handbook: handbook for the man- ricanes, floods) cause tens of thousands of deaths and adversely
agement of the public in the event of a malevolent use of ionising radi- affect the lives of hundreds of millions of people every year. The
ation. http://​www.tmthandbook.org/​ trend is for the impacts to increase alongside the continuing expan-
Waselenko JK, et al. (2004). Medical management of the acute ra- sion of human populations into regions at risk and with environ-
diation syndrome: recommendations of the Strategic National mental degradation making human settlements more vulnerable,
Stockpile Radiation Working Group. Ann Int Med, 140, 1037–​51. especially in heavily urbanized areas and megacities. This reckless
Websites development is going on in most countries of the world, even in
Advisory Group on Non-​Ionising Radiation (2002). Health effects places prone to natural disasters. Recent remarkable advances
from ultraviolet radiation. Documents of the NRPB. Vol. 13, No. 1. in forecasting weather-​related disasters (hurricanes and floods)
https://​www.gov.uk/​government/​uploads/​system/​uploads/​attach- have to be matched with adequate disaster preparedness in those
ment_​data/​file/​414185/​NRPB_​Doc_​series_​vol13_​no1.pdf communities at high risk if they are to be translated into effective
Advisory Group on Ionizing Radiation (2009). High dose radiation effects warnings, especially in low-​income countries. Earthquakes remain
and tissue injury. Documents of the Health Protection Agency RCE-​10.
notoriously unpredictable and have the greatest mortality toll of all
http://​webarchive.nationalarchives.gov.uk/​20140714084352/​ http://​
natural disasters.
www.hpa.org.uk/​webc/​HPAwebFile/​HPAweb_​C/​1237362785677
AGNIR (2012). Health effects from radiofrequency electromagnetic
For those natural disasters that are weather related, climate fore-
fields: report of the advisory group on non-​ionizing radiation, casters say that, on current trends with an increase in the world’s
Doc HPA, RCE-​20. https://​www.gov.uk/​government/​publications/​ average temperature of 2–​3°C and an associated warming of the
radiofrequency-​electromagnetic-​fields-​health-​effects oceans, there is likely to be growing potential for more intense
Armed Forces Radiobiology Research Institute (2003). Medical man- and more frequent hurricanes in regions that already suffer from
agement of radiological casualties handbook, 2nd edition. Military these extreme events and, in temperate regions, more severe winter
Medical Operations, Armed Forces Radiobiology Research Institute, storms and wider fluctuations in rainfall with flooding and more
Bethesda, MD. http://​ehs.columbia.edu/​2edmmrchandbook.pdf heat waves. Rising sea levels will increase the severity and the fre-
Health Protection Agency (2008). Protection of patients and volunteers quency of coastal floods everywhere. On the positive side, climate
undergoing MRI procedures. Documents of the Health Protection change fears have been an important catalyst in making some coun-
Agency RCE-​7. https://​www.gov.uk/​government/​uploads/​system/​ tries pay more attention to addressing the mitigation of their present
uploads/​attachment_​d ata/​f ile/​329364/​Protection_​of_​p atients_​ weather-​related disasters.
and_​volunteers_​undergoing_​MRI_​procedures.pdf
The scale of some recent catastrophes events has added a fur-
International Atomic Energy Agency and World Health Organization
ther sense of urgency. The three mega-​disasters (so-​called be-
(2000). How to recognize and initially respond to an accidental ra-
diation injury. http://​www-​pub.iaea.org/​MTCD/​publications/​PDF/​ cause mortality exceeded 100 000 people in each) —​the Southeast
IAEA-​WHO-​L-​Eng.pdf Asian tsunami (2004), Hurricane Nargis, Burma (2008), and the
National Radiological Protection Board (2004). Advice on limiting Haiti earthquake (2010) —​were followed by the Tohoku earth-
exposure to electromagnetic fields (0–​300GHz). Documents of the quake (2011), Japan, in which tsunami waves caused over 18 000
NRPB, Vol. 15, No. 2, http://​webarchive.nationalarchives.gov.uk/​ deaths and severely damaged the supposedly earthquake-​resistant
20140629102627/​ http:/​www.hpa.org.uk/​Publications/​Radiation/​ Fukushima nuclear plant that had been built along the same
NPRBArchive/​DocumentsOfTheNRPB/​Absd1502/​ coast with tsunami protection that proved to be inadequate. This
National Radiological Protection Board (2004). Review of the scien- ‘domino’ or cascading effect triggering a technological disaster in
tific evidence for limiting exposure to electromagnetic fields (0–​300 its wake demonstrated the problems that can be faced even in ad-
GHz). Documents of the NRPB, Vol. 15, No. 3. http://​webarchive. vanced industrial nations prone to natural cataclysms.
nationalarchives.gov.uk/​20140722091854/​ http:/​www.hpa.org.uk/​
Publications/​R adiation/​NPRBArchive/​DocumentsOfTheNRPB/​
Absd1503/​
National Radiological Protection Board (2005). Mobile phones Introduction
and health 2004: report by the board of NRPB. Documents of the
NRPB, Vol. 15, No. 5. http://​webarchive.nationalarchives.gov. A natural disaster is the massive ecological breakdown in the
uk/​20140714084352/​ http://​www.hpa.org.uk/​webc/​HPAwebFile/​ relation between humans and their environment, a serious and
HPAweb_​C/​1194947333240 sudden (or insidious, as in drought) event on such a scale that
1714 SECTION 10 Environmental medicine, occupational medicine, and poisoning

the stricken community needs extraordinary efforts to cope with have to repeat itself—​with the limited progress in the past over
it, often with outside help or international aid. Very high mor- strengthening building codes, reinforcing old buildings, protecting
tality is not necessary in this definition, which is not specific- health facilities, and educating the population about risks in a
ally health based. Between 300 and 400 natural disasters occur country where seismologists had warned for years about the severe
throughout the world every year. The occurrence rates of geo- earthquake risk.
physical hazards like earthquakes and volcanic eruptions have not
varied much since the time of Neanderthals over 40 000 years ago,
but there is evidence in recent years for a rise in the number of Pre-​disaster measures
weather-​related disasters, such as severe floods and windstorms.
Furthermore, the potential for increasing losses of life and prop- Accurately forecasting the timing and size of these sudden-​onset
erty as populations expand in regions of high natural risk was natural disasters is rarely possible. This fact constrains efforts to
exemplified by the Southeast Asian tsunami that devastated the prevent loss of life by timely evacuation of people from the areas
Indian Ocean region on 26th of December 2004 leaving more than at risk before disaster strikes. Disasters leave a trail of devastation
250 000 people dead and at least 1.7 million displaced from their and are quite different from the major incidents hospitals usually
homes in 10 countries. plan for, in that normal lifelines and infrastructure break down in
Natural disaster risk reduction is one of the targets embedded in the devastation. Thus, essentials such as transport, communica-
the UN Sustainable Development Goals with 187 member states tions, and power will be the first to fail or will be severely curtailed,
adopting the Sendai Framework for Disaster Risk Reduction 2015 thereby crippling the immediate emergency response. In the worst
to 2030. By 2030, the Framework calls for substantial global re- examples hospitals can be severely damaged and the staff being
ductions in the following areas: mortality, the number of people among the victims.
affected, direct economic losses, and damage to critical infrastruc- But despite their chaotic aspects, disasters are amenable to sci-
ture. Countries will have to make their own plans to support the entific study and a growing body of physical scientists in various
implementation of the Framework, with greater international co- fields are directing their energies towards disaster mitigation, par-
operation to support developing countries. For access to early ticularly in devising hazard warning systems, engineering solu-
warning systems, disaster risk information and assessment are pri- tions, and disaster risk information and assessment. There is a
orities, while health features more strongly than in the previous UN growing need for social scientist involvement in implementing risk
decadal initiatives. reduction interventions and developing community resilience in
Natural disasters are by definition chaotic, but communities disaster-​prone areas.
in disaster-​prone countries can plan and prepare against them. As well as implementing forecasts and warnings, the traditional
Scientists are working on improving forecasting and on the mod- approach to disaster risk reduction, depending upon the hazard,
elling of their impacts. Most deaths in sudden-​onset disasters relies on a platform of engineering measures such as constructing
happen before outside aid arrives, hence strengthening local river and coastal flood defences, ensuring regulations are fol-
response capacity in the first hours is crucial. However, inter- lowed to build seismic resistant buildings in earthquake zones,
national disaster relief can be rapidly and effectively dispatched cyclone shelters, and land-​use planning to minimize the occupa-
to needy countries that are politically willing to accept it: al- tion of risky zones—​the commonest example being floodplains.
though medical relief teams might arrive too late to treat most of Community preparedness and emergency planning should in-
the critically injured, teams with engineering and disaster relief clude the full involvement of the health sector. We should add to
skills will have an important role in restoring roads and bridges, this traditional list improving resilience and communicating risk,
bringing in potable water, ensuring solid waste management, as well as effectively translating into practice the findings of the
food protection, vector control, and sanitation. Even in disasters latest scientific research.
that have major human impacts, attendances at medical facilities Poverty and social marginalization in mid-​to low-​income coun-
can return to normal levels even within a few days of the acute tries, especially, remain potent sources of global vulnerability to
phase, once the injured have been cared for, when the priority natural disasters. Less well-​publicized are disasters occurring in
becomes the restoration of primary healthcare and the needs of regions of conflict and humanitarian crisis, or complex emergen-
survivors. cies, for example, in the Democratic Republic of Congo, Darfur
Rehabilitation in the post-​disaster phase should be an essential (Sudan), and Eritrea (Ethiopia). International relief organiza-
consideration in the emergency response phase, and ultimately dir- tions might not be able to safely or freely move in their response.
ected towards measures for reducing the pre-​disaster vulnerability. Hence, in the Southeast Asian tsunami, access to some regions of
Yet many financial donors view disasters as mere temporary inter- Indonesia and Thailand was prevented by security issues. In 2008,
ruptions in development. In April and May 2015 two earthquakes Burmese people living in the Irrawaddy Delta had no warning from
in Nepal killed some 8000 people and reduced 300 000 houses to the government of the approach of Cyclone Nargis and hurricane
rubble. On 25 April, a 7.8 magnitude earthquake struck with its epi- preparedness measures were non​existent. Over 138 000 people
centre 77 km northwest of the capital Kathmandu which suffered died, most from drowning, but the crisis was made worse when,
widespread destruction along with the collapse of mud and stone in the immediate aftermath, 1.5 million homeless survivors were
housing in rural areas. The impact was so widespread that an ava- left without food, water, or shelter while the Burmese government
lanche was triggered on Mount Everest. For a poor country it will vacillated for weeks over accepting international aid. International
take many years to recover—​blowing away the myth that life gets disaster relief is nowadays capable of being rapidly dispatched to
back to normal in a few weeks after a disaster. History should not needy countries and is on such a global scale that epidemics and
 10.3.8 Disasters 1715

famine are no longer the feared Horsemen of the Apocalypse they pneumonia were common among patients who had come close to
once were. drowning. Psychosocial needs were identified on a massive scale,
but the appropriateness and effectiveness of specific interventions
in such disasters to prevent post-​traumatic stress disorder remains
Earthquakes a controversial issue.
The power of tsunamis was demonstrated again in the Tohuko
Over time more deaths are caused by earthquakes than by any of the earthquake in 2011, which had its epicentre off the south-​east coast
other causes of natural disaster. Many parts of the world lie along of Japan and triggered a tsunami that swept the Japanese coastline
fault lines and are known to be vulnerable to devastating earth- leaving total devastation and 15 891 dead with 2579 missing. Many
quakes, but it remains impossible to predict precisely where and more people would have died but for the tsunami warnings that are
when a quake will strike. Most deaths and injuries are caused by routinely practised in the shoreline towns. But the tsunami waves
collapsing buildings, but secondary causes such as fires can take also overcame the engineering defences of the Fukushima nuclear
their toll. When timber, masonry, reinforced concrete, and other power plant, which in retrospect had not been built to withstand
types of buildings collapse, they inflict injuries to occupants in dif- tsunami of this size. The resultant severe damage to the plant’s nu-
ferent ways and with different degrees of severity. In the collapse of clear cores led to the release of substantial amounts of radioactive
masonry buildings, an important cause of death is often suffocation material into the environment.
from the weight and dust shaken from the wall or roof material The evacuation of 170 000 residents within a radius of 30 km of
which may also bury the victims. Falling masonry causes crush in- the power plant was urgently undertaken, but concern grew that the
juries to the head and chest, external or internal haemorrhage, and possible spread of contamination in the atmosphere could have gone
chest compression (traumatic asphyxia). Little is known about the as far afield as Tokyo and beyond. These fears were later shown to
survival times of people when they get trapped in collapsed build- be groundless, but they raised anxiety in Japan and neighbouring
ings, but most victims will die immediately or within 24 hours from countries. Studies have shown that although no discernible physical
their injuries if they are not rescued, depending upon such factors effects are expected from the radiation leak, psychological and social
as the severity of after-​shocks, fire outbreaks, cold, and rain. Rapid problems largely stemming from heightened risk perceptions have
extrication of survivors and application of first-​aid by the uninjured had a devastating effect on people’s lives. One immediate economic
immediately after the event could potentially save up to 25–​50% casualty was the fishing industry along the coast due to market fears
of injured victims. Greatest demand for emergency medical care over radioactive contamination of the sea. The evacuation itself was
is within the first 24 hours and the need for emergency treatment not without risk, however, with 50 deaths attributed in hospital pa-
quickly fades, though search and rescue teams might continue tients; in the first three months of the evacuation mortality rates in
trying to find survivors for three to five days. Multiple trauma is older people needing nursing or hospital care rose significantly.
the main feature, with the risk of doctors missing internal injuries A rare example of the importance of disaster preparedness was
in the stress of the emergency. Causes of delayed death include de- the earthquake in Bam, Iran, on 26 December 2003, which resulted
hydration, hypothermia, crush syndrome, and postoperative sepsis. in 26 271 deaths and the nearly complete destruction of the city of
Most of those requiring medical assistance suffer minor injuries 80 000 inhabitants. The loss of about one-​third of the inhabitants,
such as lacerations and contusions. including 200 out of 500 doctors, was attributed to the weak, mud
In the Southeast Asian tsunami, an earthquake of magnitude brick construction. The health infrastructure was destroyed, but
9 on the Richter scale off the coast of the island of Sumatra on 26 within 48 hours some 11 972 of the 15 000 injured survivors had
December 2004 suddenly forced the seafloor upwards by some 10 m, been air evacuated by the military to hospitals in the rest of the
creating a wave that surged through the Indian Ocean. The surface country, and others were transported to treatment facilities by re-
perturbation was initially small, but when the water grew shallow, latives. By the time foreign medical teams arrived, their main task
near the coast, the tsunami waves formed. Without warning, the was to provide routine healthcare to the residual population living
waves hit Indonesia and Thailand within an hour, and then Sri Lanka in shelters. By contrast, the Pakistan earthquake on 8 October 2005
and India, ultimately reaching as far as East Africa. The province at hit the impoverished mountainous north of the country where ac-
the north-​western end of Sumatra, Aceh, suffered overwhelming cess to hundreds of remote villages was hindered by damaged and
devastation. More than 20 000 homes were destroyed, over a 100 000 blocked roads. Over 73 000 people died and 69400 people had ser-
people were killed, and some 700 000 people were displaced. Many ious injuries; over 3 million people were left homeless. As houses
victims were health service staff, which hampered the emergency were mostly constructed of weak, rubble masonry walls supporting
response. concrete slabs for roofs, the violent shaking easily razed buildings
In all countries affected by the tsunami the main public health to the ground or triggered landslides. Roof slopes then fell on top
infrastructure remained intact as the devastation was limited to of the occupants (Fig. 10.3.8.1) and caused multiple trauma, such
coastlines, so the feared epidemics of vector-​borne diseases, such as as spinal and pelvic fractures. Significant numbers of amputations
malaria and dengue, as well as cholera and dysentery, were able to were performed, and post-​disaster reconstructive plastic surgery
be prevented. Large numbers of dead and small numbers of major was frequently needed to treat the often severe and localized soft
injuries in survivors in comparison are typical of flood disasters in tissue damage caused by entrapment (Fig. 10.3.8.2).
general, as the severely injured quickly succumb in the water; the In 2008, the recent rapid economic development and accom-
injured survivors were mainly treated by local health teams. Many panying building boom in China lay behind the destruction caused
of the patients requiring surgery had infected wounds following by the largest earthquake to strike the country in recent times (7.9 on
contamination by sand and mud. Respiratory tract infections and the Richter scale), when entire towns collapsed in the mountainous
1716 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Poverty profoundly influenced the impacts of the January 2010

earthquake in Haiti, one of the poorest countries in the world.
The earthquake ranked as the deadliest to have occurred in
western hemisphere history. Despite the island’s position along
a known major earthquake fault line, there was a total lack of
preparedness. Devastation was immense with 220 570 people
killed and 3.7 million people directly affected. Haiti was left
helpless and massive international help was desperately needed.
Casualties with multiple trauma were so numerous that they
were sent for treatment to hospitals all over the Caribbean re-
gion. Tragically, UN soldiers sent to provide logistical help
were evidently the source of the cholera epidemic that struck
the island in October 2010, leading to 8000 further deaths and
another 650 000 islanders infected at a time when half the popu-
lation still had no access to clean water.

Fig. 10.3.8.1 Pakistan earthquake, 2005. Collapsed concrete roof

slab, typical example of vulnerable building construction in the Volcanoes
impacted area (see text).
Source: Emily So.
About 500 to 600 volcanoes around the world are known to be cap-
able of eruptive activity and several major eruptions occur every
Sichuan province, leaving 80 000 people dead and at least 5 million year. The vast majority of dangerous volcanoes are explosive and
homeless. Poor building quality has been blamed for the catastrophic unpredictable in their behaviour, whereas the less common lava
failure of homes and schools, the latter being a major psychological flow eruptions normally allow people to escape from their path.
issue for parents with one child families. Despite the rapid mobil- Most deaths and injuries in explosive eruptions (such as the one that
ization of thousands of troops to the area, only a few survivors were engulfed ancient Pompeii and Herculaneum in AD79) are caused
retrieved from the rubble, sadly emphasizing the country’s failure to by pyroclastic flows and surges, which are clouds of intensely hot
incorporate seismic resistance in the new community developments. gas and ash that can travel at hurricane speeds. Survivors are un-
common, but will have severe, extensive skin burns and inhalation
thermal injuries. The scope of the destruction was shown in the
worst volcanic disaster in the 20th century at St Pierre, Martinique,
in 1902, when 28 000 people were killed in a laterally directed pyro-
clastic surge, leaving only two survivors in the totally devastated city.
Vesuvius in Italy is an example of one of the world’s most dangerous
volcanoes, and uncontrolled development has left over one million
people living in an area which could be devastated by pyroclastic
flows. Another major cause of death is the lahar (wet, debris flows)
formed by newly erupted ash mixed with heavy rain or unstable
masses that are mobilized by meltwater from glaciers or by crater
lakes. The eruption of the Nevado del Ruiz volcano, Colombia, in
1984 triggered a huge lahar through the rapid melting of ice in the
summit glacier: no warning was received in the towns below where
some 24 000 people were buried by mud. By contrast, in one of the
largest eruptions of the 20th century, at Mount Pinatubo in the
Philippines in 1991, 50 000 people were successfully evacuated from
the threat of pyroclastic flows, but over 300 died from the collapsing
of roofs burdened with accumulated rain and ash, while sheltering
inside their homes.
The eruption of the Soufrière Hills volcano on the tiny Caribbean
island of Montserrat, a UK Overseas Territory, began in July 1995
and was to last over 15 years. After a slow start it gradually escalated,
forcing the evacuation of thousands of people from their homes be-
cause of the threat of pyroclastic flows and surges. By 1997, these
currents had devastated the southern part of the island, evicting
three-​quarters of the total island population of 12 000 people. Air
Fig. 10.3.8.2 Pakistan earthquake, 2005. Treating severe soft tissue pollution from volcanic gases and ash emissions was a major con-
crush injuries in a patient rescued from a collapsed building. sideration because of the close proximity of the population to the
Source: Emily So. volcano and the frequent eruption of fine, respirable-​sized ash
 10.3.8 Disasters 1717

containing hazardous amounts of crystalline silica, a mineral that disease, in particular West Nile virus, did not occur. Increases in
causes silicosis. suicide and psychiatric morbidity were found in follow-​up studies
of evacuees, and although psychological distress was common, it re-
solved in most of the people over time.
Hurricanes Recent advances in meteorology on tracking the paths of hurri-
canes in time and space are now making inroads into reducing loss
Hurricanes are one of a broad class of extreme weather phenomena of life by forecasting their landfall far enough ahead for thousands
that include winter storms (snow, sleet, freezing rain), thunder- of people to be directed to safety, provided the warnings are effect-
storms (e.g. tornadoes, heavy rains, lightning, wind, and hail), ex- ively communicated by government officials. A dramatic example
treme precipitation (e.g. flood and flash floods), and windstorms. was in the Indian state of Odisha (Orissa). In 1999 one of the largest
Hurricanes (or typhoons as they are called in the Western Pacific) cyclones to strike the coast left 10 000 dead in its wake: although it
are tropical cyclones that form over warm oceans with ocean sur- was forecast, no warnings were disseminated, and no preparedness
face temperatures over 26°C. Once overland they soon run out of to move the population to safety was in place. In October 2013 an al-
energy and rapidly abate, but can still cause severe flooding from most identical cyclone hit the same coast, but with the loss of only 17
heavy rain. Very high wind speeds, up to 250 km/​h, are restricted to people—​the difference was that the warning was followed by 1 mil-
a relatively narrow track, usually no more than 150 km wide, within lion people being temporarily evacuated from the coastal area by the
which localized gusts may even achieve tornadoes speeds and be Indian army.
extremely destructive. Most deaths and injuries, however, are not
from the effects of wind on people (who normally shelter indoors
for protection) or from building damage (building collapse or being Floods
struck by flying debris). Instead, deaths and injuries are commonly
the result of flooding by the sea surge as the hurricane strikes land, In addition to the major losses of life that can be caused by hurri-
or concurrent heavy rainfall (typically up to 60 cm over a larger area canes and their associated sea surges, floods mostly result from mod-
and extending further inland than high winds) triggering landslides. erate to large events (heavy rainfall, snowmelt, high tides) occurring
Hurricanes lift the sea, forming a sea surge that typically rises 3–​4 m within the expected range of streamflow or tidal conditions. In the
above existing heights, and the wind generates waves on top of these. United Kingdom, as in many countries with low-​lying coastal land,
Some storm surges can hit coasts well ahead of the landfall of the the hazards of coastal flooding from sea surges and high tides dom-
actual storm and can travel with nearly the same rapidity, and de- inates over river flooding, although the latter is becoming more fre-
structiveness, as tsunami waves. quent, particularly in the last few years when there has been a trend
Over 90% of fatalities in hurricanes are drownings associated with of abnormally wet winter months and localized repeated flooding,
storm surges or floods. Other causes of death include burial beneath though it is not yet possible to attribute this to climate change. Flood
houses collapsed by wind, penetrating trauma from broken glass warning and forecasting, combined with effective land manage-
or wood, blunt trauma from floating objects or debris, or entrap- ment, community preparedness, and evacuation planning, are as
ment in mudslides. The greatest need in the post-​impact phase is the essential as engineered river and coastal defences.
provision of adequate shelter, water, food, and clothing, and sanita- The primary cause of death from floods is drowning, but trauma
tion. Most victims suffer from lacerations caused by flying glass or from impact with floating debris and by hypothermia due to cold
other debris, or minor trauma such as closed fractures and puncture exposure are also important. The proportion of survivors requiring
wounds. emergency medical care is small as most injuries are minor, such as
Katrina was the third most powerful storm ever to make land- lacerations. This absence of survivors with severe or multiple trauma
fall in the United States of America, attaining hurricane category is likely to reflect the delay in search and rescue through the flood
five status before it struck the Louisiana coast on the morning of waters, and victims drown or die from their injuries and the effects of
29 August 2005. It left breaches in the levee system of New Orleans exposure before help arrives. Increased morbidity and mortality in
that created catastrophic flooding of an area of more than 400 km², survivors of floods was reported in the year after the UK East Coast
submerging half a million homes and trapping tens of thousands of flood in 1953, in which over 300 people drowned. An increase in
people. Critically, the city’s mayor did not issue a mandatory evacu- suicides and mental health problems arose after the severe flooding
ation order until the day before the hurricane hit, which was too late caused by heavy rains in central Europe in July 1997. The mental
for many to evacuate in time, including the poor, who had no means health impacts of floods as a cause of enduring disaster morbidity re-
of transport. In Louisiana and Mississippi 1700 people died, most by quires further epidemiological study, especially as flooding is likely
drowning. The emergency response was woeful. Up to 20 000 evac- to become more disruptive and more widespread as a consequence
uees were abandoned in the city’s Superdome sports stadium for five of climate change.
days before being evacuated to other shelters. One crowded public Bangladesh is one of the most flood-​prone countries in the world.
hospital left cut off for five days without electrical power, clean A quarter of its 151 million population are at the mercy of cyc-
water, and medical supplies was rendered helpless by the engulfing lones and almost three-​quarters live in regions prone to a variety of
floodwater. flooding types: coastal floods, riverbank flooding, flash floods and
The victims were predominantly black and poor. In the aftermath, monsoon rains, and meltwater from the Himalayas. The probability
nearby states were able to absorb several hundred thousand evacuees is that under climate change the flood hazards will get worse. Over
from the city in a few days. Despite forebodings, epidemics of diar- the last 50 years, targeted improvements in disaster management, re-
rhoeal diseases, respiratory tract infections, and mosquito-​borne ducing poverty, and stepping up civic resilience measures have made
1718 SECTION 10 Environmental medicine, occupational medicine, and poisoning

a substantial difference to the health and economic impacts of these for effective health sector participation in both planning for and re-
severe events. sponding to natural disasters has never been greater.

Post-​disaster relief FURTHER READING

Cash RA, et al. (2013)Reducing the health effect of natural hazards in
Most traumatic deaths in sudden-​onset disasters will happen before Bangladesh. Lancet, 382, 2094–​103.
outside aid arrives, and so building local resilience and the capacity Fink S (2013). Five days at memorial: life and death in a storm ravaged
to react to disaster is essential. However, relief teams from outside a hospital. Atlantic Books, London.
disrupted region or country may find that they have an important Hasegawa A, et al. (2015). Health effects of radiation and other health
role in restoring roads and bridges, bringing in potable water, water problems in the aftermath of nuclear accidents, with an emphasis on
purification, ensuring solid waste management, food protection, Fukushima. Lancet, 386, 479–​88.
vector control, and sanitation. Attendances at medical facilities may Katz JM (2013). The big truck that went by: how the world came to save
return to normal within a few days of the disaster onset, and restor- Haiti and left behind a disaster. Palgrave Macmillan, New York, NY.
ation of primary care then becomes the priority rather than emer- Koenig KL, Schultz CH (2016). Disaster medicine. Cambridge
gency treatment. However, the earthquakes in Pakistan (2005) and University Press, Cambridge.
Nepal (2015) already mentioned in this chapter caused widespread Websites
destruction in remote, mountainous regions of the countries, and Centre for Research on the Epidemiology of Disasters (CRED). http://​
the damage to roads reduced accessibility even further, so the treat- www.cred.be
ment of many casualties was inevitably delayed. In Nepal, WHO Pan American Health Organization (WHO) Emergency Preparedness
working with the Ministry of Health and Population coordinated and Disaster Relief. http://​www.paho.org/​disasters
the national and international humanitarian aid, sending foreign UN International Strategy for Disaster Risk Reduction. https://​www.
unisdr.org/​
medical teams that had registered with them to deliver healthcare in
the affected districts.
Epidemiology has an important role in post-​disaster assessment
and health surveillance, particularly when large populations have
been relocated, as well as investigating the causes of mortality and
morbidity in disasters, such as mental ill health and long-​term phys-
ical health consequences. The evidence base for the effectiveness 10.3.9 Bioterrorism
of health-​directed interventions in humanitarian crises, including
natural disasters, needs strengthening and this is at last being ac- Manfred S. Green
knowledged by research grant awarding bodies and non​government
organizations.
Similarly, scientific evaluation of disaster relief efforts, in par- ESSENTIALS
ticular the knee-​jerk response of sending aid—​any type of aid, in- Bioterrorism is the deliberate use of biological agents to cause illness,
stead of aid matched to need, in the mistaken and even patronizing death, and fear for ideological or personal purposes. Most poten-
belief that the affected population is too shocked and helpless to take tial bioterrorism agents occur naturally as known pathogens and are
responsibility—​has incentivized governmental relief organizations classified by the United States Centers for Disease Control as follows:
to review their practices. Indiscriminate aid can actually hinder the (1) Category A, with greatest risk to the public and national
efforts of countries already fully under strain—​the examples are le- security
gion. Many donated medicines are out of date or simply inappro- This comprises (a) infectious and contagious diseases—​smallpox,
priate, food supplies are not tailored to requirements, international plague, and viral haemorrhagic fevers; (b) infectious but not con-
relief teams being sent without the right expertise or capable of tagious diseases—​anthrax, and tularaemia and (c) toxins—​botulism;
being self-​sufficient, including uninvited individuals or medical (2) Category B, with intermediate risk
doctors inexperienced in disaster response, and who might con- This comprises those causative agents that are relatively easy to
sequently do more harm than good. Infectious disease epidemics spread and produce diseases with moderately high death rates;
are still mistakenly and widely held to inevitably follow in the wake (3) Category C—​emerging infectious diseases that could be en-
of mass fatalities and the disposal of corpses, with the result that gineered to spread and cause high rates of morbidity and mortality.
local healthcare workers, already in short supply, might be diverted The agents might be disseminated through aerosolization, food,
into undertaking mass immunization campaigns and mass burials human carriers, infected insects, or water. The incubation periods
without good reason. of these agents can vary from hours to weeks, with early symptoms
Inevitably, the pressing priorities in most disaster settings are not mimicking many other infectious diseases. The diagnosis might not be
conducive to undertaking well-​conducted evaluations of relief prac- suspected unless cases occur in clusters. Early identification of outbreaks
tice. The medical literature on natural disasters is relatively small will depend largely on the ability of primary care and emergency room
and in recent decades the global challenge has focused on improving physicians to identify and promptly report cases to the public health
preparedness and risk reduction, but progress has been lamentably authorities. A major concern is that diagnosis of these extremely un-
slow. This global overview of progress over the last decade may not common diseases might not be considered by physicians who have
be as encouraging as many of us would like to read, but the need
 10.3.9 Bioterrorism 1719

rarely, if ever, seen such cases. Specific treatment (if available) of affected Box 10.3.9.1 Examples of bioterrorism agents by category
individuals will depend on the pathogen, and for contagious diseases Category A
such as smallpox and plague, isolation of patients and their contacts, Infectious and contagious diseases
barrier nursing, quarantine, and restriction of the movements and social • Smallpox (Variola major)
interactions of people are important control measures. Decontamination • Plague (Yersinia pestis)
is relevant mainly for anthrax and smallpox, in the environment of an • Viral haemorrhagic fevers (filoviruses, e.g. Ebola, Marburg, and arena-
aerosol attack and at places where patients were treated. viruses, e.g. Lassa, Machupo)
Public education and effective risk communication are essen- Infectious but not contagious diseases
tial in managing a bioterrorism attack: (1) clinicians and public • Anthrax (Bacillus anthracis)
health personnel need access to up-​to-​date information; (2) the • Tularemia (Francisella tularensis)
general public requires nontechnical descriptions of the diseases
Toxins
and simple instructions on how to act in an emergency situation.
• Botulism (Clostridium botulinum toxin)
Primary prevention should include addressing the root causes of
terrorism, developing comprehensive preparedness programmes, Category B
and educating health professionals to deal with an outbreak. • Brucellosis (Brucella spp.)
• Epsilon toxin of Clostridium perfringens
• Food safety threats (Salmonella, Escherichia coli 0157, Shigella)
• Glanders (Burkholderia mallei)
Introduction • Meliodosis (Burkholderia pseudomallei)
• Psittacosis (Chlamidia psittaci)
The potential public health threat posed by bioterrorism could make • Q fever (Coxiella burnetii)
exceptional demands on clinicians. Rapid diagnosis will have im- • Ricin from Ricinus communis (castor bean)
plications far beyond the individual patient. It will initiate a process • Staphylococcal enterotoxin b
of preventive actions, which could impact on the lives of thou- • Typhus fever (Rickettsia prowazekii)
sands. Clinicians might have to treat infectious disease casualties en • Viral encephalitis (alphavirus, e.g. Venezuelan equine encephalitis,
eastern equine encephalitis, western equine encephalitis)
masse under emergency situations, while ensuring the protection of
• Water-​safety threats (e.g. Vibrio cholerae, Cryptosporidium parvum)
healthcare workers and other patients. Clinical presentations might
be atypical because of the nature of the exposure and the possibility Category C
that the organism might have been genetically mutated. Antibiotic • Emerging infectious diseases such as Nipah virus and hantavirus
resistance and vaccine failure could be encountered and laboratories Source: http://​www.bt.cdc.gov/​agent/​agentlist-​category.asp
are likely to be overburdened. Public panic could exacerbate ethical
dilemmas in the triage for specialized care in limited facilities.
contagious, and toxins. Category B includes diseases that are con-
sidered an intermediate risk to the public since the causative agents
Historical perspective are relatively easy to spread and the diseases result in moderately
high death rates. Category C agents include emerging pathogens,
The use of biological agents as weapons inspires a special abhor- which could be engineered to spread and cause high rates of mor-
rence and dread. International agreements, such as the Geneva bidity and mortality.
Protocol in 1925 and the Biological Weapons Convention in 1972, Since the category A biological agents have been weaponized in
banned their use and production. However, in the early 1990s, it past programmes, they are currently of greatest concern. Here they
was revealed that anthrax spores were accidentally released from a are briefly described but more details about their clinical aspects
military facility in Russia in 1979, causing an outbreak of respira- are provided in Section 8.
tory anthrax. Evidence emerged that the former Soviet Union had
continued a bioweapons programme, generating concerns that Diseases that are both infectious and contagious
bioweapon agents and the expertise for their production might Smallpox (Chapter 8.5.4) is the prototype of potential bioterrorism
reach terrorist groups. agents that are both infectious and contagious. Although eradicated
in 1978, it is believed to have been weaponized by the Soviet Union.
Universal vaccination was phased out in the 1970s and since the
Biological weapons case fatality in unvaccinated subjects is around 30%, smallpox is one
of the most feared bioterrorism threats. Secondary cases can occur
Almost all potential bioterrorism agents occur naturally as known through droplet spread, direct contact with skin lesions or body
pathogens, although many are zoonoses, not normally affecting fluids, and rarely through airborne transmission.
humans. The United States Centers for Disease Control and The plague bacillus (Yersinia pestis) (Chapter 8.6.16) was in-
Prevention (CDC) classified potential bioterrorism agents into cluded in the bioweapons programmes of both the United States of
three categories (Box 10.3.9.1). Category A agents have the highest America and the Soviet Union. Untreated pneumonic plague has
priority since they are considered the greatest risk to the public and a case fatality approaching 100%. The organism can spread from
national security. These can be subclassified into agents that are in- person to person through droplets, causing several generations of
fectious and contagious, those that are infectious but not usually the disease.
1720 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Viral haemorrhagic fevers caused by the filoviruses (Chapter 8.5.17) periods and atypical clinical manifestations. Clinical effects are
and arenaviruses (Chapter 8.5.18) may have been weaponized by the likely to depend on the dose.
former Soviet Union, Russia, and the United States. The Soviet Union
is reported to have produced quantities of Marburg, Lassa, Ebola,
Junin, and Machupo viruses. Second and later generations of disease Epidemiology
can occur through direct contact with body fluids of the patients.
Healthcare workers are at greatest risk. Documented contemporary attempts at planning or occasionally
attempting bioterrorism have employed Salmonella typhimurium,
Infectious but not contagious diseases botulinum toxin, anthrax spores, Q fever bacteria, Ebola virus, and
Anthrax spores (Chapter 8.6.21) were among the leading agents in ricin. In 1978, a Bulgarian dissident was assassinated in London by a
biological weapons programmes, since they are highly stable, viru- pellet, probably of ricin, that was implanted into his leg. In 2001, six
lent, resistant to drying, and easily disseminated. Aerosolized spores envelopes contaminated with powdered anthrax spores were mailed
cause inhalation anthrax, which has an untreated case fatality ap- in the United States and infected 22 people. Half suffered from inhal-
proaching 100%. The spores can survive in the environment for ation anthrax and the others from cutaneous anthrax. Thousands of
many years, although once on the ground, they will tend to produce workers received prophylactic therapy, and a large-​scale decontamin-
cutaneous anthrax. ation programme was implemented (Fig. 10.3.9.1.)
The spore-​forming coccobacillus Francisella tularensis (Chapter Radiological and chemical terrorism are also potential threats.
8.6.20), has been weaponized in biowarfare programmes. The un- The only documented incident of radiological terrorism occurred
treated case fatality could be 30–​60%. There is no secondary person-​ in 2006, when a former officer in the Russian security services was
to-​person spread. assassinated by exposure to α-​emitting polonium-​210 (210Po), in
a public place in London. Although no other cases were detected,
Toxins others could have been exposed through ingestion of the material
Botulinum toxin, produced by Clostridium botulinum (Chapter 8.6.25), from contamination of their hands. The initial symptoms could be
is one of the most potent neurotoxins known and has been weapon- confused with an infectious disease. In 2018 in the UK a nerve agent,
ized. In a bioterrorist incident, it could be disseminated either through novichok, was used in an attempt to assassinate a former Russian
food or by aerosol. The untreated case fatality approaches 100%. Ricin agent and his daughter. Some weeks later a UK citizen died from ex-
is a protein cytotoxin produced from the castor bean Ricinus communis. posure to the same agent following contact with the presumed liquid
There is no antidote. Patients affected by toxins are not contagious at any containing novichok that had been left near the scene.
stage of the disease.

Prevention
Dissemination of bioweapons
Prevention of bioterrorism includes addressing the causes of ter-
Biological agents might be disseminated through aerosols, food, rorism and developing appropriate preparedness strategies. In
human carriers, infected insects, or water. Aerosolization maximizes addition to international condemnation of the development of
the number of people exposed, causing the most damage. Release bioweapons, access to production capabilities must be controlled.
of contagious agents at different sites could greatly amplify the out- Effective preparedness is in itself a deterrent and requires coordin-
break. Since most potential agents are not normally aerosol trans- ation between agencies and specialists from multiple disciplines.
mitted, the resulting illnesses could occur with shorter incubation Food supplies must be protected from deliberate contamination.

10
9
8
7
6
Per cent

5
4
3
2
1
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
Day

Fig. 10.3.9.1 Simulated epidemic curve for a point-​source outbreak of inhalation anthrax without intervention.
Reproduced from Scheulen J, Latimer C, Brown J (2006). Electronic Mass Casualty Assessment and Planning Scenarios (EMCAPS). Johns Hopkins
University. Internet http://​www.hopkins-​cepar.org/​EMCAPS/​EMCAPS accessed July 14, 2007.
 10.3.9 Bioterrorism 1721

Although water is an unlikely vehicle for bioterrorism, drinking-​ smallpox is between 7 and 14 days, but could be less following ex-
water sources require special security measures. posure to aerosol. Pneumonic plague is likely to develop within 24 h
Preparedness programmes include training and, where indicated, to 2 days after aerosol exposure. Inhalation anthrax has an incuba-
pre-​exposure vaccination of ‘first responders’. The infrastructure tion period of 1–​6 days, but is probably dose-​related, and could be
to deal with the impact of different biological agents will require longer than 40 days. For inhaled botulinum toxin, the incubation
increased clinical surge capacity and patient isolation facilities. period is estimated to be between 12 and 80 h and for ricin, perhaps
Children, pregnant women, and the immunocompromised might even less.
have special needs. Dead patients need to be handled using the same Diseases such as anthrax, smallpox, and tularemia usually present
barrier precautions as for live patients. early on with influenza-​like illnesses, but if exposure is by aerosol,
Antivirals and immunoglobulins are currently considered only the symptoms might differ from the naturally occurring diseases.
for treatment and not for prophylaxis. At present, vaccines are rele- Diseases like plague and tularemia can present as pneumonia.
vant only for smallpox and anthrax. In most countries, more than Agents such as smallpox will subsequently develop a typical rash.
50% of the population has never been vaccinated against smallpox. In the later stages, both anthrax and smallpox commonly develop
Antibody titres have been shown to decline markedly 5–​10 years neurological symptoms. The haemorrhagic fevers are characterized
following vaccination, although residual immunity might persist initially by high fever and bleeding tendencies. Inhaled botulinum
for many years. However, previously vaccinated, milder cases in the toxin causes acute, afebrile, descending flaccid paralysis starting
community could increase the risk of spread. with ptosis and muscles innervated by cranial nerves. Inhaled ricin
Several countries have carried out vaccination programmes against causes fever, chest tightness, dyspnoea, nausea, and arthralgia,
smallpox for military personnel and first responders. Anthrax vaccine within 4–​8 h, followed by acute respiratory distress syndrome and
is given routinely in some military populations. Some countries have death within 18–​24 h.
established national stockpiles of pharmaceuticals and vaccines for
use in the event of biological or chemical attacks. The global inventory
of smallpox vaccine, together with the possibility of diluting vaccine, Differential diagnosis
exceeds three billion doses. Preparedness for a potential bioterrorism
incident remains a high public health priority in most countries, but The early symptoms of diseases caused by potential bioterrorism
there are important logistic issues regarding stockpiling and mass ad- agents can mimic a large spectrum of diseases since influenza-​like
ministration of vaccines against potential bioterrorism agents, both illness is a common presentation for many. Since diseases such as
prior to and during incidents. A dual vaccine has recently been de- plague and tularemia can present with pneumonia, cases might not
veloped against both smallpox and anthrax by integrating immune-​ be suspected unless they occur in clusters. Even with the classical
enhancing cytokine IL-​15 and the protective antigen of B. anthracis sign of widened mediastinum which frequently characterizes in-
into the Wyeth vaccinia virus. This has been proven to be efficacious halation anthrax, it might not be simple to distinguish from other
against both smallpox and anthrax in laboratory animals. If human severe pneumonias. Early identification of deliberately caused out-
trials of safety and efficacy are successful, such a vaccine will have sev- breaks will depend largely on the ability of primary care and emer-
eral important advantages. First, it will be a combined vaccine against gency room physicians to identify and promptly report cases to the
two diseases. Second, as a vaccinia-​based vaccine it can be lyoph- public health authorities. A major concern is that diagnosis of these
ilized without loss of potency and so will not be dependent on the uncommon diseases will not be considered by physicians who have
cold-​chain, which will greatly simplify storage, stockpiling, and field rarely, if ever, seen such cases.
delivery. Thirdly, it is likely to reduce the number of doses necessary Many of the biological agents can be identified by hospital labora-
to achieve protection against anthrax. Hence, in practice it could be an tories. However, some require more specialized laboratories and
extremely important advance for mass vaccination in general and for international collaboration. New techniques, especially those based
vaccinating first responders in particular. The recent Ebola epidemic on polymerase chain reaction, are being developed to accelerate spe-
in West Africa has stimulated the development of effective vaccines cific diagnosis. The safety of laboratory workers must be protected.
and treatment for Ebola virus disease.
Secondary prevention depends on comprehensive surveillance
and clinical awareness, both for detecting and characterizing the Surveillance and early detection
event. This will facilitate prompt implementation of treatment and,
where appropriate, postexposure prophylaxis. Rapid implemen- The objectives of surveillance for bioterrorism incidents are twofold.
tation of measures such as vaccination, isolation of patients, and Firstly, early detection of cases can facilitate prompt treatment, iden-
quarantine of contacts can ameliorate the spread. Tertiary preven- tification of the exposure source, rapid introduction of prophylaxis
tion includes early treatment and rehabilitation of those people who and, where necessary, isolation of cases and imposition of quaran-
contract the disease and public information campaigns to reduce the tine. Secondly, surveillance systems have a major role in monitoring
long-​term psychological impact of the incident. the progress of an outbreak to support decisions on upgrading and
redistributing health services and provide reliable and timely infor-
mation to the media and the public.
Clinical features Traditional surveillance, based on routine physicians’ reports,
could have serious limitations in a bioterrorism incident. Early
The incubation periods of potential bioterrorism agents can vary cases might be missed due to a failure to suspect unusual diseases.
from as little as several hours to weeks. The incubation period for Thus, there might be considerable delays in alerting public health
1722 SECTION 10 Environmental medicine, occupational medicine, and poisoning

authorities due to the lag time between the initial symptoms and of exposure, appears to provide protection against clinical disease.
definitive diagnosis. Furthermore, access to timely, processed infor- However, since the incubation period is usually longer than 4 days,
mation during the epidemic might be seriously limited. the lag time for recognizing index cases might render postexposure
Recognizing these limitations, surveillance for symptoms and vaccination effective only for contacts of those initially exposed.
signs, known as ‘syndromic surveillance’, has been proposed as a ‘Ring vaccination’ involves intensive tracing and vaccination of all
more sensitive method for early detection of an outbreak. Although primary contacts, followed by vaccination of the secondary contacts
theoretically appealing, in practice, syndrome surveillance is likely as opposed to mass vaccination immediately following diagnosis of
to be most useful to complement early detection and reporting of the first cases. Ring vaccination accompanied by vaccination in af-
the index cases by alert physicians. Sources of data for syndromic fected regions, followed by countrywide mass vaccination, is likely
surveillance are usually recorded visits to primary care physicians to be the most effective strategy. This approach has now also been
and emergency rooms and use of prescription and non​prescription proposed for the control of Ebola virus disease epidemics.
medication. Computer analysis of the data allows temporal and geo- For some agents, postexposure prophylaxis with antimicrobials
graphical trends to be identified. Clusters in families or in age groups has a role. Ciprofloxacin, doxycycline, and ampicillin are used for
will be useful in locating the exposure source. Surveillance systems postexposure prophylaxis against anthrax and plague. In the case
must include clear procedures to be followed when a suspected in- of anthrax, it should be combined with vaccination. Results of
cident is reported. Although syndromic surveillance systems are animal studies suggest that postexposure antivirals could be ef-
highly sensitive, they tend to have both low specificity and positive fective in a smallpox outbreak. Ribavirin might have some efficacy
predictive value. Abundant false positive reports could desensitize in postexposure prophylaxis of RNA viral haemorrhagic fevers such
and paralyse the system. as arenaviruses.
Despite the limitations of syndromic surveillance, once an out-
break has been confirmed, such systems will provide timely data on
the location, nature, and evolution of the outbreak. Electronic data Isolation and quarantine
systems will, however, be important for confirming and tracking the
outbreak, and they can reduce delays in reporting and reliance on For contagious diseases, such as smallpox and plague, isolation of
reports from individual physicians. They can play a critical role in patients, barrier nursing, quarantine of contacts, and restriction
the control of the epidemic by providing information for ‘situational of the movements and social interactions of people are important
awareness’. control measures. Results of modelling studies suggest that closing
schools and reducing crowding and the use of public transport
would be effective in limiting the spread of an epidemic.
Epidemiological investigation For contagious diseases, there are specific guidelines for the use
of masks by healthcare personnel and emergency workers. Surgical
The main objectives of the investigation are to identify and charac- masks might be adequate for droplet spread, whereas N95-​type
terize the outbreak and predict its course. For bioterrorism incidents, masks would be necessary to protect against aerosols. However, they
the investigators should have specialized knowledge of the possible are more expensive, require special fitting, and cannot be worn for
biological agents and the natural history of the diseases. Close col- long periods. The efficacy and practicability of the use of masks by
laboration with the police, public health authorities, and the media the general public are less clear.
is essential. Patient details should include the date and time when
symptoms started, signs and symptoms and, when smallpox is sus-
pected, the vaccination history. It is important to establish which Public education and risk communication
public places patients have visited in the incubation period of the
suspected agent. Those patients reported to have similar symptoms The novel and largely unpredictable effects of biological weapons
and contacts should be interviewed. It is important to document the are likely to increase the uncertainty surrounding a bioterrorism
natural history of the disease for each patient. When investigating po- incident. Public education and effective risk communication are
tential bioterrorism outbreaks, there is a need to identify the source essential in order to bolster public confidence and improve co-
of the implicated pathogen. This was typified in the investigation of operation with the authorities. Clinicians and public health per-
the anthrax letters incident in the United States in 2001. Recently sonnel should have access to up-​to-​date information. The general
the investigators in that outbreak used comparative genome analysis public should be provided with nontechnical descriptions of the
and demonstrated that the genotypes detected in the B. anthracis diseases and simple instructions on how to act in an emergency
morphotypes isolated for the letters were different from the Ames situation.
strain common in the environment. This study has provided support Risk communication associated with a bioterrorist event can be
for the added value of whole-​genome sequencing, and comparative divided into five stages: prior to the event, on suspicion of an event,
genomics for potential bioterrorism outbreak investigations. on confirmation of the event, during the event, and following the
event. At each stage, the public is likely to ask questions relevant
to that stage. Since the authorities may possess very little factual
Postexposure prophylaxis information, the public might suspect that information is being
withheld, resulting in hostility. Thus, it is important that the public
Postexposure prophylaxis is appropriate for some, but not all, bio- messages be reassuring while sharing uncertainties. Overreaction or
terrorism agents. Vaccination against smallpox, within 3–​4 days panic should be anticipated. This can be exacerbated by rumours
 10.3.9 Bioterrorism 1723

or unsubstantiated statements by professionals or laypeople not in- appropriate now, in the light of the experience gained during the
volved in managing the outbreak. recent Ebola virus disease epidemic in West Africa.
A variety of problems should be anticipated during an outbreak,
including atypical presentations of cases and varying responses
to treatment and prophylaxis. Side effects of the medications and Likely future developments
vaccines might be reported. Discovery of new exposure foci and
reports of disease in apparently unexposed people could cause dis- The threat of bioterrorism is likely to increase, demanding greater
quiet and mistrust. There might be inadequate isolation of patients resources to deter attacks and improve surveillance, vaccines, and
and a breakdown of the implementation of quarantine. Untried new medications.
treatments might be proposed by unauthorized professionals or lay
people.
Following a bioterrorist incident, residual public fear and anx- Conclusions
iety is likely to persist. Inevitably, there will be questions about the
extent to which the authorities were able to control the incident, Bioterrorism is a low-​risk but high-​impact public health emergency.
criticism of actions taken or not taken, and general recriminations. Deterrence remains the prime goal. Reducing the motivation for
Public messages should be broadcast about the lessons learned from terror and banning internationally the use of biological weapons
the incident and actions that will be taken to address deficiencies. should be promoted at all levels. Sensible preparedness for bioter-
It is essential that the authorities maintain transparency in order to rorist incidents is a deterrent in itself and ensures that public health
strengthen public trust. systems and society will deal effectively with an incident. Risk com-
munication needs to be strengthened. Such measures will also im-
prove general emergency preparedness and the control of infectious
Decontamination diseases.

Decontamination is relevant, mainly for anthrax and smallpox, in

the environment of an aerosol attack and at places where patients
FURTHER READING
were treated. Sodium hypochlorite solution is effective in most set-
tings. Bedding and clothing of patients should be sterilized or dis- Adalja AA, Toner E, Inglesby TV (2015). Clinical management of
potential bioterrorism-related conditions. New England Journal of
posed of where indicated. Low humidity and temperature prolong
Medicine, 372, 954–62.
survival of the smallpox virus in the environment, and on scab ma-
Armengaud J (2017). Striking against bioterrorism with advanced
terial; it can remain viable for months.
proteomics and reference methods. Proteomics, 17, (1–2).
Arnon SS, Schechter R, Ingelsby TV, et al (2001). Botulism toxin
as a biological weapon. Medical and public health management.
Legal and ethical aspects Journal of the American Medical Association, 285, 1059–70.
Banada PP, Deshpande S, Chakravorty S, et al (2016). Sensitive
Bioterrorism preparedness requires the necessary legislation to en- detection of Francisella tularensis directly from whole blood by
able the public health authorities to carry out measures with ad- use of the GeneXpert System. Journal of Clinical Microbiology 55,
equate legal backing. Laws that are of particular importance relate 291–301.
to closing buildings, taking over hospitals, ordering isolation and Banada PP, Deshpande S, Russo R, et al (2017). Rapid Detection of
quarantine, and active surveillance of presumed infected individ- Bacillus anthracis bloodstream infections by use of a novel assay in
uals and their contacts. Ethical issues might arise in the triage of the GeneXpert System. Journal of Clinical Microbiology 55, 2964–71.
patients for admission to overburdened hospital wards and inten- Bonin S (2007). In A Wegner, V Mauer, M Dunn, series ed.
International Biodefense Handbook. An inventory of national and
sive care units.
international biodefense practices and policies; Center for Security
Studies at ETH Zurich.
Borio L, Ingelsby T, Peters CJ, et al (2002). Hemorrhagic fever viruses
Areas of uncertainty or controversy as biological weapons. Journal of the American Medical Association,
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Mortimer PP (2003). Can postexposure vaccination against smallpox 8, 687.
succeed? Clinical Infectious Diseases, 36, 622–8. Titball RW, Burtnick MN, Bancroft GJ, Brett P (2017). Burkholderia
Pennisi E (2016). Pocket DNA sequencers make real-time diagnostics pseudomallei and Burkholderia mallei vaccines: Are we close to
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10.4
Poisoning

CONTENTS Diagnosis is based on the history, circumstantial evidence (if avail-

10.4.1 Poisoning by drugs and chemicals 1725 able), the presence of typical features, and, occasionally, on the re-
John A. Vale, Sally M. Bradberry, and D. Nicholas Bateman sults of toxicological and other investigations. The medical approach
should never be confined to the poison and its effects (e.g. deliberate
10.4.2 Injuries, envenoming, poisoning, and allergic
self-​harm may be indicative of a significant psychiatric disorder that
reactions caused by animals 1778
requires diagnosis and treatment).
David A. Warrell
Biochemical abnormalities due to disturbed metabolic pro-
10.4.3 Poisonous fungi 1817 cesses are common in severely poisoned patients. These may be
Hans Persson and David A. Warrell of diagnostic value, but mostly their recognition and treatment are
10.4.4 Poisonous plants 1828 important in management. Acid–​base disturbances, particularly re-
Michael Eddleston and Hans Persson spiratory acidosis (due to central nervous system depression or pul-
monary toxicity), and metabolic acidosis (due to lactic acidaemia or
derangements of intermediary metabolism), are common. Plasma
electrolyte abnormalities, particularly hypo-​or hyperkalaemia, are
observed and are most often due to redistribution of potassium
across cell membranes. Hypoglycaemia and, less commonly, hyper-
glycaemia may also occur.
10.4.1 Poisoning by drugs Management
and chemicals Initial management involves the treatment of any potentially life-​
threatening conditions, such as airway compromise, breathing difficul-
John A. Vale, Sally M. Bradberry, and D. Nicholas ties, haemodynamic instability, and clinically significant arrhythmias.
Bateman Thereafter, convulsions and temperature disturbances should be
treated and fluid, acid–​base, and electrolyte abnormalities corrected.
There is no evidence that the use of methods to reduce absorption
ESSENTIALS from the gastrointestinal tract—​such as activated charcoal, gastric
Poisoning is usually an acute, short-​lived event which necessitates lavage, syrup of ipecacuanha, cathartics, or whole-​bowel irrigation—​
immediate care, though complications such as rhabdomyolysis may improves the clinical outcome in poisoned patients. However, ac-
persist for a few days. Less commonly, symptoms may arise only tivated charcoal and gastric lavage may be considered in patients
after prolonged exposure, as occurs with many heavy metals. Rarely, who have ingested life-​threatening amounts of a toxic agent up to
sequelae may not occur until many years after exposure (e.g. with 1 h previously.
vinyl chloride). It must be stressed that exposure does not necessarily Antidotes exert their beneficial effects by a variety of mechan-
equate with poisoning as uptake of the agent involved is required isms, including forming an inert complex with the poison, acceler-
but, even if this occurs, poisoning does not necessarily result as the ating detoxification of the poison, reducing the rate of conversion of
amount absorbed may be too small. the poison to a more toxic compound, competing with the poison
Poisoning may be accidental or deliberate; it is usually accidental for essential receptor sites, blocking essential receptors through
in small children, but in adults it is almost invariably deliberate. Less which the toxic effects are mediated, and bypassing the effect of
commonly, it may be iatrogenic. Occupational poisoning is frequent the poison. There are, however, only a small number of poisons for
in developing countries. which there is a specific antidote, and few antidotes are employed
regularly in clinical practice; these include acetylcysteine, naloxone,
Clinical assessment and flumazenil.
Assessment of a poisoned patient involves taking an appropriate To increase poison elimination, treatment with multiple-​dose ac-
history and performing a physical examination (including an as- tivated charcoal (in patients who have ingested carbamazepine, dap-
sessment of the level of consciousness, ventilation, and circulation). sone, phenobarbitol, quinine, or theophylline), urine alkalinization
1726 SECTION 10 Environmental medicine, occupational medicine, and poisoning

are encountered or if there is clinical uncertainty about optimal

(in patients with moderately severe salicylate poisoning) or haemo-
management.
dialysis (which significantly increases the elimination of ethanol,
ethylene glycol, isopropanol, lithium, methanol, and salicylate) should
be considered, although there is no conclusive evidence that these
treatments improve outcome.
Epidemiology
Most countries have a poisons information service, which pro-
Poisoning, either accidental or deliberate, is a common presentation
vides advice to medical staff (e.g. in the United Kingdom healthcare
in all countries throughout the world. This phenomenon is, how-
professionals may obtain online advice from https://​ www.
ever, a relatively new one. Before the 1950s, hospital admissions
TOXBASE.org and by telephone), and in most cases, to the general
from self-​harm, now the most frequent cause of poisoning presen-
public as well. Advice should always be sought if unfamiliar poisons
tation to healthcare, was extremely rare worldwide. The reasons for
are encountered or if there is clinical uncertainty about optimal
this changing pattern of poisoning are poorly understood.
management.
Patients who have suffered toxic exposures present to healthcare
facilities in a variety of ways, including to primary care physicians,
hospital emergency departments, and hospital outpatients; rarely,
Introduction patients are discovered dead. Collecting statistics on poisoning
is, therefore, a complex issue and there is currently no universally
Poisoning is usually an acute event demanding immediate care agreed system for documenting and comparing rates of poisoning
and attention, but the consequences of exposure sometimes per- in different countries. Most statistics refer to hospital admissions (as
sist. Distinctive sequelae may not appear until many years have opposed to hospital presentations in emergency departments) or
elapsed (e.g. with carcinoma of the oesophagus following ingestion poisoning-​related deaths.
of corrosives or hepatic haemangiosarcoma from vinyl chloride Health statistical data from developed countries are usually more
exposure). Symptoms may arise only after prolonged exposure, as sophisticated than those from the developing world, although local
with many metals. Exposure by oral, inhalational, dermal, or other surveys suggest that the incidence of self-​harm is little different in
routes on their own does not necessarily indicate poisoning. Uptake these different types of society. Poisons information centres also col-
is required for there to be a toxic effect, but even if this occurs, poi- lect information about the types of agent people are exposed to or
soning does not necessarily result as the amount absorbed may be ingest, many of which do not result in clinical ill health, further com-
too small. plicating health statistics.
If poisoning does occur, the ensuing clinical syndrome may be There are clear age differences in the frequencies and causes of
distinctive; for example, fixed dilated pupils, exaggerated tendon re- poisoning. In children under the age of 10, accidental poisoning
flexes, extensor plantar responses, depressed respiration, and car- is extremely common, particularly in the very young who tend to
diac tachyarrhythmias suggest tricyclic antidepressant poisoning; place household objects into their mouths. From the age of 10 up-
anaemia, constipation, colic, and motor nerve palsies are indicative wards, self-​harm becomes predominant, peaking in the late teens
of lead poisoning. However, with many psychotropic medicines to late twenties and then gradually declining in incidence in higher
there may only be non​specific central nervous depression, respira- age groups. The health departments of most developed countries
tory impairment, and hypotension. publish data on poisoning mortality on the internet; collection of
Poisoning may be accidental or deliberate. It is usually accidental hospital admission data is less routine and is best in countries which
in small children, but in adults it is almost invariably deliberate (de- have centralized healthcare provision.
liberate self-​harm) or, rarely, it may be with homicidal intent. It may
also be iatrogenic in those aged under six months (e.g. involving Hospital admissions due to poisoning
overtreatment with paracetamol). Occupational poisoning is Poisoning causes 5–​10% of acute hospital medical presentations in
common in developing countries and continues to occur in the developed countries. In the United Kingdom, there are currently
developed world. 350 000 to 400 000 per annum. Since deliberate self-​harm is a risk
The medical approach to poisoning should never be confined factor for further such episodes, approximately 25% of these cases
to the poison and its effects. All the circumstances surrounding occur in the same patient group.
the episode must be considered, especially in cases where litiga- Self-​harm in women and men is somewhat different, and other
tion may follow (e.g. in the event of an occupational mishap with than young children, mortality data for out-​ of-​
hospital deaths
a chemical). It is therefore important that the doctor concerned, show that men are more likely to succeed in killing themselves
having instituted any necessary life-​ saving measures, should than women. The severity of poisoning depends on the quantities
take a careful history, retain all pertinent evidence such as a sui- ingested, but hospital statistics do not provide adequate data to as-
cide note and biological specimens, make a meticulous record of sess this. Mortality data provide information on the relative toxicity
symptoms, signs, progress, and outcome, and remember issues of of different compounds if it can be expressed per head of popula-
confidentiality. tion exposed. This is a technique that is best used for assessing the
Most countries have a poisons information service, which pro- toxicity of prescription medicines; it is much less easily applied to
vides advice to medical staff (e.g. in the United Kingdom healthcare chemicals and household products when measures of availability are
professionals may obtain online advice from https://​ www. not so readily obtained.
TOXBASE.org and by telephone), and in most cases, to the general Many cases of ‘poisoning’ in children are more accurately de-
public as well. Advice should always be sought if unfamiliar poisons scribed as ‘exposures’, since symptomatic poisoning is uncommon,
 10.4.1 Poisoning by drugs and chemicals 1727

particularly in developed countries. While drug errors can result in significantly reduced mortality rates from this cause in the United
poisoning, data are very difficult to collect. Kingdom.
Patients who harm themselves often do so because they are
acutely stressed. Few have formal psychiatric diagnoses, such as Childhood poisoning
depression or psychosis, or are truly suicidal, since the incident is Accurate data on childhood poisoning are difficult to obtain.
impulsive rather than planned. Such differences in behaviour affect Many children with relatively mild features will be managed at
mortality rates. Mortality is often higher in older age groups where home or in emergency departments, where national statistical
overdose planning has been more careful, and has involved prescrip- data are not routinely collected, and so in this population national
tion medicines which typically are more toxic than over-​the-​counter statistics are unreliable, except for agents that cause death. Deaths
preparations taken by younger patients. Impulsive behaviour is often in children are usually attributable to inappropriate storage,
associated with ingestion of alcohol and as many as two-​thirds of including toxic pharmaceuticals, such as digoxin and quinine,
men, and nearly one-​half of women, take alcohol in association with household products and, increasingly, drugs of abuse. The pattern
an overdose. In many cases of self-​harm more than one drug is in- of child poisoning varies in different countries. Herbicide expos-
cluded in the cocktail, making clinical management more complex, ures are common in agricultural countries where these materials
particularly if two or more agents acting on the same body system are stored in the home. In developed countries, exposures may
are involved. This applies particularly to drugs acting on the brain, occur when a young child finds and takes a relative’s medicines.
kidney, and cardiovascular system. Child-​resistant containers have reduced poisoning rates in chil-
The increasing worldwide use of drugs of abuse has also in- dren, but tragedies still occur.
fluenced patterns of poisoning, and many cases of poisoning
in this population result from variations in quality of supply or
experimentation. Diagnosis
Prescription medicines are used in most self-​harm episodes in the
United Kingdom, the rest of Europe, North America, and countries Diagnosis of acute poisoning requires that the doctor not only es-
in the developed world and their availability, therefore, influences tablish that exposure to a poison has occurred, but also its chem-
the numbers of patients seen. The diagnoses for which the drug is ical composition and the route and magnitude of exposure, so that
used will also affect how often it is taken as a self-​harm agent. Thus, the features likely to develop can be anticipated and risk assessed.
self-​harm with drugs for peptic ulcer disease is very uncommon, As in any other branch of medicine, diagnosis of acute poisoning is
whereas overdose with antidepressants is much more frequent. based on the patient’s history and on a combination of circumstan-
The type of agent taken in overdose is culturally determined. In tial evidence, the findings on physical examination and appropriate
the United Kingdom, paracetamol contributes approximately one-​ investigations.
third of all poisonings seen in hospitals but, although common in However, in acute poisoning, there are many obstacles to
North America and other parts of Western Europe, the proportion establishing the information required. Young children may not be
of cases is lower. In developing countries, such as Sri Lanka and able to give a history; adults are often unreliable; physical signs are
India, drugs are much more expensive and the agents ingested are rarely diagnostic; circumstantial evidence may be unavailable, tenta-
either plants, such as yellow oleander, or the widely available pes- tive, or misleading; and laboratory diagnosis is rarely comprehensive.
ticides. Agrichemicals cause less than 0.05% of hospital admissions
for poisoning in England and Wales, whereas in Sri Lanka they are History
associated with around 70% of all cases of self-​harm. Consequently, Since accidental poisoning in childhood is most common between
although the numbers of patients self-​harming per head of popula- the ages of 9 months and 5 years, an unequivocal history is unlikely
tion are quite similar, the mortality rates in Sri Lanka are orders of to be forthcoming from the victim but may be obtainable from older
magnitude higher than in Western Europe. witnesses. However, statements about quantities must be interpreted
cautiously since an accurate assessment of the amounts in original
Deaths from poisoning containers is rarely available.
In developed countries, most deaths from poisoning occur before In contrast, since 90% or more of adults presenting with acute poi-
admission, and less than 1% of patients presenting to hospital with soning are conscious or drowsy, it should be possible to obtain a his-
poisoning are likely to die. The risk of mortality is very dependent on tory of self-​poisoning. A few patients adamantly deny having taken
agent, and heroin, cocaine, and other high-​risk recreational drugs poisons but most usually admit to it without hesitation, although
are associated with higher death rates. In England and Wales, the problems arise in trying to establish precisely the nature and quan-
mortality from drug-​related poisoning was falling but has recently tity of what has been taken. Comparison of patients’ statements with
increased and in 2015 was higher than any time since 1993 with poisons detected by laboratory analysis of blood or urine consist-
3674 deaths; 2479 (67%) involved illegal drugs. ently reveals major differences in about half the cases. Consequently,
In previous decades, carbon monoxide (from coal gas) and barbit- patients are often thought to be deliberately untruthful. However,
urates were common causes of death. Substitution of natural gas for self-​poisoning is commonly an impulsive act. The patient ingests the
coal gas and changes in prescribing patterns have altered the agents contents of the first bottle that comes to hand, often while under the
most frequently associated with death. For example, the United influence of alcohol, and so inaccuracies in the history are not sur-
Kingdom and European Medicines Agencies have enacted legisla- prising. Although about 60% of episodes involve drugs prescribed
tion on co-​proxamol (paracetamol plus dextropropoxyphene) in re- for the victims or their relatives, like many other patients they are
sponse to concerns about its toxicity in overdose. Such changes have often ignorant of the names.
1728 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Assessment of the amounts of drugs ingested are even more dif- Conscious patients with abnormal behaviour, perhaps in com-
ficult. Few patients count the number of tablets they consume and bination with auditory and visual hallucinations, may have ingested
neither patient nor doctor can accurately interpret a ‘handful’, a amfetamines or other psychoactive stimulants, such as phen-
‘strip’, or similar arbitrary quantity. cyclidine, lysergic acid diethylamide (LSD), ‘magic’ (psilocybin-​
containing) mushrooms (see Chapter 10.4.3), or drugs such as
Circumstantial evidence the older antihistamines and tricyclic antidepressants, which have
In the diagnosis of acute poisoning, circumstantial evidence be- marked anticholinergic actions.
comes important when patients are unable to give a history (as is Drowsiness, ataxia, dysarthria, and nystagmus are common after
likely with young children), are confused, or are unconscious, or are ingestion of benzodiazepines. Coma with hypotonia and hyporeflexia
unwilling to do so. However, although circumstantial evidence may may follow, particularly if alcohol has also been taken. Hypotension,
strongly suggest poisoning, it is seldom incontrovertible. It takes hypothermia, and respiratory depression are rare. Poisoning with
several forms. tricyclic antidepressants causes hypertonia, hyperreflexia, extensor
plantar responses, and dilated pupils. Sinus tachycardia and pro-
Circumstances under which found longation of the QRS interval on the electrocardiogram support a
In the case of infants, the mother may return to the kitchen or bath- diagnosis of intoxication with these drugs; hypotension and hypo-
room to find her child with some substance all over their hands, face, thermia are uncommon. Tricyclic antidepressants and mefenamic
and clothing, or surrounded by pills, one of which the child may be acid are common causes of seizures.
eating. The assumption that some has been ingested may not be cor- Coma with pinpoint pupils and a reduced respiratory rate is
rect, and the amount swallowed is a matter of speculation. virtually diagnostic of poisoning with opioid analgesics and is an
Self-​poisoning is a common cause of coma in previously healthy indication for a therapeutic trial of naloxone. Many patients with
young adults. Adults may be found unconscious with tablet particles opioid poisoning will be habitual drug abusers and have vene-
around the mouth or on clothing as the only clue to diagnosis. More puncture marks and evidence of venous tracking, particularly
often, the presence of empty drug containers with occasional tablets in the antecubital fossae. Alcohol may be smelt on the breath, as
or capsules near the patient suggests the diagnosis. Less commonly, might solvents such as toluene, acetone, or xylene as the result
they are found unconscious or dead in some remote location. The of ‘sniffing’ glues, cleaning agents, or other preparations. Burns
lack of personal effects to indicate who they are or where they live around the lips or in the buccal cavity or pharynx indicate inges-
may suggest a desire not to be identified and should arouse suspicion tion of corrosives.
of poisoning. Protestations by relatives that the patient would never
take an overdose are often incorrect and should not prevent full Skin blisters
investigation in appropriate circumstances. Skin blisters may be found after poisoning with a wide variety of
Suicide notes drugs including barbiturates, tricyclic antidepressants, benzodi-
azepines, and non​drug toxins. They often occur over bony prom-
Suicide notes are reliable indicators of poisoning in the absence of inences that have been subjected to pressure and, less frequently, at
physical violence as a cause of coma. The note may specify what has sites where two skin areas have been in contact (e.g. the inner aspects
been taken in addition to expressing despair, futility, worthlessness, of the knees) and are not specific for any poison.
and remorse.

Features Neurological signs

There are few symptoms or physical signs that cannot be attributed Lateralizing neurological signs
to one poison or another. However, a clinical feature rarely arises Since most serious poisonings are associated with impairment
in isolation and clusters of features are of much greater diagnostic of consciousness, neurological signs are particularly important.
value. Those most commonly encountered in present-​day practice Lateralizing signs (unless they are attributable to a known neuro-
are given in Table 10.4.1.1. logical disease) virtually exclude a diagnosis of acute poisoning.

Table 10.4.1.1 Common feature clusters in the poisoned patient

Feature cluster Likely poisons

Coma, hypertonia, hyperreflexia, extensor plantar responses, myoclonus, Tricyclic antidepressants: less commonly antihistamines, orphenadrine,
strabismus, mydriasis, sinus tachycardia thioridazine
Coma, hypotonia, hyporeflexia, flexor or non​elicitable plantar responses, Barbiturates, benzodiazepines, and alcohol combinations, severe tricyclic
hypotension antidepressant poisoning
Coma, miosis, reduced respiratory rate Opioid analgesics
Nausea, vomiting, tinnitus, deafness, sweating, hyperventilation, vasodilatation, Salicylates
tachycardia
Hyperthermia, tachycardia, delirium, agitation, mydriasis MDMA (Ecstasy) Amfetamines
Miosis, hypersalivation, rhinorrhoea, bronchorrhoea Organophosphorus and carbamate insecticides, nerve agents
 10.4.1 Poisoning by drugs and chemicals 1729

Such findings have been recorded with barbiturate and phenytoin Loss of oculocephalic and oculovestibular reflexes
poisoning, but so rarely that the general rule is not compromised. It is widely accepted that absence of oculocephalic and oculovesti­
Pyramidal tract signs bular responses indicates severe brainstem damage and the likeli-
hood that the patient will not survive. However, this is not the case
The usual features of pyramidal tract involvement (hypertonia, in acute poisoning where these reflexes may be abolished in patients
hyperreflexia, and extensor plantar responses) are commonly who subsequently make a full recovery.
found in tricyclic antidepressant poisoning and with other drugs
with marked anticholinergic actions (e.g. the older antihistamines). Visual impairment
However, these signs may be abolished in deep coma. Visual impairment is associated most commonly with quinine and
Abnormal movements methanol poisoning.

Unconscious patients may respond to painful stimuli with flexor and

extensor limb movements of the type seen in decorticate and decere- Investigations
brate states. However, in poisoning, these signs do not indicate irre-
versible brain damage, and patients showing them can be expected Haematological and biochemical
to recover fully; hypoglycaemia must be excluded in these cases.
Acute dystonic movements (including acute torticollis, orolingual Information about the nature of poisons ingested can occasionally
dyskinesias, and oculogyric crises) are also produced; these are be deduced from standard haematological and biochemical investi-
usually caused by first-​generation antipsychotics such as chlorpro- gations, and from arterial blood gas analysis (Table 10.4.1.2).
mazine, haloperidol, or prochlorperazine. Choreoathetosis has been Toxicological screening
reported as a rare presenting feature of poisoning with organophos-
phorus insecticides. Toxicological screening for poisons in an unconscious patient is
often requested when the cause of coma is unknown. Although
Pupillary changes in poisoning identification of a drug or other chemical may reassure the clin-
Inequality of the pupils is not uncommon in poisoned patients. ician, this alone is not a good reason for the request. The clinician
Widely dilated pupils that react poorly to light may be caused by should consider how the result of a screen will alter management.
poisons with anticholinergic actions (e.g. tricyclic antidepressants) The pattern of drugs involved in poisoning in most developed
or sympathomimetic effects (e.g. amfetamines) or agents causing countries is such that specific treatment (e.g. antidotes, techniques
blindness (e.g. quinine, methanol). Miosis is usually caused by to enhance elimination of the poison) is unlikely to be available,
opioid analgesics or poisons with cholinergic or anticholinesterase and management will therefore be supportive. Screening is labour-​
actions (e.g. organophosphorus insecticides, nerve agents). intensive, time-​consuming, and expensive, and in most cases,
The degree and speed of reaction of the pupils to light is of no cannot be justified on an emergency basis because it will not alter
clinical value. the management of the patient, though there are important excep-
tions (Table 10.4.1.3).
Ocular signs
A variety of ocular signs including strabismus, internuclear oph-
thalmoplegia, and total external ophthalmoplegia, may be found Table 10.4.1.2 Haematological and biochemical investigations
in acutely poisoned patients. Strabismus has been described in poi- that assist in management
soning with phenytoin, carbamazepine, and tricyclic antidepres-
• Serum sodium concentration (e.g. hyponatraemia in ecstasy (MDMA)
sants. Usually the optic axes diverge in the horizontal plane but, in poisoning)
some patients, there is additional vertical deviation. It is present
transiently and only in patients who are unconscious. Dysconjugate, • Serum potassium concentration (e.g. hypokalaemia in theophylline
poisoning, hyperkalaemia in digoxin poisoning, rhabdomyolysis,
roving eye movements may also be seen if both eyes are observed haemolysis)
for a period. It is important to know that such abnormalities occur
• Plasma creatinine concentration (e.g. renal failure in ethylene glycol and
so that they are not misattributed to intracranial vascular lesions or diethylene glycol poisoning)
some other pathology requiring surgical intervention.
• Blood sugar concentration (e.g. hypoglycaemia in insulin and severe
Dysconjugate eye movements may become apparent only when untreated paracetamol poisoning, hypoglycaemia, and hyperglycaemia
oculovestibular reflexes are examined by caloric stimuli. Installation in salicylate poisoning)
of ice-​cold water into the external auditory meatus should make • Serum calcium concentration (e.g. hypocalcaemia in ethylene glycol
both eyes turn to the side irrigated, and failure of one eye to de- poisoning)
viate is evidence of internuclear ophthalmoplegia and a lesion of the • Serum alanine aminotransferase/​aspartate aminotransferase activities
medial longitudinal fasciculus. This has been reported in poisoning (e.g. increased in paracetamol poisoning)
with a variety of drugs including tricyclic antidepressants, pheno- • Acid–​base disturbances, including metabolic acidosis
thiazines, benzodiazepines barbiturates, and ethanol, and can be de-
tected in 10% of cases if caloric tests are carried out. Both sides are • Methaemoglobin concentration (e.g. in nitrite poisoning)
usually affected, but internuclear ophthalmoplegia on testing one • RBC cholinesterase activity (e.g. organophosphorus insecticide and nerve
agent poisoning)
side only also occurs in acute poisoning.
1730 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Table 10.4.1.3 Poisons for which emergency measurement is hypoventilating patient within seconds and, even if it is given in-
important for management appropriately, it is highly unlikely to have adverse effects.
Unconscious patients need scrupulous attention to respiration,
• Carboxyhaemoglobin
hypotension, hypothermia, and other complications, if they are to
• Digoxin survive. Expert nursing is as important as medical measures.
• Ethanol (when monitoring treatment in ethylene glycol and methanol
poisoning) Airway
• Ethylene and diethylene glycols Establishment and maintenance of an adequate airway is of para-
mount importance in the management of unconscious poisoned
• Iron
patients. The airway may be obstructed by the tongue falling back,
• Lithium dental plates being dislodged, other foreign bodies, buccal secre-
• Methanol tions, vomitus, and flexion of the neck. In the first instance, the neck
• Paracetamol should be extended and the tongue and jaw held forwards. Secretions
in the oropharynx must be removed, and an oropharyngeal airway
• Salicylate
should be inserted before turning the patient into a semi-​prone pos-
ition. If the cough reflex is absent, an endotracheal tube should be
inserted to prevent aspiration into the lungs and allow regular suc-
However, emergency measurement of the serum or plasma con- tion of bronchial secretions. It is then important to ensure that the
centration of the agents in Table 10.4.1.3 is important to ensure ap- inspired air is adequately warmed and humidified.
propriate clinical management.
Ventilation
ECG Once a clear airway has been established, the adequacy of spontan-
A routine ECG is of limited diagnostic value but is important in pa- eous ventilation should be assessed. Pulse oximetry can be used to
tients who are unconscious or thought to have ingested a cardiotoxic measure oxygen saturation. The displayed reading may be inaccurate
drug. Sinus tachycardia with prolongation of the QRS interval in when the saturation is below 70%, when peripheral perfusion is poor,
an unconscious patient suggests tricyclic antidepressant poisoning. and in the presence of carboxyhaemoglobin or methaemoglobin.
With increasing cardiotoxicity, it may be impossible to detect P-​ Only measurement of arterial blood gases, however, indicates the
waves, and the pattern then resembles ventricular tachycardia. presence both of hypercapnia and hypoxia. The presence of venti-
Overdose with cardiac glycosides or potassium salts also induces latory insufficiency (as determined by arterial partial pressure of
characteristic ECG changes. Q–​T interval prolongation is a recog- oxygen ≤9 kPa on air and/​or arterial partial pressure of CO2 ≥6 kPa)
nized adverse effect of several drugs in overdose (e.g. quetiapine, should lead to consideration of the need for intubation and assisted
terfenadine, and quinine) and predisposes to ventricular arrhyth- ventilation if the central respiratory depression cannot be reversed
mias, notably torsade de pointes. by administration of a specific antidote such as naloxone.
Unconscious poisoned patients often have a mild, mixed respira-
X-​rays tory and metabolic acidosis with CO2 tensions at the upper limit of
Routine radiology is of little diagnostic value. It can be used to con- normal, and oxygen tensions that fall with increasing depth of coma.
firm ingestion of metallic objects (e.g. coins, button batteries) or in- Increasing the oxygen contents of the inspired air is often sufficient
jection of globules of metallic mercury. Rarely, hydrocarbon solvents to correct hypoxia. High-​inspired oxygen concentrations are impera-
(e.g. carbon tetrachloride) may be seen as a slightly opaque layer tive in patients with carbon monoxide and cyanide poisoning, and in
floating on the top of the gastric contents with the patient upright, or pulmonary oedema resulting from inhalation of irritant gases.
outlining the small bowel. Ingested packets of illicit substances may
be discernible on a plain radiograph, but CT or MRI is more reliable Cardiovascular function
in detecting such objects. Cardiovascular function should be assessed by measuring pulse,
blood pressure and temperature (core and peripheral). ECG should
be monitored in moderately or severely poisoned patients, par-
General management ticularly when a drug with a cardiotoxic action has been ingested.
Echocardiography may occasionally be useful in such patients.
Antidotes and methods to enhance elimination are available for only
very small number of poisons, and the management of the great ma- Hypotension
jority of poisoned patients is based on what has been called ‘an or- Although hypotension (systolic blood pressure <80 mm Hg) is a rec-
derly if unspectacular regimen of supportive therapy’. ognized feature of acute poisoning, the classical features of shock
A small but significant number of poisoned patients arrive at (tachycardia and pale, cold skin) are seen only rarely because only a
hospital with respiratory obstruction, ventilatory failure, or in car- minority of patients are severely poisoned.
diorespiratory arrest. In these cases, conventional resuscitation Hypotension and shock may be caused by a direct cardiodepressant
takes precedence over detailed assessment of the patient and at- action of the poison (e.g. β-​blockers, calcium channel blockers, tri-
tempts to obtain a history. The opioid antagonist naloxone is safe cyclic antidepressants); vasodilatation and venous pooling in the
and should be used whenever there is the slightest suspicion that an lower limbs (e.g. angiotensin-​converting enzyme (ACE) inhibitors,
opioid is involved. Its use intravenously will resurrect a comatose, phenothiazines); decrease in circulating blood volume because of
 10.4.1 Poisoning by drugs and chemicals 1731

gastrointestinal losses (e.g. theophylline), increased insensible way that it will not further compromise cardiac function. For ex-
losses (e.g. salicylates), increased renal losses (e.g. diuretics), and in- ample, in tricyclic antidepressant poisoning, arrhythmias are due
creased capillary permeability. Hypotension may be exacerbated by to sodium channel blockade exacerbated by acidosis and are best
coexisting hypoxia, acidosis, and dysrhythmias. treated with hypertonic sodium bicarbonate, 50–​100 mmol.
Correct management of individual cases depends on accurate
Convulsions
identification of the cause. Young patients are generally not at risk
of cerebral or renal damage unless the systolic blood pressure falls Convulsions are potentially life-​threatening because they cause
below 80 mm Hg but, in those over the age of 40 years, it is preferable hypoxia and metabolic acidosis and may precipitate cardiac ar-
to keep the systolic blood pressure above 90 mm Hg. rhythmias and arrest. Short, isolated convulsions do not require
The treatment of hypotension depends on the cause. In all cases treatment but those which are recurrent or protracted should be
restoration of perfusion and oxygenation is the aim. While it is rea- suppressed with intravenous diazepam 10–​20 mg in an adult (lor-
sonable initially to administer a bolus of intravenous crystalloid, azepam 4 mg is an alternative). This drug is highly effective in ad-
care must be taken to avoid volume overload in cases of primary equate doses and alternatives are seldom needed. However, it is
cardiac failure. Such patients may require inotropic support with important to remember that giving benzodiazepines in this way
a sympathomimetic inotrope, such as dobutamine 2.5–​10 micro- may potentiate the respiratory depressant effects of the drugs
grams/​kg/​min or dopamine 2–​5 micrograms/​kg/​min. inducing seizures.
Hypotension caused by vasodilatation that does not respond to The combination of convulsions, coma, and vomiting, which may
intravascular volume expansion may warrant a vasoconstrictor occur with theophylline poisoning, is particularly dangerous and,
sympathomimetic drug, such as noradrenaline (norepinephrine) in these circumstances, it may be preferable to paralyse the patient,
40 micrograms (base)/​ml at an initial rate of 0.16–​0.33 ml/​min, insert an endotracheal tube, and start assisted ventilation. However,
or metaraminol (which has the potential advantage that it can although this ensures control of the airway and oxygenation, thus
be administered via a peripheral line) 15–​100 mg by intravenous avoiding the risk of inhalation of gastric contents, it does not sup-
infusion. It must be recognized, however, that blood pressure press seizure activity; cerebral function must therefore be moni-
may be raised at the expense of perfusion of vital organs, such tored, and parenteral anticonvulsants given as required.
as the kidneys. Response to treatment should be monitored not Temperature disturbances
only by blood pressure but also other markers of improved per-
fusion and oxygenation including skin colour and temperature, Hypothermia
urine output, cerebration, and resolution of metabolic (lactic) Any poison which depresses the central nervous system may impair
acidosis. temperature regulation and cause hypothermia, especially when dis-
covery of the patient is delayed and environmental temperatures are
Hypertension
low. This important complication may be missed unless tempera-
A few drugs (e.g. cocaine and amfetamines), when taken in over- ture is recorded rectally using a low-​reading thermometer. In se-
dose, may produce systemic hypertension. If this is mild and as- vere cases, peripheral and core temperatures should be monitored.
sociated with agitation, a benzodiazepine may suffice. In more Treatment includes nursing the patient in a warm room (27–​29°C)
severe cases, there may be a risk of arterial rupture, particularly and a heat-​conserving ‘space blanket’. Cold intravenous fluids should
intracranially. To prevent this, intravenous isosorbide dinitrate 2–​ be avoided and fluid bags for use should be stored in the room, or the
10 mg/​h (up to 20 mg/​h if necessary), or glyceryl trinitrate 10–​200 lines should pass through a heating device.
micrograms/​min by intravenous infusion (paediatric dose 0.2–​0.5
micrograms/​kg/​min) should be administered until blood pressure Hyperthermia
elevation is controlled. Rarely, body temperature may increase to potentially fatal levels
after poisoning with central nervous system stimulants such as
Arrhythmias
cocaine, amfetamines (including ecstasy (MDMA)), monoamine
Although many poisons are potentially cardiotoxic, the incidence of oxidase inhibitors, or theophylline. In such cases, muscle tone is
serious cardiac arrhythmias in acute poisoning is very low. Tricyclic often grossly increased, and convulsions and rhabdomyolysis are
antidepressants, β-​adrenoceptor blocking drugs, calcium channel common. Cooling measures should be instituted, sedation with di-
blockers, cardiac glycosides, amfetamines, cocaine, bronchodila- azepam should be given and, in severe cases, dantrolene 2–3 mg/kg,
tors (particularly theophylline and its derivatives) and antimalarial then 1 mg/​kg should be administered intravenously.
drugs are the most likely causes. Cardiotoxicity usually occurs to-
gether with other features of severe poisoning, including metabolic Acid–​base disturbances
acidosis, hypoxia, convulsions, respiratory depression, and abnor- Acid–​base disturbances commonly accompany coma due to drugs.
malities of electrolyte balance, which should be corrected before Acute respiratory acidosis is less common than might be expected,
considering the use of antiarrhythmic drugs. The latter have narrow but some elevation of arterial CO2 tensions towards the upper limit
therapeutic ratios and their use may further impair myocardial of normal is usual. This, in combination with mild hypoxia in the
function. deeper grades of coma, produces overall acidaemia. In general,
In general, drug therapy should only be given for persistent, acidosis should be prevented and managed by ensuring adequate
life-​threatening arrhythmias associated with peripheral circula- ventilation, oxygenation and tissue perfusion, and control of convul-
tory failure. The drug used must be selected from knowledge of the sions rather than by giving bicarbonate. However, several poisons,
pharmacology and toxicology of the poison involved and in such a particularly methanol and ethylene glycol, cause life-​threatening
1732 SECTION 10 Environmental medicine, occupational medicine, and poisoning

metabolic acidosis which should be corrected by infusion of sodium antibody fragments, HI-​ 6, hydroxocobalamin, obidoxime,
bicarbonate (see individual poisons). pralidoxime, protamine, Prussian (Berlin) blue, sodium calcium
Acute respiratory alkalosis, often in combination with a minor edetate, succimer (DMSA), unithiol (DMPS))
metabolic acidosis, is commonly found in acute salicylate poisoning. • accelerating detoxification of the poison (e.g. acetylcysteine, so-
The metabolic component may require treatment if it is the dom- dium thiosulfate)
inant feature and is causing overall acidaemia. Respiratory alkalosis • reducing the rate of conversion of the poison to a more toxic com-
should not be treated. pound (e.g. ethanol, fomepizole)
• competing with the poison for essential receptor sites (e.g. oxygen,
Electrolyte abnormalities
naloxone, phytomenadione)
Electrolyte abnormalities may result from acid–​base disturbances • blocking essential receptors through which the toxic effects are
or the direct effects of poisons. Massive tissue damage, usually mediated (e.g. atropine)
rhabdomyolysis, may allow potassium to leak from cells leading • bypassing the effect of the poison (e.g. oxygen, glucagon)
to potentially lethal hyperkalaemia. Cardiac glycosides cause
hyperkalaemia, secondary to loss from cells due to inhibition of the The most frequently used antidote in the developed world is
membrane sodium–​potassium pump, while the reverse occurs with acetylcysteine for paracetamol poisoning. Naloxone for opioid an-
sympathomimetic drugs. algesics, oxygen for carbon monoxide and, possibly, flumazenil for
Oxalic acid and ethylene glycol (which is metabolized to oxalic benzodiazepines are the only antidotes commonly needed in the
acid) may cause hypocalcaemia by leading to the formation of in- management of unconscious poisoned patients. Other antidotes
soluble calcium oxalate, which is deposited in tissues. Similarly, in- of proven value are listed in Table 10.4.1.4. The reader is recom-
gestion of fluorides is also a possible cause of hypocalcaemia; but mended to read the relevant section in the chapter to obtain further
the amounts children tend to ingest in the form of tablets to pre- advice. Antivenoms for bites and stings by venomous animals are
vent dental caries seldom cause serious problems. Ingestion of po- discussed in Chapter 10.4.2.
tassium salts, even in sustained release formulations, may lead to Table 10.4.1.4 Poisons for which there are specific antidotes
hyperkalaemia and fatal arrhythmias.
Poison Antidote
Bladder care Aluminium Deferoxamine (Desferrioxamine)
Urinary retention is a common complication of acute poisoning, par- Arsenic Dimercaprol (BAL), succimer (DMSA)
ticularly with tricyclic antidepressants and other drugs which have Benzodiazepines Flumazenil
marked anticholinergic actions. However, bladder catheterization is
β-​adrenoceptor-​blocking Atropine, glucagon
all too often an unconsidered measure in unconscious poisoned pa- drugs
tients. Coma itself is not an indication for bladder catheters in poi-
Calcium channel blockers Atropine
soned patients, the great majority of whom regain consciousness
within 12 h. The bladder can usually be induced to empty reflexively Carbamate insecticides Atropine
(provided it is not allowed to become grossly overdistended) by ap- Carbon monoxide Oxygen
plying gentle suprapubic pressure. Catheterization should be reserved Copper d-​Penicillamine, unthiol (DMPS)
for those patients in whom suprapubic pressure is insufficient to Cyanide Dicobalt edetate, hydroxocobalamin,
empty the bladder, and in those thought to be developing renal failure. oxygen, sodium nitrite, sodium thiosulfate
Diethylene glycol Fomepizole, ethanol
Skin, muscle, and nerve lesions
Digoxin and digitoxin Digoxin-​specific antibody fragments
Bullous lesions should be left intact until they burst, to reduce the Ethylene glycol Fomepizole, ethanol
risk of infection. De-​roofing should be performed when the blister
Hydrogen sulphide Oxygen
bursts; a non​adhesive dressing is then applied.
Rhabdomyolysis is a further possible result of immobility and may Iron salts Deferoxamine (Desferrioxamine)
occur in combination with skin lesions or independently. Poisoning Lead (inorganic) Succimer (DMSA), sodium calcium edetate
is the most common non​traumatic cause of this condition and it Methaemoglobinaemia Methylthioninium chloride (methylene blue)
may lead to acute renal failure and, rarely, to ischaemic muscle con- Methanol Ethanol, fomepizole
tractures and long-​term disability. Urgent orthopaedic referral is in- Mercury (inorganic) Unithiol (DMPS)
dicated if a compartment syndrome is suspected. Peripheral nerves
Nerve agents Atropine, obidoxime, pralidoxime, HI-​6
such as the radial, ulnar, and common peroneal may also be dam-
aged by direct pressure while the patient is unconscious. Oleander Digoxin-​specific antibody fragments
Unconscious patients should be turned from side to side at least Opioids Naloxone
every 2 h. Organophosphorus Atropine, obidoxime, pralidoxime
insecticides
Antidotes Paracetamol Acetylcysteine
Antidotes may exert a beneficial effect by: Thallium Prussian (Berlin) blue
• forming an inert complex with the poison (e.g. deferoxamine, Warfarin and other Phytomenadione (vitamin K1)
anticoagulants
D-​penicillamine, dicobalt edetate, dimercaprol, digoxin-​specific
 10.4.1 Poisoning by drugs and chemicals 1733

Reduction of poison absorption that whole-​bowel irrigation improves outcome. Based on volunteer
Prevention of absorption of volatile poisons through the lungs ob- studies, whole-​bowel irrigation may be considered following poten-
viously requires removal from the toxic atmosphere and occasion- tially toxic ingestion of sustained release or enteric-​coated drugs and
ally removal of soiled clothing as well. The latter is also necessary in body packers.
when absorption is thought to have been percutaneous. In addition, Cathartics
the contaminated skin should be thoroughly washed with soap
and water. Cathartics have been used alone and with activated charcoal.
Although it appears logical to assume that removal of unabsorbed Cathartics alone have no role in the management of poisoned pa-
drug from the gastrointestinal tract (‘gut decontamination’) will be tients. Based on available data, routine use of a cathartic with acti-
beneficial, the efficacy of current methods remains unproven, and vated charcoal is not endorsed.
efforts to remove small amounts of ‘safe’ drugs are clearly not worth-
while or appropriate.
Methods to increase poison elimination
Activated charcoal
Activated charcoal adsorbs a wide variety of drugs and toxic agents; Once a poison has been absorbed and providing there is no antidote,
the exceptions are acids and alkalis, ethanol, ethylene glycol, iron, it is reasonable to consider the use of treatments that might speed its
lithium, and methanol. elimination from the body.
In studies in volunteers given 50 g activated charcoal, the mean
reduction in absorption was 40%, 16%, and 21% at 60 min, 120 min, Multiple-​dose activated charcoal
and 180 min, respectively, after ingestion. Based on these studies, ac- Use of multiple-​dose activated charcoal involves repeated admin-
tivated charcoal 50–100 g should be considered in those who have istration of oral activated charcoal to increase the elimination of
ingested a potentially toxic amount of a poison (known to be ad- a drug that has already been absorbed into the body. Elimination
sorbed by charcoal) up to 1 h previously. There are insufficient data of a drug with a small volume of distribution (<1 litre/​kg), low pKa
to support or exclude its use after 1 h. There is no evidence that ad- (which maximizes transport across membranes), low binding af-
ministration of activated charcoal improves the clinical outcome. finity, and prolonged elimination half-​life following overdose is par-
ticularly likely to be enhanced by multiple-​dose activated charcoal.
Gastric aspiration and lavage Multiple-​dose activated charcoal also improves total body clearance
Gastric emptying studies in volunteers provide no support for the of the drug when endogenous processes are compromised by liver
use of gastric lavage. In the single clinical study in which benefit was and/​or renal failure.
claimed for lavage within 1 h of overdose, patients also received acti- Activated charcoal adsorbs material in the gut, which may be rele-
vated charcoal. There was also selection bias, and hence conclusions vant in cases of poisoning with slow-​release drug preparations. It
based on these data are limited. Thus, gastric lavage should not be also adsorbs drugs that are secreted in the bile, thereby preventing
used routinely in the management of poisoned patients as there is intestinal reabsorption, and binds any drug that diffuses from the
no evidence that it improves outcome, and it may cause significant circulation into the gut lumen. After absorption, drugs re-​enter the
morbidity. gut by passive diffusion if the concentration in the gut is lower than
The efficacy with which lavage removes gastric contents decreases that in the blood. The rate of passive diffusion depends on the con-
with time; therefore, lavage should be considered only in patients centration gradient and the intestinal surface area, permeability, and
who have ingested life-​threatening amounts of a toxic agent up to blood flow. Occasionally, drugs such as digoxin may be secreted ac-
1 h previously. tively by the intestinal mucosa, though the contribution of active
secretion to the effect of multiple-​dose activated charcoal on drug
Emesis with syrup of ipecacuanha clearance is unlikely to be greater than that of passive diffusion.
Syrup of ipecacuanha contains the active alkaloids emetine and Although many studies have demonstrated that multiple-​dose ac-
cephaeline. Although syrup of ipecacuanha is an effective emetic, tivated charcoal significantly increases drug elimination, it has not
there is no evidence that its use prevents significant absorption been shown to reduce morbidity and mortality in controlled studies
of toxic material and, moreover, its adverse effects (e.g. persistent in poisoned patients. At present, use of multiple-​dose activated
vomiting, diarrhoea, lethargy, drowsiness) may complicate diag- charcoal should be considered only in patients who have ingested a
nosis. It is not recommended. life-​threatening amount of carbamazepine, dapsone, phenobarbital,
quinine, and theophylline.
Whole-​bowel irrigation Clinical experience in adults suggests that charcoal should be ad-
Theoretically, the more quickly a slowly absorbed poison passes ministered in an initial dose of 50–​100 g and then at a rate of not
through the gut, the less it is absorbed. The opposite may apply to less than 12.5 g/​h, preferably via a nasogastric tube. Smaller initial
rapidly absorbed drugs. Whole-​bowel irrigation using polyethylene doses (10–​25 g) can be used in children because, generally, smaller
glycol electrolyte solutions does not result in absorption of fluid and overdoses have been ingested and the capacity of the gut lumen is
electrolytes, even though large volumes are administered rapidly smaller. If the patient has ingested a drug that induces protracted
via a nasogastric tube. Some volunteer studies have shown substan- vomiting (e.g. theophylline), intravenous ondansetron is effective as
tial decreases in the bioavailability of ingested drugs, but no con- an antiemetic and thus enables administration of multiple-​dose ac-
trolled clinical trials have been conducted and there is no evidence tivated charcoal. A total dose of 200 g (in adults) is usually sufficient.
1734 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Urine alkalinization Treatment

Increasing the urine pH enhances elimination of salicylate, phenobar- ACE inhibitors are likely to bind to activated charcoal, which
bital, and chlorophenoxy herbicides (e.g. 2,4-​dichlorophenoxyacetic should be administered in early presentations. The principles of
acid, mecoprop). However, except for salicylate poisoning, urine supportive care include volume expansion and subsequent use of
alkalinization is not recommended as first-​line therapy for poisoning inotropes. Since most patients who take these drugs in overdose
with these agents, as multiple-​dose activated charcoal is superior for are on treatment for hypertension or heart failure, careful manage-
phenobarbital, and a substantial diuresis is required in addition to ment is necessary as they may already have impaired myocardial
urine alkalinization to achieve clinically important elimination of function.
chlorophenoxy herbicides.
Urine alkalinization is a metabolically invasive procedure re- Antibacterial agents
quiring frequent biochemical monitoring and medical and nursing Most patients who take an antibiotic overdose are asymptom-
expertise. Before commencing urine alkalinization, it is important atic and require no treatment. There have been single case re-
to correct plasma volume depletion, electrolytes (administration ports of renal failure after overdose with co-​ trimoxazole or
of sodium bicarbonate exacerbates pre-​ existing hypokalaemia), aminoglycosides, pancreatitis with erythromycin, haemorrhagic
and metabolic abnormalities. Sodium bicarbonate is most con- cystitis with amoxicillin, and seizures with amoxicillin and other
veniently administered intravenously as an 8.4% solution (1 mmol β-​
lactam antibiotics. Rifampicin may induce metabolism of
bicarbonate/​ ml). Sufficient bicarbonate should be administered other drugs, an effect that takes several days. Erythromycin may
(225 mmol was the mean amount required in one study) to ensure cause QT prolongation and torsade de pointes. Isoniazid is dealt
that the pH of the urine, which is measured by narrow-​range indi- with next.
cator paper or a pH meter, is more than 7.5 and preferably close to
8.5. As the administration of sodium bicarbonate forces potassium Anticoagulants
into cells, it is important that the patient has a normal serum po- Warfarin is an antagonist of the synthesis of the vitamin K de-
tassium concentration before sodium bicarbonate is administered. pendent clotting factors II, VII, IX, and X. Newer oral anticoagulant
Sodium bicarbonate 8.4% is highly irritant to veins and severe tissue agents, such as dabigatran, a thrombin inhibitor, and rivaroxaban
damage can ensue if extravasation occurs. A secure, preferably wide-​ and apixaban, both direct factor Xa inhibitors, impact specific tar-
bore cannula (or central venous line), must therefore be used. gets in the coagulation cascade. Toxicity is more likely to occur
in the setting of therapeutic anticoagulation, or because of a drug
Dialysis, haemodialfiltration, haemofiltration, interaction, than as a consequence of acute overdose. Pre-​existing
and haemoperfusion renal impairment is the major factor affecting the toxicity of newer
Haemodialysis, haemodialfiltration, and haemoperfusion are agents.
of no value in patients poisoned by drugs with large volumes of
Clinical features
distribution (e.g. tricyclic antidepressants), because the plasma
contains only a small proportion of the total amount of drug in Epistaxis, gingival bleeding, spontaneous bruising, haematomas,
the body. haematuria, bilateral flank pain, rectal bleeding, and haemor-
Haemodialysis, and to a lesser extent haemodialfiltration, sig- rhage into any organ. Spontaneous haemoperitoneum has been re-
nificantly increases elimination of ethanol, ethylene glycol, isopro- ported. Severe blood loss may result in hypovolaemic shock, coma,
panol, lithium, methanol, and salicylate, and is the treatment of and death.
choice in all cases of severe poisoning with these agents. Although
Treatment
haemofiltration is widely available, it is much less efficient than
haemodialysis and haemodialfiltration and, therefore, should not be For warfarin if major bleeding occurs, give phytomenadione
used unless the alternatives are unavailable. (vitamin K1) 5 mg by slow intravenous injection together with
Charcoal haemoperfusion can significantly reduce the body prothrombin complex dried 25–​50 units/​kg or if unavailable fresh
burden of phenobarbital, carbamazepine, and theophylline, but frozen plasma 15 ml/​kg.
multiple-​dose activated charcoal is as effective and simpler to use. If the INR is 8.0 or more and there is no active bleeding discon-
tinue warfarin (restart when the INR <5.0), give phytomenadione
1–​3 mg by slow intravenous injection and repeat the dose if the INR
Drugs is 8.0 or more 24 h later. If the INR is 6.0–​8.0, and there is no active
bleeding or only minor bleeding, warfarin should be discontinued
Angiotensin-​converting enzyme inhibitors and restarted when the INR is less than 5.0.
If continued anticoagulation is unnecessary and the INR is 4.0 or
Clinical features less and there is no active bleeding, treatment with phytomenadione
Hypotension is the principal feature, occasionally accompanied by is not required. If the INR is 4.0 or more, phytomenadione 5 mg
drowsiness. Angioedema, hyperkalaemia, and renal failure are rec- by slow intravenous injection (100 µg/​kg body weight for a child)
ognized. The fall in blood pressure is often much greater than from should be administered.
therapeutic doses and the suggestion that ACE inhibitors have a A specific monoclonal antibody, idarucizumab 5–10g should be
‘ceiling’ effect on blood pressure is incorrect. given, to reverse the effects of dabigatran. Rivaroxaban and apixaban
 10.4.1 Poisoning by drugs and chemicals 1735

have no specific antidotes, but clotting factor concentrate or fresh Anticonvulsants: Tiagabine
frozen plasma should be tried in active bleeding. Clinical features and treatment
Anticonvulsants: Carbamazepine Lethargy, facial grimacing, nystagmus, posturing, agitation, coma,
Clinical features hallucinations, and seizures have been reported. Management is
supportive.
Carbamazepine is structurally related to the tricyclic antidepressants
and has similar anticholinergic actions. Overdose causes dry mouth, Anticonvulsants: Topiramate
coma, convulsions, nystagmus, ataxia, and incoordination. The pu- Clinical features and treatment
pils are often dilated, divergent strabismus may be present and com-
plete external ophthalmoplegia has been reported. Hallucinations Lethargy, ataxia, nystagmus, myoclonus, coma, seizures, and a
may occur, particularly in the recovery phase. normal anion gap metabolic acidosis have been observed; the latter
may be due to inhibition of renal cortical carbonic anhydrase.
Treatment Metabolic acidosis can appear within hours of ingestion and persist
Multiple-​dose activated charcoal has been shown to increase elimin- for days. Management is supportive.
ation of carbamazepine significantly. Antidepressants
Anticonvulsants: Phenytoin These come in a variety of pharmacological groups, but share the
Clinical features common effect of altering central monoamine function. Toxicity is
largely dependent on other properties of these drugs.
Acute overdose results in nausea, vomiting, headache, tremor, cere-
bellar ataxia, nystagmus, and rarely, loss of consciousness. Antidepressants: Tricyclic antidepressants

Treatment Several different pharmacological actions determine the features of

overdose. Reuptake of monoamines (noradrenaline and serotonin)
Multiple-​dose activated charcoal may increase phenytoin elimin- into central and peripheral neurones is blocked. Anticholinergic ac-
ation though this has not been confirmed. tions cause reduced gut motility, dry mouth, and tachycardia; sodium
Anticonvulsants: Sodium valproate channel blockade (e.g. amitriptyline) with class I antiarrhythmic ac-
tion prolongs the QRS complex; α-​adrenergic and histamine antag-
Clinical features onism results in hypotension and sedation.
Most frequently there is drowsiness, impairment of consciousness,
and respiratory depression. In severe poisoning, myoclonic jerks and Clinical features
seizures may occur and cerebral oedema has been reported. Liver Clinical features evolve as the drug is absorbed, usually within 30–​
damage, pancreatitis, and metabolic acidosis, perhaps due to changes 60 min of ingestion. Patients who remain conscious 6 h after in-
in fatty acid metabolism, are very unusual but potential complications. gestion are unlikely to have taken a large overdose. Early features
include drowsiness, sinus tachycardia, dry mouth, and dilated pupils.
Treatment Urinary retention, increased reflexes, extensor plantar responses,
Treatment is symptomatic and supportive. Haemodialysis is ef- and gaze palsies may then develop. Patients who become uncon-
fective in removing sodium valproate and should be employed in scious, Glasgow Coma Score (GCS) less than 8, or are unresponsive
severe poisoning, particularly if severe hyperammonaemia and to pain, are at increased risk of more serious complications, particu-
electrolyte and acid–​base disturbances are present. larly seizures. The risk of ventricular arrhythmias may be predicted
from the length of the QRS complex. Changes in repolarization pat-
Anticonvulsants: Gabapentin tern may also be seen with abnormal T-​waves and apparent changes
Clinical features and treatment in the ventricular axis. This pattern mimics the Brugada syndrome,
Lethargy, ataxia, slurred speech, and gastrointestinal symptoms the congenital abnormality associated with ventricular fibrillation.
may develop. Management is supportive. Features include ST elevation in leads V1–​3, with right bundle block
often associated with serious ventricular arrhythmias.
Anticonvulsants: Lamotrigine
Treatment
Clinical features and treatment
Patients with depressed consciousness and prolonged QRS interval
Lethargy, coma, ataxia, nystagmus, seizures, and cardiac are at risk of seizures and arrhythmias. Maintenance of acid–​base
conduction abnormalities have been reported. Management is balance in these patients is crucial. Early and prompt treatment
supportive. with sodium bicarbonate, even in patients who are not overtly acid-
Anticonvulsants: Levetiracetam otic, ameliorates cardiac effects of tricyclics. Sodium bicarbonate
50–100 mmol (50–100 ml of 8.4%) should be administered. If given
Clinical features and treatment into a peripheral vein, there is a risk of necrosis if it extravasates.
Lethargy, coma, and respiratory depression have been observed. Indications for bicarbonate include QRS duration greater than
Management is supportive. 120 msec, existing arrhythmias or hypotension resistant to fluid
1736 SECTION 10 Environmental medicine, occupational medicine, and poisoning

resuscitation. The aim is to maintain the arterial pH in the range Treatment

7.5–​7.55 without producing greater alkalaemia. Class 1a and class Management of metabolic acidosis is important to reduce the risk
1c antiarrhythmic drugs are contraindicated because they have of arrhythmias, which are more common in patients who have had
the same sodium channel blocking activity as tricyclic antidepres- convulsions. Convulsions are managed conventionally with di-
sants. Convulsions should be treated conventionally with diazepam azepam 10–​20 mg intravenously or lorazepam 4​ mg intravenously.
10–​20 mg intravenously, in an adult or lorazepam 4 mg. Activated charcoal should be considered if more than 12.5 mg/​kg
The α-​adrenoceptor blocking properties of tricyclics can cause was ingested within the previous hour. Venlafaxine prolongs the QT
severe hypotension. Noradrenaline is the most appropriate interval so that torsade de pointes is a risk which, should it occur, is
inotrope to use in this situation. treated conventionally by correcting acidosis and with intravenous
In the past, physostigmine was advocated to counteract the anti- magnesium 1–2 g over 30–60 sec, repeated in 5–15 min.
cholinergic action of tricyclic antidepressants, but most European
toxicologists do not recommend this. Antidepressants: Monoamine oxidase inhibitors (MAOIs)
During recovery from tricyclic poisoning, there may be a pro- These have well-​ established adverse interactions with foods
longed period of delirium with auditory and visual hallucinations. containing tyramine. The classical MAOIs such as phenelzine,
Sedation with diazepam is appropriate until the patient recovers. isocarboxazid, and tranylcypromine are now rarely used, and the
All tricyclic antidepressants may cause these features but new more specific inhibitors of MAOI type A (moclobemide) and
dosulepin (dothiepin) is the most toxic in overdose, followed by type B (selegiline) produce less serious adverse effects in overdose.
amitriptyline. Classical MAOIs prevent the breakdown of catecholamines within
the nerve ending, and result in excess sympathomimetic effects per-
Antidepressants: selective serotonin reuptake
ipherally, and excess adrenergic effects centrally. In patients who are
inhibitors (SSRIs)
naïve to the drugs, onset of inhibition of enzyme takes several hours,
Citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline are and clinical features may not be seen immediately. In patients on
antidepressants that inhibit serotonin reuptake (SSRIs) and lack the chronic therapy, the onset will be more rapid.
anticholinergic actions of tricyclic antidepressants.
Clinical features
Clinical features
Principal effects are central nervous system stimulation with excite-
Clinical features of these agents are principally due to serotonin-​like ment, restlessness, hyperpyrexia, hyperreflexia, convulsions, and
effects, and include nausea and vomiting, agitation, and tachycardia. coma. These may go on to cause rhabdomyolysis. Cardiovascular ef-
Convulsions may occur after larger ingestions. Hypertonia and fects include tachycardia and changes in blood pressure, depending
marked clonus are common features of significant poisoning, and on whether the effects of epinephrine (vasodilation) or norepineph-
increased muscle activity results in a rise in serum creatine kinase rine (vasoconstriction) predominate.
activity. Citalopram is the most toxic of the group in overdose.
All SSRIs occasionally cause arrhythmias. Treatment
Treatment is supportive, with careful monitoring. Patients who
Treatment
develop central excitation should be treated with large doses of di-
In patients who consume more than one drug affecting serotonin azepam. This will reduce centrally stimulated muscle contraction
receptors (e.g. tricyclic antidepressants, monoamine oxidase in- and hence pyrexia and muscle damage. Cardiovascular monitoring
hibitors, drugs of abuse, including, in particular, ecstasy), the is essential. Changes in blood pressure should be managed where
serotonin syndrome may occur. Features include marked agi- possible with drugs that are not sympathomimetic agonists. Use
tation and increased muscle activity resulting in hyperpyrexia. of β-​blockade can result in an unopposed α-​agonist effect causing
About half the patients have central nervous system features large rises in blood pressure. Hypertension is best controlled with an
including delirium and hallucinations. Other features include intravenous nitrate, such as glyceryl trinitrate.
autonomic instability with tachycardia and labile blood pressure.
Specific serotonin antagonists such as cyproheptadine may be Antidiabetic agents
useful though cannot be administered parenterally. Alternatively, Intentional overdose with insulin and oral hypoglycaemic agents is
benzodiazepines (e.g. diazepam orally or parenterally) may help uncommon. However, deaths from hypoglycaemia following poi-
reduce agitation. soning with insulin and sulfonyureas have been reported. Metformin
rarely causes hypoglycaemia since its mode of action is to increase
Antidepressants: Venlafaxine
glucose utilization. Risk of hypoglycaemia in overdose is low from
Venlafaxine is a drug that inhibits the reuptake of serotonin and nor- more recently introduced antidiabetics. These include subtype 2
adrenaline (SNRI). In overdose, it has features of both SSRIs and sodium-​glucose transport protein (SGLT2) inhibitors, meglitinides,
tricyclic antidepressants but it lacks anticholinergic activity. thiazolidinediones, α-​glucosidase inhibitors, GLP-​1 analogues, and
DDP-​IV inhibitors.
Clinical features
Drowsiness and convulsions are the main central nervous system Clinical features
effects. Tachycardia, ventricular arrhythmias, and changes in blood Features of hypoglycaemia include drowsiness, coma, twitching,
pressure are the main cardiovascular effects. convulsions, depressed limb reflexes, extensor plantar responses,
 10.4.1 Poisoning by drugs and chemicals 1737

tachypnoea, pulmonary oedema, tachycardia, and circulatory abnormalities, bradyarrhythmias, and tachyarrhythmias are
failure. Hypokalaemia, cerebral oedema, and metabolic acidosis common and are similar to those seen in quinine poisoning. Visual
might occur. Neurogenic diabetes insipidus and persistent vegeta- disturbance, agitation, drowsiness, acute psychosis, dystonic reac-
tive state are possible long-​term complications. Lactic acidosis is tions, seizures, and coma may ensue. Hypokalaemia is common and
a potentially serious complication of metformin overdose. SGLT2 is due to potassium channel blockade.
inhibitors increase renal glucose clearance and, in overdose, cause
polyuria, hypovolaemia, hypotension, and acute renal injury. Treatment
Thiazolidinediones may cause hepatic dysfunction and SGLT2 in- Supportive measures should be employed and hypokalaemia
hibitors cause diabetic ketoacidosis and renal impairment. corrected. There is no specific antidote. Sodium bicarbonate
50–​200 mmol (50–​200 ml of 8.4%) is indicated if the ECG shows
Treatment
intraventricular block but will exacerbate hypokalaemia, which
In all cases of poisoning with insulin or a sulfonylurea, prompt diag- should be corrected first. Mechanical ventilation, the administra-
nosis and treatment are essential if death or cerebral damage from tion of epinephrine 1–​10 µg/​kg per minute and high doses of di-
neuroglycopenia are to be prevented. The blood or plasma glucose azepam (1 mg/​kg as a loading dose and 0.25–​0.4 mg/​kg per hour
concentration should be measured urgently and intravenous glucose maintenance) may reduce the mortality to 10% in severe poisoning.
given. Glucagon may be ineffective in hypoglycaemia due to exhaus- Multiple-​dose activated charcoal may enhance chloroquine elim-
tion of hepatic stores of glucose. ination. Extracorporeal elimination techniques do not have a role.
Recurring hypoglycaemia is highly likely. A continuous infu- Extracorporeal life support has been utilized successfully in severely
sion of glucose, together with carbohydrate-​rich meals, is required poisoned patients unresponsive to conventional measures.
in cases of severe insulin poisoning, though there may be difficulty
in maintaining normoglycaemia. In the case of sulfonylurea poi- Antimalarials: quinine
soning, however, further glucose (although its administration may Quinine cardiotoxicity is due to sodium channel blockade.
be unavoidable) only serves to increase the already high-​circulating
insulin concentrations. Octreotide 50 microgram IV, followed by Clinical features
an infusion of 25 microgram/h is preferred in severe sulfonylurea Cinchonism (tinnitus, deafness, vertigo, nausea, headache, and diar-
poisoning. rhoea) is common at plasma concentrations greater than 5 mg/​litre.
Antihistamines In more serious poisoning, collapse with impairment of conscious-
ness (due to ventricular arrhythmias), convulsions, hypotension, pul-
First-​
generation antihistamines include brompheniramine, monary oedema, and cardiorespiratory arrest may be observed. The
chlorphenamine, cyclizine, diphenhydramine, promethazine, latter is often preceded by ECG conduction abnormalities, particu-
and trimeprazine. Second-​ generation drugs include cetirizine, larly QT prolongation. Hypoglycaemia, resulting from insulin release,
loratidine, and fexofenadine. occurs even with therapeutic doses and must be excluded in all cases.
Clinical features About 40% of patients develop ocular features, which may be unilat-
eral, including blindness, contracted visual fields, scotomata, dilated
Older antihistamines have anticholinergic actions but less potent pupils, blurred disc margins, macular oedema, arteriolar spasm, and
central nervous system toxicity than other anticholinergic drugs. late optic atrophy. Oculotoxicity is likely when plasma concentrations
Delirium may be a particular problem in very young children and exceed 10 mg/​litre. Visual loss is permanent in about 50% of cases.
older people following a substantial acute overdose. Rhabdomyolysis
is a well-​recognized complication of severe antihistamine poisoning. Treatment
The second-​generation drugs generally cause less sedation and less
Multiple-​dose activated charcoal increases quinine clearance.
psychomotor impairment, but some have been associated with
Extracorporeal elimination techniques and stellate ganglion block
cardiotoxicity causing QTc interval prolongation and ventricular
are of no value. Electrolyte and acid–​base disturbances and hypo-
tachycardia, including torsade de pointes.
glycaemia should be corrected. Hypertonic sodium bicarbonate will
Treatment correct acidosis that persists despite fluid resuscitation and adequate
oxygenation and is recommended first-​line therapy for conduction
A 12-​lead ECG and cardiac monitoring for at least 12 h is recom-
abnormalities due to sodium channel blockade, including QRS and
mended after a substantial overdose. Management should otherwise
QT prolongation. Overdrive pacing may be required if torsade de
follow the same principles as for tricyclic antidepressant poisoning
pointes occurs and does not respond to magnesium sulfate 1–2 g
(see earlier).
over 30–60 sec, repeated in 5–15 min.
Antimalarials: chloroquine
Antimalarials: Primaquine
Toxicity can result from doses greater than 1 g (c. 6 tablets) in adults.
Clinical features
Clinical features The main concern about primaquine is its ability to cause methaemo-
Cardiac arrest is commonly the first clinical manifestation of poi- globinaemia in overdose. Other adverse effects reported are head-
soning, but hypotension usually precedes it and may progress to ache, nausea, abdominal pain, haemolytic anaemia, particularly in
cardiogenic shock with pulmonary oedema. Electrocardiographic patients with glucose-​6-​dehydrogenase deficiency, and leucopenia.
1738 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Treatment Treatment
Treatment is supportive. Clinically significant methaemoglobin- The use of flumazenil is potentially hazardous in patients who
aemia (generally >30%) is treated conventionally with intravenous have co-​ingested proconvulsant drugs, particularly tricyclics, or
methylthioninium chloride (methylene blue), 1–​ 2 mg/​kg body who are habituated to benzodiazepines from therapeutic use (risk
weight. of acute withdrawal and fits). Flumazenil should therefore not be
used routinely in benzodiazepine poisoning, nor as a diagnostic test.
Antipsychotics It should be given to avoid assisted ventilation in a patient who is
Antipsychotic drugs are thought to act predominantly by effects on otherwise going to require intubation, particularly in those with ex-
dopamine D2 receptors. Older antipsychotics were phenothiazines, isting chronic airways obstruction. Flumazenil has a short half-​life
such as chlorpromazine, and butyrophenones, such as haloperidol. (40–​80 mins) and therefore repeated doses of 0.5–2 mg IV (or an
Selective (‘atypical’) antipsychotic drugs include amisulpride, infusion) may be required.
aripiprazole, clozapine, olanzapine, quetiapine, and risperidone.
Conventional antipsychotics have many actions, including anti- β-​Adrenoceptor blocking drugs (β-​blockers)
histamine and anticholinergic activity. Chlorpromazine blocks β-​adrenoceptor blocking drugs (β-​blockers) exert their toxic effects
α-​, β-​, and 5HT-​receptors in vitro. Features such as postural hypo- in overdose not only by blocking the β1-​and β2-​adrenoceptors, but
tension are likely to be due to the sum of these effects. also by virtue of their membrane stabilizing activity, which results in
a quinidine-​like effect on the action potential as a result of sodium
Clinical features channel blockade; this produces QRS widening, which predisposes
In overdose, the predominant clinical features of all antipsychotics to ventricular arrhythmias.
are sedation, loss of consciousness, and hypotension. Respiratory
depression may occur in more severe cases. Hypotension and vaso- Clinical features
dilatation are features of chlorpromazine poisoning. Some have Symptoms usually occur within 6 h of ingestion of non​sustained re-
caused QT prolongation in overdose. A 12-​lead ECG should be lease preparations. Sinus bradycardia may be the only feature after a
obtained to check QT duration. Occasionally seizures are reported. small overdose, but if a substantial amount has been ingested, coma,
ECG abnormalities have been seen with some of the newer atyp- convulsions (particularly with propranolol), profound bradycardia,
ical antipsychotics, but they cause less cardiovascular disturbance and hypotension may occur. Other effects include drowsiness, de-
than the older drugs. Muscle contraction due to central extra- lirium, hallucinations, low-​output cardiac failure and cardiorespira-
pyramidal effects may result in rhabdomyolysis in severe cases. tory arrest (asystole or ventricular fibrillation). Bronchospasm and
Neuroleptic malignant syndrome, seen during therapeutic use of hypoglycaemia occur rarely.
these compounds, is uncommon in acute poisoning and should be First-​
degree heart block, intraventricular conduction defects,
treated conventionally. right and left bundle branch block, ST segment elevation, ventricular
extrasystoles, and disappearance of the P-​wave may be noted on the
Treatment electrocardiogram. Sotalol has been reported to cause QT interval
Management is supportive. Dystonic reactions may occur, particu- prolongation and ventricular arrhythmias and asystole may follow
larly in young adults. These should be treated conventionally with severe overdose from any β-​adrenoceptor blocking drug.
procyclidine 5–​10 mg intravenously, or diazepam 10–​20 mg intra-
venously or orally. Treatment
A delay in treatment may be fatal in patients who are severely poi-
Benzodiazepines soned. The blood pressure and cardiac rhythm of the patient should
These are widely used as tranquillizers, hypnotics, sedatives, and for be monitored immediately in an intensive care area and supportive
emergency management of convulsions and hyperthermia. They measures implemented.
also have abuse potential. Glucagon is the drug of choice for severe hypotension; it bypasses
the blocked β-​receptor, thus activating adenyl cyclase and pro-
Clinical features moting the formation of cAMP (which has a direct β-​stimulant ef-
Although many benzodiazepines have active metabolites ac- fect on the heart) from adenosine triphosphate (ATP). It should be
counting for their sometimes-​prolonged sedative effects, all are given in a bolus dose of 50–​150 µg/​kg (typically 10 mg in an adult)
remarkably safe when taken in excess alone. However, there is in- over 1 min, followed by an infusion of 1–​5 mg/​h according to re-
dividual variation in response, influenced by habituation and tol- sponse. Conventional inotropes are less effective than glucagon in
erance, which develop during chronic therapy. Otherwise healthy severe cases.
elderly people may respond to an overdose with prolonged toxicity. If bradycardia is refractory to atropine 0.6–​1.2 mg intravenously,
Benzodiazepines potentiate the effects of other central nervous repeated as necessary, transcutaneous or transvenous pacing should
system depressants, particularly alcohol, tricyclic antidepressants, be considered. Sodium bicarbonate may reverse the cardiotoxic ef-
and barbiturates. Dizziness, drowsiness, ataxia, and slurred speech fects of β-​blockers with membrane stabilizing activity and should
are the usual features; coma, respiratory depression, and hypoten- be considered for the treatment of ventricular dysrhythmias.
sion are uncommon and usually mild. Flurazepam is most likely Occasionally, diazepam 10–​20 mg intravenously may be needed for
to cause significant central nervous system depression. Amnesia of convulsions. If bronchospasm supervenes, salbutamol (albuterol) by
events during the period of drug effect is also seen. nebulizer, should be employed. Hypoglycaemia should be corrected.
 10.4.1 Poisoning by drugs and chemicals 1739

β2-​Adrenoceptor agonists preparation has been ingested, the onset of severe features may be
Poisoning with β2-​adrenoceptor stimulants, including fenoterol, delayed for more than 12 h. Cardiac complications are usually more
pirbuterol, reproterol, rimiterol, salbutamol (albuterol), and ter- serious following overdose with verapamil or diltiazem than with
butaline, has followed deliberate and accidental ingestion of these the dihydropyridines, such as nifedipine and amlodipine. Large
drugs and has also resulted from confusion over the difference be- overdoses carry a poor prognosis, particularly in patients with is-
tween oral and parenteral doses. chaemic heart disease and in those taking β-​blockers.
β2-​agonists act on β2-​adrenergic receptors and increase intracel- Treatment
lular cAMP. In addition to initiating relaxation of bronchial, vas-
cular, and uterine smooth muscle, β2-​agonists cause glycogenolysis Calcium chloride (10%, 5–​ 10 ml at 1–​ 2 ml/​
min) or calcium
in skeletal muscle and hepatic glycogenolysis and gluconeogenesis. gluconate (10% solution) 10–​20 ml intravenously may reverse pro-
Hypokalaemia is caused by β2-​receptor-​mediated activation of longed intracardiac conduction times. If significant hypotension
Na+-​ K+-​ATPase, with extracellular potassium being shifted into persists despite volume replacement, intravenous glucagon 10 mg
the intracellular compartment; hypokalaemia may precipitate (150 µg/​kg) should be given to an adult and can be followed by
supraventricular and ventricular arrhythmias. an infusion 5–​10 mg/​h depending on response. If hypotension
persists, administer a sympathomimetic amine intravenously.
Clinical features Insulin–​dextrose euglycaemia has been shown to improve myo-
Tremor, sinus tachycardia, agitation, convulsions, supraventricular cardial contractility and systemic perfusion and may be used as an
and ventricular arrhythmias, hypokalaemia, hyperglycaemia, adjuvant to a sympathomimetic amine. There is some evidence that
and ketoacidosis are the typical features of severe poisoning with intravenous intralipid is useful in patients who do not respond to
β2-​agonists. Psychosis and hallucinations are observed occasionally. other measures. Cardiac pacing may have a role if there is evidence
of atrioventricular conduction delay, but there may be failure to
Treatment capture. Successful use of intra-​aortic balloon pumping, cardiac
Severe hypokalaemia should be corrected as soon as possible bypass, and extracorporeal membrane oxygenation (ECMO) have
by the administration of an infusion of potassium at a rate of been reported in extremely severe cases.
40–​60 mmol/​h diluted in 5% dextrose. A non​selective β-​blocker, Dapsone
such as propranolol 1–​5 mg by slow intravenous injection, will also
reverse hypokalaemia and tachyarrhythmias, but its use may ex- Dapsone is a sulfone antibiotic used in the management of leprosy
acerbate pre-​existing obstructive airways disease. Supraventricular and dermatitis herpetiformis.
tachycardia has been treated successfully with adenosine 6 mg IV. Clinical features
Convulsions are usually single and short-​lived but, if necessary,
diazepam, 10–​20 mg intravenously, may be given. Dapsone poisoning is potentially very severe, resulting in meth-
aemoglobinaemia, haemolysis, hepatitis, and central nervous system
Bismuth chelate (tripotassium dicitratobismuthate) effects including drowsiness, coma, and seizures.
Although bismuth absorption from bismuth chelate is low after Treatment
a therapeutic dose, a significant quantity may be absorbed after
overdose. Multiple-​dose activated charcoal increases dapsone elimination.
Methaemoglobin concentrations above 30% should be treated with
Clinical features methylthioninium chloride (methylene blue) 1–​2 mg/​kg intraven-
Self-​poisoning with large doses of bismuth chelate has caused re- ously. Dapsone-​induced methaemoglobinaemia may persist for sev-
versible renal failure. Bismuth encephalopathy has occurred fol- eral days necessitating repeated doses of methylthioninium chloride
lowing chronic excess ingestion. or an infusion. Haemodialysis enhances dapsone elimination and
has been used successfully in the management of life-​threatening
Treatment ingestions.
Chelation with unithiol or succimer enhances urine bismuth clear-
Digoxin and digitoxin
ance but there is no evidence that these agents prevent nephrotox-
icity. Extracorporeal renal support may be required for renal failure. Digoxin and digitoxin toxicity occurs in:

Calcium channel blockers • patients on regular therapy who gradually accumulate drug due to
excess dosing, or development of incipient renal impairment
Calcium channel blockers act by blocking voltage-​gated calcium
• patients who take a single, large overdose, both in those on chronic
channels at cardiac conducting and contractile tissue and vascular
therapy and those naïve to the drug
smooth muscle.
Interpretation of the clinical and biochemical features differs be-
Clinical features tween these situations.
In overdose, calcium channel blockers cause nausea, vomiting, In acute poisoning, the most significant feature normally seen
dizziness, slurred speech, confusion, sinus bradycardia and tachy- is bradycardia. Since digoxin acts on a Na+-​K+-​ATPase, and subse-
cardia, prolonged atrioventricular conduction, atrioventricular dis- quent changes in the myocardium develop following this, onset of
sociation, hypotension, pulmonary oedema, convulsions, coma, the effects of digoxin in overdose may take up to 12 h. In very large
hyperglycaemia, and metabolic acidosis. When a sustained release overdoses, however, severe features may develop sooner than this,
1740 SECTION 10 Environmental medicine, occupational medicine, and poisoning

although in clinical practice very large overdoses are uncommon. diuretic and potassium formulations are ingested, the potassium
Because of the action on Na+-​K+-​ATPase, the serum potassium content is likely to pose the greater risk. More serious consequences
concentration increases, and a very high serum potassium concen- are likely if a potassium-​sparing diuretic has been ingested.
tration is therefore a useful, rapidly measurable marker for severe di-
goxin poisoning. Measurement of the plasma digoxin concentration Clinical features
will confirm the diagnosis. This is particularly the case in patients on Symptoms and signs of toxicity include anorexia, nausea, vomiting,
chronic therapy who may have less dramatic changes in serum po- diarrhoea, profound diuresis, dehydration, and hypotension. In
tassium, perhaps because of coexistent diuretic therapy, and where addition, dizziness, weakness, muscle cramps, tetany and, occasion-
clinical features may be more predominantly tachycardias. ally, gastrointestinal bleeding may be seen. The electrolyte and meta-
Patients require treatment for cardiovascular compromise, not bolic disturbances that may be observed include hyponatraemia,
for blood concentrations. In acute poisoning, blood concentrations hypoglycaemia or hyperglycaemia, hyperuricaemia, hypokalaemia,
may rise to quite high values (above 5 µg/​litre) without necessarily and metabolic alkalosis. Hyperkalaemia develops following the
causing severe clinical features. These rises may be transient as ingestion of combined diuretic and potassium preparations and
the drug redistributes into fatty stores after absorption. In chronic potassium-​sparing diuretics, such as amiloride, spironolactone, or
therapy, plasma concentrations give a better indication of the quan- triamterene. Small-​bowel ulceration and stricture formation have
tities of digoxin present in the body, and in acute overdose several followed poisoning due to diuretics with an enteric-​coated core of
plasma concentration measurements may need to be taken over a potassium chloride.
short period to assess the dose absorbed.
Treatment
Clinical features Symptomatic and supportive therapy should be employed with
Nausea, vomiting, and bradycardia may occur. Sinus bradycardia correction of fluid and electrolyte imbalance. Patients with severe
is the most important and earliest feature in acute poisoning. hyperkalaemia may need a glucose and insulin infusion followed by
Malignant ventricular arrhythmias are seen in patients with severe oral or rectal administration of an ion-​exchange resin.
poisoning. At high doses, central nervous system features including
drowsiness and hallucinations may be present. Iron
Most medicinal preparations of iron are as the ferrous salt. Ferrous
Treatment iron is oxidized to the ferric state before being absorbed. It is im-
In patients who are vomiting, the airway needs to be protected, portant to differentiate vitamin preparations that contain iron
and consideration should be given to administering charcoal later from medicinal preparations, since the former generally do not
than 1 h in patients who have ingested significant quantities, as cause significant clinical problems unless very large amounts are
this is such a toxic compound. The temptation to treat moderate taken. Since iron toxicity is quite closely related to dose per kilo-
hyperkalaemia should be resisted, as this will interfere with moni- gram ingested, serious poisoning is more likely to occur in young
toring clinical response. Patients should be treated on the basis children than in adults. The anticipated toxicity of iron is nor-
of their cardiovascular status, not the plasma concentrations of mally estimated by calculating the dose of elemental iron present
digoxin alone. in the preparation, which varies from salt to salt. Ingestions above
Patients with bradycardia who are symptomatic should receive 150 mg/​kg of elemental iron are generally extremely severe and
atropine and have any acid–​base disturbance corrected. In patients may be fatal.
with significant bradycardia or malignant ventricular arrhythmias, Iron salts are both locally corrosive within the gastrointestinal
the most effective therapy is neutralization of digoxin with digoxin tract and in the cell act as cellular toxins, probably by altering the
antibody. Doses of antibody recommended by the manufacturers function of mitochondria. In severe poisoning, patients are uncon-
are designed to completely neutralize all digoxin present in the pa- scious and suffer from circulatory collapse and hepatic injury.
tient. Such an approach is unwarranted, particularly in patients on
chronic therapy with digoxin in whom complete reversal of digoxin Clinical features
will unmask the disorder for which they are being treated. Initially, Depending on the severity of poisoning features may vary, and in
half the calculated total neutralizing dose should be given. Further severe cases, features would be expected within the first 6 h and
doses can be given subsequently, if necessary. include nausea, vomiting, and abdominal pain. Iron will stain the
In patients who receive the antibody, clinical improvement will vomit and faeces (diarrhoea) and may also cause intestinal ulcer-
occur rapidly, usually within 20 min. Failure to respond indicates ation and result in haemorrhage. Large amounts of iron may be vis-
either an incorrect diagnosis or continued absorption of digoxin. ible on a straight abdominal radiograph, but this should not be done
Measurement of serum digoxin concentration is not possible once routinely to confirm iron ingestion in children.
the digoxin antibody has been administered, since currently avail- Following absorption of iron there is often a period of relative calm
able assays measure both bound and free compound. Extracorporeal during which iron is taken into cells before its toxic effects mani-
elimination techniques are ineffective in removing digoxin though fest. In severe poisoning, profound hypotension, metabolic acidosis,
multiple-​dose activated charcoal may increase elimination. coma, and features of hepatic necrosis and renal failure ensue. Such
patients require intensive supportive care and mortality rates are
Diuretics high. In patients who recover from severe poisoning, gut strictures
Most diuretic overdoses are minor, although inevitably some dis- following scarring from ulceration may be problematic. The com-
turbance of fluid and electrolyte balance will result. When combined monest site is around the pylorus, particularly in young children.
 10.4.1 Poisoning by drugs and chemicals 1741

Treatment (lactic) acidosis is common. Less commonly, hyperglycaemia, keto-

Although dose is related to toxicity, patients may be sometimes in- acidosis, glycosuria, and ketonuria are found.
accurate in their history, and since vomiting is a frequent early fea- Treatment
ture it may be difficult to assess exactly how much iron has been
Supportive measures, including the correction of metabolic acid-
absorbed. Plasma concentration measurements on more than one
osis, should be instituted immediately if the patient is unconscious.
occasion may assist this process. High serum iron concentrations
Pyridoxine 1 g for 1 g of isoniazid ingested should be given intra-
(>90 micromol/litre or 5 mg/​litre) in the first 4–​6 h after overdose are
venously to control convulsions. When the ingested dose of iso-
more likely to indicate severe poisoning. In this situation, iron will
niazid is unknown, an initial intravenous dose of pyridoxine 5 g
be circulating free in plasma and may result in toxicity.
should be given. Due to the mechanism of toxicity, diazepam alone
As iron does not bind to charcoal, patients who present early
may be ineffective but the use of diazepam and pyridoxine is syner-
with suspected large iron ingestions should be considered for
gistic and both should be used for convulsions. Pyridoxine 5 g may
gastric aspiration or lavage, though in practice this is rarely per-
be repeated if convulsions persist (in one case 52 g pyridoxine was
formed since vomiting is a prominent early feature in these cases.
given intravenously without ill effects).
Whole-​bowel irrigation has been advocated following ingestion
of slow-​release iron preparations, though data on its efficacy is an- Lithium carbonate
ecdotal. In patients with significant elevated iron concentrations Lithium carbonate remains the drug of choice for the treatment of
(>90 micromol/​litre or 5 mg/litre) and features suggestive of sig- recurrent bipolar illness. It has a low therapeutic index and toxicity
nificant poisoning, the specific iron-​chelating agent deferoxamine is usually the result of therapeutic overdosage (chronic toxicity) ra-
(desferrioxamine) should be administered intravenously. There are ther than deliberate self-​poisoning (acute toxicity). Chronic tox-
few human data to support the usual dose regimen of deferoxamine icity is usually explained by a reduction in lithium renal clearance
15 mg/​kg/​h up to a maximum of 80 mg/​kg, which binds relatively without a reduction in dose. Single large doses are occasionally in-
little elemental iron. gested by individuals on long-​term treatment with the drug (acute
Toxicity with reported during its use in the management of chronic on therapeutic toxicity).
disorders, such as haemachromatosis and haemoglobinopathies,
is not a feature of its use in the management of iron poisoning Clinical features
and should not, therefore, be used as a guide to limit dosing in Features of intoxication include thirst, polyuria, diarrhoea, and
severe cases. Deferoxamine may cause hypotension and there are vomiting, and, in more serious cases, tremor, impairment of con-
occasional reports of anaphylactoid reactions. Once deferoxamine sciousness, hypertonia, and convulsions; irreversible neurological
has been administered, interpretation of iron concentrations damage may occur. Measurement of the serum lithium concentra-
becomes impossible because the iron bound to deferoxamine is tion confirms the diagnosis. Chronic toxicity is usually associated
detected in the laboratory assay. Iron-deferoxamine complex col- with concentrations above 1.5 mmol/​litre. However, acute massive
ours urine red. overdosage may produce much higher concentrations without
Patients who have not developed features of poisoning within causing toxic features, at least initially. This is explained by plasma
6 h have probably not ingested very large quantities of iron, unless lithium concentrations that are substantially higher than cen-
they have taken a slow-​release product. Most patients merely re- tral nervous system lithium concentrations before distribution is
quire treatment for their gastrointestinal disturbance. Since iron complete.
preparations are more commonly given to women who are preg-
nant than other groups of the population, iron overdose may be Treatment
seen more frequently in pregnant women. There is currently no Activated charcoal does not adsorb lithium. Treatment is sup-
evidence to suggest these patients should be treated differently portive together with measures to enhance the rate of lithium
because of pregnancy, and deferoxamine, should certainly not be elimination. Haemodialysis should be considered if neurological
withheld in patients who are deemed to require it. features are present, if renal function is impaired and if chronic
toxicity or acute on therapeutic toxicity are the modes of presen-
Isoniazid
tation. The efficacy of haemodialysis is limited by the relatively
Poisoning with isoniazid is potentially very serious, but uncommon. slow movement of lithium ions across cell membranes. It is easy
Isoniazid depresses brain concentrations of γ-​aminobutyric acid to reduce serum lithium concentrations, but they frequently re-
(GABA), thus leading to seizures. bound when treatment is stopped and clinical improvement is
much slower. Repeated haemodialysis sessions are usually re-
Clinical features
quired. Continuous haemodialfiltration can be used if conventional
The ingestion of isoniazid 80–​150 mg/​kg body weight is likely to haemodialysis is not available, though clearance of lithium is less
cause severe poisoning. Nausea, vomiting, slurred speech, dizzi- efficient.
ness, and visual hallucinations may develop. Stupor, coma, and con-
vulsions follow rapidly and may be associated with hyperthermia, Nitrates
hyperreflexia, extensor plantar responses and, later, rhabdo- Organic nitrates such as isosorbide mononitrate and isosorbide
myolysis. In addition, dilated pupils, sinus tachycardia, and urinary dinitrate are vasodilators that act by relaxing vascular smooth
retention may be observed. In severe cases, hypotension, acute muscle. These drugs are essentially nitric oxide donors, which in-
renal failure, and respiratory failure may ensure. Marked metabolic crease nitric oxide-​induced activation of guanylate cyclase with
1742 SECTION 10 Environmental medicine, occupational medicine, and poisoning

subsequent elevation of cGMP concentrations. Their effects in over- Clinical features

dose are directly related to their therapeutic actions. These drugs Most NSAIDs cause only nausea except in severe cases. Mefenamic
undergo extensive first pass metabolism in the liver. Exposure to in- acid is an exception and produces nausea, vomiting and, occasion-
organic nitrates is principally via drinking water. ally, bloody diarrhoea; drowsiness, dizziness and headaches are
Clinical features common; and hyperreflexia, muscle twitching, convulsions, cardio-
respiratory arrest, hypoprothrombinaemia, and acute renal failure
The symptoms and signs caused by pharmaceutical nitrates in have also been reported.
overdose are due primarily to excessive arteriolar and venous
dilatation. Headache and vomiting are common, accompanied Treatment
by flushing of the skin and dizziness. Sinus tachycardia, severe
Treatment of poisoning with NSAIDs is generally supportive. It is
orthostatic hypotension, and syncope may develop. Convulsions
important to check renal function at an interval after ingestion in
and coma may be seen in severely poisoned patients. In contrast
patients who have ingested large doses. Changes in serum potas-
to poisoning by inorganic nitrates, methaemoglobinaemia is seen
sium and elevations in serum creatinine concentrations are to be
very rarely with organic nitrates. Methaemoglobinaemia caused by
expected in patients ingesting toxic doses. Treatment of renal im-
inorganic nitrates is in fact due to conversion of nitrate to nitrite
pairment is conventional. Dialysis may be required in very severe
by gastrointestinal bacteria, following ingestion. This is encoun-
cases. Activated charcoal should only be considered in patients who
tered primarily among infants bottle-​fed with formula milk that
have ingested very large doses of non​steroidals (generally >20 tab-
has been made up with water with high nitrate content.
lets). Convulsions with mefenamic acid are unlikely to be persistent
Treatment but, if they are, should be managed by diazepam 10–​20 mg intra-
venously or lorazepam ​4 mg intravenously.
Treatment is supportive. Methaemoglobin concentrations exceed­
ing 30% should be treated with intravenous methylthioninium Opiates and opioids
chloride (methylene blue) 1–​2 mg/​kg.
See section later on in this chapter, ‘Opiates and opioids’.
Non​steroidal anti-​inflammatory drugs
Paracetamol (acetaminophen)
These include a variety of different groups of drugs, all acting by
inhibition of cycloxygenase enzymes. The newer, so-​ called Mechanisms of toxicity
selec­tive, agents are thought to inhibit the inducible form of The toxicity of paracetamol is related to its metabolism
cycloxygenase (COX-​2) more than the other forms of the enzyme. (Fig. 10.4.1.1). In therapeutic doses, 60–​90% is metabolized by
These drugs, therefore, all tend to inhibit prostaglandin synthesis, conjugation to form paracetamol glucuronide and sulphate.
and the main toxicity seen in overdose is on the kidney. In very A much smaller amount (5–​10%) is oxidized by mixed function
large doses, central nervous system effects may be seen but these oxidase enzymes to form a highly reactive compound (N-​acetyl-​
are uncommon. p-​benzoquinoneimine, NAPQI), which is then immediately con-
Non​ steroidal anti-​
inflammatory drugs (NSAIDs) come in jugated with glutathione and subsequently excreted as cysteine
different chemical groupings: oxicams (meloxicam, piroxicam,
­ and mercapturate conjugates. Only 1–​4% of a therapeutic dose of
tenoxicam) and phenylpropionic (arylpropionic) acid derivatives the drug is excreted unchanged in urine.
(e.g. fenbufen, ibuprofen, naproxen, tiaprofenic acid, mefenamic In overdose, larger amounts of paracetamol are metabolized
acid). The COX-​2 selective agents are also potentially nephrotoxic in by oxidation because of saturation of the sulphate conjugation
overdose due to inhibition of renal prostaglandin synthesis. pathway. As a result, liver glutathione stores become depleted so

NHCOCH3 NHCOCH3
NHCOCH3
GSH
δ+ GSH
O O
OSO3H NHCOCH3
N-Acetyl-p-benzoquinone- Glutathione conjugate
Paracetamol imine (NAPQI)
sulphate

OH NHCOCH3 NHCOCH3
NHCOCH3
Paracetamol
NHCOCH3
SCH2CHCO2H SCH2CHCO2H
OH OH
OC6H9O6
Paracetamol Cysteine conjugate
Paracetamol mercapturic acid
glucuronide

Fig. 10.4.1.1 Metabolism of paracetamol.

 10.4.1 Poisoning by drugs and chemicals 1743

that the liver is unable to deactivate the toxic metabolite. NAPQI is Table 10.4.1.6 Biochemical and haematological abnormalities
believed to have two separate but complementary effects. in paracetamol poisoning
Firstly, it reacts with glutathione, thereby depleting the cell of its
Biochemical abnormalities Haematological abnormalities
normal defence against oxidizing damage. Secondly, it is a potent
AST/​ALT ↑↑ PT ↑
oxidizing as well as arylating agent; it inactivates key sulphydryl
groups in certain enzymes, particularly those controlling calcium Bilirubin ↑ Platelets ↓
homeostasis. Blood sugar ↓ Clotting factors II ↓ V ↓ VII ↓
Paracetamol-​ induced renal damage probably results from a Creatinine ↑
mechanism similar to that causing for hepatotoxicity (i.e. by for- Lactate ↑
mation of NAPQI).
Phosphate ↓
As would be expected from the mechanism of toxicity, the severity
Amylase ↑
of paracetamol poisoning is dose related. An absorbed dose of 15 g
(200 mg/​kg) or more is potentially serious in most patients. There is, Potassium ↓ early due to kaluresis
↑ later in renal failure
however, some variation in individual susceptibility to paracetamol-​
induced hepatotoxicity. Those with a high alcohol intake and poor nu-
trition, and those suffering from anorexia nervosa or acute starvation
have glutathione depletion and are at higher risk. Individuals hepatic damage and in a few without evidence of serious disturb-
with HIV-​related disease also appear to be more susceptible to ance of liver function. Other features, including hypoglycaemia
paracetamol-​induced hepatic damage. Those receiving enzyme-​ and hyperglycaemia, cardiac arrhythmias, pancreatitis, gastrointes-
inducing drugs are also at greater risk. tinal haemorrhage, and cerebral oedema may all occur with hepatic
failure due to any cause and are not direct consequences of para-
Clinical features cetamol toxicity.
The features of paracetamol poisoning are summarized in Table Paracetamol can cause metabolic acidosis at two distinct periods
10.4.1.5. Biochemical and haematological abnormalities may also after overdosage. Transient hyperlactataemia is frequently found
occur (Table 10.4.1.6). within the first 15 h in all but minor overdoses and appears to be
Following the ingestion of an overdose of paracetamol, patients due to inhibition of mitochondrial respiration at the level of ubi-
usually remain asymptomatic for the first 24 h, or at most develop quinone and increased lactate production. It is rarely of clinical con-
anorexia, nausea, and vomiting. Paracetamol-​induced kaluresis sequence, although in very severe paracetamol poisoning (plasma
may cause hypokalaemia. Liver damage is not usually detectable paracetamol concentration >500 mg/​ litre at 4 h after ingestion)
by routine liver function tests until at least 12 h after ingestion of the acidosis may be very rarely associated with coma. The second
the drug, and hepatic tenderness and abdominal pain are seldom phase of hyperlactataemia and acidosis occurs in those patients who
exhibited before the second day. Liver damage reaches a peak, as present late and go on to develop hepatic damage; in this instance,
assessed by plasma alanine or aspartate aminotransferase (ALT, decreased hepatic lactate clearance appears to be the major cause,
AST) activity or prothrombin time (international normalized ratio, compounded by poor peripheral perfusion and increased lactate
INR), 72–​96 h after ingestion. More often there is prolongation of production.
the prothrombin time and a marked rise in aminotransferase ac- Hypophosphataemia is a recognized complication of acute liver
tivity (activities of several thousand are not uncommon) without failure, including that due to paracetamol, and may contribute
the development of fulminant hepatic failure. Renal failure due to to morbidity and mortality by inducing mental confusion, irrit-
acute tubular necrosis develops in about 25% of patients with severe ability, coma, and abnormalities of platelet, white cell, and erythro-
cyte functions. Phosphaturia appears to be the principal cause of
hypophosphataemia in paracetamol poisoning; it may occur in the
absence of fulminant hepatic failure and indicates paracetamol-​
Table 10.4.1.5 Clinical features of untreated paracetamol induced renal tubular damage.
poisoning (>200 mg/​kg)
Prediction of liver damage
Day 1 Day 2 Day 3
In the early stages following ingestion of a paracetamol overdose,
Asymptomatic May become (in severe untreated
asymptomatic or develop poisoning) most patients have few symptoms and no physical signs. There is
symptoms de novo thus a need for some form of assessment that estimates the risk of
Nausea Vomiting Jaundice → liver failure → liver damage at a time when the liver function tests are still normal.
hepatic encephalopathy Details of the dose ingested may be used but, in many cases, the his-
Vomiting Hepatic tenderness ± Back pain + renal angle tory is unreliable and, even when the dose is known for certain, it
generalized abdominal tenderness → renal failure does not take account of early vomiting and individual variation in
tenderness
response to the drug.
Abdominal pain Occasionally, mild Cardiac arrhythmias However, a single measurement of the plasma paracetamol con-
jaundice
centration is an accurate predictor of liver damage provided that it is
Anorexia Disseminated intravascular taken not earlier than 4 h after ingestion of the overdose. Information
coagulation
gained from several studies has enabled the production of graphs
Pancreatitis
which may be used for prediction of liver damage and which serve as
1744 SECTION 10 Environmental medicine, occupational medicine, and poisoning

a guide to the need for specific treatment (Fig. 10.4.1.2). These may Prognostic factors
not be accurate with slow-​release products. The overall mortality of paracetamol poisoning in untreated pa-
In patients who have taken several overdoses of paracetamol over tients is only of the order of 5%. A rise in transaminase (ALT/​AST)
a short period of time, the plasma paracetamol concentration will be activity is usually the first liver function test to become abnormal,
meaningless in relation to the treatment graph. Such patients should but a rise in INR is of particular value in assessing the prognosis
be considered at risk and treated. Patients who regularly consume al- of an individual patient. The more rapid the increase in ALT and
cohol in excess of currently recommended limits (particularly those INR, the worse the prognosis of the patient. A prothrombin time
who are malnourished), those who regularly take enzyme-​inducing of more than 20 s at 24 h after ingestion indicates that significant
drugs (e.g. carbamazepine, phenytoin, phenobarbital, and rifam- hepatic damage has been sustained, and a peak prothrombin time
picin) and those with conditions causing glutathione depletion (e.g. of more than 180 s is associated with a chance of survival of less
malnutrition and HIV infection) may be at risk of liver damage. than 8%.
Studies in the early 1970s showed that 60% of patients whose Acid–​base disturbances are also a good guide to prognosis.
plasma paracetamol concentration was above the line drawn between Systemic acidosis developing more than 24 h after overdose in-
200 mg/​litre (1.32 mmol/​litre) at 4 h and 50 mg/​litre (0.33 mmol/​ dicates a poor prognosis; patients with a blood pH below 7.30
litre) at 12 h after the ingestion of the overdose were likely to sustain at this time have only a 15% chance of survival. In addition, a
liver damage (ALT or AST >1000 u/​litre), unless specific protective rise in the serum creatinine concentration is associated with
treatment were given. poor survival; patients with a serum creatinine concentration
There are now two approaches to risk management used world- above 300 µmol/​litre have only a 23% chance of survival. A study
wide. In the United Kingdom, following a decision by the MHRA in of prognostic indicators in patients who died of paracetamol-​
2012 to abandon a detailed risk assessment in the decision to treat, induced fulminant hepatic failure treated conventionally com-
it is deemed that patients with concentrations above a ‘treatment pared measurement of factors V and VIII with conventional tests.
line’ starting at 100 mg/​litre (0.66 mmol/​litre 4 h after ingestion An admission pH below 7.30 with a serum creatinine concentra-
(Fig. 10.4.1.2) require therapy with antidote. In North America and tion above 300 µmol/​litre and a prothrombin time above 100 s
Australasia, a parallel line starting at 150 mg/​litre 4 h after ingestion in patients with grade III–​IV encephalopathy had a sensitivity,
is used. The MHRA decision aims to prevent one death in the United predictive accuracy, positive prediction value, and specificity of
Kingdom approximately every 2.1 years, and has been criticized as 91, 86, 83, and 91%, respectively. However, a factor VIII/​V ratio
being too cautious and resulting in many unnecessary treatments. above 30 had comparable values of 91, 95, 100, and 100%. Novel
Patients who ingest multiple overdoses, or take repeated thera- biomarkers (e.g. microRNAs) are now being studied which may
peutic excess, are at greater risk of liver damage and decisions to give an earlier more accurate risk assessment than is possible
treat them are generally based on dose ingested. Current UK advice with conventional approaches.
is very conservative with a treatment cut-​off of paracetamol dose
above 75 mg per kilogram in 24 h. Treatment
Consider administering activated charcoal for patients presenting
within 1 h of overdose. Parenteral fluid replacement should be given
if nausea persists or vomiting occurs.
Paracetamol nomograms Patients who have taken staggered overdoses should be treated
240 1.6 with an antidote irrespective of the plasma paracetamol concentra-
1.5
tions. They can be discharged after antidotal treatment, provided
Plasma paracetamol concentration (mmol/litre)

220
Plasma paracetamol concentration (mg/litre)

Original ‘200 mg’ Line 1.4

200 1.3
they are asymptomatic and the INR, plasma creatinine concentra-
International ‘150 mg’ Line
180 UK ‘100 mg’ Line 1.2 tion, and ALT activity are normal.
160 1.1 Patients who present 15 h or more after overdose tend to be more
1.0 severely poisoned and at greater risk of developing serious liver
140 0.9 damage and should receive antidotal treatment as the plasma con-
120 0.8 centration alone may not be an accurate guide of severity; it may be
0.7
100 non​detectable at the time of late presentation. The INR, venous pH,
0.6
80 0.5 plasma creatinine concentration, and liver function tests are helpful
60 0.4 in determining prognosis.
40 0.3
0.2 Acetylcysteine
20 0.1 Acetylcysteine acts by replenishing cellular glutathione stores and
0 0.0
0 2 4 6 8 10 12 14 16 18 20 22 24
may also repair oxidation damage caused by NAPQI either directly
Time (hours) or, more probably, through the generation of cysteine and/​or gluta-
thione. It may also act as a source of sulphate and so ‘unsaturate’
Fig. 10.4.1.2 Paracetamol treatment nomograms. Those above the sulphate conjugation.
treatment lines are regarded at risk and treated with acetylcysteine.
Thresholds differ in different countries, the ‘100 mg’ line being used in the Two principal regimens for acetylcysteine have been em-
United Kingdom. There is a scarcity of data after 15 h and the dotted lines ployed. The most widely utilized worldwide is a 21-​h protocol
show extrapolations used in clinical practice. (Table 10.4.1.7); the oral protocol previously used in the United
 10.4.1 Poisoning by drugs and chemicals 1745

Table 10.4.1.7 Dosing regimen for acetylcysteine (21 h regimen) Aspirin

• 150 mg/​kg over 60 min, then 50 mg/​kg over the next 4 h and 100 mg/​kg Hydrolysis
over the next 16 h
• Total dose, 300 mg/​kg over 21 h Salicylic acid

Conjugation Hydroxylation Conjugation with

with glucuronic acid
States being replaced by IV therapy. An alternative 12 h IV glycine
protocol (100 mg/​kg over 2h, 200 mg/​kg over 10 h) that is associ- Gentisic acid
ated with far fewer antidote-​induced adverse events is also being
employed. Salicyluric Salicylacyl Salicylphenolic
Provided that acetylcysteine is administered within 8–​10 h of acid glucuronide glucuronide
overdose, the development of hepatic damage is normally pre-
Fig. 10.4.1.3 Metabolism of aspirin.
vented; thereafter, the protective effects decline rapidly. Up to
10% of patients treated with intravenous acetylcysteine (20–​21 ​h
regimen) develop rash, angioedema, hypotension, and broncho- salicyluric acid and salicylphenolic glucuronide (Fig. 10.4.1.3) is
spasm. Far higher proportions (up to 70%) develop nausea and saturable with the following clinical consequences: (1) the time
vomiting, with treatment required in up to 30%. These reactions, needed to eliminate a given fraction of a dose increases with
which are due to the initial bolus, cause very few fatalities but cause increasing dose; (2) the steady state plasma concentration of sa-
treatment interruption and patient distress. Anaphylactoid reac- licylate, particularly that of the pharmacologically active non-​
tions are far more common at lower paracetamol concentrations, so protein-​bound fraction, increases more than proportionately with
more aggressive use of the antidote increases the incidence of these increasing dose; and (3) renal excretion of salicylic acid becomes
reactions. Antihistamines, such as chlorpheniramine and broncho- increasingly important; a pathway which is extremely sensitive to
dilators (e.g. salbutamol), may be given if such anaphylactoid reac- changes in urinary pH.
tions do occur, but discontinuing the infusion temporarily may be When ingested in overdose, salicylates directly stimulate the re-
all that is required. spiratory centre to produce both increased depth and rate of res-
piration, thereby causing a respiratory alkalosis (Fig. 10.4.1.4). At
Management of severe liver damage least part of this effect is due to local uncoupling of oxidative phos-
A 10% glucose solution should be administered to prevent the phorylation within the brainstem. In an attempt to compensate,
onset of hypoglycaemia. If fulminant hepatic failure supervenes, bicarbonate, accompanied by sodium, potassium, and water, is
the use of a continued intravenous acetylcysteine (the 16-​h infu- excreted in the urine resulting in dehydration and hypokalaemia.
sion is continued until recovery or death) will reduce morbidity More importantly, the loss of bicarbonate diminishes the buffering
and mortality. capacity of the body and allows an acidosis to develop more easily.
In one prospective study, the survival rate in 25 patients with Very high salicylate concentrations in the brain depress the re-
paracetamol-​induced fulminant hepatic failure was 20%, with an in- spiratory centre and may further contribute to the development
cidence of cerebral oedema and of hypotension requiring inotropic of acidaemia.
support of 68 and 80%, respectively. With acetylcysteine, the com- Simultaneously, a variable degree of metabolic acidosis develops,
parable figures in 25 matched patients were 48% (survival rate), 40% not only because of the presence of salicylic acid itself, but also be-
(cerebral oedema), and 48% (hypotension). cause of interference with carbohydrate, lipid, protein, and amino
A proton pump inhibitor will reduce the risk of gastrointestinal acid metabolism by salicylate ions (Fig. 10.4.1.4). Inhibition of
bleeding from ‘stress’ ulceration/​erosion. There is no evidence that citric acid cycle enzymes causes an increase in circulating lactic
fresh frozen plasma prevents gastrointestinal haemorrhage in pa- and pyruvic acids. Salicylates stimulate fat metabolism and cause
tients with severe coagulation abnormalities (prothrombin time increased production of the ketone bodies, β-​hydroxybutyric acid,
>100 s). If acute renal failure supervenes, then this should be man- acetoacetic acid, and acetone. Dehydration and lack of food intake,
aged conventionally. because of vomiting, further contribute to the development of ke-
Liver transplantation has been performed successfully in patients tosis. Protein catabolism is accelerated and synthesis diminished.
with paracetamol-​induced fulminant hepatic failure. Aminotransferases (responsible for the interconversion of amino
acids) are inhibited. Increased circulating blood concentrations of
Salicylates amino acids result, together with aminoaciduria; inhibition of active
Salicylate poisoning may result from overdose of aspirin tablets, per- tubular reabsorption of amino acids also contributes. Aminoaciduria
cutaneous absorption of salicylic acid (used in keratolytic agents), increases the solute load on the kidneys and, thereby, increases water
and ingestion of methyl salicylate (‘oil of wintergreen’). loss from the body.
In therapeutic doses, aspirin is absorbed rapidly from the stomach A primary toxic effect of salicylates in overdose is uncoupling
and small intestine, but in overdose, absorption may occur more of oxidative phosphorylation (Fig. 10.4.1.4). ATP-​dependent re-
slowly, and plasma salicylate concentrations may continue to rise actions are inhibited, and oxygen utilization and CO2 production
for up to 24 h. are increased. Energy normally used for the conversion of inorganic
The pharmacokinetics of elimination of aspirin are important phosphate to ATP is dissipated as heat. Hyperpyrexia and sweating
determinants of salicylate toxicity. Biotransformation to both result, causing further dehydration. Fluid loss is enhanced because
1746 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Hyperglycaemia Catecholamines Tissue glycolysis Hypoglycaemia Neuroglycopenia

Glucocorticoids

Uncoupling of Stimulation of Depression of Respiratory

Hepatic glycogenolysis oxidative lipid metabolism respiratory acidosis
phosphorylation centre
Stimulation of O2 consumption Ketone body Inhibition of
respiratory centre CO2 production formation Krebs cycle
Hyperpyrexia Circulating enzymes
and sweating pyruvic and
Respiratory rate lactic acid
Buffering levels
capacity Circulating
Respiratory HCO3−(and Na+ Metabolic acidosis amino-acid
alkalosis K+and H2O) excretion levels

Cardiac Renal clearance of Inhibition of

output sulphuric and amino acid
phosphoric acids metabolism
Stimulation of Vomiting and
chemoreceptor Dehydration and
decreased oral Aminoaciduria
trigger zone electrolyte imbalance
fluid intake

Fig. 10.4.1.4 Pathophysiology of salicylate poisoning.

salicylates stimulate the chemoreceptor trigger zone and induce concentrations that lie between 300–​500 mg/​litre some 6 h after in-
nausea and vomiting and, thereby, diminish oral fluid intake. If de- gestion of an overdose are associated with only mild toxicity, concen-
hydration is sufficiently marked, low cardiac output and oliguria will trations between 500 and 700 mg/​litre are associated with moderate
aggravate the metabolic acidosis already present which, if severe, toxicity, and concentrations in excess of 700 mg/​litre confirm severe
can itself diminish cardiac output. poisoning.
Glucose metabolism also suffers as a result of uncoupled oxi- Salicylate poisoning of any severity is associated with sweating,
dative phosphorylation because of increased tissue glycolysis vomiting, epigastric pain, tinnitus, and deafness (Table 10.4.1.8).
and peripheral demand for glucose (Fig. 10.4.1.4). This is seen Young children quickly develop metabolic acidosis following
principally in skeletal muscle and may cause hypoglycaemia. the ingestion of aspirin in overdose, but by the age of 12 years the
The brain appears to be particularly sensitive to this effect and usual adult picture of a combined dominant respiratory alkalosis
neuroglycopenia can occur in the presence of a normal blood and mild metabolic acidosis is seen. To some extent, the presence
sugar level when the rate of utilization exceeds the rate at which of an alkalaemia protects against serious salicylate toxicity because
glucose can be supplied from the blood. Increased metabolism salicylate remains ionized and unable to penetrate cell membranes
and peripheral demand for glucose activates hypothalamic easily. Development of acidaemia allows salicylates to penetrate tis-
centres, resulting in increased adrenocortical stimulation and re- sues more readily and leads, in particular, to central nervous system
lease of adrenaline. Increased glucose 6-​phosphatase activity and toxicity characterized by excitement, tremor, delirium, convulsions,
hepatic glycogenolysis contribute to the hyperglycaemia, which is stupor, and coma. Very high plasma salicylate concentrations cause
sometimes seen following ingestion of large amounts of salicylate.
Increased circulating adrenocorticosteroids exacerbate fluid and
electrolyte imbalance.
Table 10.4.1.8 Clinical features of salicylate poisoning
Although this is rarely a practical problem, salicylate intoxi-
cation may be accompanied by hypoprothrombinaemia due to a • Nausea, vomiting, and epigastric discomfort
warfarin-​like action of salicylates on the physiologically important
• Irritability, tremor, tinnitus, deafness, blurring of vision
vitamin K epoxide cycle. Vitamin K is converted to vitamin K
2,3-​epoxide and then reconverted to vitamin K by a liver mem- • Hyperpyrexia, sweating, dehydration
brane reductase enzyme, which is competitively inhibited by war- • Tachypnoea and hyperpnoea
farin and salicylates. • Non​cardiogenic pulmonary oedema
Clinical features and assessment of severity of salicylate • Acute renal failure
intoxication • Mixed respiratory alkalosis and metabolic acidosis (except in children who
usually develop metabolic acidosis alone)
The dose of salicylate ingested and the age of the patient are the
principal determinants of the severity of an overdose. The plasma • Hypokalaemia, hypernatraemia, or hyponatraemia
salicylate concentration should be determined on admission, but it • Hyperglycaemia or hypoglycaemia
is important to repeat it 2 h later to ensure that the concentration
• Hypoprothrombinaemia (rare)
is not rising. If the concentration has risen, the level should be re-
peated after a further 2 h. Generally speaking, plasma salicylate • Confusion, delirium, stupor, and coma (in severe cases)
 10.4.1 Poisoning by drugs and chemicals 1747

paralysis of the respiratory centre and cardiovascular collapse due to Clinical features
vasomotor depression. Symptoms include nausea, vomiting, hyperventilation, haematem-
Pulmonary oedema is seen occasionally in salicylate poisoning esis, abdominal pain, diarrhoea, sinus tachycardia, supraventricular,
and, although this is often due to fluid overload as a result of treat- and ventricular arrhythmias, hypotension, restlessness, irritability,
ment, it may be non​cardiac and occur in the presence of hypovol- headache, hyperreflexia, tremor, and convulsions. Hypokalaemia
aemia. In these circumstances, the pulmonary oedema fluid has the results from Na+-​K+-​ATPase activation. A mixed respiratory alkal-
same protein and electrolyte composition as plasma, suggesting in- osis and metabolic acidosis is common. Most symptomatic patients
creased pulmonary vascular permeability. have plasma theophylline concentrations in excess of 25 mg/​litre.
Although aspirin overdose may be complicated by inhibition of Convulsions are seen more commonly when concentrations are
platelet aggregation and hypoprothrombinaemia, gastric erosions, greater than 50 mg/​litre.
and gastrointestinal bleeding are rare following acute salicylate
overdose. Treatment
Oliguria is sometimes seen in patients following the ingestion of Multiple-​dose activated charcoal (e.g. 50 g 4-​hourly) enhances the
salicylates in overdose. The most common cause is dehydration but, systemic elimination of theophylline. Intractable vomiting may
rarely, acute renal failure or inappropriate secretion of antidiuretic be alleviated by ondansetron, 8 mg intravenously in an adult.
hormone may occur. Gastrointestinal haemorrhage may require blood transfusion
Although the urine pH may be alkaline in the early stages of and the administration of a proton pump inhibitor intravenously.
salicylate overdose, it soon becomes acidic. Measurement of ar- Tachyarrhythmias may be induced by the rapid flux of potassium
terial blood gases, pH, and standard bicarbonate may show a re- across cell membranes and early correction of hypokalaemia may
spiratory alkalosis in the early stages of salicylate intoxication prevent their development. The plasma potassium concentration
accompanied by the development of a metabolic acidosis. The should therefore be measured on admission and at regular intervals
plasma potassium concentration is often low; rarely, the blood thereafter while the patient is symptomatic. Potassium supplements
sugar may be high. will be needed in almost all cases and doses of up to 60 mmol/​h may
Treatment be required at the outset in severe cases. Non​selective β-​adrenoceptor
blocking drugs, such as propranolol, may also be useful in the treat-
The plasma salicylate concentration should be re-​measured 2–​3 h ment of tachyarrhythmias secondary to hypokalaemia. There may
after the first measurement. Dehydration, electrolyte imbalance be a role for extracorporeal elimination techniques in very severe
and, most importantly, metabolic acidosis should be corrected. poisoning (plasma theophylline concentration >100 mg/​litre).
The role of multiple-​dose activated charcoal in increasing
salicylate elimination is controversial and it cannot be recom- Thyroxine
mended on current evidence. As the relationship between renal Clinical features
clearance of salicylates and urine pH is logarithmic, urine
alkalinization should be undertaken in patients with a plasma Only a small percentage of patients who ingest large amounts of
salicylate concentration greater than 500 mg/​litre, particularly thyroid hormones develop features of toxicity. Symptoms develop
if an acidosis is present. The therapeutic aim is to make the within a few hours with triiodothyronine (T3) and after 3–​6 days
urine alkaline (ideally, pH 7.5–​8.5), and in adults this may be with thyroxine (T4). They tend to resolve in about the same time
achieved by administration of sodium bicarbonate, 225 mmol as they take to develop. Sinus tachycardia, tremor, anxiety, irrit-
(225 ml of 8.4%); further doses of bicarbonate are given as re- ability, insomnia, hyperactivity, sweating, diarrhoea, and fever are
quired. Hypokalaemia should be corrected before administration most common. Atrial fibrillation and convulsions have also been re-
of sodium bicarbonate, because this lowers the serum potassium ported. Myocardial necrosis occurs rarely.
concentration further. In patients with severe poisoning (plasma Treatment
salicylate concentration >700 mg/​litre or >5.1 mmol/​litre), haemo-
dialysis should be considered, particularly when severe acid–​base Serum T4 and T3 concentrations should be measured approximately
abnormalities are present. 12 h after ingestion (this need not be measured as an emergency).
Pulmonary oedema occasionally complicates salicylate toxicity. Those with high T4 concentrations should be reviewed for evidence
Fluid overload should be excluded as far as possible but, if increased of toxicity on the fourth or fifth day after ingestion. Patients who
pulmonary vascular permeability is suspected, measurement of the develop toxicity should be given propranolol 10–40 mg, 3–4 times
pulmonary artery wedge pressure may be needed both for confirm- a day for 5 days.
ation of the diagnosis and to monitor subsequent fluid adminis-
tration. Positive end-​expiratory pressure ventilation appears to be
beneficial. Drugs of abuse

Theophylline Amfetamines and MDMA (ecstasy)

Poisoning may complicate therapeutic use, as well as being the re- Amfetamines, particularly methamfetamine (‘crystal meth’, ‘ice’)
sult of deliberate self-​poisoning. If a sustained-​released formula- and MDMA, are abused widely. Features of poisoning are related
tion has been ingested, peak plasma concentrations of the drug are predominantly to stimulation of central and peripheral adren-
frequently not attained until 6–​12 h after overdose and the onset of ergic receptors and, in addition, hyperthermia and hyponatraemia
toxic features is correspondingly delayed. (secondary to inappropriate anti-diuretic hormone) may
1748 SECTION 10 Environmental medicine, occupational medicine, and poisoning

develop in severe MDMA toxicity. Poisoning is usually the result of Cannabis infusions injected intravenously may cause nausea,
recreational use. vomiting, and chills within minutes; after about 1 h, profuse watery
diarrhoea, tachycardia, hypotension, and arthralgia may develop.
Clinical features
Marked neutrophil leucocytosis is often present, and hypoglycaemia
These drugs cause increased alertness and self-​confidence, euphoria, has been reported occasionally.
extrovert behaviour, increased talkativeness with rapid speech, lack
of desire to eat or sleep, tremor, dilated pupils, tachycardia, and Chronic use
hypertension. More severe intoxication is associated with excit- Heavy users suffer impairment of memory and attention and poor
ability, agitation, paranoid delusions, hallucinations with violent academic performance. There is an increased risk of anxiety and de-
behaviour, hypertonia, and hyperreflexia. Convulsions, rhabdo- pression. Regular users are at risk of dependence. Cannabis use re-
myolysis, hyperthermia, and cardiac arrhythmias can develop in the sults in an overall increase in the relative risk for later schizophrenia
most severe cases. Rarely, intracerebral and subarachnoid haemor- and psychotic episodes. Cannabis smoke is probably carcinogenic.
rhage and acute cardiomyopathy occur and may be fatal.
In the case of MDMA, hyperthermia, disseminated intra- Treatment
vascular coagulation, rhabdomyolysis, acute renal failure, and Most acutely intoxicated patients require no more than reassurance
hyponatraemia are observed commonly in severe cases, in addition and supportive care. Sedation with diazepam, 10 mg intravenously,
to those features described earlier. Death occurred in 2 of 17 pa- repeated as necessary, should be administered to patients who are
tients with serum sodium concentrations of 107–​128 mmol/​litre. disruptive or distressed. Haloperidol, 2.5–​5 mg intramuscularly re-
Their clinical course was remarkably similar; initial vomiting and peated as necessary, is occasionally required.
disturbed behaviour was followed by seizures, drowsiness, a mute
state, and disorientation. Severe hepatic damage, including ful- Synthetic cannabinoid receptor agonists
minant hepatic failure, has also been reported. The serotonin syn- Synthetic cannabinoid receptor agonists (SCRAs) are full canna-
drome has been described. binoid type 1 (CB1) receptor agonists and bind to these receptors
with a higher affinity than Δ9-​tetrahydrocannabinol. Furthermore,
Treatment
unlike the metabolites of Δ9-​tetrahydrocannabinol, the metabol-
Intravenous fluids should be given for dehydration. Diazepam ites of several synthetic cannabinoids retain high affinity for, and
10–​20 mg intravenously or haloperidol 2.5–​5.0 mg intramuscu- exhibit a range of intrinsic activities at, CB1 and CB2 receptors.
larly are effective in controlling agitation. The peripheral sym- Cannabinoids also bind non​specifically to cellular membranes and
pathomimetic actions of amfetamines may be antagonized by act on opioid and benzodiazepine receptors, prostaglandin syn-
β-​adrenergic blocking drugs. Although acidification of the urine thetic pathways, and protein metabolism. These interactions have
increases renal elimination of amfetamines, sedation is usu- the potential for complex effects and are likely to contribute to
ally all that is required. Dantrolene 1 mg/​kg intravenous should toxicity.
be administered for hyperthermia that does not respond to
conventional cooling methods. In most cases, hyponatraemia Clinical features
responds to fluid restriction alone. Transplantation may be Current third and fourth generation synthetic cannabinoid receptor
indicated in patients who develop MDMA-​induced fulminant agonists (SCRAs) produce more severe clinical features than earlier
hepatic failure. SCRAs. A reduced level of consciousness, tonic–​clonic convulsions,
Cannabis transient respiratory failure, and severe agitation, particularly on re-
covery, are typical.
Cannabis is obtained from the plant Cannabis sativa which con-
tains over 400 compounds including over 60 cannabinoids. The Treatment
most potent cannabinoid is Δ9-​tetrahydrocannabinol (THC), Treatment is symptomatic and supportive. As impaired ventilation
which is responsible for the psychoactive effects seen with use; is transient, supported ventilation is not usually necessary.
other cannabinoids include Δ8-​tetrahydrocannabinol, cannabinol,
and cannabidiol. Smoking is the usual route of use, but cannabis Cathinones, benzofurans, and related compounds
is occasionally ingested as a ‘cake’, made into a ‘tea’ or injected Cathinones are derivates of cathionine, which occurs naturally in
intravenously. the herb Catha edulis (Khat). Structurally these are phenylethyla­
Clinical features mines, similar in structure to catecholamines and amfetamines.
Mephedrone (4-​methylmethcathinone) is one of the most widely
Acute use abused cathinones, others include mexedrone, methylone, butylone,
Features include euphoria, distorted and heightened images, col- and fluoromethcathinone. Purity of these street drugs varies
ours, and sounds; altered tactile sensations, sinus tachycardia, widely. These are usually insufflated (snorted) or swallowed. Other
hypotension, and ataxia. Visual and auditory hallucinations, de- phenylethylamines, such as bromofurans (‘Benzofury’), have many
personalization, and acute psychosis are particularly likely to occur similar effects to amfetamines, but some have more hallucinogenic
after substantial ingestion in naïve cannabis users. Cannabis im- effects due to the receptor specificity of the individual compounds.
pairs all stages of memory including encoding, consolidation, and Methylenedioxypyrovalerone (MDPV, ‘ivory wave’) inhibits the re-
retrieval. Memory impairment following acute use may persist for uptake of dopamine and norepinephrine centrally, and is a potent
months following abstinence. cause of psychiatric features.
 10.4.1 Poisoning by drugs and chemicals 1749

Clinical features caused paradoxical hypertension. Accelerated idioventricular

These agents act as stimulants, causing agitation, hallucin- rhythm should not normally require treatment but ventricular fib-
ations, increased muscle activity with bruxism (teeth grinding), rillation and asystole should be managed in the usual way.
hyperpyrexia, sweating, dilated pupils, tachycardia, and arrhyth- Ethanol
mias. Toxicity is increased if co-​ingested with other stimulants, or
drugs affecting central amine mechanisms (e.g. antidepressants, Ethanol is commonly ingested in beverages before, or concomitantly
tramadol). Metabolic complications include hypokalaemia, hyper- with, the deliberate ingestion of other substances in overdose. It is
glycaemia, and metabolic acidosis. Complications include seizures also used as a solvent and is found in many cosmetic and antiseptic
and rhabdomyolysis. preparations. It is rapidly absorbed through the gastric and intestinal
mucosae. Gastric alcohol dehydrogenase isoenzyme has a role in
Treatment metabolizing ethanol before absorption, thereby preventing ethanol
Intravenous fluids should be given for dehydration. Diazepam, ini- entering the systemic circulation, particularly following ingestion
tially 10–​20 mg intravenously, is the drug of choice for agitation: this of moderate amounts of alcohol. Absorbed ethanol is initially and
is also appropriate to control excess muscle activity. Large doses principally converted to acetaldehyde by an NAD-​dependent hep-
may be required. ECG and cardiovascular monitoring is necessary. atic alcohol dehydrogenase. A small proportion is oxidized by the
Management of other features is symptomatic. microsomal ethanol oxidizing system and the catalase pathway.
Acetaldehyde is removed by oxidation via the NAD-​dependent en-
Cocaine zyme aldehyde dehydrogenase, to yield acetate and, subsequently,
In recent decades, there has been a considerable increase in the rec- CO2 and water. About 95% of ingested ethanol is oxidized to acet-
reational use of cocaine. It is a powerful local anaesthetic and vaso- aldehyde and acetate; the remainder is excreted unchanged in the
constrictor and may be abused by smoking, ingestion, injection or urine, and, to a lesser extent, in the breath and through the skin.
by ‘snorting’ it intranasally. Users, body packers, and those who Ethanol is a central nervous system depressant that interferes with
swallow the drug to avoid being found in possession of it (‘stuffers’), cortical processes in small doses and may depress medullary function
are at risk of overdose. ‘Street’ cocaine is cocaine hydrochloride, in large doses. The effects of ethanol on the central nervous system
which is water soluble, so can be injected or snorted. It may be dis- are generally proportional to the blood ethanol concentration.
solved in an alkaline solution from which the cocaine is extracted Ethanol is also a peripheral vasodilator. In the severely intoxicated,
into ether, which is then evaporated to leave relatively pure (‘free- it may cause hypothermia and hypotension. Ethanol metabolism
base’) cocaine. ‘Crack’ (cocaine also without the hydrochloride results in accumulation of free NADH, with resulting increase in
moiety) is extracted by using baking soda (sodium bicarbonate). the NADH:NAD ratio and inhibition of hepatic gluconeogenesis,
Other drugs, such as ethanol, cannabis, and conventional hypnotics which may cause hypoglycaemia, particularly in children or when
and sedatives, are frequently taken with cocaine to reduce the inten- poisoning follows fasting, exercise, or chronic malnutrition. An in-
sity of its less pleasant effects. crease in the lactate:pyruvate ratio may also ensue, with develop-
ment of hyperlactataemia.
Clinical features
Clinical features
The features of cocaine poisoning are similar to those of
amfetamine. In addition to euphoria, it also has sympathomimetic Ethanol exacerbates the effects of other central nervous system de-
effects including agitation, tachycardia, hypertension, sweating, pressants, in particular, hypnotic agents. In those not tolerant, the
and hallucinations. Prolonged convulsions with metabolic acid- fatal dose of ethanol alone is between 300 and 500 ml absolute al-
osis, hyperthermia, rhabdomyolysis, ventricular arrhythmias, and cohol, if this is ingested in less than 1 h. The features of ethanol poi-
cardiorespiratory arrest may follow in the most severe cases. Less soning are summarized in Table 10.4.1.9.
common features include dissection of the aorta, myocarditis, myo-
cardial infarction, dilated cardiomyopathy, subarachnoid haemor-
rhage, cerebral haemorrhage, and cerebral vasculitis. Table 10.4.1.9 Clinical features of ethanol poisoning
Several rare complications of the method of use of cocaine
have been reported. These include pulmonary oedema after intra- Mild intoxication (500–​1500 mg/​litre)
venous injection of freebase cocaine and pneumomediastinum and Emotional lability, and slight impairment of visual acuity, muscular
coordination, and reaction time
pneumothorax after sniffing it. In addition, chronic ‘snorting’ has
caused perforation of the nasal septum, rhinorrhoea of cerebro- Moderate intoxication (1500–​3000 mg/​litre)
spinal fluid due to thinning of the cribriform plate, and pulmonary Visual impairment, sensory loss, muscular incoordination, slowed reaction
granulomata. time, slurred speech
Severe intoxication (3000–​5000 mg/​litre)
Treatment Marked muscular incoordination, blurred or double vision, sometimes stupor
Users who are intoxicated may require sedation with diazepam to and hypothermia, occasionally hypoglycaemia and convulsions
control agitation or convulsions; very large doses of diazepam may Coma (>5000 mg/​litre)
be required. Measures to prevent further absorption are not usually Depressed reflexes, respiratory depression, hypotension, and hypothermia.
relevant. Hypertension and severe tachycardia may be controlled Death may occur from respiratory or circulatory failure or as the result of
with a β-​blocker but, in one case at least, the use of propranolol aspiration of stomach contents in the absence of a gag reflex
1750 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Severe hypoglycaemia typically occurs within 6–​36 h of inges- Treatment

tion of a moderate to large amount of alcohol by either a previously Supportive measures to maintain adequate ventilation and circula-
malnourished individual or one who has fasted for the previous tion should be employed, and this is often all that is required. GHB
24 h; it is common in children 5 years of age or less. The patient is withdrawal should be managed as for acute alcohol withdrawal.
often comatose, hypothermic, and convulsing, with conjugate de- Baclofen, a specific GABAB receptor agonist, has been used success-
viation of the eyes, trismus, and extensor plantar reflexes; the usual fully in conjunction with benzodiazepines, to control withdrawal
features of hypoglycaemia (e.g. flushing, sweating, tachycardia) from GHB and GBL.
are often absent. Convulsions are the most common presenting
sign in children with hypoglycaemia. Lactic acidosis (usually Ketamine
only mild) is an uncommon but potentially serious complication Ketamine is a dissociative anaesthetic acting on NMDA-​R recep-
of acute ethanol intoxication and occurs particularly in patients tors. It is used as a drug of abuse for its hallucinogenic effects. In
with severe liver disease, pancreatitis, or sepsis. Hypovolaemia, repeated doses it is toxic to the bladder causing irreversible bladder
which may accompany severe intoxication, predisposes to lactic wall thickening and infiltration, with smaller capacity, muscle in-
acidosis. stability, and urothelial ulceration. Urinary frequency, incontinence,
and hydronephrosis are complications. Several synthetic derivates
Treatment
are also abused in the hope they are ‘bladder safe’.
Supportive measures are all that are required for most patients with
acute ethanol poisoning, even if the blood ethanol concentration is Clinical features
very high. Particular care should be taken to protect the airway. In The main features are psychological with dissociative agitation, ag-
more severe cases, acid–​base status should be determined. Lactic gression, and paranoia. There is a risk of physical harm both to pa-
acidosis requires correction of hypoglycaemia, hypovolaemia, and tient and carers. Hallucinations may result in injury from ‘flying’
circulatory insufficiency, if present. An infusion of sodium bicar- or walking into traffic. Chronic use may result in dependency, GI
bonate may be necessary in severely poisoned patients in whom a symptoms and, most importantly, urological tract damage.
lactic acidosis persists.
Blood sugar should be determined hourly in severe cases and Treatment
the rate of intravenous glucose adjusted accordingly. If blood sugar Agitation should be managed supportively. Diazepam 10–​20 mg IV
concentrations decrease despite an infusion of 5–​10% dextrose, a initially may be used for severe agitation. Patients should be coun-
50% glucose solution, 50 ml intravenously, should be given because selled about the risks of abuse.
hypoglycaemia is usually unresponsive to glucagon.
Haemodialysis may be considered if the blood ethanol concentra- Lysergic acid diethylamide
tion exceeds 7500 mg/​litre and if a severe metabolic acidosis is pre- Lysergic acid diethylamide (LSD) acts as an antagonist at periph-
sent, which has not been corrected by the measures outlined earlier. eral 5-​HT receptor subtypes, but as a 5-​HT2A receptor agonist in the
Fructose is of negligible clinical benefit in accelerating ethanol oxi- central nervous system. LSD and MDMA (ecstasy) are sometimes
dation and may cause acidosis; it should not be used. combined (‘XL’; ‘candyflipping’) to increase the response to MDMA.
γ-hydroxybutyric acid and analogues Clinical features
γ-hydroxybutyric acid (GHB) is a liquid that is abused as a body-​ The ability of LSD to distort reality is well known. Visual hallucin-
building agent (it stimulates growth hormone release) and as a seda- ations, distortion of images, agitation, excitement, dilated pupils,
tive drug of abuse. It is a precursor of gamma-​aminobutyric acid tachycardia, hypertension, hyperreflexia, tremor, and hyperthermia
(GABA) and acts as an agonist at GABAB receptors as well as at a are common; auditory hallucinations are rare. Time seems to pass
GHB-​specific receptor in the brain. γ-​butyrolactone (GBL) and 1,4-​ very slowly, and behaviour may become disturbed with paranoid
butane-​diol (1,4-​BD) are GHB precursors, converted into it after in- delusions. Panic attacks are relatively common, but frank psychotic
gestion. They are organic industrial solvents found in products such episodes (which may result in homicide) are not. The psychoactive
as acetone-​free nail polish removers and paint strippers. 1,4-​BD is effects can last for 48 h.
also marketed as a dietary supplement. Episodic visual disturbances (‘flashbacks’; hallucinogen per-
sisting perception disorder) occur in which the effects of LSD are
Clinical features
re-​experienced without further exposure to the drug. The symp-
Low doses cause mild agitation, excitement, nausea, and vomiting, toms include false fleeting perceptions in the peripheral fields,
with euphoria and hallucinations at higher doses. Coma, brady- flashes of colour, geometric pseudohallucinations, and positive
cardia, and respiratory depression occur in the most severely poi- afterimages. These disturbances may persist for several years
soned. The most unique aspect of GHB poisoning is its very brief but are often treatable with benzodiazepines and exacerbated by
duration. Patients may progress from deep coma, requiring intub- phenothiazines.
ation, to self-​extubation and full alertness over only a few hours.
A GHB withdrawal syndrome can occur in chronic abusers with Treatment
clinical features occurring within 6–​12 h of the last dose. Features Most patients will require little more than reassurance and sedation.
include insomnia, tremor, and confusion, which may progress to de- Supportive measures are all that can be offered to those who are
lirium not dissimilar to the alcohol withdrawal syndrome. seriously ill.
 10.4.1 Poisoning by drugs and chemicals 1751

Opiates and opioids supportive care should be administered as necessary, including re-
Opioids are a large group of drugs, which act on opioid receptors and spiratory support.
are usually used as analgesics. Abuse of opiates, particularly heroin, Significant hypotension due to pure opioid effects will usually re-
causes many patients to present with unintentional overdose, which spond to naloxone; patients who are managed just by ventilation may
is normally from intravenous injection (needle marks visible) but therefore be treated unnecessarily aggressively with fluid replace-
may occur from inhalation (‘chasing the dragon’). Oral ingestion in ment. In some patients, high concentrations of opioids, such as co-
addicts is less common. Many addicts abuse other drugs in addition deine, cause histamine release and whealing and itching of the skin,
to opioids, and the combination of benzodiazepines and opioids are effects that should be treated conventionally with antihistamines.
particularly hazardous. Some opioids have other effects not medi- Tryptamines—​synthetic and natural
ated through opioid receptors. Methadone has been shown to in-
hibit potassium channels at high doses and is also associated with This group of drugs are hallucinogens and include the naturally
sudden death in susceptible patients due to QT prolongation and occurring mushroom hallucinogenic alkaloids psilocin and psilo-
torsade de pointes. Buprenorphine, a partial agonist opioid, is now cybin, and synthetic compounds such as dimethyltryptamine and
used as an alternative to methadone in replacement programmes. α-​methyltryptamine; there are also 4-​and 5-​substituted deriv-
Fentanyl is a very potent opioid available in a range of formula- ates (e.g. 4-​hydroxy-​N,N,-​diethyltryptamine (4-​HO-​DET) and 5-​
tions, particularly transdermal. Illicit extraction into an IV prepar- methoxy-​N,N-​diisopropyltryptamine (5-​MeO-​DIPT)). Toxicity is
ation has been reported. Tramadol is an opioid with serotonergic related to stimulation of serotonin 2A receptors (5HT2A).
metabolites. It causes both convulsions and respiratory depression Clinical features
in overdose.
The features of toxicity are almost universally related to the hallucino-
Clinical features genic potential and psychosis induced by these agents. Additional
Cardinal signs of opiate overdose are pinpoint pupils, reduced re- features including dizziness, weakness, and tremor are common. In
spiratory rate, and coma. Vomiting may also occur, particularly severe toxicity seizures, tachycardia, arrhythmias, abdominal symp-
after intravenous injection in naïve users, and complicates the clin- toms, and renal injury are seen. Rarely vasospasm may occur.
ical pattern due to aspiration pneumonia. Methadone acts slowly Treatment
(peak effects usually 4–​6 h after ingestion), though its onset may be
more rapid when given intravenously. Non​cardiogenic pulmonary This is generally supportive, with reassurance the main approach.
oedema is seen in a proportion of severe opioid overdoses and is Agitation should be managed by diazepam (10–​20 mg IV). Severe
treated by positive pressure ventilation. Hypothermia may occur vasospasm should be managed aggressively by intra-​arterial α-
in patients lying outside. Rhabdomyolysis has also been associated adrenoceptor antagonists or nitrates.
with opioid ingestion.
Buprenorphine is potentially seriously toxic if given intraven- Metals
ously, and in some countries, has been combined with naloxone to
reduce the acute hazard. Aluminium
Treatment Aluminium hydroxide is used as an antacid and occasionally as
Naloxone is a pure opioid antagonist. It will reverse the central ef- a phosphate binder in the management of chronic renal failure.
fects of all opioids if given in sufficient dose. In the event of veins not Aluminium sulphate is employed in water purification and paper
being accessible, intramuscular use is an alternative, but the onset manufacture. Aluminium may be absorbed orally and by inhalation.
will be slower. Use of naloxone by nebulizer has also been used in More than 90% of absorbed aluminium is bound to transferrin.
methadone poisoning. Failure of a suspected opioid poisoning to Though some accumulates in brain tissue, most body aluminium is
respond to an adequate dose of naloxone (at least 2.4 mg IV in an stored in bone and the liver. It is excreted mainly via the kidneys so
adult) should prompt reassessment of the diagnosis. It may indicate accumulation may occur in the presence of renal failure.
co-​ingestion of other central nervous system depressants, or inges- Clinical features
tion of γ-​hydroxybutyrate, which also causes small pupils and loss of
consciousness. Naloxone has a half-​life of approximately 45–​90 min Acute poisoning
so its duration of action is, therefore, much shorter than that of the Ingestion of a significant quantity of a soluble aluminium salt such
opioids for which the patient is being treated. Naloxone may there- as aluminium sulphate causes burning in the mouth and throat,
fore be given by infusion; the normal advised dose is approximately nausea, vomiting, diarrhoea, abdominal pain, hypotension, seizures,
two-​thirds of that required to fully wake a patient, every hour. This haemolysis, haematuria and, rarely, hepatorenal failure. Topical alu-
dose can be reassessed at regular intervals depending on the ex- minium sulphate may be irritant to the skin and eyes. By contrast,
pected half-​life of the ingested product. insoluble aluminium salts, such as aluminium oxide, do not produce
Morphine has active metabolites (morphine 6-​ glucoronide), an acute toxic response.
which may become relevant in large overdoses. This metabolite is
renally excreted and more potent than the parent compound, thus Chronic poisoning
poisoning may be prolonged in older people or in patients with Inhalation of ‘stamped aluminium powder’ can cause a persistent
renal impairment or renal damage following rhabdomyolysis. Other cough and breathlessness due to lung fibrosis or occupational asthma.
1752 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Increased death rates from some types of cancer have been observed have been reported and include QT prolongation and ventricular
in aluminium production, but these effects are believed to be the arrhythmias.
result of exposure to other substances, such as benzopyrene, rather
than exposure to aluminium. Aluminium may cause contact allergy. Chronic poisoning
Aluminium encephalopathy is a potential, though now very un- The ingestion of arsenic in contaminated drinking water or ‘tonics’
usual, complication in patients with chronic renal failure adminis- leads to progressive weakness, anorexia, nausea, vomiting, stoma-
tered aluminium-​containing phosphate binders or dialysed using titis, colitis, increased salivation, epistaxis, bleeding gums, conjunc-
aluminium-​contaminated water. The latter is fortunately now very tivitis, weight loss, and low-​grade fever. Characteristically, there is
rare as a result of advancements in dialysis water filtration. The ac- hyperkeratosis of the palms and soles of the feet, ‘raindrop’ pigmen-
cumulation of aluminium in the brain produces cognitive decline, tation of the skin, and Mee’s lines on the nails. A symmetrical periph-
ataxia, dysarthria, myoclonic jerks, and seizures. Aluminium intoxi- eral neuropathy is typical. Hearing loss, psychological impairment,
cation may also contribute to renal osteodystrophy and anaemia in and EEG changes have been reported. Other chronic effects include
patients with chronic renal impairment. Aluminium has been im- disturbances of liver function and ulceration and perforation of the
plicated in Alzheimer’s disease, but a definitive causative association nasal septum. In Taiwan, chronic arsenic exposure has been shown
has not been established. to cause blackfoot disease, a severe form of peripheral vascular dis-
ease, which leads to gangrenous changes.
Treatment
Arsenic is classified by the International Agency for Research on
Deferoxamine forms a stable complex with aluminium which it mo- Cancer (IARC) as a class 1 (confirmed) carcinogen. Chronic ex-
bilizes primarily from bone with subsequent urinary elimination of posure to arsenic in drinking water has been causally linked to lung,
the chelate. Deferoxamine is absorbed poorly from the gastrointes- skin, kidney, and bladder cancer, while occupational exposure to ar-
tinal tract and must be administered parenterally. senic is associated with lung cancer.
The deferoxamine chelate is dialysable and all published clin-
ical studies of aluminium chelation using deferoxamine have Treatment
involved patients in renal failure undergoing either dialysis or The traditional chelator dimercaprol has been superseded by
haemofiltration. There is evidence that deferoxamine can improve succimer (DMSA) and unithiol (DMPS). Both chelators are effective,
aluminium-​induced encephalopathy, bone disease, and anaemia in but unithiol is thought to be superior. The intravenous dose of unithiol
dialysis patients. Specialist advice should be sought. is 30 mg/​kg/​day for 5 days. Alternatively, unithiol 77 mg/​kg/​day
orally may be administered for 5 days if the IV formulation is un-
Arsenic
available. However, nausea and vomiting may limit oral unithiol ad-
Arsenic forms organic and inorganic compounds in trivalent and ministration. Convulsions, cardiovascular effects, and respiratory
pentavalent states. Inorganic arsenical compounds may generate arsine symptoms should be treated conventionally. Haemodialysis may be
gas (see ‘Arsine’, later in this chapter) when in contact with acids, re- required to increase elimination if renal failure develops.
ducing metals, sodium hydroxide, and aluminium. Common sources
of exposure include fish consumption, traditional medicines, and Cadmium
groundwater contamination in Asian countries. In addition, arsenic If hygiene is poor, workers can be exposed to cadmium from the
trioxide has been used in the treatment of acute promyelocytic leu- smelting and refining of metals, from soldering or welding metal
kaemia. Most inorganic arsenicals are well absorbed following inges- that contains cadmium, or in plants that make cadmium products
tion and skin absorption may occur from prolonged exposure. Soluble such as batteries, coatings, or plastics. Itai-​itai disease (literally
arsenic compounds can also be absorbed by inhalation. Arsenic crosses ‘ouch-​ouch’ disease, so named because of the effects of severe pain in
the placental and blood–​brain barriers rapidly. Following distribution the joints), occurred in Toyama Prefecture, Japan, in 1950 and was
arsenic accumulates in bone, hair, and nails. The half-​life is generally due to mass cadmium poisoning as a result of mining.
2–​10 days and excretion is predominantly in the urine.
Clinical features
Clinical features
Cadmium compounds are poorly absorbed orally but are well ab-
Acute poisoning sorbed through the lungs. Cadmium is deposited in the liver and
This can follow accidental, or deliberate ingestion, the toxicity being kidneys and very slowly excreted in the urine (half-​life 10–​30 years).
largely dependent on the water solubility of the ingested compound.
Within 2 h of substantial ingestion of a soluble arsenical compound, Acute poisoning
severe haemorrhagic gastroenteritis may ensue with collapse and The ingestion of cadmium salts (>3 mg/​kg body weight) may lead to
death usually within four days. A metallic taste, salivation, mus- gastrointestinal disturbance which, in severe cases, may progress to cir-
cular cramps, facial oedema, difficulty in swallowing, hepatorenal culatory collapse, acute renal failure, pulmonary oedema, and death.
dysfunction, convulsions, and encephalopathy are reported. A per- Inhalation of cadmium oxide fumes produced in welding or cut-
ipheral neuropathy (predominantly sensory), bone marrow de- ting has led to the development of severe lung damage and death.
pression, striate leukonychia (Mee’s lines), and hyperkeratotic, Often, there are no initial symptoms but after some 4–​10 h, there is
hyperpigmented skin lesions are common in those surviving a increasing respiratory distress. Dyspnoea, cough, and chest pain are
substantial ingestion. In moderate or severe arsenic poisoning, in- accompanied by chills and tremor. Severe pulmonary oedema may
vestigations may show anaemia, leucopenia, thrombocytopenia develop, or chemical pneumonitis in less severe cases. Recovery may
and disseminated intravascular coagulation. ECG abnormalities be complicated by progressive pulmonary fibrosis.
 10.4.1 Poisoning by drugs and chemicals 1753

Chronic poisoning Despite claims that topically applied ascorbic acid and sodium cal-
Repeated exposure to cadmium, such as occupationally, leads to cium edetate protect against dermal toxicity, there is insufficient
renal tubular dysfunction with glycosuria, aminoaciduria, and evidence to advocate their use. Immediate surgical assessment is
hypercalciuria, an increased incidence of renal stones and osteomal- recommended in cases of severe ingestion, as resection of necrotic
acia. Less common features include anosmia, anaemia, teeth dis- gastrointestinal tissue may be life-​saving. There is no evidence that
coloration, and neuropsychological impairment. Later, emphysema any chelating agent improves outcome in cases of systemic poi-
may develop. Workers repeatedly exposed to high concentrations of soning. Haemodialysis removes chromium from the blood, but the
cadmium have developed carcinoma of the prostate or lung. high tissue uptake limits the value of this treatment when used alone.

Treatment Cobalt
There is no clinical evidence that a substantial body burden of cad- Cobalt is an essential trace element and is a constituent of vitamin
mium may be chelated by any currently available antidote. B12 (cyanocobalamin). Cobalt salts have been used as blue colour-
ants for thousands of years. Cobalt composited with tungsten car-
Chromium bide (‘hard metal’) is a very durable and temperature-​resistant metal
Chromium exists mainly in two oxidation states: trivalent (Cr3+) used in the manufacture of drills and other tools. Historically, cobalt
and hexavalent (Cr6+). Cr3+ exposure has limited toxicological salts were used in brewing to enhance the ‘head’ on beer and in the
relevance, due to its low absorption and inability to cross cell treatment of anaemia. In recent years, poorly functioning cobalt-​
membranes. In contrast, Cr6+ compounds are highly reactive, containing hip prostheses have become an important further source
powerful oxidizing agents that inflict severe local damage. They of exposure.
are also well absorbed through most routes of exposure and cross Cobalt exerts its toxicity through generating reactive oxygen species,
cell membranes readily. Somewhat paradoxically, Cr6+ induces inflicting DNA damage and disrupting ionic, enzymatic, and haemato-
its devastating systemic toxicity by intracellularly reducing to poietic homeostasis. Cobalt can be absorbed orally and by inhalation
Cr3+, releasing highly reactive oxygen free radicals in the process. and most undergoes renal excretion over 7 days, but a small proportion
In addition, the Cr3+ formed is able to bind and damage nuclear is retained with a biological half-​life of approximately 2 years.
DNA, inducing genotoxicity. Chromium exposure and absorption
Clinical features
through inhalation, ingestion, and dermal routes is primarily oc-
cupational, with excretion occurring through the kidney. Acute poisoning
Acute poisoning is rare, though ingestion causes gastrointestinal
Clinical features
irritation.
Acute poisoning
Soluble Cr6+ compounds include sodium and potassium chromate Chronic poisoning
and dichromate and chromic acid (Cr6+ trioxide). Inhalation of these Hard metal lung disease is a now rare form of interstitial lung dis-
highly irritant compounds causes mucous membrane inflammation, ease that occurs in susceptible patients exposed to hard metal and in
cough, headache, chest pain, and dyspnoea; pulmonary oedema and some diamond workers who use cobalt-​containing polishes. Patients
respiratory failure may ensue. Ingestion of highly water-​soluble Cr6+ usually present with exertional dyspnoea and cough. There may be
compounds causes a burning sensation in the mouth and throat, associated constitutional symptoms of fever, weight loss, or malaise.
nausea, abdominal pain, diarrhoea, and a risk of gastrointestinal haem- Inspiratory crackles are the earliest physical sign, but finger club-
orrhage. Hypovolaemic shock may follow. Methaemoglobinaemia, bing, cyanosis, and eventually cor pulmonale can ensue. Interstitial
haemolysis, coagulopathy, and renal and hepatic failure have been re- fibrosis is seen on chest X-​ray (primarily the lower zones), and a
ported. Chromic acid splashes produce severe burns. Percutaneous restrictive ventilatory defect is often present. Cobalt is also a recog-
absorption may lead to systemic toxicity; fatalities have occurred. nized cause of occupational asthma.
Historically, those consuming large amounts of cobalt-​
Chronic poisoning contaminated beer developed ‘beer-​drinkers’ cardiomyopathy’ with
Inhalation of Cr6+ compounds has led to atrophy, ulceration, and heart failure often accompanied by a pericardial effusion and poly-
perforation of the nasal septum. Pharyngeal and laryngeal ulcers cythaemia. Systemic cobalt toxicity also developed in patients re-
may also occur. Asthma may be precipitated by exposure to fumes. ceiving cobalt chloride as treatment for anaemia (cobalt stimulates
Lung fibrosis, bronchitis, emphysema, and renal proximal tubular erythropoietin release), with manifestations including hypothyroid
damage result from occupational exposure. Cr6+ is classified by the goitre (cobalt inhibits the uptake of iodine by the thyroid gland),
IARC as a group I carcinogen and chronic occupational exposure is deafness, visual disturbances, and/​or peripheral neuropathy. More
strongly associated with an increased incidence of lung cancer. recently, systemic cobalt toxicity has been encountered occasionally
‘Chrome ulcers’ may develop after repeated topical exposure to in recipients of cobalt-​containing hip prostheses. This is far more
Cr6+ compounds. Cr6+ compounds are also skin sensitizers and con- likely in those with an ill-​fitting prosthesis where there is increased
tribute to the development of cement dermatitis and contact derma- friction between metal surfaces, and in those who have a metal-​
titis from paint primer, tanned leather, tattoo pigments, and matches. containing hip as a revision of a damaged ceramic prosthesis (re-
sidual ceramic shards abrading the metal surface).
Treatment Cobalt is classified as a group 2B carcinogen by the IARC, with
The principal management of chromium poisoning is avoidance of limited evidence to suggest a causal relationship between cobalt and
exposure. Inhalational exposure should be treated conventionally. cancer.
1754 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Treatment corrosive damage is suspected. An early surgical opinion should be

Hard metal pneumoconiosis may respond to steroid therapy. Systemic sought if there are clinical signs of an acute abdomen or deep ulcers
features are usually at least partly reversible providing the cobalt and/​or areas of necrosis on endoscopy or CT. Methaemoglobinaemia
source is removed. There is no antidote for systemic poisoning. should be treated with intravenous methylthioninium chloride
1–​2 mg/​kg. Oral D-​penicillamine, 1.5–​2 g daily, enhances urinary
Copper copper elimination in patients with Wilson’s disease but confirmed
Copper is used for pipes and roofing materials, in alloys and as a pig- benefit in acute copper salt poisoning has not been demonstrated.
ment. It is a component of several endogenous enzymes, including Experimental studies suggest unithiol (DMPS) may be the most ef-
tyrosinase and cytochrome oxidase, and is essential for the utiliza- fective antidote in copper poisoning but the presence of acute kidney
tion of iron. Copper sulphate is used as a fungicide, an algicide, and injury in severely poisoned patients often limits the value of anti-
in some fertilizers. dotes which enhance urine copper excretion. Extracorporeal elim-
Following ingestion, copper transport across the intestinal mucosa ination techniques do not enhance copper elimination significantly.
is facilitated by cytosolic metallothionein. In blood, copper is initially Exchange transfusion has been undertaken successfully in patients
albumin-​bound and transported via the hepatic portal circulation with copper sulphate-​induced haemolysis.
to the liver where it is incorporated into caeruloplasmin. Ninety-​ Lead
eight (98%) per cent of copper in the systemic circulation is bound
to caeruloplasmin and free copper is excreted via a lysosome-​to-​bile Occupational lead exposure occurs mainly by inhalation, for ex-
pathway. This process is essential to normal copper homeostasis ample, in the reclamation of lead from scrap metal, in the demoli-
and provides a protective mechanism in acute copper poisoning. tion and flame-​cutting of structures painted with lead-​containing
An impaired or overloaded biliary copper excretion system results paint, in the manufacture of storage batteries, ceramics, and pig-
in hepatic copper accumulation, as occurs in Wilson’s disease (see ments and in radiation shielding. Non​occupational lead exposure
Chapter 12.7.2) and copper poisoning. predominantly involves ingestion and important sources include
Free reduced Cu(I) can bind to sulfhydryl groups and inactivates ‘traditional’ remedies (particularly among ethnic minorities) and
enzymes such as glucose-​6-​phosphate dehydrogenase and gluta- children with pica who pick at surfaces coated with lead-​containing
thione reductase. In addition, copper may interact with oxygen spe- paint or eat lead-​contaminated soil. Application of lead-​containing
cies (e.g. superoxide anions and hydrogen peroxide) and catalyse the cosmetics such as ‘surma’ has also resulted in lead intoxication.
production of reactive toxic hydroxyl radicals. Copper(II) ions can Both ingested and inhaled lead are absorbed readily. Most (98.5%)
oxidize haem iron to form methaemoglobin. lead is deposited in the bones and teeth, where it remains for 10–​
15 years. Of the lead in the blood, 99% is associated with erythro-
Clinical features cytes. Lead can cross both the blood–​brain and placental barriers.
Elimination is predominantly renal. As the body accumulates lead
Acute poisoning
over many years, even small doses can accumulate over time and
Acute copper poisoning usually results from the ingestion of contam- cause toxicity.
inated foods or from accidental or deliberate ingestion of copper salts. There are two principal mechanisms of lead toxicity. First, lead
Copper salt ingestion causes profuse vomiting with abdominal pain, complexes with important functional chemical groups including –​
diarrhoea, headache, dizziness, and a metallic taste. Gastrointestinal COOH, –​NH2, and –​SH, and so disrupts the function of enzymes
haemorrhage, haemolysis, and hepatorenal failure may ensue and fa- and other biologically important molecules. Lead inhibits several
talities have occurred. Body secretions may be green or blue. enzymes involved in haem synthesis (including δ-​aminolaevulinate
Occupational exposure to copper fumes (during refining or dehydratase and ferrochelatase) and erythrocyte maturation
welding) or to copper-​containing dust causes ‘metal fume fever’ with (erythrocyte pyrimidine 5’ nucleotidase), causing a microcytic or
upper respiratory tract symptoms, headache, fever, and myalgia. normocytic hypochromic anaemia. Secondly, lead substitutes for di-
valent ions, particularly calcium, which explains why lead accumu-
Chronic poisoning
lates in bone. The critical role of calcium in neuronal differentiation,
Chronic copper poisoning has been reported predominantly as myelination, and synapse development and functionality explains
‘vineyard sprayer’s lung’ in those spraying fungicides containing why lead poisoning can induce devastating neurotoxicity. The
copper sulphate. Features include progressive dyspnoea, cough, developing nervous system is particularly susceptible to irrevers-
wheeze, myalgia, malaise, anorexia, micronodular, and reticular ible damage. Lead substitution for calcium also causes widespread
opacities on chest X-​ray (which may coalesce), and a restrictive lung chemical interactions, disrupts second messenger cellular signalling
function defect. Lung biopsy may show pulmonary granulomata and triggers calcium-​activated apoptosis.
and fibrosis. Other features include hepatic copper-​ containing
granulomas, hypergammaglobulinaemia, and hepatomegaly. There Clinical features
is no convincing evidence that copper is carcinogenic in humans. Lead poisoning frequently presents with non​ specific features,
including abdominal pain, anorexia, constipation, headache, and
Treatment lethargy. Anaemia presents due to impaired haem synthesis and re-
Blood copper concentrations correlate well with the severity of in- duced erythrocyte lifespan. Classically, lead poisoning presents with
toxication following acute ingestion. Serum caeruloplasmin con- peripheral neuropathy in the form of foot or wrist drop, although
centrations will also be increased in acute copper salt poisoning. this manifestation is now uncommon. In moderate intoxication,
Supportive measures are paramount following copper salt inges- reversible renal tubular dysfunction occurs (causing glycosuria,
tion. Early endoscopy or CT scan with contrast is recommended if aminoaciduria, and phosphaturia), which progresses to irreversible
 10.4.1 Poisoning by drugs and chemicals 1755

interstitial fibrosis and progressive renal insufficiency in severe better absorbed following ingestion than are inorganic mercuric
cases. Hypertension may result from renal toxicity. Lead encephal- salts. Organic mercury compounds cross the blood–​brain barrier
opathy (delirium, seizures, and coma) only occurs in very severe poi- readily. In contrast, the kidney is the main storage organ for inorganic
soning (blood lead concentrations >100 μg/​dl (4.8 micromol/​litre)) mercury compounds. In vivo mercury is bound to metallothionein,
and is much more common in children than adults. Transplacental which serves a protective role, since renal damage is caused only by
transfer of lead from mother to fetus results in reduced fetal viability, the unbound metal. Mercury is excreted mainly in urine and faeces
low birth weight, and premature birth. although a small amount of absorbed inorganic mercury is exhaled as
Despite unequivocal evidence that even low blood lead concen- mercury vapour. The half-​life of most body mercury is 1–​2 months,
trations are detrimental to health, the current practice in the United but a small fraction has a half-​life of several years.
Kingdom is to only enforce stopping work with lead when a worker’s The exact mechanism of toxicity of mercury remains unclear, but
blood lead concentration exceeds 60 µg/​dl (2.9 micromol/​litre); involves binding of the Hg2+ form to the sulfhydryl groups present
30 µg/​dl (1.4 micromol/​litre) for a woman of reproductive capacity; on structural proteins, receptors, enzymes, intracellular organelles
50 µg/​dl (2.4 micromol/​litre) for an employee aged under 18 years. and DNA and to selenoproteins. The central nervous system is par-
There is no safe blood lead concentration for children, particularly ticularly susceptible.
those below the age of 5 years.
Clinical features
Treatment
Acute poisoning
Primary prevention aimed at eliminating lead hazards for chil-
dren and workers is crucial. The importance of primary preven- Acute mercury vapour inhalation causes headache, nausea, cough,
tion in children is emphasized particularly by the observation that chest pain and bronchitis/​pneumonitis. Repeated exposure to low
chelation does not improve scores on tests of cognition, behav- mercury vapour concentrations presents typically with characteristic
iour, and neuropsychological function in children with moderate neurological features including fine tremor, lethargy, memory loss,
lead poisoning (blood lead concentrations of 22–​45 µg/​dl (1.0–​2.2 insomnia, personality changes, and ataxia. Other features include
micromol/​litre)). The social dimension of the problem must also be stomatitis, gingivitis, hypersalivation, and renal tubular damage.
recognized: simply giving children chelation therapy and then re- Mixed motor and sensory peripheral neuropathy may develop.
turning them to a contaminated home environment is of no value. Ingestion of metallic mercury is usually without systemic effects as
Similarly, if an occupational source of lead exposure is implicated, a it is poorly absorbed from the gastrointestinal tract. However, inges-
thorough evaluation of the workplace, other exposed workers and tion of inorganic mercury (II) (mercuric) or aromatic mercuric salts
the systems for handling lead at work are appropriate. causes an irritant gastroenteritis with corrosive ulceration, which may
The decision to use chelation therapy is based on the symptoms lead to circulatory collapse and shock. Inorganic mercury(I) (mer-
present and the blood lead concentration. All symptomatic patients curous) compounds are less soluble, less corrosive, and less toxic than
with blood lead concentrations of 50 µg/​dl (2.4 micromol/​litre) or mercuric salts. Ingestion of mercurous chloride in teething powder
higher should be considered for chelation therapy. Parenteral so- has led to ‘pink disease’ or acrodynia in infants. This is a hypersen-
dium calcium edetate, 75 mg/​kg per day, has been the chelating sitivity reaction characterized by a desquamating erythematous rash
agent of choice for more than 50 years but oral succimer (DMSA) of the extremities, irritability, profuse sweating, tachycardia, and
30 mg/​kg per day is of similar efficacy. hypertension. Systemic toxicity in the form of renal and neurological
damage can present following exposure to mercury salts.
Mercury There are reports of deliberate intravenous or subcutaneous me-
Mercury is the only metal that is liquid at room temperature. It exists in tallic mercury injection. Accidental injection also has occurred
three forms: metallic (Hg0), mercury(I) (mercurous), and mercury(II) after injury from broken thermometers. Intravascular mercury
(mercuric). Metallic mercury is very volatile and when spilt has a large may result in pulmonary venous or peripheral arterial embolism.
surface area so that high atmospheric concentrations may be pro- Subcutaneous mercury initiates a soft-​tissue inflammatory reaction
duced in enclosed spaces, particularly when environmental temperat- with granuloma formation. Signs of systemic mercury toxicity are
ures are high. In addition to simple salts, such as chloride, nitrate, and rare following metallic mercury injection.
sulphate, mercury(II) forms organometallic compounds where mer-
cury is covalently bound to carbon, such as methyl-​, ethyl-​, phenyl-​, Chronic poisoning
and methoxyethyl mercury. Inorganic mercury is used extensively in Chronic poisoning from inorganic mercury compounds or mercury
industrial and pharmaceutical settings; exposure is predominantly vapour causes anorexia, insomnia, abnormal sweating, headache,
occupational though minor non​occupational exposure occurs via lassitude, increased excitability, tremor, peripheral neuropathy, gin-
dental amalgam. By contrast, exposure to organomercury compounds givitis, hypersalivation, personality changes, and memory or intel-
most commonly occurs from dietary intake, as organomercury can lectual deterioration. Glomerular and tubular damage may occur,
accumulate up the food chain of aquatic species. and renal tubular acidosis has been described in children.
The absorption of mercury depends on its chemical form. Inhaled Most cases of human poisoning from alkyl mercury compounds
mercury vapour is absorbed rapidly and oxidized to mercury (II) in result from ingestion of contaminated foods over a long period.
erythrocytes and other tissues. Prior to oxidation, absorbed mercury There is often a latent period of several weeks between exposure
vapour can cross the blood–​brain barrier, but the divalent ion oxida- and the development of symptoms which are predominantly
tion product serves to trap mercury in the brain. Mercury vapour is neurological, with paraesthesiae of the lips, hands, and feet, ataxia,
also absorbed via the skin. Less than 1% of an ingested dose of metallic tremor, dysarthria, constriction of visual fields, and emotional and
mercury reaches the systemic circulation. Organic mercuric salts are intellectual changes. Gastrointestinal disturbances may precede or
1756 SECTION 10 Environmental medicine, occupational medicine, and poisoning

accompany these features. Seizures, coma, and death have occurred. A significant increase in deaths from non​malignant respiratory
Chronic exposure to methylmercury has been associated with an in- disease or pneumoconiosis has been observed in nickel refinery
creased incidence of liver cancer, cirrhosis, renal disease, and cere- workers. Nickel compounds are classified by the IARC as class I car-
bral haemorrhage. cinogens, with evidence that occupational exposure increases the
risk of cancer of the lung and nasal sinuses.
Treatment Metallic nickel and nickel salts cause allergic contact dermatitis in
Although there are no controlled clinical data to show that chela- up to 10% of females and 1% of males and is due to a type IV delayed
tion therapy improves outcome in patients with neurological fea- hypersensitivity.
tures of mercury poisoning, unithiol 30 mg/​kg/​day intravenously
(or 77 mg/​kg/​day orally) increases urinary mercury elimination Treatment
and reduces blood mercury concentrations. Where extracorporeal Blood nickel concentrations immediately following exposure to
renal support is required for the treatment of renal failure, there is nickel carbonyl provide a guide to severity of exposure and the need
evidence that continuous veno–​venous haemodialfiltration is more for chelation therapy. Unithiol (DMPS) enhances the urinary excre-
effective than haemodialysis at removing unithiol–​mercury com- tion of nickel in nickel-​intoxicated animals. Diethyldithiocarbamate
plexes. Substantial exposure to corrosive mercury salts may warrant and disulfiram (which is metabolized to diethyldithiocarbamate)
immediate surgical assessment, as resection of necrotic gastrointes- are effective agents in the treatment of nickel dermatitis, but their
tinal tissue may be life-​saving. role in the treatment of acute severe nickel carbonyl poisoning has
not been confirmed in a controlled clinical study.
Nickel
Nickel is a ubiquitous trace metal mined in the form of sulphide ore. Phosphorus
It is used primarily for producing stainless steel and other alloys. Elemental phosphorus exists in several crystalline forms (allo-
Nickel forms inorganic soluble (sulphate, chloride) and insoluble tropes), of which yellow phosphorus (sometimes referred to as
(oxide, sulphide) salts, used in electroplating and battery manufac- white) is the most important toxicologically. Phosphorus oxidizes
ture. Nickel carbonyl (Ni(CO)4) is a colourless, volatile liquid used spontaneously in contact with air to form phosphorus pentoxide
as a catalyst in the petroleum, plastic, and rubber industries. It is which, by an exothermic reaction, forms phosphoric acid on contact
an intermediate compound in nickel purification and is released with water. Hence, dermal and gastrointestinal exposures to phos-
as fumes when nickel is thermally decomposed. Nickel metal and phorus rapidly become exposures to phosphoric acid.
inorganic salts can be absorbed orally and by inhalation, though
absorption is generally poor. By contrast, nickel carbonyl is highly Clinical features
lipophilic and rapidly absorbed. Nickel is principally bound to al- Typically, patients who have ingested phosphorus present with ei-
bumin in the blood and is concentrated in the kidneys, liver, and ther gastrointestinal features (most commonly) or central nervous
lungs prior to renal excretion. The mechanism of nickel toxicity is system features; 20% have a combination of both. Features gener-
thought to involve the induction of oxidative stress through reactive ally begin within minutes of ingestion and include nausea, vomiting,
oxygen species production. abdominal pain, burns of the pharynx, oesophagus, and stomach,
which may lead to gastrointestinal haemorrhage. Shock in part due
Clinical features to fluid loss and GI haemorrhage follows. In other cases, central
Acute poisoning nervous system features (restlessness, irritability, delirium, coma,
Nickel carbonyl inhalation leads within a few minutes to dizziness, convulsions, and cerebral oedema) predominate. Metabolic compli-
headache, vertigo, nausea, vomiting, cough, and dyspnoea. In many cations (metabolic acidosis, hypoglycaemia, hyperphosphataemia
cases these symptoms disappear and there follows a symptom-​free and hypocalcaemia) and hepatorenal failure ensue.
period lasting 12–​36 h before tachypnoea, dyspnoea, haemoptysis, Cardiovascular collapse and arrhythmias are the most common
cyanosis, chest pain, vomiting, tachycardia, weakness, and muscle cause of death following ingestion, but in other cases cerebral oe-
fatigue supervene. Paraesthesiae, diarrhoea, abdominal distension, dema and haemorrhage complicating fulminant hepatic failure are
delirium, and convulsions have also been reported. Death from car- responsible.
diorespiratory failure may occur 4 to 11 days after exposure.
Treatment
At high concentrations, soluble nickel salts are primary skin,
gut, and eye irritants. Workers at an electroplating plant who drank Treatment is supportive. Hypotension/​shock should be corrected
water accidentally contaminated with nickel sulphate experienced vigorously with intravenous fluid and inotropes. If metabolic acid-
nausea, vomiting, diarrhoea, abdominal pain, headache, cough, and osis is not responsive to fluid resuscitation, give intravenous sodium
breathlessness, which persisted for up to 2 days. A 2-​year-​old child bicarbonate. Early fibreoptic endoscopy and CT is indicated to grade
died 4 h after ingesting 15 g nickel sulphate crystals. the severity of the injury in any patient who is symptomatic or has
evidence of oropharyngeal burns.
Chronic poisoning
Chronic exposure to aerosols of nickel salts may lead to chronic rhin-
Thallium
itis and sinusitis and, in rare cases, anosmia and perforation of the Thallium sulphate was previously used as a rodenticide but is now
nasal septum. Inhaled nickel can produce a type I hypersensitivity re- banned for this use in many countries. Thallium salts have also been
action, manifest as bronchial asthma with circulating IgE antibodies employed in the manufacture of optical and electrical equipment,
to nickel. Pulmonary eosinophilia (Loeffler’s syndrome) due to a type as catalysts in organic synthesis, and in isotopic form for medical
III hypersensitivity reaction to nickel has also been described. imaging of the myocardium.
 10.4.1 Poisoning by drugs and chemicals 1757

Clinical features In contrast to the relatively mild clinical course after zinc oxide in-
Initial symptoms (if ingested) include nausea, vomiting, abdominal halation, exposure to zinc chloride ammunition bombs (hexite) pro-
pain, and, less commonly, gastrointestinal bleeding. Constipation duces a chemical pneumonitis with marked dyspnoea, a productive
follows in most patients. After a few days (usually between two and cough, fever, chest pain, and cyanosis. The acute respiratory distress
five), paraesthesiae develop, which start in the feet and progress to syndrome may ensue.
the hands and fingers; painful and tender extremities (‘burning feet Metal fume fever occurs most commonly in individuals who per-
syndrome’) and ascending sensory neuropathy then supervene. In form welding involving zinc. It presents generally with influenza-​like
severe cases confusion, delirium, convulsions, renal failure, respira- symptoms, fever, shaking chills, arthralgias, myalgias, headache, and
tory failure, heart failure, and coma occur; the mortality is high. malaise, some 4–​10 h following exposure. In patients with ongoing
If death does not occur within the first week, tremor, ataxia, and metal fume exposure over the course of a workweek, tachyphylaxis
(usually lower limb) muscle weakness develops, due to the onset of occurs resulting in improvement in symptoms over the course of the
motor neuropathy, which is usually distal. Ocular features include workweek and maximal symptoms occurring after an exposure-​free
nystagmus, ptosis, and abnormalities of gaze due to involvement of period such as a weekend.
the third, fourth, and sixth cranial nerves. Retrobulbar neuritis, fa- Treatment
cial paralysis, decreased visual acuity, optic atrophy, and defective
colour vision may develop. Management is supportive. Endoscopy and CT should be performed
Characteristically, alopecia develops within 1–​3 weeks and it following zinc chloride ingestion to assess the severity of oesopha-
is often this sign which leads to the diagnosis being made. If the geal or gastric burns.
patient survives, the hair usually regrows, but is often abnormally
fine and unpigmented. Nail growth is impaired with the develop-
ment of ridges, Mees’ lines, and erosion of the proximal parts of Pesticides
the nails.
Aluminium and zinc phosphides
Treatment Aluminium and zinc phosphides are highly effective insecticides and
As thallium ions are excreted into the gastrointestinal tract via the rodenticides, which are used to protect grain during transport and
saliva, the bile, and through the intestinal mucosa, it is possible to storage. The phosphide interacts with moisture in the surrounding
sequester thallium ions in the gut and prevent reabsorption by the air to liberate phosphine, which is the active pesticide. Acute poi-
oral administration of colloidally soluble Prussian blue (potassium soning, therefore, results either from the ingestion of the salts them-
ferric hexacyanoferrate (II)) 250–​300 mg/​kg/​day (approximately selves or inhalation of the phosphine generated during their use; the
10 g twice daily for an adult). Thallium ions are exchanged for po- latter is discussed later on in this chapter.
tassium ions in the lattice of the Prussian blue molecule and are sub- In cases of poisoning by phosphide ingestion, toxic effects are due
sequently excreted in faeces. During treatment with Prussian blue, to phosphine release when the phosphide comes into contact with
plasma concentrations of thallium fall and urine excretion declines gut fluids. Phosphine is absorbed through the alimentary mucosa
exponentially. In contrast, faecal excretion of thallium is detectable and widely distributed to tissues.
even when urine excretion of the metal has ceased and, therefore,
administration of Prussian blue should be continued until thallium Clinical features
can no longer be detected in the faeces. Early features include nausea, vomiting, retrosternal, and epigas-
tric pain, gastric, or duodenal erosions causing haematemesis and
Zinc dyspnoea. Diarrhoea is less common. Shock and circulatory failure
Zinc oxide fumes are emitted in any process involving molten zinc occurring early in the course of poisoning are of ominous prognostic
and are the most common cause of metal fume fever. Exposure to importance, as circulatory failure is a common and frequent cause
zinc chloride occurs in soldering; in the manufacture of dyes, paper, of death. Impaired myocardial contractility and global dyskinesia
and deodorants; and on military exercises when it is used as a smoke are frequent in those severely poisoned. This group of patients is
screen. Poisoning has followed the accidental or deliberate inges- characterized by severe hypotension, reduced cardiac output, raised
tion of elemental zinc and zinc chloride and fatal intoxication has systemic venous pressure, normal pulmonary artery wedge pressure
followed inadvertent intravenous administration. Inhalation of zinc and inadequate systemic vasoconstriction. Severe metabolic acid-
chloride and oxide may lead to nasopharyngeal and respiratory tox- osis, renal failure, and disseminated intravascular coagulation are
icity. Zinc may be absorbed through broken skin when zinc oxide common accompaniments.
paste is used to treat wounds and burns.
Treatment
Clinical features Treatment is symptomatic and supportive. Gastric lavage should be
Zinc sulphate ingestion causes gastrointestinal irritation, sometimes avoided as it might increase the rate of disintegration of the product
in association with headache and dizziness. Zinc chloride is highly ingested and increase toxicity. Activated charcoal does not bind
corrosive, and ingestion has led to erosive pharyngitis, oesophagitis, metal phosphides.
and haematemesis. Acute renal failure and pancreatitis have also
been recorded after ingestion of zinc salts. Topical exposure to zinc Anticoagulant rodenticides
chloride causes ulceration and dermatitis of the exposed skin. Zinc Warfarin was widely used as a rodenticide until target species de-
chloride is highly irritant to the eye. veloped resistance to it. The newer anticoagulant rodenticides
1758 SECTION 10 Environmental medicine, occupational medicine, and poisoning

(sometimes termed ‘super warfarins’), such as brodifacoum, weeks after cessation of treatment. Failure to do so may result in
bromodialone, chlorophacinone, coumatetralyl, difenacoum, recurrence of anticoagulation and risk haemorrhage being missed.
diphacinone and flocoumafen, are more potent and longer-​acting
antagonists of vitamin K1 than warfarin. While accidental ingestion Bipyridyl herbicides
of small amounts rarely results in altered coagulation, deliberate in- The bipyridyl herbicides include diquat, morfamquat, and para-
gestion may result in prolongation of the INR for several weeks or quat. Paraquat has been removed from the market in the EU; diquat
months and fatal haemorrhage has occurred. remains widely available and morfamquat is not readily available.
These anticoagulants inhibit vitamin K1-​2,3-​epoxide reductase
and thus the synthesis of vitamin K and subsequently clotting fac- Clinical features
tors II, VII, IX, and X. There is no anticoagulant effect until existing The features of toxicity are largely dependent on the amount of para-
stores of vitamin K and clotting factors are depleted. The greater po- quat swallowed. Ingestion of more than 6 g paraquat ion is likely to
tency and duration of action of long-​acting anticoagulant rodenti- be fatal within 24–​48 h, while 3–​6 g is likely to lead to a more pro-
cides compared to warfarin is attributed to their greater affinity for tracted, but still fatal, outcome. After the ingestion of more than 6 g
vitamin K1-​2,3-​epoxide reductase, their ability to disrupt the vitamin paraquat ion, nausea, vomiting, abdominal pain, and diarrhoea, are
K1-​epoxide cycle at more than one point, hepatic accumulation, and rapidly followed by peripheral circulatory failure, metabolic acidosis,
unusually long biological half-​lives due to high lipid solubility and impaired consciousness, convulsions, and increasing breathlessness
enterohepatic circulation. secondary to acute pneumonitis. Breathlessness, tachypnoea, wide-
spread crepitations, and central cyanosis progress relentlessly until
Clinical features the patient dies from hypoxia a few days later. Mild jaundice may be
Gastrointestinal bleeding, haematuria, and bruising are the most seen and renal failure is usually severe.
common features, though the most common site of fatal haemor- After 3–​6 g paraquat ion, the cardiovascular and central nervous
rhage is intracranial. The onset of bleeding may be delayed for sev- system complications are not seen, and the course of poisoning is
eral days since the peak anticoagulant effect does not occur until dominated by alimentary features, particularly painful ulceration of
some 72–​96 h after ingestion. the mouth, tongue, and throat, which makes it difficult to swallow,
speak, and cough. Perforation of the oesophagus with subsequent
Treatment mediastinitis has been reported.
Routine measurement of the INR is generally not indicated in chil- Ingestion of 1.5–​2.0 g of paraquat causes nausea, vomiting, and
dren as the amounts they ingest are almost invariably small. In all diarrhoea, mild renal tubular necrosis, and pain in the throat.
other cases, the INR should be measured on presentation and 36 Respiratory involvement may not be apparent until 10–​21 days after
to 48 h after exposure. If the INR is normal at this time, no further ingestion, but may progress till the patient dies of respiratory failure
action is required. as late as 5 or 6 weeks after taking the paraquat.
If a patient presents within 1 h of a large ingestion, the adminis- The features of diquat poisoning are similar. In severe and usu-
tration of activated charcoal (50 g for adults; 10–​15 g for children) ally fatal cases, gastrointestinal mucosal ulceration, paralytic ileus,
should be considered, as it is known that warfarin is adsorbed to hypovolaemic shock, acute renal failure, and coma predominate.
charcoal. In patients with severe poisoning who have ingested a
long-​acting formulation, oral cholestyramine 4 g three times daily Treatment
for an adult should be considered in order to shorten the plasma The diagnosis of paraquat poisoning can be confirmed by a simple
half-​life of the rodenticide. qualitative test on urine passed within 4 h of ingestion using alka-
If active bleeding occurs, dried prothrombin complex (which line sodium dithionite (a blue colour indicates paraquat is present);
contains factors II, VII, IX, and X) 25–​50 units/​kg, or fresh frozen a negative test indicates that not enough paraquat has been taken to
plasma 15 ml/​kg (if no concentrate is available) should be given, to- cause problems. In the case of diquat poisoning, the urine goes a green
gether with phytomenadione 5 mg by slow intravenous injection colour in the alkaline sodium dithionite test. The outcome of paraquat
(100 µg/​kg body weight for a child). If active bleeding occurs in a pa- poisoning can be predicted with reasonable confidence within a few
tient who is being prescribed an anticoagulant, warfarin (or another hours of ingestion by relating the plasma paraquat concentration to
anticoagulant) should be discontinued. the time after ingestion, but this assay is not readily available in Europe
If there is no active bleeding and the INR is less than 4.0, treat- following the withdrawal of paraquat from the market.
ment with phytomenadione is not required. If the INR is more than There is no evidence that the outcome of paraquat or diquat poi-
4, phytomenadione 5 mg by slow intravenous injection (100 µg/​kg soning can be altered by any form of intervention. Symptomatic
body weight for a child) should be administered, unless the patient measures including antiemetics, mouth washes and analgesics are
is anticoagulated for therapeutic reasons. indicated, and intravenous fluids may be necessary to replace gastro-
If the patient is prescribed anticoagulants, the INR is more than 8, intestinal losses.
and there is no active bleeding or only minor bleeding, stop warfarin
(restart when the INR <5), give phytomenadione 0.5 mg by slow Carbamate insecticides
intravenous injection and repeat the dose if the INR is more than 8 Carbamate insecticides inhibit acetylcholinesterase, causing ac-
12–24 h later. If the INR is between 6.0 and 8.0, and there is no active cumulation of acetylcholine at central and peripheral cholinergic
bleeding or only minor bleeding, warfarin should be discontinued nerve endings, including neuromuscular junctions. The duration of
and restarted when the INR is less than 5. this effect is comparatively short-​lived (compared to organophos-
Patients who require reversal of coagulopathy after exposure to phorus insecticides) as the carbamate–​enzyme complex tends to
long-​acting formulations should have their INR measured for two dissociate spontaneously.
 10.4.1 Poisoning by drugs and chemicals 1759

Clinical features features include nausea, vomiting, diarrhoea, abdominal pain, and
After substantial carbamate ingestion, patients usually develop cho- cyanosis secondary to methaemoglobinaemia. The combination of
linergic symptoms within a few minutes, and in most severe cases, methaemoglobinaemia and haemolysis results in varying degrees of
constriction of the pupils, muscle twitching, profound weakness, hypoxaemia and symptoms such as general weakness, fatigue, diz-
profuse sweating, excessive salivation, bronchorrhoea, chest tight- ziness, agitation, anxiety, confusion, and headache. Chest pain and
ness, coughing, incontinence, confusion, and progressive cardiac dyspnoea may also be experienced. Intravascular haemolysis causes
and respiratory failure ensue. Seizures are relatively uncommon as a hyperkalaemia and jaundice. Poisoning with chlorate is also com-
primary complication, because carbamate penetration into the cen- monly complicated by acute renal failure, though the underlying
tral nervous system is limited, though they may occur secondary to mechanisms are not fully understood.
hypoxia. Death is usually due to respiratory failure. In less substan- Treatment
tial ingestions, cholinergic symptoms are evident within 2 h in most
cases and typically resolve within 24 h. Methaemoglobinaemia can be corrected by slow intravenous injec-
tion of methylthioninium chloride (methylene blue) 1–2 mg/​kg body
Treatment weight as a 1% solution, although this treatment is less effective in
Bronchorrhoea requires removal of secretions by suction and the presence of major intravascular haemolysis. Blood transfusion
prompt relief with intravenous atropine 2 mg (0.02–​0.1 mg/​kg in a may be required. Plasma potassium concentrations should be moni-
child) intravenously together with supplemental oxygen to maintain tored and reduced if necessary. Haemodialysis/​haemodialfiltration
arterial PaO2 greater than 10 kPa (>75 mm Hg). The atropine dose may remove chlorate and will also be required for the management
should be titrated to control rhinorrhoea and bronchorrhoea. If the of renal failure and hyperkalaemia. Plasmapheresis and plasma ex-
initial dose produces only a partial response, it should be doubled change or exchange transfusion have also been employed to remove
and doubled again if there is only a limited clinical response. If these chlorate, circulating free haemoglobin, and red cell stroma, but data
measures fail, the patient should be intubated and mechanical ven- are too limited to make a firm recommendation.
tilation instituted. Chlorophenoxy herbicides
At present there is insufficient evidence to either recommend or ad-
vise against the use of pralidoxime in severe poisoning with carbamate Chlorophenoxy (phenoxyacetate) herbicides are weed killers that
insecticides. Pralidoxime seldom should need to be administered in less act as synthetic auxins (plant ‘hormones’) and cause plant death by
severe cases since carbamates have a relative short duration of action. disrupting nutrient transport and growth. They comprise an aliphatic
However, if intoxication is life-​threatening and unresponsive to atro- carboxylic acid moiety attached to a chlorine-​or methyl-​substituted
pine and supportive measures, pralidoxime chloride 30 mg/​kg body aromatic ring. Important examples are listed in Table 10.4.1.10.
weight by intravenous injection over 20 minutes should be given. These herbicides are usually formulated as salts or esters of the
active compound and sometimes coformulated with the chemically
Chloralose related herbicides ioxynil, bromoxynil and/​or dicamba. Most in-
Chloralose is marketed for amateur use as cereal or paste baits con- stances of serious poisoning have been due to deliberate ingestion,
taining 2 to 4% rodenticide. Technical α-​chloralose (c. 90% pure) is mainly in the developing world. Mechanisms of toxicity include
used by professionals against bird pests and rodents. dose-​dependent cell membrane damage, chemical mimicry of acetyl
coenzyme A and uncoupling of oxidative phosphorylation.
Clinical features
Clinical features
Toxic amounts of chloralose cause severe central nervous system ex-
citation with hypersalivation, increased muscle tone, hyperreflexia, Ingestion causes nausea and vomiting which may be accompanied by
opisthotonus, myoclonic jerks, and convulsions. Rhabdomyolysis is burning in the mouth and throat and abdominal pain. Severe corro-
a potential complication. Coma, generalized flaccidity, and respira- sive injury to the gastrointestinal tract is rare. Hypotension, which is
tory depression may follow. common, is due predominantly to intravascular volume loss, although
vasodilation and direct myocardial toxicity may also contribute.
Treatment Coma, hypertonia, hyperreflexia, ataxia, nystagmus, miosis, hallu-
Children who ingest small amounts of baits (amateur formulations) cinations, convulsions, fasciculation, and paralysis may then ensue.
containing chloralose are unlikely to develop symptoms. In contrast, Hypoventilation is commonly secondary to central nervous system
patients who have deliberately ingested large amounts of bait or the
technical compound are likely to require admission to intensive care
for management of convulsions, myoclonus, and coma. Table 10.4.1.10 Chlorophenoxy herbicides

Chlorates Chemical name Other names

2,4-​Dichlorophenoxy acetic acid 2,4-​D
Sodium and potassium chlorates are non​ selective herbicides.
Potassium chlorate is also used in matchstick heads, explosives, and 4-​(2,4-​Dichlorophenoxy) butyric acid 2,4-​DB
fireworks. Sodium chlorate and potassium chlorate are powerful oxi- 2-​(2,4-​Dichlorophenoxy) propionic acid 2,4-​DP, dichlorprop
dizing agents that induce methaemoglobinaemia and haemolysis. 4-​Chloro-​2-​methylphenoxyacetic acid MCPA
4-​(4-​Chloro-​2-​methylphenoxy) butyric acid MCPB
Clinical features
2-​(4-​Chloro-​2-​methylphenoxy) propionic acid Mecoprop
Features of chlorate toxicity may develop within as little as two hours
2-​(2, 4-​Dichloro-​m-​tolyoxy) propionanilide Clomeprop
of ingestion and are usually due to gastrointestinal irritation. Early
1760 SECTION 10 Environmental medicine, occupational medicine, and poisoning

depression, but respiratory muscle weakness is a factor in the devel- including jaw clenching in the absence of overt seizures, superior
opment of respiratory failure in some patients. Myopathic symptoms, lateral gaze fixation, and opisthotonus have all been described. This
including limb muscle weakness, loss of tendon reflexes, myotonia, increase in motor activity, in turn, results in raised creatine kinase ac-
and increased creatine kinase activity, have been observed. Metabolic tivity, rhabdomyolysis, hyperpyrexia, and metabolic acidosis in some
acidosis, rhabdomyolysis, renal failure, increased aminotransferase cases. Less frequent complications include hyperventilation, respira-
activities, pyrexia, and hyperventilation have been reported. tory alkalosis, minor elevation of transaminase activities, upper
gastrointestinal bleeding, and mildly deranged coagulation.
Treatment
In addition to supportive care, urine alkalinization with high-​flow Treatment
urine output will enhance herbicide elimination and should be con- Treatment is supportive. Intravenous diazepam 10 mg IV or lor-
sidered in all seriously poisoned patients. Haemodialysis produces azepam 4 mg IV in an adult should be given to suppress convulsions
similar herbicide clearances to urine alkalinization and should be and a clear airway and adequate ventilation ensured, using endo-
considered if high-​flow urine alkalinization cannot be performed tracheal intubation if necessary. Rhabdomyolysis and its complica-
for clinical reasons. tions should be managed conventionally.

Glyphosate Methyl bromide

Glyphosate-​containing herbicides are very popular because their mode The uses of methyl bromide (bromomethane) have gradually be-
of action is plant-​specific (by inhibition of an enzyme pathway not come restricted as it is an ozone-​depleting chemical. It is currently
present in mammals), they act only on contact with plant foliage and used to fumigate mills, warehouses, shipping containers, stored
are inactivated on contact with soil. Formulations usually contain the products, and soil in greenhouses to eradicate pests such as wood-
isopropylamine salt of glyphosate, together with a surfactant. The latter worm and rodents that damage crops and buildings. In most coun-
is often an animal fat derivative (a tallow amine) polyoxyethylene amine tries application is now restricted to trained and licensed personnel.
(POEA), which contributes substantially to the toxicity of the formu- Methyl bromide is absorbed readily through the lungs and is ex-
lation. Dilute, ready-​to-​use glyphosate/​POEA preparations are rarely creted largely unchanged by the same route.
associated with systemic toxicity, which usually requires the deliberate
ingestion of a concentrate (typically 41% glyphosate/​15% POEA). Clinical features
Inhalation causes respiratory tract irritation with shortness of breath,
Clinical features cough, and varying degrees of pulmonary oedema. Hypoxaemia
Ingestion of more than 85 ml of the concentrated glyphosate/​POEA and respiratory failure are inevitable consequences. Neurotoxicity
formulation is likely to cause significant toxicity in adults. Fatal in- manifests hours or days later with agitation, delirium, ataxia, in-
gestions have usually involved more than 200 ml. The most prom- tention tremor, nystagmus, dysdiadochokinesis, and hyperreflexia.
inent effects are on the alimentary tract with burning in the mouth, Abnormal movements of the limbs are common and convulsions
throat, nausea, vomiting, dysphagia, and diarrhoea. Upper gastro- occur frequently. Consciousness may be impaired to the point of
intestinal haemorrhage is a much less common complication. Renal coma in severe cases. Proteinuria, oliguria (due to renal tubular and
and hepatic impairment are also frequent and usually reflect reduced cortical necrosis), and jaundice have been described.
organ perfusion. Respiratory distress, impaired consciousness, pul-
monary oedema, infiltration on chest radiograph, shock, arrhyth- Treatment
mias, renal failure requiring haemodialysis, metabolic acidosis, and The casualty should be removed promptly from the contamin-
hyperkalaemia may supervene in severe cases and, together with ated atmosphere and undressed, as methyl bromide can penetrate
advancing age and late presentation, are poor prognostic indicators. clothing and rubber gloves. Contaminated skin should be washed
with water. Treatment is supportive. Systemic uptake can be quanti-
Treatment fied by measuring serum and urine bromide concentrations.
Management is symptomatic and supportive. Intravenous fluids or
blood transfusion may be required. Respiratory and renal failure should Neonicotinoids
be managed conventionally. The fatality rate in case series of glypho- Neonicotinoids are now employed widely as systemic insecticides
sate concentrate ingestion is approximately 6%. Death most frequently and some (imidacloprid, dinotefuran, thiamethoxam, nitenpyram)
ensues within 72 h and is related to refractory cardiovascular collapse. are used as flea control agents for dogs and cats. They block
postsynaptic nicotinic receptors (nAChRs), particularly the α4ß2
Metaldehyde subtype. The high specificity of neonicotinoids for insect nicotinic
Metaldehyde in the form of pellets is used widely for killing slugs receptors, their low affinity for human nAChRs and relatively poor
and in some countries as a solid fuel. penetration of the human blood–​brain barrier should result in
much lower toxicity to humans than nicotine-​containing pesticides.
Clinical features Human poisoning with neonicotinoids is well recognized and may
Nausea, vomiting, diarrhoea, abdominal pain, agitation, dizzi- be severe and fatal, though the solvents and surfactants present in
ness, and tachycardia are common, but it is central nervous system many formulations may also contribute to toxicity.
and skeletal muscle complications that characterize the most se-
vere toxicity. Convulsions may develop within 3 h of ingestion and Clinical features
recur frequently, and over days. Consciousness is impaired. Tremor, Poisoning with neonicotinoids is characterized by the rapid onset of
hypertonia, exaggerated limb reflexes, muscle twitching or spasms, symptoms including nausea and vomiting, fever, sweating, increased
 10.4.1 Poisoning by drugs and chemicals 1761

salivation, bronchorrhoea, agitation, lack of coordination, disorienta- nervous system depression by the pesticide and solvents in the com-
tion, muscle weakness, seizures, and coma. Breathlessness, depressed mercial formulation. Aspiration pneumonia is common.
respiration, cyanosis, and respiratory arrest have been reported. Though bradycardia would be expected from the mode of action
Bradycardia is sometimes present, but tachycardia is observed more of organophosphorus insecticides, it is present in only about 20%
frequently; ventricular tachycardia/​fibrillation has occurred occasion- of cases; sinus tachycardia is more common. Rarely, complete heart
ally, as has cardiac arrest. Severe hypotension and shock supervene in block and arrhythmias occur.
those severely poisoned. Miosis is present in some cases but not the Relapse after apparent resolution of cholinergic symptoms has
majority. Metabolic acidosis and renal failure have been observed. been reported, particularly in patients who have ingested highly
lipophilic insecticides, and is termed the intermediate syndrome.
Treatment This involves the onset syndrome of muscle paralysis affecting
In patients who are unconscious a clear airway should be established particularly upper limb muscles, neck flexors, and cranial nerves
and, if ventilation is impaired, assisted ventilation should be com- some 24–​96 h after exposure, though there are reports of paralysis
menced. Hypotension and cardiac dysrhythmias should be managed occurring before 24 h and even after 96 h. It is often associated with
conventionally and acid–​base and electrolyte balance corrected. the development of respiratory failure.
Since the clinically important features, notably bronchorrhoea, are Delayed neuropathy is a rare complication of acute exposure
caused by cholinergic overactivity, atropine sulphate 2 mg intraven- to some insecticides. It results from phosphorylation and subse-
ously (in an adult) should be given and the dose repeated until the quent ageing of at least 70% of neuropathy target esterase (NTE).
signs of atropinization are present (dry skin and sinus tachycardia). Only a small number of marketed insecticides, for example
There is some evidence that activated charcoal can bind methamidophos, are capable of causing this syndrome. The fea-
neonicotinoids and if administered within 1 h of ingestion may tures resulting from distal degeneration of some axons in both the
reduce absorption; gastric lavage is contraindicated because of peripheral and central nervous systems occur 1–​4 weeks after ex-
the presence of solvents unless it can be performed with a cuffed posure. Cramping muscle pain in the lower limbs, distal numbness,
endotracheal tube in situ. and paraesthesiae are followed by progressive weakness, depres-
sion of deep tendon reflexes in the lower limbs and, in severe cases,
Organophosphorus insecticides in the upper limbs. Signs include a high-​stepping gait from bilat-
Organophosphorus insecticides are among the most widely used eral foot drop and, in severe cases, quadriplegia with foot and wrist
pesticides throughout the world. They inhibit acetylcholinesterase drop, as well as pyramidal signs. In time, there might be significant
causing accumulation of acetylcholine at central and peripheral recovery of peripheral nerve function but, depending on the de-
cholinergic nerve endings, including neuromuscular junctions. The gree of pyramidal involvement, spastic ataxia may be permanent
clinical presentation and severity of OP poisoning depends not only The diagnosis is confirmed by measuring erythrocyte acetyl-
on the pesticide and the magnitude of exposure but also on several cholinesterase activity; plasma butyrylcholinesterase activity is a less
other factors, including the route of exposure, the age of the patient, preferable alternative.
whether exposure was a suicidal attempt (when a substantial inges-
tion is more likely), and the presence of a solvent in the formula- Treatment
tion. Not only may skin absorption of the OP itself be enhanced by Management involves supportive measures and judicious admin-
the presence of the solvent, but also ingestion of a solvent may in- istration of antidotes. Bronchorrhoea requires prompt relief with
duce vomiting with risk of aspiration; depressed consciousness may intravenous atropine 2 mg (0.02–​0.1 mg/​kg in a child). The atropine
follow. In addition, there is increasing evidence that the solvents in dose should be titrated to control rhinorrhoea and bronchorrhoea, to
formulations are responsible for the high morbidity and mortality. raise the pulse rate above 80 bpm, and restore systolic blood pressure
to more than 80 mm Hg. If the initial dose produces only a partial
Clinical features response, it should be doubled and doubled again if there is only a
The first symptom of mild poisoning, particularly in individuals oc- limited clinical response. In addition, supplemental oxygen should be
cupationally exposed, is often a feeling of exhaustion and weakness. given to maintain PaO2 greater than 10 kPa (75 mm Hg). If neces-
Vomiting, cramping abdominal pain, sweating, and hypersalivation sary, the patient should be intubated and mechanical ventilation (with
may follow. Constriction of one or both pupils and a sensation of positive end-​expiratory pressure) should be instituted.
tightness in the chest during inspiration also may occur at an early There are consistent animal data supporting the effectiveness of
stage, but these signs are not reliable indices of the severity of systemic oximes, when given early. While there are also some clinical studies
poisoning because they may be caused by local anticholinesterase ef- which support the benefit of oxime therapy, others do not. Recent
fects of spray mist on the eye or bronchi. studies indicate that solvents in the formulations play a crucial role
In cases of more severe poisoning, the nicotinic features tend to in toxicity, which could explain why oximes seem to be less effective
appear first, but a combination of muscarinic, nicotinic, and cen- clinically than in experimental studies where pure insecticide is often
tral nervous system symptoms is apparent in many severe cases. employed. Pralidoxime chloride 30 mg/​kg by intravenous injection
Muscle twitching may affect the eyelids, tongue, face muscles, and over 20 min, repeated at 4–​6 h intervals, should be administered as
calf muscles; respiratory muscles then become involved, and gen- soon as possible in any patient requiring atropine; alternatively, an
eral muscle weakness ensues. Convulsions may occur, though OPs intravenous infusion of 8–​10 mg/​kg/​h in an adult may be employed
vary in their potency to induce seizures. Bronchial hypersecretion/​ after the bolus injection. Administration of pralidoxime should con-
bronchorrhoea, with bronchoconstriction, is followed in severe tinue for as long as atropine is required, that is, until clear, irrevers-
cases by cyanosis, respiratory depression, and coma. Death may ible clinical improvement is achieved, which may take many days
follow from respiratory failure. Coma is usually due to direct central while residual insecticide is cleared from the body stores.
1762 SECTION 10 Environmental medicine, occupational medicine, and poisoning

The use of diazepam 5–​10 mg intravenously in an adult will reduce paints, nail polish, and nail polish removers. It is absorbed rapidly
anxiety and restlessness, but larger doses may be required to control through the lungs and gut and metabolized in the liver to pyruvate.
convulsions; diazepam also reduces morbidity and mortality. Metabolism is saturable with elimination of the parent compound in
expired air (it can be smelt on the breath) and urine at high doses.
Phosphine
Phosphine is used extensively as a fumigant to control rodents and Clinical features
a wide variety of insects in sealed containers or structures. It is also There is irritation of mucous membranes of eyes, nose, and throat.
used in the semiconductor industry. Systemic toxicity causes headache, excitement, restlessness, chest
tightness, incoherent speech, nausea and vomiting and, occasion-
Clinical features ally, gastrointestinal bleeding, coma, convulsions, and hypergly-
The initial symptoms are often alimentary rather than respiratory. caemia (resulting from the metabolism of pyruvate to glucose).
Indeed, the nausea, vomiting, diarrhoea, and epigastric pain may be
so striking that physicians are misled into making a diagnosis of acute Treatment
gastroenteritis. However, respiratory complaints do occur. Chest If toxicity has followed inhalation, remove from exposure, give sup-
tightness, breathlessness, chest pain or soreness, and palpitations portive treatment, and correct hyperglycaemia. Since acetone is a
are commonly reported. Inhaled phosphine is as cardiotoxic as in- small molecule, there may be a role for dialysis in the management
gested metal phosphides (see earlier). Acute heart failure, pulmonary of seriously poisoned patients, particularly if plasma acetone con-
oedema (which may be both cardiogenic and non​cardiogenic) and centrations are high.
cardiac arrhythmias have been observed, particularly in children.
Convulsions, ataxia, and intention tremor have also been reported. Acids
Acids commonly involved in cases of poisoning include the inor-
Treatment ganic acids hydrochloric, hydrofluoric (see ‘Hydrogen fluoride/​
The casualty should be removed from exposure as soon as possible. hydrofluoric acid’, further on in this chapter), nitric, phosphoric,
Thereafter, treatment is supportive and symptomatic. and sulphuric acids; and organic acids such as acetic, formic, lactic,
and trichloroacetic acids. Car battery acid typically contains 28%
Pyrethroids sulphuric acid. Proprietary cleaning agents and antirust compounds
Pyrethroids are used widely as insecticides both in the home and com- often comprise a mixture of hydrochloric and phosphoric acids.
mercially, and in medicine for the topical treatment of scabies and Inorganic acids generally are of concentrations more likely to be cor-
head lice. In tropical countries, mosquito nets are commonly soaked rosive at the normally available solution.
in pyrethroid solutions as part of antimalarial strategies. Pyrethroid
sprays are used to ‘disinsect’ the interiors of aircraft. Despite their ex- Clinical features
tensive worldwide use, severe poisoning with pyrethroids is extremely Acid burns of the skin cause erythema, blistering and, in severe
rare. The most important mechanism of toxicity is modification of the cases, ulceration and necrosis. In the eyes, intense pain and bleph-
gating characteristics of voltage-​sensitive sodium channels, causing arospasm are common, and corneal burns may occur.
delayed closure. A protracted sodium influx ensues, which, if it is suf- When ingested, acids tend to damage the stomach more than the oe-
ficiently large and/​or long, lowers the action potential threshold and sophagus, but oropharyngeal and oesophageal injuries may also occur.
causes repetitive firing which manifests as paraesthesiae. Immediate pain is followed by vomiting and/​or haematemesis. Severe
injury results in inability to swallow saliva with drooling. Gastric and
Clinical features oesophageal perforation may occur, resulting in chemical peritonitis
Pyrethroids are best known for their ability to cause facial paraes- and shock. Other effects include hoarseness, stridor, and respiratory
thesiae following occupational cutaneous exposure; these symptoms distress secondary to laryngeal and epiglottic oedema, metabolic acid-
last only a few hours at most. Inhalation of pyrethroid-​containing osis leucocytosis, acute tubular necrosis, renal failure, hypoxaemia, re-
dust or aerosol droplets may cause respiratory tract irritation, but spiratory failure, intravascular coagulation, and haemolysis.
systemic toxicity is unusual. Ingestion causes irritation of the gastro-
intestinal tract with nausea and vomiting, increased salivation, and Treatment
mouth ulceration. Coma, convulsions, and pulmonary oedema may Acid burns to the skin should be irrigated liberally with water or sa-
ensue in the most severe cases and fatalities have occurred rarely. line and managed as a thermal burn. Skin grafting may be necessary
and specialist advice should be sought.
Treatment After ocular exposure with acid, the eye should be irrigated, pref-
Symptomatic and supportive measures should be employed, and erably with saline for 15–​30 min. Topical local anaesthetic is usually
reassurance given that facial paraesthesiae will not be a long-​term required to relieve pain and to overcome blepharospasm. Specialist
problem. advice should be sought.
After ingestion, a clear airway should be established. Opioids
are often necessary for analgesia. Dilution and/​or neutralization
Other chemicals is contraindicated. Features of severe tissue injury (severe abdom-
inal pain, abdominal distension, circulatory collapse, or lactic acid-
Acetone osis) may indicate the presence of bowel necrosis or perforation.
Acetone is a clear liquid with a characteristic pungent odour and sweet Immediate surgical assessment is recommended because early re-
taste, used widely in industrial and household products including section of necrotic tissue and intraluminal stenting has been shown
 10.4.1 Poisoning by drugs and chemicals 1763

to improve survival and reduce the risk of oesophageal stricture for- cases of severe haemolysis. If renal failure ensues, haemodialysis/​
mation. Both CT scan and fibreoptic endoscopy have been shown to haemodialfiltration should be undertaken. Antidotes to remove ar-
be useful in assessing the severity of injury, risk of mortality, and risk senic are of no value.
of subsequent stricture formation. These two imaging modalities are
complimentary and when combined provide the best understanding Benzene
of the injury and risk. If there are severe clinical features, then en- Benzene is a colourless, volatile liquid with a pleasant odour. It is an
doscopy is best performed by a surgeon capable of undertaking de- ingredient in many paints and varnish removers, and in some petrols.
finitive treatment. Corticosteroids confer no benefit and may mask About 10% of inhaled benzene is excreted unchanged in the
abdominal signs of perforation; antibiotics should be given for es- breath. The remainder is metabolized by mixed function oxidase en-
tablished infection only. zymes predominantly in the liver, but also in the bone marrow, the
Acid ingestion may result in antral, pyloric, or jejunal strictures, target organ of benzene toxicity. Benzene is a human carcinogen.
achlorhydria, protein-​losing enteropathy, and gastric carcinoma.
Clinical features
Alkalis Acute exposure
Alkalis are commonly found in the home and those encountered in Following inhalation or ingestion, euphoria, dizziness, weakness,
cases of poisoning include sodium hydroxide (drain, lavatory, pipe headache, blurred vision, mucous membrane irritation, tremor,
cleaners), sodium carbonate, sodium silicate, sodium perborate, ataxia, chest tightness, respiratory depression, cardiac arrhyth-
sodium phosphate, sodium carbonate (denture cleaning tablets), mias, coma, and convulsions occur. Direct skin contact with liquid
sodium dichloroisocyanurate (water sterilizing tablets), sodium benzene may produce marked irritation.
hypochlorite (a bleaching agent), and alkaline batteries.
Chronic exposure
Clinical features
The toxic effects of chronic poisoning may not become apparent for
The features of eye, skin and laryngeal contamination with alkalis are months or years after initial contact and may develop after all ex-
similar to those produced by acids (see ‘Acids’) though when ingested, posure has ceased.
alkalis are more likely to damage the oesophagus. Oropharyngeal Anorexia, headache, drowsiness, nervousness, and irritability are
pain, together with epigastric pain are followed by vomiting and diar- well described. Anaemia (including aplastic anaemia), leucopenia,
rhoea. Oesophageal ulceration with or without perforation may be thrombocytopenia, pancytopenia, leukaemia, lymphomas, chromo-
complicated by mediastinitis or pneumonitis. Oesophageal perfor- somal abnormalities, and cerebral atrophy have been reported. There
ation may result in catastrophic aorto-​enteric fistula formation. is also an association between occupational benzene exposure and
non-​Hodgkin’s lymphoma. Patients have recovered after as long as
Treatment
a year of almost complete absence of formation of new blood cells.
The treatment of corrosive injuries caused by alkalis is largely the A dry, scaly dermatitis may develop on prolonged or repeated skin
same as for those produced by acids (see ‘Acids’). In severe cases, exposure to liquid benzene.
following resuscitation and stabilization, early assessment by endos-
copy and/​or CT imaging is the priority. Alkali ingestion may result Treatment
in stricture formation and there is a risk of malignancy. The mean Following removal from the contaminated atmosphere, treatment
latent period for development of carcinoma of the oesophagus fol- should be directed towards symptomatic and supportive measures.
lowing alkali ingestion is more than 40 years. Gastric lavage is hazardous as aspiration is likely to occur.
Arsine Benzyl alcohol
Arsine is a colourless, non​irritating gas. Arsine binds with oxidized Benzyl alcohol has been used as a preservative in intravascular flush
haemoglobin causing massive intravascular haemolysis. solutions and in drug formulations, which has led to severe toxicity
in neonates.
Clinical features
Benzyl alcohol is metabolized to benzoic acid, which is then con-
There is usually a delay of some 2–​24 h after exposure before the onset jugated with glycine in the liver and excreted as hippuric acid. The
of headache, malaise, weakness, dizziness, breathlessness, migratory immature liver’s capacity to metabolize benzoic acid is limited and,
abdominal pain, fever, tachycardia, tachypnoea, nausea, and vomiting. when exceeded, leads to accumulation of this metabolite and meta-
A bronze skin colour is noted in some patients, but most have the typ- bolic acidosis.
ical appearance of a jaundiced patient. Acute renal failure is observed
by the third day after substantial exposure, and the urine is dark red, Clinical features
then brown (from haemoglobinuria), before anuria (due to acute In 1982, a syndrome consisting of metabolic acidosis, convulsions,
renal tubular necrosis) ensues. Investigations will show leucocytosis, neurological deterioration (due to intraventricular haemorrhage),
reticulocytosis, elevated plasma haemoglobin, and haemoglobinuria. gasping respirations, hepatic and renal abnormalities, cardiovas-
cular collapse, and death was described in small premature infants
Treatment between 2 to 14 days of age. This was due to IV solutions containing
If haemolysis is severe, the use of red cell exchange and plasma benzyl alcohol. In contrast, healthy adult humans are able to tolerate
exchange may be more beneficial than red cell exchange alone, as much as 30 ml of 0.9% benzyl alcohol by rapid intravenous in-
though plasma exchange alone is also effective in the treatment fusion without signs of toxicity. However, a 5-year-old girl devel-
of intravascular haemolysis. Blood transfusion will be required in oped hypernatraemia and metabolic acidosis due to the infusion of
1764 SECTION 10 Environmental medicine, occupational medicine, and poisoning

diazepam for 36 hours to control status epilepticus. The presence of Treatment

benzyl alcohol has been used as marker of toluene exposure. Treatment involves removal from exposure, washing contaminated
Treatment skin, irrigation of the eyes with water and supportive measures. In
most cases, however, preventive measures to keep carbon disul-
Metabolic acidosis, hepatic and renal failure should be treated con- phide concentrations in the workplace as low as possible are more
ventionally and administration of fluids or drugs containing benzyl important.
alcohol should be discontinued.
Carbon monoxide
Carbon dioxide
Carbon monoxide is a tasteless, odourless, colourless, non​irritating
Carbon dioxide is a colourless gas that is also available commer- gas produced by incomplete combustion of organic materials.
cially as a solid for refrigeration purposes (‘dry ice’). High concen- Normal endogenous carbon monoxide production is sufficient to
trations may accumulate in wells, silos, manholes, mines, and in maintain a resting carboxyhaemoglobin concentration of 1 to 3% in
several volcanic lakes in Africa. In 1986, Lake Nyos in Cameroon urban non​smokers and 5–​6% in smokers.
emitted a cloud of carbon dioxide that killed 1700 villagers and Common sources of carbon monoxide are car exhaust fumes (in
3500 of their livestock. the absence of a catalytic converter), improperly maintained and
ventilated heating systems, and smoke from all types of fire, typically
Clinical features charcoal barbecues used indoors. Carbon monoxide derived from
Dyspnoea, cough, headache, dizziness, sweating, restlessness, par- domestic heating systems is a major cause of accidental death in
aesthesiae, and sinus tachycardia are features after modest exposure. the developing world. Inhalation of methylene chloride (from paint
Higher concentrations (>10%) produce psychomotor agitation, strippers) may lead to carbon monoxide poisoning due to break-
myoclonic twitches, eye flickering, coma, and convulsions. Death down of the parent compound.
occurs from acute cardiorespiratory depression, typically at concen- Symptoms and signs that follow inhalation of carbon monoxide
trations exceeding 17%. are the result of tissue hypoxia. The affinity of haemoglobin for
Skin contact with solid carbon dioxide (dry ice) may result in carbon monoxide is approximately 240 times greater than that for
frostbite and local blistering. oxygen. Carbon monoxide combines with haemoglobin to form
carboxyhaemoglobin, reducing the total oxygen-​carrying capacity
Treatment of the blood. In addition, the oxygen dissociation curve shifts to
The casualty should be removed from the contaminated envir- the left due to modification of oxygen-​binding sites. As a result, the
onment and oxygen administered. Thereafter, care is supportive. affinity of the remaining haem groups for oxygen is increased, the
Dry ice burns are treated similarly to other cryogenic burns, with oxygen dissociation curve is distorted as well as being shifted and
thawing of the affected tissue and suitable analgesia. the resulting tissue hypoxia is thus far greater than that which would
result from simple loss of oxygen-​carrying capacity.
Carbon disulphide Carbon monoxide may also inhibit cellular respiration as a result
Carbon disulphide is used as a fumigant for grain and as a solvent, of reversible binding to cytochrome oxidase a3. At higher concentra-
particularly in the rayon industry. It is a clear, colourless, volatile li- tions, carbon monoxide causes brain lipid peroxidation and it has
quid with an odour like that of decaying cabbage. been suggested this may be relevant to the development of delayed
neuropsychiatric sequelae.
Clinical features
Clinical features
Acute exposure
The clinical features of carbon monoxide poisoning may be divided
Acute poisoning is rare. Absorption occurs through the skin as well
into those caused acutely, predominantly due to hypoxia, and those
as by inhalation. Because of its potent defatting activity, carbon di-
that result from tissue damage by the mechanisms detailed earlier.
sulphide causes reddening, cracking, and peeling of the skin, and a
These later toxicities are therefore related to the initial amounts
burn may occur if contact continues for several minutes. Splashes in
of carbon monoxide inhaled and length of time before rescue and
the eye cause immediate and severe irritation. Acute inhalation may
treatment. In acute poisoning, organs with high oxygen demand are
result in irritation of the mucous membranes, blurred vision, nausea
at special risk of damage and this includes, in particular, the heart
and vomiting, headache, delirium, hallucinations, coma, tremor,
and brain.
convulsions, and cardiac and respiratory arrest.
The symptoms of mild to moderate exposure are non​specific and
Chronic exposure include headache, nausea, and confusion. These non​specific symp-
toms require a high degree of suspicion in patients at potential risk
There is an increased incidence of cardiovascular disease (hyperten- of poisoning with the gas. As concentrations increase, metabolic
sion, arteriosclerosis, ischaemic heart disease, elevated cholesterol) acidosis ensues from interference with metabolic processes, and
among workers exposed to carbon disulphide. In addition, sleep central nervous system features progress to cause loss of conscious-
disturbances, fatigue, anorexia, and weight loss are common com- ness with hypertonia and hypereflexia, extensor plantar responses,
plaints. Intellectual impairment, cerebellar signs, diffuse vascular papilloedema, and convulsions. Cardiovascular changes include ar-
encephalopathy, parkinsonism, peripheral polyneuropathy, hepatic rhythmias and ischaemic myocardial damage.
damage, and permanent impairment of reproductive performance Other complications tend to be detected later and include per-
have been described. sistent neurological damage in any part of the brain, which may
 10.4.1 Poisoning by drugs and chemicals 1765

result in either paralysis or midbrain damage causing parkinsonism Chronic exposure

or akinetic mutism, deafness due to central ischaemia of the brain Chronic exposure results predominantly in neurological damage
stem nuclei and cochlea, muscle necrosis causing rhabdomyolysis which can include ataxia, peripheral neuropathies, amblyopia, optic
and renal failure and skin changes (bullae) due to prolonged atrophy, and nerve deafness.
unconsciousness.
The degree of intoxication is correlated to some extent with carb- Treatment
oxyhaemoglobin concentrations but, by the time patients arrive The immediate administration of oxygen is of paramount import-
in hospital, they will often have received oxygen in an ambulance, ance, as there is evidence that it prevents inhibition of cytochrome
which may lower carbon monoxide concentrations from those pre- oxidase a3 and accelerates its reactivation. Treatment thereafter de-
sent at the scene of the injury. Very severe features are to be expected pends on the severity and type of exposure. If hydrogen cyanide has
with carboxyhaemoglobin above 60%, but significant features would been inhaled and the patient remains conscious 10 min after ex-
not generally be expected at concentrations below 30%. posure has ceased, no antidotal treatment is required. In more severe
Neuropsychiatric problems may occur after recovery from carbon cases an antidote is invariably necessary.
monoxide intoxication and are said to develop insidiously over several Methaemoglobin binds cyanide, forming cyanmethaemoglobin.
weeks. Defining limits of these changes may be difficult in patients Methaemoglobinaemia may be induced efficiently by the adminis-
with relatively mild exposure, and ascribing causation is particularly tration of intravenous sodium nitrite 300 mg over 5 min. Because
difficult in low-​level exposures where formal studies suggest no effect. the effect of sodium nitrite is relatively rapid and methaemoglobin
formation slower, the benefit of sodium nitrite may also be from its
Treatment vasodilator action and the consequent improved tissue perfusion.
Removal from exposure and administration of 100% oxygen using Intravenous sodium nitrite is usually given with intravenous sodium
a tightly fitting facemask are essential. If patients are unconscious, thiosulfate; they have been shown to act synergistically in experi-
endotracheal intubation and mechanical ventilation is required. mental cyanide poisoning by providing sulphane sulphur to en-
Prolonged administration of oxygen is necessary to ensure carbon hance endogenous metabolism. Sodium thiosulfate is administered
monoxide bound in tissues is released. intravenously in a dose of 12.5 g over 10 min.
Traditionally, hyperbaric oxygen has been used in carbon mon- Dicobalt edetate solutions contain free cobalt, which complexes
oxide poisoning, although there remains significant controversy six times more cyanide than dicobalt edetate. Cobalt is toxic, how-
about its efficacy. A trial in the United States of America has shown ever, and use of this formulation in the absence of cyanide poisoning
some suggestion of benefit, but commentators are divided about the may cause cobalt toxicity. Dicobalt edetate should, therefore, be
relevance of the relatively small changes noted, and the wider appli- given only when the diagnosis is certain. Dicobalt edetate is admin-
cation of these results. In part, this is because patients were brought istered intravenously in a dose of 300 mg over 1 min, with a further
for treatment for quite some distance, and the debate remains as to 300 mg being given if recovery does not occur.
whether any potential small therapeutic benefit warrants transfer to One mole of hydroxocobalamin inactivates one mole of cyanide,
a distant treatment facility. but, on a weight-​for-​weight basis, 50 times more hydroxocobalamin
is needed than cyanide because hydroxocobalamin is a far larger
Cyanide molecule. If available, hydroxocobalamin 5 g is given intravenously
Hydrogen cyanide and its derivatives are used widely in industry over 30 min; a second dose (5 g) may be required in severe cases.
and are released during the thermal decomposition of polyurethane Diethylene glycol
foams. Cyanide poisoning may also result from the ingestion of the
cyanogenic glycoside amygdalin, which is found in the kernels of Diethylene glycol is used as a coolant, as a building block in organic
almonds, apples, apricots, cherries, peaches, plums, and other fruits. synthesis and as a solvent. It can be also found in some hydraulic fluids
Cyanide reversibly inhibits cellular enzymes which contain ferric and brake fluids. Occupational exposure is by the dermal route, but
iron notably cytochrome oxidase a3 so that electron transfer is blocked, the most common route of exposure is ingestion, often unintention-
the tricarboxylic acid cycle is paralysed, and cellular respiration ceases. ally as a result of contamination of medicines. Diethylene glycol has
been responsible for several mass poisonings in Australia, Bangladesh,
Clinical features Haiti, India, Nigeria, South Africa, and the United States of America.
Diethylene glycol is metabolized by alcohol dehydrogenase to
Acute poisoning
2-​hydroxyethoxyacetaldehyde and by aldehyde dehydrogenase to
The ingestion by an adult of 50 ml of (liquid) hydrogen cyanide or 2-​hydroxyethoxyacetate and a small amount of diglycolic acid. The
200–​300 mg of one of its salts is likely to prove fatal. Inhalation of metabolic acidosis observed in diethylene glycol poisoning is pri-
hydrogen cyanide gas may produce symptoms within seconds and marily due to 2-​hydroxyethoxyacetate, but lactate also plays a part
death within minutes. in severe poisoning. Diglycolic acid is the metabolite responsible for
Acute poisoning is characterized by dizziness, headache, palpitation, the development of proximal tubular necrosis.
anxiety, a feeling of constriction in the chest, dyspnoea, pulmonary oe-
dema, confusion, vertigo, ataxia, coma, and paralysis. Cardiovascular Clinical features
collapse, respiratory arrest, convulsions, and metabolic acidosis are Nausea and vomiting, headache, abdominal pain, coma, seizures,
seen in severe cases. Cyanosis may occur, and the classical ‘brick red’ metabolic acidosis, and acute renal failure have most commonly been
colour of the skin is noted occasionally. There is sometimes an odour of reported. Renal dysfunction in those who do not develop dialysis de-
bitter almonds on the breath, but the ability to detect this is genetically pendence often improves over several months. Pancreatitis and hepa-
determined and some 40% of the population are unable to do so. titis have been observed, together with cranial neuropathies, such as
1766 SECTION 10 Environmental medicine, occupational medicine, and poisoning

facial nerve motor deficits, and demyelinating peripheral neuropathy, Table 10.4.1.11 Clinical features of ethylene glycol poisoning
demonstrated clinically as bilateral lower extremity numbness.
Stage 1 (30 min–​12 h): gastrointestinal and nervous system involvement
Treatment • Apparent intoxication with alcohol (but no ethanol on breath)
Supportive measures to correct metabolic acidosis should be in- • Nausea, vomiting, haematemesis
stituted promptly. If the patient presents early after ingestion,
• Coma and convulsions (often focal)
the priority is to inhibit metabolism using either intravenous
fomepizole or ethanol. Fomepizole requires less monitoring, but • Nystagmus, ataxia, ophthalmoplegias, papilloedema, depressed reflexes,
myoclonic jerks, tetanic contractions
is more expensive than ethanol.
After a loading dose of fomepizole 15 mg/​kg over 30 min, four • Cranial nerve II, V, VII, VIII, IX, X, XII palsies
12-​hourly doses of 10 mg/​kg should be given, followed by 15 mg/​ Stage 2 (12–​24 h): cardiorespiratory involvement
kg 12-​hourly until the glycol concentration is not detectable. If • Tachypnoea, tachycardia
haemodialysis is used, the frequency of dosing should be increased
• Mild hypertension
to 4-​hourly as fomepizole is dialysable.
Alternatively, a loading dose of intravenous ethanol 50 g for an • Metabolic acidosis
adult (50 ml of absolute ethanol in 1 L 5% dextrose, i.e. a 5% ethanol • Myocarditis
solution) should be given, followed by an intravenous infusion of • Pulmonary oedema
ethanol, 10–​12 g/​h (most easily given as 1 L 5% ethanol solution
over 4–​5 h), to achieve a blood ethanol concentration of approxi- • Congestive cardiac failure
mately 1000 mg/​litre. Administration of ethanol should be con- Stage 3 (24–​72 h): renal involvement
tinued until the glycol is undetectable in the blood. If haemodialysis/​ • Flank pain, renal angle tenderness
haemodialfiltration is used, greater amounts of ethanol (17–​22 g/​h) • Hypocalcaemia
must be given, because ethanol is readily dialysable.
Haemodialysis/​haemodialfiltration will remove diethylene glycol, • Acute tubular necrosis
but it is not known whether the metabolites are also removed. • Calcium oxalate crystalluria

Ethylene glycol
ethylene glycol poisoning, the onset and progression of the clinical
Ethylene glycol has a variety of commercial applications and is com- course is frequently not as consistent or predictable.
monly used as an antifreeze fluid in car radiators. Its sweet taste and After a brief period of inebriation due to the intoxicating effect of
ready availability have contributed to its popularity as a suicide agent ethylene glycol itself, metabolic acidosis develops, followed by tachyp-
and as a poor man’s substitute for alcohol. noea, coma, seizures, hypertension, and hypocalcaemia, together with
It is thought that the minimum lethal dose of ethylene glycol is calcium oxalate crystalluria, the appearance of pulmonary infiltrates,
about 100 ml for an adult, although recovery after treatment has and oliguric renal failure. If untreated, death from multiorgan failure
been reported following the ingestion of up to 1 L. usually occurs 24–​36 h after ingestion. Severe acidosis, hyperkalaemia,
The toxicity of ethylene glycol depends predominantly on its seizures, and coma carry a poor prognosis. A serum ethylene glycol
metabolites (Fig. 10.4.1.5) though the initial inebriation is due to concentration more than 500 mg/​litre indicates severe poisoning.
ethylene glycol itself. Central nervous system symptoms coincide
with the peak production of glycolaldehyde; aldehydes inhibit many Treatment
aspects of cellular metabolism. Glycolate is largely responsible for Supportive measures to combat cardiorespiratory depression should
the marked acidosis seen in severe cases; lactate concentrations are be employed and metabolic acidosis, hypocalcaemia, and renal failure
generally not very high. Lactate is produced as a result of the large should be treated conventionally. (For further information on treatment
amount of NADH formed by the oxidation of ethylene glycol and with fomepizole or ethanol, please see the section ‘Diethylene glycol’.)
by inhibition of the tricarboxylic acid cycle by the condensation If admission plasma concentrations show that the ethylene glycol in-
products of glyoxylate. There is increasing evidence that calcium ox- gested has already been metabolized, fomepizole or ethanol adminis-
alate monohydrate crystals are the cause of renal failure and cerebral tration will not be of benefit and ethanol might exacerbate the acidosis.
oedema. Haemodialysis/​ haemodialfiltration removes ethylene glycol,
glycolaldehyde, and glycolate (but not oxalate), and will also correct
Clinical features acid–​base disturbances. Dialysis should be employed particularly if
The clinical features of ethylene glycol poisoning may be divided into presentation is late and marked metabolic acidosis is present. It should
three stages depending on the time after ingestion (Table 10.4.1.11). be continued until the glycol and glycolate are no longer detectable in
Although the three stages are useful theoretical descriptions of the blood.

Ethylene ADH ALDH GO LDH or GO

Glycoaldehyde Glycolate Glyoxylate Oxalate
glycol AO
Ethanol
Fomepizole

Fig. 10.4.1.5 Metabolism of ethylene glycol. ADH, alcohol dehydrogenase; ALDH, aldehyde
dehydrogenase; AO, aldehyde oxidase; GO, glycolate oxidase; LDH, lactate dehydrogenase.
 10.4.1 Poisoning by drugs and chemicals 1767

Formaldehyde cold water and for this reason it fumes strongly in moist air. Aqueous
Formaldehyde is a flammable, colourless gas with a pungent odour. solutions dissolve glass.
It is most commonly available commercially as a 30–​50% w/​w Hydrogen fluoride is particularly dangerous because of its unique
aqueous solution and is an important raw material in the synthesis ability among acids to penetrate tissue. The reason for this is the high
of organic compounds such as plastics and resins. It is added to cos- electronegativity of fluorine, which forms a strong covalent bond
metics and foodstuffs as a preservative and antimicrobial agent and with the hydrogen. The result is a weak acid that exists predomin-
is used in embalming. Formaldehyde also occurs naturally in the antly in the undissociated state. In this state, hydrogen fluoride can
environment. It is released during the combustion of organic ma- penetrate skin and soft tissue by non​ionic diffusion. Once in the tis-
terials (e.g. in forest fires, wood-​burning stoves, and waste inciner- sues, hydrogen fluoride dissociates and causes liquefactive necrosis
ators), and is a product of incomplete petrol combustion in internal of soft tissue, bony erosion, and extensive electrolyte abnormalities
combustion engines. Absorption may follow ingestion, inhalation, by binding the cations calcium and magnesium.
or dermal contact. Once absorbed, formaldehyde is oxidized rapidly Clinical features
to formate then converted more slowly to carbon dioxide and water.
Hydrogen fluoride can cause severe systemic toxicity from even rela-
Clinical features tively small dermal exposures. Inhalation or ingestion of hydrogen
fluoride causes severe corrosive damage similar to other acids (see
Severe irritation of the mucous membranes of the eyes, nose, and
‘Acids’ section). Following absorption by whatever route, fluoride
upper airways occurs after minimal exposure to low (<5 ppm) for-
chelates calcium and lowers the serum ionized calcium concentra-
maldehyde concentrations, which tends to prevent higher exposure
tion and causes weakness, paraesthesiae, tetany, and convulsions.
in even the most tolerant subjects. Substantial exposure may result
Hypotension and cardiac arrhythmias, including ventricular fibrilla-
in severe bronchospasm, pulmonary oedema, and death.
tion, may be observed. Central effects of fluoride include confusion,
Formaldehyde is a recognized cause of occupational asthma.
clouding of consciousness, and coma. Hepatic and renal failure may
Formaldehyde solutions splashed into the eye have caused corneal
develop.
damage and skin contamination has resulted in dermatitis. Spillage
Skin contact with anhydrous hydrogen fluoride produces li-
of phenol-​formaldehyde resin on to the skin has produced extensive
quefactive necrosis and severe burns that are felt immediately.
necrotic skin lesions, fever, hypertension, adult respiratory distress
Concentrated aqueous solutions also cause an early sensation of
syndrome, proteinuria, and renal impairment. Ingestion of for-
pain but more dilute solutions may give no warning of injury. If
maldehyde solution has resulted in severe corrosive damage to the
the solution is not removed promptly, penetration of the skin by
buccal cavity and tonsils, oesophagus, and stomach with ulceration,
fluoride ion may occur, leading to painful ulcers that heal only
necrosis, and subsequent fibrosis and contracture. Shock, metabolic
slowly.
acidosis (due in part to high formate concentrations), respiratory in-
sufficiency, and renal impairment usually ensue. Treatment
Death may follow ingestion of less than 100 ml in an adult.
Inhalation
Treatment
Following inhalation of hydrogen fluoride, the casualty should be
Supportive measures, including the correction of acid–​base disturb- removed immediately from the contaminated atmosphere. Further
ance, should be employed. Folinic acid 50 mg (1mg/kg in children) treatment is symptomatic and supportive. Mechanical ventilation
IV 6 hourly accelerates formate metabolism. Haemodialysis is only with positive end-​expiratory pressure may be needed to treat pul-
moderately effective in increasing formate elimination. monary oedema.
n-​Hexane Ingestion
n-​Hexane is an extremely volatile liquid that is used as a solvent. If hydrofluoric acid has been ingested, management is as for other
It is metabolized oxidatively to several compounds, including 2,5-​ acids (see ‘Acids’). An intravenous injection of 10 ml of 10% calcium
hexanedione, which is eliminated through the urine and is impli- gluconate solution should be given.
cated in the neurotoxic effect of this solvent.
Eye and skin exposure
Clinical features
Skin contact requires immediate thorough washing of the af-
When ingested n-​hexane causes nausea, dizziness, central nervous fected area, for 1 min, even if there is no apparent burn or pain.
system excitation, and then depression, and presents an acute as- Contaminated clothing should be removed, with rescuers protecting
piration hazard. Following inhalation, either inadvertently or delib- their hands with suitable gloves. Skin burns should be coated repeat-
erately, similar symptoms occur. The development of a progressive edly with 2.5% calcium gluconate gel; the gel should be massaged
sensorimotor neuropathy is the principal hazard of chronic exposure. continuously into the skin until at least 15 min after pain is relieved.
Treatment The area should then be covered with a dressing soaked in the gel
and lightly bandaged. Eye contact requires immediate thorough
Treatment is supportive and symptomatic. washing with water. An urgent opthalmological opinion should be
Hydrogen fluoride/​hydrofluoric acid sought.

Hydrogen fluoride is a corrosive, fuming, nearly colourless liquid Hydrogen sulphide

(hydrofluoric acid) at atmospheric pressures and temperatures below Hydrogen sulphide is a colourless gas that smells of rotten eggs, al-
19°C; above 19°C it is gaseous. Hydrogen fluoride is very soluble in though high concentrations cause olfactory nerve paralysis. The gas
1768 SECTION 10 Environmental medicine, occupational medicine, and poisoning

is also found in mines and sewers and is liberated from decomposing airway puncture) may be necessary. Pulmonary complications
fish (a hazard in fishing boats if the hold is filled with ‘trash’ fish used should be treated with humidified supplemental oxygen, broncho-
for making fish meal) and liquid manure systems. dilators and, if necessary, assisted ventilation with positive end-​
The serious sequelae following exposure to high concentrations of expiratory pressure. Early administration of corticosteroids for a
hydrogen sulphide are due principally to inhibition of cytochrome few hours may be beneficial, though later administration offers no
oxidase a3, in which respect it is more potent than cyanide. benefit. Prophylactic antibiotics have not been shown to be of value.

Clinical features Eye and skin exposure

Exposure to low concentrations leads to blepharospasm, pain and If there is no mucosal irritation of the eyes or nose, it can be con-
redness of the eyes, blurred vision, and coloured haloes round lights. cluded that the exposure was not severe and that the individual is not
Headache, nausea, dizziness, drowsiness, sore throat, and cough may at risk of delayed pulmonary oedema, and there is no need to admit
also occur. With exposure to higher concentrations, cyanosis, con- such patients to hospital for observation. If the eyes are affected, they
fusion, pulmonary oedema, coma, and convulsions are common. should be irrigated with water or saline 0.9% for 15–​30 min and an
Death ensues in some 6% of cases. ophthalmic opinion sought. Eye irrigation is facilitated by the use of a
topical anaesthetic. If exposed, the skin should be irrigated with water.
Treatment
Ingestion
The casualty should be moved to fresh air from the contaminated
atmosphere by a rescuer who has donned breathing apparatus be- Neutralizing agents should not be administered after ingestion of
forehand. Thereafter the treatment is symptomatic and supportive. ammonia water because the resultant exothermic reaction may
worsen the injury. Induction of vomiting and gastric lavage are
Irritant gases (ammonia, chlorine, sulphur dioxide) contraindicated. Urgent endoscopy and CT should be performed
Ammonia, chlorine, and sulphur dioxide are water soluble (forming to identify the damage and to insert a nasogatric tube under direct
ammonia water, hypochlorite and hydrochloric acid, and sulphurous observation. If endoscopy is delayed in severe cases, the mucous
acid, respectively) and, therefore, dissolve easily in the mucus of the membranes become very swollen, increasing the risk of perforation.
upper airways. These compounds react with elements of the cell walls, Healing of oesophageal lesions is often accompanied by strictures.
resulting in release of mediators causing an inflammatory cascade Systemic corticosteroids do not improve the outcome in patients
that alters vascular permeability and acts as chemotactic factors. The with severe oesophageal lesions.
altered vascular permeability may lead to influx of plasma that can
Isopropanol
decrease airway calibre, and consequently increase airway resistance.
Isopropanol is used as a sterilizing agent and as ‘rubbing alcohol’. It is
Clinical features also found in aftershave lotions, disinfectants, and window-​cleaning
Inhalation solutions. Intoxication can result from both ingestion and skin ab-
sorption. The accidental use of an isopropanol-​containing enema
Following exposure to these gases, the clinical symptoms appear has resulted in death. Isopropanol is oxidized in the liver to acetone.
immediately and consist of lacrimation, nasal discharge, broncho-
spasm, increased mucus production, and cyanosis. In more severe Clinical features
cases bronchospasm, bronchial oedema, glottal oedema, and in- The major features of severe poisoning are due to central nervous
creased mucus production may be present. Although pulmonary system and respiratory depression, shock, and circulatory collapse.
oedema is observed, it is never the sole presenting feature. Patients The most common metabolic effects are an increased osmolal gap,
with chronic bronchitis or asthma are usually more susceptible. ketonaemia, and ketonuria. There may also be the odour of acetone
Eye and skin exposure on the breath, gastritis, haematemesis, hypothermia, renal tubular
necrosis, acute myopathy, and haemolytic anaemia.
Exposure of the skin and eyes to concentrated ammonia water (li-
quid ammonia) may cause corrosive damage; evaporation of am- Treatment
monia may cause extreme cooling when spilled on the skin or eyes; In addition to supportive measures, haemodialysis/​haemodialfiltra­
cold burns may result. tion should be employed in severely poisoned patients as it removes
Ingestion isopropanol and acetone. No advantage is gained by administering
ethanol or fomepizole to block alcohol dehydrogenase, because the
Ingestion of ammonia water induces severe caustic lesions of the toxicity of isopropanol is caused principally by the parent com-
mucous membranes of the oropharynx, oesophagus, and stomach. pound and not by acetone. Moreover, such treatment will enhance
Oesophageal or gastric perforation may occur, causing mediastinitis the toxicity of isopropanol.
or peritonitis, respectively.
Methanol
Treatment
Methanol is used widely as a solvent. It is also found in antifreeze
Inhalation solutions, paints, duplicating fluids, paint removers and varnishes,
The priority is to remove the casualty from exposure. Early inspec- and shoe polishes. The ingestion of as little as 10 ml of pure methanol
tion of the upper airways is important because the mucosal mem- has caused permanent blindness and 30 ml is potentially fatal, al-
branes may be very oedematous in severe cases, precluding oral though individual susceptibility varies widely. Toxicity may also
endotracheal intubation; tracheostomy or coniotomy (emergency occur as a result of inhalation or percutaneous absorption.
 10.4.1 Poisoning by drugs and chemicals 1769

ADH FDH 10-FTS stupor have been reported. Severe and prolonged exposure may lead
Methanol Formaldehyde Formate CO2 + H2O
to irritant conjunctivitis, lacrimation, and respiratory depression.
Ethanol Hepatorenal dysfunction and pulmonary oedema have also been
Fomepizole described. Fatalities have occurred.
Fig. 10.4.1.6 Metabolism of methanol. ADH, alcohol dehydrogenase;
If high concentrations of carboxyhaemoglobin are present, the
FDH, formaldehyde dehydrogenase; 10-​FTS, 10-​formyltetrahydrofolate features of acute carbon monoxide poisoning may also ensue, al-
synthetase. though these tend to be mild even in the presence of such high
concentrations.
Methanol is metabolized by alcohol dehydrogenase and catalase Methylene chloride ingestion causes corrosive injury to the
enzyme systems to formaldehyde and formate (Fig. 10.4.1.6). The gastrointestinal tract, agitation, diaphoresis, and drowsiness with
concentration of formate increases greatly and is accompanied by ac- rapid progression to coma in severe cases. Consciousness is typically
cumulation of hydrogen ions, causing metabolic acidosis. regained after several hours unless hypoxic encephalopathy ensues.
Pancreatitis, hepatic dysfunction, and renal and respiratory failure
Clinical features are potential complications. Carboxyhaemoglobin concentrations
Ingested alone, methanol causes mild and transient inebriation and may remain raised for days.
drowsiness. After a latent period of 8–​36 h, nausea, vomiting, ab-
Treatment
dominal pain, headaches, dizziness, and coma supervene. Blurred
vision and diminished visual acuity may occur and the presence of Prompt removal from exposure prior to death usually results in
dilated pupils, unreactive to light, suggests that permanent blindness complete recovery. Thereafter, treatment is supportive and should
is likely to ensue. A severe metabolic acidosis may develop, and this include the use of supplemental oxygen.
may be accompanied by hyperglycaemia and raised serum amylase
Nitrites
activity. A blood methanol concentration of more than 500 mg/​litre
confirms serious poisoning. Mortality increases with the severity and Volatile alkyl nitrites, for example, amyl and butyl (predominantly
duration of the metabolic acidosis. Survivors may show permanent isobutyl) nitrite, are recreational drugs marketed as aphrodisiacs or
neurological sequelae including blindness, rigidity, hypokinesis, and ‘room odourizers’. They are alleged to improve sexual performance
other parkinsonian-​like signs; these features follow the development by enhancing and prolonging orgasm and/​or as a smooth muscle re-
of optic neuropathy and necrosis of the putamen. laxant to relax the anal sphincter. They also are claimed to promote
a sense of increased well-​being with temporary detachment from
Treatment reality. The intended route of exposure is inhalation, but they are oc-
The treatment of methanol poisoning is directed towards the inhib- casionally also ingested, either accidentally or deliberately.
ition of methanol metabolism by the administration of fomepizole or Alkyl nitrites cause vasodilatation via nitric oxide mediated vas-
ethanol (see the section ‘Diethylene glycol’), the correction of metabolic cular smooth muscle relaxation. Vasodilatation accounts for many
acidosis and the removal of circulating methanol and its toxic metabol- of the effects observed or described by users following abuse. More
ites by haemodialysis or haemodialfiltration. Substantial quantities of important toxicologically is the ability of these agents to oxidize fer-
bicarbonate may be required and since this must be accompanied by rous haem from the Fe2+ to the ferric (Fe3+) state, resulting in meth-
sodium, hypernatraemia, and hypervolaemia may result. aemoglobinaemia after substantial inhalation or ingestion.
If admission plasma concentrations show that the methanol in-
Clinical features
gested has already been metabolized, fomepizole, or ethanol ad-
ministration will not be of benefit and ethanol might exacerbate These reflect vasodilation with headache, flushing, blurred vision,
the acidosis. postural hypotension, and syncope, followed by reflex vasoconstric-
Dialysis is indicated when a patient has ingested more than 30 g tion with sinus tachycardia. With continued exposure, methaemo-
of methanol, or develops metabolic acidosis, mental, visual, or globinaemia results. Irritant effects including burning in the nose and
fundoscopic abnormalities attributable to methanol, or a blood eyes; cough and facial dermatitis are recognized; and transient ECG
methanol concentration in excess of 500 mg/​litre. Folinic acid 50 mg changes (T wave inversion and ST segment depression) have been
(1 mg/​kg in children) intravenously 6-​hourly may protect against reported. Methaemoglobin concentrations less than 20% are usually
ocular toxicity by accelerating formate metabolism. asymptomatic though they cause slate-​grey ‘cyanosis’ due predomin-
antly to the presence of pigmented methaemoglobin. When 20–​40%
Methylene chloride (dichloromethane) total haemoglobin is replaced by methaemoglobin, there may be diz-
Methylene chloride is a common ingredient in paint removers and is ziness and headache, features not dissimilar to those caused by vaso-
used as a solvent for plastic films and cements and also as a degreaser dilatation. Higher methaemoglobin concentrations reflect increasing
and aerosol propellant. Exposures usually follow inhalation, though tissue hypoxia and are unusual following volatile nitrite abuse, unless
deliberate ingestion is recognized. Methylene chloride is metabol- inhalation is substantial or ingestion has occurred. However, in these
ized to CO2 and carbon monoxide. Carboxyhaemoglobin concen- circumstances, life-​threatening methaemoglobinaemia may result.
trations of 3–​10% (exceptionally 40%) are attained.
Treatment
Clinical features The vasodilatory effects of volatile nitrite abuse are not usually se-
Skin contact with liquid methylene chloride can cause a chemical vere and can be managed supportively. In healthy adults, meth-
burn. Following inhalation, dizziness, tingling and numbness of the aemoglobin concentrations less than 30% total haemoglobin are
extremities, throbbing headache, nausea, irritability, fatigue, and unlikely to warrant specific treatment. At higher methaemoglobin
1770 SECTION 10 Environmental medicine, occupational medicine, and poisoning

concentrations, or where clinical features suggest tissue hypoxia, pulmonary oedema may occur. Other complications include hepatic
antidotal therapy with intravenous methylthioninium chloride dysfunction and, in severe cases, atrial fibrillation and ventricular
(methylene blue) 1–​2 mg/​kg body weight as a 1% solution should fibrillation.
be given over 5–​10 min. Treatment is effective within 30 min and a
second dose is required rarely. Treatment
Gastric lavage and emesis should be avoided because of the increased
Nitrogen dioxide risk of chemical pneumonitis. There is no evidence that corticoster-
Nitrogen dioxide is the most toxic nitrogen oxide and causes hyp- oids and antibiotics reduce morbidity or mortality; mechanical ven-
oxic asphyxia by displacing oxygen. It dissolves poorly in water and tilation with positive end-​expiratory pressure may be necessary in
therefore penetrates deeper into the lung (i.e. to the alveoli and ter- severe cases of aspiration.
minal bronchioles). The ciliated cells of the bronchioles and the al-
veolar type I cells are especially susceptible to injury. Following the Petrol (gasoline)
alveolar damage, an influx of plasma and inflammatory cells occurs, Petrol is a complex mixture of volatile hydrocarbons containing a
causing acute lung injury. small proportion of non​hydrocarbon additives.

Clinical features Clinical features

The clinical features following acute exposure depend on the con- Following the inhalation of petrol, dizziness, and irritation of the
centration and duration of exposure to the gas. Modest acute ex- eyes, nose and throat may occur within 5 min followed by euphoria,
posure (<50 ppm) for a short time often produces no immediate headache, and blurred vision. If inhalation continues, or if significant
symptoms, although throat irritation, cough, transient choking, quantities of petrol are ingested, then excitement and depression of
tightness in the chest, and sweating have been observed. By contrast, the nervous system occurs; incoordination, restlessness, excitement,
exposure to a massive concentration of nitrogen dioxide, such as confusion, disorientation, hallucinations, ataxia, nystagmus, tremor,
that found in a silo, can produce severe and immediate hypoxaemia, delirium, coma, and convulsions may be seen. Inhalation of high
which may be fatal. concentrations of petrol may cause immediate death, probably from
As symptoms can be absent during the first hours after exposure, ventricular fibrillation or respiratory failure. Chemical pneumonitis
physical examination of the patient immediately after exposure may may occur as in paraffin oil ingestion (see ‘Paraffin oil (kerosene)’)
not provide information regarding the full extent of the clinical se- and the clinical features and management are then identical.
verity of the intoxication. However, if 6 h after exposure, the patient
has normal arterial blood gases and chest X-​ray, there is little like- Treatment
lihood that life-​threatening lung damage will develop. Patients can Following removal from exposure, supportive measures provide the
then be discharged with instructions that they must undergo med- basis of treatment.
ical observation again if increased dyspnoea occurs after discharge.
Bronchiolitis obliterans may develop within 2–​6 weeks. Phenol
Phenol (‘carbolic acid’) is nearly always recognizable by its odour
Treatment and, distinctively, the pain to which it gives rise is much less than
Adequate supportive therapy such as supplemental oxygen and might be expected. This is due to its ability to damage afferent nerve
bronchodilators should be given. Early administration of cortico- endings.
steroids for a few hours may be beneficial, though later adminis-
tration offers no benefit. Use of prophylactic systemic antibiotics is Clinical features
not recommended because of the increased risk of infection with If phenol is spilt on the skin, pain is followed promptly by numb-
resistant organisms. When intubation is required, the largest prac- ness. The skin becomes blanched, and a dry opaque eschar forms
ticable tube should be introduced to allow adequate bronchial toilet. over the burn. When the eschar sloughs off, a brown stain remains.
Assisted ventilation with positive end-​expiratory pressure offers the Phenol penetrates intact skin rapidly and is well absorbed through
best hope of reducing the mortality. the lungs.
After ingestion, nausea, vomiting, and abdominal pain result.
Paraffin oil (kerosene) Depending on the concentration of the solution corrosive injury may
Paraffin oil has three physical properties accounting for its tox- result in bleeding, perforation, and subsequent stricture formation.
icity. Its low viscosity and surface tension allow it to spread rapidly Systemic toxicity may follow exposure by any route. Signs of sys-
throughout the lungs when aspirated after ingestion, and its low va- temic toxicity include sweating, headache, tinnitus, and dizziness.
pour pressure makes it unlikely to cause poisoning by inhalation. An initial rise in blood pressure is followed by hypotension precipi-
tated by phenol-​induced loss of vasoconstrictor tone. Loss of con-
Clinical features sciousness, respiratory depression, coma, seizures, and shock follow,
Repeated local application to the skin results in dryness, dermatitis, which may result in renal failure. An initial phase of central nervous
and, rarely, epidermal necrolysis. Paraffin ingestion causes a burning system stimulation, and rarely convulsions, has sometimes been ob-
sensation in the mouth and throat, vomiting, diarrhoea, and ab- served in children.
dominal pain. Pulmonary features may occur within 1 h of ingestion Phenol poisoning is associated with grey or black urine and though
with cough, tachypnoea, tachycardia, basal crackles, and cyan- this is due in part to metabolites of phenol, Heinz body haemolytic
osis. Non​segmental consolidation or collapse is seen radiologic- anaemia, as well as methaemoglobinaemia and hyperbilirubinaemia,
ally. Pneumatocoele formation, pneumothorax, pleural effusion, or contribute.
 10.4.1 Poisoning by drugs and chemicals 1771

Treatment of acute alcohol withdrawal) may cause convulsions, coma, cardiac

Fluid resuscitation and prompt assessment of the extent of corro- arrhythmias, hepatorenal damage, intravascular haemolysis, meta-
sive damage is crucial following ingestion. Management is otherwise bolic acidosis, and increased serum osmolality.
supportive. Skin and eye contamination, renal failure and meth- Treatment
aemoglobinaemia are managed conventionally.
Metabolic acidosis, renal failure, and respiratory depression should
Phosgene be treated conventionally. Haemodialysis removes propylene glycol
Phosgene is used in the synthesis of isocyanates, polyurethane and efficiently. Ethanol or fomepizole may be used to inhibit propylene
polycarbonate resins, and dyes. It is also produced in fires and has glycol metabolism in a similar way to their use in ethylene glycol
been used as a chemical weapon. poisoning, but in practice the diagnosis is often not made until a sig-
When combined with water, phosgene produces hydrogen nificant acidosis is present and thus it is too late for antidotal treat-
chloride and carbon dioxide, although as the gas is poorly soluble ment to be useful.
in water, only small amounts of hydrochloric acid are produced
Tetrachloroethylene
under normal physiological conditions. It is thought that this is
only relevant in causing mucus membrane and eye symptoms when Tetrachloroethylene is used widely as an industrial solvent, par-
phosgene is present at relatively high concentrations. Biologically, ticularly for dry-​cleaning and degreasing. Poisoning may occur by
acylation and free radical-​mediated reactions occur between phos- inhalation or ingestion. A considerable proportion of an inspired
gene and important cellular constituents. Acylation reactions dose is exhaled unchanged, and that retained is excreted only slowly
involving phosgene occur with biological molecules containing (half-​life c.144 h), mainly by metabolism to trichloroacetic acid, the
sulfhydryl, amino and hydroxyl moieties. major urine metabolite.

Clinical features Clinical features

Exposure to phosgene causes irritation of the eyes, dryness or Following inhalation or ingestion, there is depression of the central
burning sensation in the throat, cough, chest pain, and nausea and nervous system; nausea and vomiting may occur and persist for sev-
vomiting. There is usually a latent period lasting between 30 min and eral hours. Irritation of the eyes, nose, and throat may occur from
24 h (rarely, 72 h) during which the casualty suffers little discomfort direct exposure. Hepatic and renal dysfunction may also develop
and has no abnormal chest signs. Subsequently, pulmonary oedema and ventricular arrhythmias and non​cardiogenic pulmonary oe-
develops due to increased capillary permeability; circulatory col- dema have been reported.
lapse may follow.
Treatment
Treatment After removal from exposure, treatment is supportive and
Treatment is supportive. There are experimental data to sug- symptomatic.
gest that an intravenous bolus of high-​dose corticosteroid (e.g.
Toluene
methylprednisolone 1 g) < 6h after exposure may be of benefit. There
is no benefit from nebulized steroid even when administered 1 h Toluene has much lower volatility and toxicity than benzene. It is
after exposure. Consideration should also be given to administra- used extensively as a solvent in the chemical, rubber, paint, glue, and
tion of nebulized acetylcysteine 1–​2 g, though there is no substantive pharmaceutical industries and as a thinner for inks, perfumes, and
evidence of benefit outside a small animal, isolated lung model. If the dyes. Following inhalation or ingestion, toluene is oxidized to ben-
oxygen saturation falls below 94%, patients should receive the lowest zoic acid, then to hippuric acid benzoylglucuronates, which are ex-
concentration of supplemental oxygen to maintain their SaO2 in the creted in the urine.
normal range. Once patients require oxygen, nebulized β-​agonists
Clinical features
(e.g. salbutamol (albuterol) 5 mg by nebulizer every 4 h) may reduce
lung inflammation if administered within 1 h of exposure. Elective Acute poisoning results in euphoria, excitement, dizziness, confu-
intubation should be considered early using an ARDSNet protective sion, increased lacrimation, headache, nervousness, nausea, tin-
ventilation strategy. nitus, ataxia, tremor, and coma.
A review of adults who had abused toluene indicated three major
Propylene glycol patterns of presentation: (1) muscle weakness, (2) gastrointestinal
Propylene glycol is used widely as a preservative and solvent for oral, complaints (abdominal pain, haematemesis), and (3) neuropsychi-
intravenous, and topical medications. It is oxidized to lactic acid atric disorders (altered mental status, cerebellar abnormalities, per-
and pyruvate via hepatic alcohol and aldehyde dehydrogenases in ipheral neuropathy). In addition, hypokalaemia, hypophosphataemia
a similar way to the metabolism of other glycols such as ethylene and hyperchloraemia were common. Rhabdomyolysis occurred in
glycol. 40% of cases. Distal renal tubular acidosis and urinary calculi were
also reported. Cardiac and haematological toxicity due to toluene
Clinical features appears to be uncommon.
The ingestion of substantial quantities of propylene glycol or its ad-
ministration to neonates, those in renal failure, or in exceptionally Treatment
large doses (such as patients requiring massive parenteral doses of If poisoning results from inhalation, whether accidental or in-
propylene glycol-​containing benzodiazepines in the management tentional, the patient should be removed from the contaminated
1772 SECTION 10 Environmental medicine, occupational medicine, and poisoning

environment. Thereafter, treatment consists of symptomatic and sodium tripolyphosphate, and sodium silicate, which reduce water
supportive measures. hardness. The pH once dissolved in water is alkaline.

1,1,1-​Trichloroethane Clinical features

1,1,1-​Trichloroethane is a liquid of high volatility used as a solvent Toxicity from hydrogen peroxide occurs as a result of its corro-
in industry. Most of an inhaled dose is expired unchanged, though sive effects and release of oxygen causing embolism. Ingestion may
small amounts of trichloroacetic acid and trichloroethanol are cause irritation of the gastrointestinal tract with nausea, vomiting,
formed. Concomitant ingestion of ethanol is known to enhance foaming at the mouth, paraesthesia around the mouth, blistering in
toxicity. the mouth, stomatitis, mouth bleeding, laryngitis, pharyngitis, and
haematemesis. The foam may then obstruct the respiratory tract re-
Clinical features sulting in stridor or pulmonary aspiration. Sodium carbonate in-
Following inhalation of a sufficiently large dose, central nervous gestion has led to stridor, drooling, coughing, and oedematous lips.
system depression occurs; hepatic and renal dysfunction may also
result. Deaths have followed exposure to very high concentrations Treatment
in unventilated tanks. In such cases, death may either be due to cen- If several tablets have been ingested, upper gastrointestinal endos-
tral nervous system depression, culminating in respiratory arrest, or copy and CT oesophagus should be considered.
to fatal arrhythmias as a result of myocardial sensitization to circu-
lating catecholamines in the presence of hypoxia. Batteries
Batteries are usually swallowed accidentally. They contain metal
Treatment salts, usually of nickel, lithium, cadmium, manganese, zinc, or silver.
The casualty should be removed from the contaminated environ- Code numbers on button batteries will help identify the content.
ment. Thereafter treatment is symptomatic and supportive. While most batteries are passed without complications, problems
may arise if the battery becomes lodged, particularly in the oe-
Trichloroethylene sophagus, where local necrosis, bleeding, and perforation are po-
Trichloroethylene is a volatile liquid used as an industrial solvent, tential complications. Fatalities have occurred in young children
particularly in metal degreasing and extraction processes. Following following button battery ingestion, although toxicity from metal
exposure, it is excreted unchanged in the breath and metabolized via content is a potential risk, in reality this is vanishingly rare.
chloral hydrate to trichloroethanol and trichloroacetic acid, which
are excreted in the urine. Clinical features
These relate to whether or not the battery lodges or leaks. Symptoms
Clinical features are uncommon. Lodged batteries may perforate within 2–​4 h, and
Following exposure by any route, central nervous system depres- delayed bleeding is a further hazard after battery removal.
sion occurs with nausea and vomiting, hepatic and renal dysfunc-
tion, cranial nerve damage, cerebellar dysfunction, and convulsions Treatment
have been described. ‘Degreaser’s flush’ (in which the skin of the A chest X-​ray is necessary in those who have swallowed a battery,
face and arms becomes markedly reddened) may occur if ethanol and those lodged in the oesophagus must be removed as soon as
is consumed shortly before or after exposure to trichloroethylene. possible. Further X-​rays 48 h later may be needed if batteries
have not passed per anus. If symptoms develop, particularly of GI
Treatment
bleeding or obstruction, urgent surgical intervention is required, if
The casualty should be removed from the contaminated environ- possible by endoscopy.
ment. Thereafter treatment is symptomatic and supportive.
Bleaches
Most household bleaches contain sodium hypochlorite, but some
Household products chlorine–​free bleaches contain 6% hydrogen peroxide. Chlorine is
not released from bleach solutions in appreciable amounts under
Automatic dishwashing tablets normal use conditions. However, the mixing of hypochlorite with
The traditional tablets for automatic dishwashing machines are acids (e.g. when cleaning the toilet bowl) can result in the substantial
contained within an external wrapper that requires removal prior release of chlorine and lung injury.
to loading the enclosed tablet into the machine. Soluble film auto- Mixing bleach with ammonia produces chloramine compounds
matic dishwashing tablets are enclosed by a water-​soluble poly- (mainly monochloramine) which can produce severe chemical
vinyl alcohol film and are loaded straight into the dishwashing pneumonitis.
machine, unlike their traditional counterparts. However, the in-
tegrity of the soluble film can be compromised and the contents of Clinical features
the tablet can be released prematurely when in contact with moist Following the ingestion of weak concentrations of sodium hypo-
hands or saliva. chlorite (<5%), symptoms are usually mild. With stronger bleaches,
The tablets most commonly contain a source of hydrogen per- particularly of over 10% sodium hypochlorite, features are more se-
oxide (often as sodium percarbonate) and non​ionic surfactants. vere. Small amounts cause a sensation of burning. Larger doses cause
Other constituents in some formulations include sodium carbonate, nausea, retching, vomiting, diarrhoea and, rarely, haematemesis. In
 10.4.1 Poisoning by drugs and chemicals 1773

severe cases a hypernatraemic hyperchloraemic acidosis, hypoten- enzyme activities can occur. Dermal burns have been reported and
sion, coma, convulsions, and cardiorespiratory arrest can occur. The eye exposures can cause corneal damage.
gastrointestinal mucosa may become haemorrhagic, ulcerated, and
perforated. Treatment
For the features of hydrogen peroxide, please see the earlier Treatment is symptomatic and supportive.
section ‘Automatic dishwashing tablets’.

Treatment
FURTHER READING
If concentrated bleach (>10% sodium hypochlorite) or hydrogen
peroxide-​containing bleaches are ingested, upper gastrointes- Epidemiology
tinal endoscopy and CT should be considered. Bateman DN, et al. (2006). Legislation restricting paracetamol sales
and patterns of self-​harm and death from paracetamol-​containing
Detergents preparations in Scotland. Br J Clin Pharmacol, 62, 573–​81.
Dart RC, et al. (2015). Poisoning in the United States: 2012 emergency
Liquid laundry detergent capsules (also called single-​use detergent
medicine report of the national poisons data system. Ann Emerg
sacs; laundry pods) are a pouch of concentrated liquid laundry de-
Med, 65, 416e22.
tergent in a water-​soluble polyvinyl alcohol membrane that can
Martins SS, et al. (2015). Worldwide prevalence and trends in unin-
be placed directly in washing machines. In Europe, these liquid tentional drug overdose: a systematic review of the literature. Am J
detergents most commonly contain anionic surfactants (20–​35% Public Health, 105, e29e49.
per capsule), non​ionic surfactants (10–​20%), propylene glycol McCarthy M (2015). Drug overdose has become leading cause of death
(8–​20%) and ethanol (2–​5%), and have a pH of 7–​9. The capsules from injury in US. Br Med J, 350, h3328.
are designed to release their contents when they come into contact Morrison EE, Dear JW, Sandilands EA (2015). Self-​poisoning in the
with water and this can happen prematurely if they come into con- elderly: a 10-​year observational study. Clin Toxicol, 53, 284e5.
tact with moisture (e.g. in the hands or mouth). Immediate treatment
Barceloux D, et al. (2004). Position paper: cathartics. Clin Toxicol, 42,
Clinical features
243–​53.
As a result, there have been a substantial number of exposures to Benson B E, et al. (2013). Position paper update: gastric lavage for
laundry liquid detergent capsules, predominantly involving children gastrointestinal decontamination. Clin Toxicol, 51, 140–​6.
less than 5 years of age. Although most patients remain asymptom- Chyka PA, et al. (2005). Position paper: single-​dose activated charcoal.
atic or suffer only minor features, a small proportion develop fea- Clin Toxicol, 43, 61–​87.
tures such as central nervous system depression, stridor, pulmonary Höjer J, et al. (2013). Position paper update: ipecac syrup for gastro-
aspiration and/​or airway burns following ingestion and conjunctiv- intestinal decontamination. Clin Toxicol, 51, 134–​39.
itis leading to corneal ulceration from eye exposure. Thanacoody R, et al. (2015). Position paper update: whole bowel ir-
rigation for gastrointestinal decontamination of overdose patients.
Treatment Clin Toxicol, 53, 5–​12.
Treatment is symptomatic and supportive. Methods to increase poison elimination
Eddleston M, et al. (2008). Multiple-​dose activated charcoal in
Disinfectants acute self-​poisoning: a randomised controlled trial. Lancet, 371,
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tinuous veno–​venous hemodiafiltration in the management of se-
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von Mach MA, et al. (2006). Antidiabetic medications in overdose: a
between dapsone-​induced methemoglobinemia and other toxic-​
comparison of the inquiries made to a regional poisons unit re-
agent-​induced methemoglobinemia. Clin Toxicol, 54, 581–​4.
garding original sulfonylureas, biguanides and insulin. Int J Clin
Pharmacol Ther, 44, 51–​6. Digoxin and digitoxin
Antihistamines Chan BS, et al. (2016). Efficacy and effectiveness of anti-​digoxin
antibodies in chronic digoxin poisonings from the DORA study
Pragst F, Sieglinde H, Bakdash A (2006). Poisonings with
(ATOM-​1). Clin Toxicol, 54, 488–​94.
diphenhydramine—​a survey of 68 clinical and 55 death cases.
Roberts DM, et al. (2016). Pharmacological treatment of cardiac glyco-
Forens Sci Int, 161, 189–​97.
side poisoning. Br J Clin Pharmacol, 81, 488–​95.
Antimalarials
Diuretics
Langford NJ, et al. (2003). Quinine intoxication reported to the Scottish
Lip GY, Ferner RE (1995). Poisoning and anti-​hypertensive drugs: di-
Poisons Information Bureau 1997–​2002: a continuing problem. Br J
uretics and potassium supplements. J Hum Hypertens, 9, 295–​301.
Clin Pharmacol, 56, 576–​8.
Mégarbane B, et al. (2010). Blood concentrations are better predictors Iron
of chloroquine poisoning severity than plasma concentrations: a Chang TP, Rangan C (2011). Iron poisoning: a literature-​based review
prospective study with modelling of the concentration/​effect rela- of epidemiology, diagnosis and management. Pediatr Emerg Care,
tionships. Clin Toxicol, 48, 904–​15. 27, 978–​85.
Antipsychotics Tenenbein M (1996). Benefits of parenteral deferoxamine for acute
iron poisoning. Clin Toxicol, 34, 485–​9.
Burns MJ (2001). The pharmacology and toxicology of atypical anti-
psychotic agents. Clin Toxicol, 39, 1–​14. Isoniazid
Glassman AH, Bigger Jr JT (2001). Antipsychotic drugs: prolonged Bateman DN, Page CB (2016). Antidotes to coumarins, isoniazid,
QTc interval, torsade de pointes, and sudden death. Am J Psychiatry, methotrexate and thyroxine; toxins that work via metabolic pro-
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 10.4.1 Poisoning by drugs and chemicals 1775

Lithium carbonate Ethanol

Bradberry S (2016). Lithium. Medicine GBR, 44, 180–​1. Vale A (2016). Alcohols and glycols. Medicine GBR, 44, 128–​32.
Nitrates Gamma hydroxybutyric acid and analogues
Vignal-​Clermont C, et al. (2010). Poppers-​associated retinal toxicity. N Busardò FP, Jones AW (2015). GHB pharmacology and toxi-
Engl J Med, 363, 1583–​5. cology: acute intoxication, concentrations in blood and urine in
Non​steroidal anti-​inflammatory drugs forensic cases and treatment of the withdrawal syndrome. Curr
Sandilands EA, Bateman DN (2016). Non-​steroidal anti-​inflammatory Neuropharmacol, 13, 47–​70.
drugs. Medicine GBR, 44, 185–​6. Tarabar AF, Nelson LS (2004). The gamma-​hydroxybutyrate with-
drawal syndrome. Toxicol Rev, 23, 45–​9.
Paracetamol (acetaminophen)
Bateman DN, Dear JW, Thomas SHL (2016). New regimens for intra- Ketamine
venous acetylcysteine, where are we now? Clin Toxicol, 54, 75–​8. Liu Y, Lin D, Wu B, Zhou W (2016). Ketamine abuse potential and use
Bateman DN, Vale A (2016). Paracetamol (acetaminophen). Medicine disorder. Brain Res Bull, 126, 68–​73.
GBR, 44, 190–​192. LSD
Sandilands EA, Morrison EE, Bateman DN (2016). Adverse reactions
Vale A (2007). LSD. Medicine GBR, 35, 654–​5.
to intravenous acetylcysteine in paracetamol poisoning. Adverse
Drug React Bull, 297, 1147–​50. Opiates and opioids
Salicylates Sandilands EA, Bateman DN (2016). Opioids. Medicine GBR,
44, 187–​9.
Chapman BJ, Proudfoot AT (1989). Adult salicylate poisoning: deaths
and outcome in patients with high plasma salicylate concentrations. Tryptamines
Q J Med, 72, 699–​707. Kamour A, et al. (2014). Patterns of presentation and clinical tox-
Proudfoot AT, et al. (2003). Does urine alkalinization increase sali- icity after reported use of alpha methyltryptamine in the United
cylate elimination? If so, why? Toxicol Rev, 22, 129–​36. Kingdom. A report from the UK National Poisons Information
Theophylline Service. Clin Toxicol, 52, 192–​7.
Shannon M (1999). Life-​threatening events after theophylline overdose—​ Metals
a 10-​year prospective analysis. Arch Int Med, 159, 989–​94.
Aluminium
Thyroxine McCarthy JT, Milliner DS, Johnson WJ (1990). Clinical experience
Nygaard B, et al. (2015). Levothyroxine poisoning—​symptoms and with desferrioxamine in dialysis patients with aluminium toxicity.
clinical outcome. Basic Clin Pharmacol Toxicol, 117, 280–​5. Q J Med, 74, 257–​76.
Spinelli JJ, et al. (2006). Cancer risk in aluminium reduction plant
Drugs of abuse (including ethanol) workers (Canada). Cancer Causes Control, 17, 939–​48.
Amphetamines
Arsenic
Schep LJ, Slaughter RJ, Beasley DM (2010). The clinical toxicology of
Aposhian HV, Aposhian MM (2006). Arsenic toxicology: five ques-
metamfetamine. Clin Toxicol, 48, 675–​94.
tions. Chem Res Toxicol, 19, 1–​15.
Seger D (2010). Cocaine, metamfetamine, and MDMA abuse: the role
International Agency for Research on Cancer (2004). Some
and clinical importance of neuroadaptation. Clin Toxicol, 48, 695–​708.
drinking-​water disinfectants and contaminants, including arsenic.
Cannabis International Agency for Research on Cancer, Lyon.
Moore THM, et al. (2007). Cannabis use and risk of psychotic or affective
mental health outcomes: a systematic review. Lancet, 370, 319–​28. Cadmium
Greim H, (ed) (2006). Cadmium and its inorganic compounds.
Synthetic cannabinoid receptor agonists
In: The MAK-​c ollection for occupational health and safety.
Tait RJ, et al. (2016). A systematic review of adverse events arising from Part I: MAK value documentations, pp. 1–​4 1. Wiley-​VCH,
the use of synthetic cannabinoids and their associated treatment. Weinheim.
Clin Toxicol, 54, 1–​13.
Waugh J, et al. (2016). Epidemiology and clinical features of tox- Chromium
icity following recreational use of synthetic cannabinoid receptor Barceloux DG (1999). Chromium. J Toxicol Clin Toxicol, 37,
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Information Service. Clin Toxicol, 54, 512–​18. Bradberry SM, Vale JA (1999). Therapeutic review: is ascorbic acid of
value in chromium poisoning and chromium dermatitis. J Toxicol
Cathinones, benzofurans, and related compounds
Clin Toxicol, 37, 195–​200.
Roberts L, et al. (2017). 11 analytically confirmed cases of mexedrone
use among polydrug users. Clin Toxicol, 55, 181–​6. Cobalt
Umebachi R, et al. (2016). Clinical characteristics of α-​pyrrolidino- Bradberry SM, Wilkinson JM, Ferner RE (2014). Systemic toxicity
valerophenone (α-​PVP) poisoning. Clin Toxicol, 54, 563–​7. related to metal hip prostheses. Clin Toxicol, 52, 837–​47.
Wood DM, et al. (2015). Prevalence of use and acute toxicity associated Copper
with the use of NBOMe drugs. Clin Toxicol, 53, 85–​92.
Barceloux DG (1999). Copper. J Toxicol Clin Toxicol, 37, 217–​30.
Cocaine Takeda T, Yukioka T, Shimazaki S (2000). Cupric sulfate intoxica­
Richards JR, et al. (2016). Treatment of cocaine cardiovascular tox- tion with rhabdomyolysis, treated with chelating agents and blood
icity: a systematic review. Clin Toxicol, 54, 345–​64. purification. Int Med, 39, 253–​5.
1776 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Lead Glyphosate
Bradberry S, Sheehan T, Vale A (2009). Use of oral dimercaptosuccinic Bradberry SM, Proudfoot AT, Vale JA (2004). Glyphosate poisoning.
acid (succimer; DMSA) in adult patients with inorganic lead poi- Toxicol Rev, 23, 159–​67.
soning. Q J Med, 102, 721–​32. Metaldehyde
Bradberry SM, Vale JA (2009). A comparison of sodium calcium
Bleakley C, et al. (2008). Self-​poisoning with metaldehyde. Emerg Med
edetate (edetate calcium disodium) and succimer (DMSA) in the
J, 25, 381–​2.
treatment of inorganic lead poisoning. Clin Toxicol, 47, 841–​58.
Methyl bromide
Mercury
Yamano Y, Nakadate T (2006). Three occupationally exposed cases
Bradberry SM, et al. (2009). DMPS can reverse the features of se-
of severe methyl bromide poisoning: accident caused by a gas leak
vere mercury vapor-​induced neurological damage. Clin Toxicol,
during the fumigation of a folklore museum. J Occup Health, 48,
47, 894–​8.
129–​33.
O’Carroll RE, et al. (1995). The neuropsychiatric sequelae of mer-
cury poisoning: the Mad Hatter’s disease revisited. Br J Psychiatry, Neonicotinoids
167, 95–​8. Cimino AM, et al. (2017). Effects of neonicotinoid pesticide exposure
on human health: a systematic review. Environ Health Perspect, 125,
Nickel
155–​62.
Bradberry SM, Vale JA (1999). Therapeutic review: do
diethyldithiocarbamate and disulfiram have a role in acute nickel Organophosphorus insecticides
carbonyl poisoning. J Toxicol Clin Toxicol, 37, 259–​64. Vale A, Lotti M (2015). Organophosphorus and carbamate insecticide
Seet RCS, et al. (2005). Inhalational nickel carbonyl poisoning in waste poisoning. Handb Clin Neurol, 131, 149–​68.
processing workers. Chest, 128, 424–​9. Phosphine
Phosphorus Willers-​Russo LJ (1999). Three fatalities involving phosphine gas, pro-
Bradberry SM, Vale JA (2014). Poisoning due to metals, and their duced as a result of methamphetamine manufacturing. J Forensic Sci,
salts: phosphorus. In: Bateman DN, et al. (eds). Oxford desk refer- 44, 647–​52.
ence: toxicology, pp. 284–​5. Oxford University Press, Oxford. Pyrethroids
Thallium Bradberry SM, et al. (2005). Poisoning due to pyrethroids. Toxicol Rev,
Hoffman RS (2003). Thallium toxicity and the role of Prussian blue in 24, 93–​106.
therapy. Toxicol Rev, 22, 29–​40. Other chemicals
Zinc Acetone
Hantson P (2001). Zinc toxicity. Clin Toxicol, 39, 239–​40. International Programme on Chemical Safety (1998). Environmental
Pesticides Health Criteria 207. Acetone. World Health Organization, Geneva.
Aluminium and zinc phosphide Acids and alkalis
Proudfoot AT (2009). Aluminium and zinc phosphide poisoning. Clin Dargan PI (2016). Corrosives. Medicine GBR, 44, 153–​6.
Toxicol, 47, 89–​100. Arsine
Anticoagulant rodenticides Pakulska D, Czerczak S (2006). Hazardous effects of arsine: a short re-
Watt BE, et al. (2005). Anticoagulant rodenticides. Toxicol Rev, 24, view. Int J Occup Med Environ Health, 19, 36–​44.
259–​69. Benzene
Bipyridyl herbicides Bradberry SM, Vale JA (2014). Common chemical poisonings: benzene
Jones GM, Vale JA (2000). Mechanisms of toxicity, clinical features and and toluene. In: Bateman DN, et al. (eds). Oxford desk reference: toxi-
management of diquat poisoning: a review. J Toxicol Clin Toxicol, cology, pp. 214–​15. Oxford University Press, Oxford.
38, 123–​8. Carbon dioxide
Vale JA, Meredith TJ, Buckley BM (1987). Paraquat poisoning: clin- Langford NJ (2005). Carbon dioxide poisoning. Toxicol Rev, 24,
ical features and immediate general management. Hum Toxicol, 229–​35.
6, 41–​7.
Carbon disulphide
Carbamate insecticides
Greim H (2005). Carbon disulfide. In: Hartwig A (ed) The MAK-​
Vale A, Lotti M (2015). Organophosphorus and carbamate insecticide collection for occupational health and safety. Part I: MAK value docu-
poisoning. Handb Clin Neurol, 131, 149–​68. mentations, pp. 171–​85. Wiley-​VCH, Weinheim.
Chloralose
Carbon monoxide
Hamouda C, et al. (2001). A graded classification of acute chloralose
Buckley NA, et al. (2005). Hyperbaric oxygen for carbon monoxide
poisoning based on 509 cases. Presse Med, 30, 1055–​8.
poisoning: a systematic review and critical analysis of the evidence.
Chlorates Toxicol Rev, 24, 75–​92.
Lee E, et al. (2013). Severe chlorate poisoning successfully treated with Cyanide
methylene blue. J Emerg Med, 44, 381–​84.
Marrs TC, Thompson JP (2016). The efficacy and adverse effects of
Chlorophenoxy herbicides dicobalt edetate in cyanide poisoning. Clin Toxicol, 54, 609–​14.
Bradberry SM, Proudfoot AT, Vale JA (2004). Poisoning due to Thompson JP, Marrs TC (2012). Hydroxocobalamin in cyanide poi-
chlorophenoxy herbicides. Toxicol Rev, 24, 65–​73. soning. Clin Toxicol, 50, 875–​85.
 10.4.1 Poisoning by drugs and chemicals 1777

Diethylene glycol Petrol (gasoline)

Conrad T, et al. (2016). Diglycolic acid, the toxic metabolite of di- Franzen D, et al. (2014). Fire eater’s lung: retrospective analysis of 123
ethylene glycol, chelates calcium and produces renal mitochondrial cases reported to a National Poison Center. Respiration, 87, 98–​104.
dysfunction in vitro. Clin Toxicol, 54, 501–​11. Phenol
Schep LJ, et al. (2009). Diethylene glycol poisoning. Clin Toxicol, 47,
Bradberry SM, Vale JA. (2014). Common chemical poisonings: phenol
525–​35.
and related compounds. In: Bateman DN, et al. (eds). Oxford desk
Ethylene glycol reference: toxicology, pp. 257–​9. Oxford University Press, Oxford.
McMartin K (2009). Are calcium oxalate crystals involved in the Phosgene
mechanism of acute renal failure in ethylene glycol poisoning?
Grainge C, Rice P (2010). Management of phosgene-​induced acute
Clin Toxicol, 47, 859–​69.
lung injury. Clin Toxicol (Phila), 48, 497–​508.
Reddy NJ, Sudini M, Lewis LD (2010). Delayed neurological sequelae
Holmes WW, et al. (2016). Conceptual approaches for treatment of
from ethylene glycol, diethylene glycol and methanol poisonings.
phosgene inhalation-​induced lung injury. Toxicol Lett, 244, 8–​20.
Clin Toxicol, 48, 967–​73.
Vale A (2016). Alcohols and glycols. Medicine GBR, 44, 128–​32. Propylene glycol
Bouchard NC, et al. (2005). Severe lactic acidemia and systemic tox-
Formaldehyde
icity following oral propylene glycol ingestion: a role for fomepizole
Liteplo RG, et al. (eds) (2002). Concise international chemical as-
and hemodialysis. Clin Toxicol, 43, 740.
sessment document no. 40. Formaldehyde. Inter-​Organization
Programme for the Sound Management of Chemicals. World Tetrachloroethylene (perchloroethylene)
Health Organization, Geneva. http://​www.inchem.org/​documents/​ Garnier R, et al. (1996). Coin-​operated dry-​cleaning machines may
cicads/​cicads/​cicad40.htm be responsible for acute tetrachloroethylene poisoning: report of 26
Pandey CK, et al. (2000). Toxicity of ingested formalin and its manage- cases including one death. J Toxicol Clin Toxicol, 34, 191–​7.
ment. Hum Exp Toxicol, 19, 360–​6. Toluene
n-​Hexane Bradberry SM, Vale JA (2014). Common chemical poisonings: benzene
International Programme on Chemical Safety (1991). Environmental and toluene. In: Bateman DN, et al. (eds) Oxford desk reference: toxi-
Health Criteria 122. n-​Hexane. World Health Organization, Geneva. cology, pp. 214–​15. Oxford University Press, Oxford.

Hydrogen fluoride/​hydrofluoric acid 1,1,1-​Trichloroethane

Burd A (2004). Hydrofluoric acid revisited. Burns, 30, 720–​2. House RA, et al. (1996). Paresthesias and sensory neuropathy due to
1,1,1-​trichloroethane. J Occup Environ Med, 38, 123–​4.
Hydrogen sulphide
Liss GM, House RA (1995). Toxic encephalopathy due to 1,1,1-​
Guidotti TL (2015). Hydrogen sulfide intoxication. Handb Clin Neurol, trichloroethane. Am J Ind Med, 27, 445–​6.
131, 111–​133.
Trichloroethylene
Irritant gases (ammonia, chlorine, sulphur dioxide)
Yoshida M, et al. (1996). Concentrations of trichloroethylene and its
Meulenbelt J (2016). Irritant gases. Medicine GBR, 44, 175–​8. metabolites in blood and urine after acute poisoning by ingestion.
Isopropanol Hum Exp Toxicol, 15, 254–​8.
Slaughter RJ, et al. (2014). Isopropanol poisoning. Clin Toxicol, 52, Household products
470–​8. Day R, et al. (2016). Toxicity of soluble film automatic dishwashing
Methanol products as reported to the United Kingdom National Poisons
Barceloux DG, et al. (2002). American Academy of Clinical Toxicology Information Service 2008–​2015. Clin Toxicol, 54, 862–​6.
practice guidelines on the treatment of methanol poisoning. Clinl Day R, et al. (2017). Exposures to traditional automatic dishwashing
Toxicol, 40, 415–​46. tablets and a comparison with exposures to soluble film tablets
reported to the United Kingdom National Poisons Information
Methylene chloride
Service 2008–​2015. Clin Toxicol, 55, 206–​12.
Greim H (ed) (2002). Dichloromethane. In: Occupational toxicants: Day R, et al. (2017). Toxicity from automotive screenwashes reported
critical data evaluation for MAK values and classification of carcin- to the United Kingdom National Poisons Information Service
ogens, pp. 147–​61. Wiley-​VCH, Weinheim. (NPIS) from 2012 to 2015. Clin Toxicol, 55, 221–​6.
Nitrites Harley EH, Collins MD (1997). Liquid household bleach ingestion in
Ringling S, Boo T, Bottei E (2003). Methemoglobinemia from nitrite-​ children: a retrospective review. Laryngoscope, 107, 122–​5.
contaminated punch. Clin Toxicol, 41, 730–​1. Litovitz T, Whitaker N, Clark L (2010). Preventing battery inges-
tions: an analysis of 8648 cases. Pediatrics, 125, 1178–​83.
Nitrogen dioxide
Panchal B, et al. (2016). 754 exposures to reed diffusers reported to the
Karlson-​Stiber C, et al. (1996). Nitrogen dioxide pneumonitis in ice
United Kingdom National Poisons Information Service 2010–​2014.
hockey players. J Int Med, 239, 451–​6.
Clin Toxicol, 54, 333–​8.
Rosenlund M, Juncnelius S, Bluhm G, Svartengren M (2004). A 5-​year
Williams H, et al. (2012). Hazard of household cleaning products: a
follow-​up of airway symptoms after nitrogen dioxide exposure in an
study undertaken by the UK National Poisons Information Service.
indoor ice arena. Arch Environ Health, 59, 213–​17.
Clin Toxicol, 50, 770–​5.
Paraffin (kerosone) Williams H, et al. (2014). Reported toxicity in 1486 liquid detergent
Balme KH, et al. (2015). The efficacy of prophylactic antibiotics in the capsule exposures to the UK National Poisons Information Service
management of children with kerosene-​associated pneumonitis: a 2009–​ 2012, including their ophthalmic and CNS effects. Clin
double-​blind randomised controlled trial. Clin Toxicol, 53, 789–​96. Toxicol, 52, 136–​40.
1778 SECTION 10 Environmental medicine, occupational medicine, and poisoning

of other signs of envenoming. Assisted ventilation, renal dialysis, and

10.4.2 Injuries, envenoming, cardiovascular support may be required. Necrotic tissue requires
surgical debridement. Signs of compartment syndrome may be
poisoning, and allergic reactions misleading and fasciotomy is almost never justified.
caused by animals Venomous fish
David A. Warrell Many fish of temperate and tropical seas can inflict dangerous
stings—​stingrays, catfish, weevers, scorpionfish, stonefish, and
lionfish. Prevention is by wearing foot protection when wading and
ESSENTIALS avoiding contact with tropical reef fish. Immediate agonizing pain is
alleviated by immersing the stung limb in uncomfortably hot but not
Mechanical injuries
scalding water (less than 45°C). Erythematous swelling and necrosis
Attacks by wild and domesticated animals are increasing worldwide. may develop with the risk of infection by marine bacteria. Stingray
They are best prevented by taking local advice about minimizing ex- spines can cause fatal penetrating injuries. Systemic envenoming is
posure. Injuries usually occur in places remote from medical care. uncommon. Stonefish antivenom is available.
They may involve extensive trauma, haemorrhagic shock, and a high
risk of bacterial contamination. First aid consists of resuscitation, Poisonous aquatic animals
control of bleeding and perforating injuries, intravenous fluid re- Ciguatera poisoning from eating tropical reef fish is prevalent in
placement, and rapid evacuation to hospital for emergency surgery Pacific and Caribbean regions. Fish acquire polyether toxins from
and treatment of infection. dinoflagellates. Acute gastroenteritis develops 1–​6 h after ingestion,
followed by neurotoxic and cardiovascular disturbances, notably
Venomous snakes
persistent paraesthesiae and myalgias.
Bites by venomous snakes can cause death or permanent physical Tetrodotoxin poisoning is attributable to the Japanese delicacy
and mental morbidity. Snakebite is largely an occupational/​environ- ‘fugu’ (puffer fish). Neurotoxic symptoms caused by this sodium
mental hazard of agricultural workers and their children in rural areas channel blocker develop 10–​45 min after ingestion. Fatal respiratory
of the tropics. Bites are commonly inflicted on the lower limbs and paralysis may ensue 2–​6 h later.
could be prevented by wearing protective footwear, by using a light Scombroid poisoning results when bacterial decompos-
and prodding with a stick while walking at night, and by sleeping off ition of tuna and other dark-​ fleshed fish generates histamine.
the ground or under a mosquito net. Anaphylactic-​type symptoms develop within minutes to a few
Snake venoms are complex mixtures of toxic proteins causing ne- hours after ingestion.
crosis, shock, haemostatic disturbances, paralysis, rhabdomyolysis, Paralytic shellfish poisoning is caused by eating bivalve molluscs
and acute kidney injury. Envenoming by Elapidae (cobras, kraits, contaminated with tetrahydropurine neurotoxins from dinofla-
mambas, coral snakes, Australian snakes, and sea snakes) can cause gellates whose mass blooming manifests as ‘red tide’. Neurotoxic
descending flaccid paralysis, starting with ptosis and progressing symptoms appear within 30 min of ingestion, progressing to fatal
to respiratory paralysis. Some elapid venoms cause local necrosis, respiratory paralysis within 12 h.
rhabdomyolysis, and haemostatic disturbances. Bites by Viperidae Prevention is by not eating scaleless (tetrodotoxic) fish at any time,
(vipers, adders, and pit vipers—​rattlesnakes, moccasins, lanceheads) very large (ciguatera-​toxic) reef fish, and shellfish when there is a red
can cause severe local swelling, bruising, blistering, and necrosis tide. Correct processing prevents scrombroid poisoning. Cooking
together with shock, consumption coagulopathy, spontaneous does not destroy any of these toxins.
systemic bleeding, acute kidney injury, and, with some species,
neuromyotoxicity. Venomous marine invertebrates
First aid involves reassurance, immobilization of the whole pa- Cnidarians ( jellyfish, stinging corals, sea anemones, and so on)
tient, especially the bitten limb, rapid evacuation to the nearest hos- have tentacles studded with stinging nematocysts. Lethal species
pital, and avoidance of dangerous traditional methods. When the are Indo-​ Australian box jellyfish, Irukandji, Portuguese man-​ o’-​
necessary skills and equipment are available, pressure-​pad immo- war (Physalia), and Chinese Stomolophus nomurai. Prevention is by
bilization should be applied immediately unless the possibility of a observing warning notices on affected beaches, bathing in ‘stinger-​
neurotoxic elapid bite can be excluded. resistant’ enclosures, or wearing protective clothing. Stings produce
In hospital, specific antivenom (hyperimmune equine or ovine immediately painful irritant weals. Box jellyfish cause the most se-
immunoglobulins) is given if there is evidence of systemic or se- vere systemic symptoms: respiratory and cardiac arrest, generalized
vere local envenoming. Polyspecific antivenoms cover envenoming convulsions, and pulmonary oedema within minutes of the acci-
by medically important snakes in the geographical area for which dent. ‘Irukandji’ syndrome is distinctive: severe persisting musculo-
they are intended. Early anaphylactic or pyrogenic reactions and late skeletal pain, anxiety, trembling, headache, piloerection, sweating,
serum sickness antivenom reactions are common but not predict- tachycardia, hypertension, and pulmonary oedema starting about
able by hypersensitivity tests. Incidence of severe early reactions is 30 min after stings by tiny cubomedusoids. Vinegar inactivates box
reduced by prophylactic low-​dose subcutaneous adrenaline. After jellyfish and Irukandji nematocysts. Hot water relieves the pain of
the initial dose of antivenom, the indication for repeated dosage is Physalia and box jellyfish stings. Box jellyfish antivenom is available
failure of restoration of blood coagulability after 6 h, or progression in Australia.
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1779

Echinoderm (starfish and sea urchin) spines become embedded distress or simulate an acute abdomen. Antivenoms widely used for
in waders’ feet, sometimes penetrating bones and joints. Pain is re- Loxosceles and neurotoxic bites are of uncertain effectiveness.
lieved by hot water. Systemic envenoming is rare but there is a risk Ticks—​mainly in North America and Australia, both ixodid (hard)
of marine bacterial infection. and argasid (soft) ticks can inject a salivary neurotoxin during their
Molluscs—​cone shells and small Australasian blue-​ringed octo- blood meal, causing an ascending flaccid paralysis. The tick must be
puses can cause fatal envenoming. detached as soon as possible.
Centipedes-cause painful stings in tropical countries, while toxic
Venomous arthropods
secretions of millipedes may be applied to skin, lips, and eyes by chil-
Hymenoptera—​stings by bees (Apidae); wasps, yellow jackets, and dren who are handling or trying to eat them.
hornet (Vespidae), and ants commonly cause allergic reactions, while
rare mass attacks (e.g. by Africanized ‘killer’ bees) can result in fatal Leeches
direct envenoming. Leeches have anticoagulant saliva. Land leeches infest rainforests
People in whom systemic anaphylaxis has been provoked by a and can invade clothing while aquatic leeches are swallowed in fresh
hymenopteran sting should always carry—​and be competent to water or they may penetrate body orifices of swimmers. Prevention
use—​self-​injectable adrenaline (epinephrine). Desensitization with is by applying repellents to skin, clothes, and footwear, by boiling
purified venom should be considered if type I hypersensitivity is con- or filtering drinking water and by avoiding affected waters. Clinical
firmed by detecting venom-​specific IgE. Massive envenoming by effects are local pain, itching, blood loss, secondary infection, and
Apidae or Vespidae causes histamine toxicity, generalized rhabdo- phobia. Ingested aquatic leeches may obstruct pharynx, bronchi,
myolysis, intravascular haemolysis, hypertension, pulmonary oe- or oesophagus. Use of medicinal leeches may be complicated by
dema, myocardial damage, bleeding, hepatic dysfunction, and acute Aeromonas hydrophila infection.
kidney injury.
Lepidoptera—​stinging hairs of many species of moths and their
caterpillars can excite cutaneous irritation and allergy, sometimes Mechanical injuries caused by animals
causing epidemics. In South America, caterpillars of atlas moths
(Lonomia) cause many stings. Their venom contains antihaemostatic Epidemiology
toxins causing spontaneous bleeding, polyarthralgia, and acute
kidney injury. An antivenom is available in Brazil. Many species of wild animals have mauled and killed humans.
Coleoptera—​contact with ‘Spanish fly’ and ‘Nairobi eye’ beetles Attacks by wild mammals are increasingly reported. Tigers, lions,
causes blistering. leopards, and other big cats, hyenas, domestic dogs, jackals, wolves,
Scorpions—​stings still cause numerous fatalities in North and bears, elephants, rhinos, hippopotamuses, buffaloes, bison, moose,
South Africa, the Middle East, Mexico, Latin America, and India. elk, other large deer and antelopes, wild pigs, tapirs, chimpan-
Prevention is by excluding scorpions from homes. Severe local zees, baboons, ostriches, and cassowaries have killed people. The
pain is the commonest symptom. Systemic symptoms vary ac- big cats, wolves, bears, elephants, hippopotamuses, and buffaloes
cording to the species of scorpion involved. ‘Autonomic storm’ is are the most dangerous. Since 2000, about 60–​80 confirmed un-
caused by massive release of acetylcholine and catecholamines provoked attacks by sharks with an average of 4.3 fatalities (case
by ion channel toxins. Cardiorespiratory effects include hyperten- fatality c.8%) have been reported each year. Other fish, such as
sion, shock, tachy-​, and bradyarrhythmias, electrocardiographic barracudas, moray, and conger eels, garfish, groupers, stingrays,
changes, and pulmonary oedema. Neurotoxic effects include er- and piranhas can inflict lethal injuries. Electric ‘eels’ Electrophorus
ratic eye movements, fasciculation, and muscle spasms (pseudo-​ electricus (Gymnotidae) (Fig. 10.4.2.1) of rivers and coastal
convulsions) causing respiratory distress. Pain is best controlled by waters in Florida and South American and marine torpedo rays
digital block with local anaesthetic. Antivenom is available in some (e.g. Torpedo spp., Torpediniformes) can impart stunning electric
countries, but pharmacological treatment with prazosin and other shocks but are unlikely to be lethal. Even the 5-​cm Amazonian
vasodilators is preferred elsewhere. catfish (genus Vandellia, Trichomycteridae; Spanish ‘canero’;
Spiders—​bites are common in the Americas, Mediterranean, Portuguese ‘candirú’), the only vertebrate human ectoparasite, can
South Africa, and Australia but there are few fatalities. Only recluse traumatize humans by burrowing into their urethra, vagina, or
spiders (Loxosceles) are reliably associated with necrotic araneism anus, causing pain, bleeding, and obstruction. Crocodilians (alliga-
(arachnidism), but many innocent peridomestic species have been tors, caimans, and crocodiles) kill, eat, and scavenge dead humans
vilified. Local pain and swelling develop slowly, followed by the classic in Africa, Asia, and Oceania. In the United States of America, es-
‘red-​white-​and-​blue sign’ and eventually an eschar, which sloughs pecially Florida, alligators Alligator mississippiensis are responsible
leaving a necrotic ulcer. Systemic symptoms, including fever, rash, for a few deaths but in Africa, Nile crocodiles Crocodilus niloti-
haemolysis, and acute kidney injury, are unusual. Bites by cosmopol- cus kill about 1000 people each year, and in South Asia, northern
itan black and brown widow spiders, Latin American banana spiders, Australia, and New Guinea the saltwater crocodile C. porosus kills
and Sydney funnel web spiders and their relatives, cause neurotoxic hundreds each year. Giant pythons very rarely kill humans in Africa
araneism. Immediate pain is followed by sweating with gooseflesh (Python sebae), India (Python molurus), Indonesia (Python reticula-
at the site of the bite. Systemic symptoms quickly evolve: headache, tus), Australia (Morelia amethistina), and South America (Eunectes
nausea, vomiting, profuse generalized sweating, fever, priapism, and murinus). Occasional human deaths have been attribute to attacks
painful muscle spasms, tremors, and rigidity that may cause respiratory by Komodo dragons (Varanus komodoensis). To put these incidents
into perspective, in the United States, collisions between vehicles
1780 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Fig. 10.4.2.1 Electric ‘eel’ Electrophorus electricus (Gymnotidae).

and deer and injuries to horseback riders are much more common on land, run; in the water, fight back, hitting the animal on its nose
than attacks by wild animals. and eyes with any available weapon. To avoid shark attacks, never
Bites by domestic dogs are common worldwide. In England and bathe in shark-​infested waters, between sand bars and the deep
Wales, where the estimated dog population is 6 million, more than ocean, where dead fish have been dumped, flocks of sea birds are
200 000 bite victims attend hospital each year. In the United States, feeding, or sewage is discharged. If attacked by a shark, fight back,
dogs are responsible for 80–​90% of all animal bites. They bite about hitting it on the nose and clawing at its eyes and gills. Chemical and
4.7 million people each year (1.8% of the population), 800 000 of electrical-​field repellents and chain mail suits have been developed
whom (0.3% of the population) require medical attention, and 12 are to protect divers.
killed. Children are especially vulnerable. Other domestic animals
that have caused severe injuries or deaths include camels, cattle, Clinical features
water buffalo, sheep, pigs, cats, and even ferrets. Teeth, tusks, horns, claws, and spines gouge, tear, crush, avulse,
and puncture soft tissues and break bones. Big cats, bears, pigs,
Prevention pythons, crocodilians, and sharks will eat their victims. Bovines and
It is essential to obtain local advice about these environmental haz- elephants trample and kneel on the prostrate body. Body cavities
ards. Where dangerous wild animals abound, wandering alone may be punctured, resulting in pneumothorax, haemothorax, her-
and unprotected between dusk and dawn incurs the highest risk of niation and strangulation of bowel, and rupture of liver and spleen.
attacks. Staying in a vehicle and travelling in groups reduces risk. Horse and camel bites and kicks can fracture, dislocate, crush, and
Pet dogs may attract large predators. In bear country, hikers should concuss. Wild and feral pigs, armed with lethal tusks, can inflict
travel in groups, making plenty of noise. Bears should never be ap- abdominal evisceration, pneumothorax and fractures and lacer-
proached (e.g. for photography), especially if there are cubs. Faced ations of tendons, arteries, and nerves. Giant pythons asphyxiate
by a charging bear, avoid eye contact and do not attempt to hide, by constriction. Sharks amputate whole limbs, causing rapidly fatal
run away, or climb a tree. At a distance of 30 feet (c.10 m), a bear haemorrhage. Garfish (needle fish) and sting rays can fatally im-
may be repelled by discharging a commercial pepper spray (10% pale. Infection is likely with all these traumas: rabies, tetanus, gas
capsicum oleoresin) towards its eyes. If attacked by a dog, avoid gangrene, cat scratch disease (Bartonella henselae), Pasteurella mul-
eye contact, shout, and fight back with sticks and stones. Young tocida, Capnocytophaga canimorsus, leptospires, Spirillum minus,
children should not be left alone with dogs, even family pets, and Streptobacillus moniliformis, and aquatic organisms such as Vibrio
notoriously dangerous breeds should be banned. Elephants are dan- vulnificus and Aeromonas hydrophila (see Section 8, Infectious
gerous whether wild or tamed. They should be treated with extreme diseases).
respect or avoided, especially if they are in ‘musth’. Swimming or
canoeing in hippo-​infested waters or blocking their retreat to water Treatment
is highly dangerous. To prevent crocodilian attacks, keep well away Since wild animal attacks are most likely to happen in areas remote
from the water’s edge, do not bathe between dusk and dawn, and from medical care, delayed hospital treatment makes first aid espe-
avoid canoeing in croc-​infested waters. If attacked by a crocodilian cially crucial for the survival of the victim.
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1781

First aid of severe injuries There is immediate, agonizing, persistent local pain, as well as pro-
First, the patient and rescuers must be made safe from further longed local swelling, chronic pain on movement, hyperaesthesia,
danger and drowning. Bleeding is controlled by local pressure or wasting, inflammation, and regional lymphadenopathy. These ef-
tourniquets, perforating injuries are closed with pressure dress- fects are not life-​threatening in humans, but dogs have died of
ings, circulating volume repletion is started as soon as possible with envenoming. In the absence of specific treatment, non​steroidal
intravenous fluids, and the casualty is evacuated promptly to hos- anti-​inflammatory agents (NSAIDs) or corticosteroids have proved
pital. Some regions have flying doctor services (e.g. AMREF in East effective. The venom contains a C-​type natriuretic peptide (which
Africa). All injuries inflicted by animals must be assumed to be in- causes mast-​cell degranulation), nerve growth factor, several α-​and
fected by a range of organisms (see earlier paragraphs) and so it may β-​defensin-​like peptides, enzymes, and other peptides and proteins,
be appropriate to start antibiotic treatment immediately. including a sildenafil-​like phosphodiesterase-​5 inhibitor. Male ech-
idnas, the other egg-​laying mammal, possess a similar but smaller
Medical treatment in the hospital venom apparatus.
Emergency surgery may be required. Blood loss should be replaced Several species of Insectivora produce venomous saliva con-
and attention given to local mechanical complications such as frac- ducted into bite wounds by curved and sometimes grooved lower
tures, tension pneumothorax, damage to large blood vessels, per- incisors. Venomous species include the Hispaniolan and Cuban so-
foration of the bowel, and lacerations of other abdominal viscera. lenodons (Solenodon paradoxus, S. (Apotogale) cubanus), northern
Thorough debridement or amputation of dead tissue may be re- water shrew Neomys fodiens, southern water shrew N. anomalus, and
quired with removal of foreign material, teeth, and so on, and irriga- North American short-​tailed shrew Blarina brevicauda. Their bites
tion and drainage. Except for wounds on the head and neck, which can kill rodents and lagomorphs, but in humans the effect is local
can be sutured immediately, primary suturing should be delayed pain, swelling, and inflammation.
for 48–​72 h, after which further debridement, suturing, or covering The saliva of vampire bats (Desmodontinae) contains permeability-
with split-​skin grafts should be considered. ​increasing factors, a platelet inhibitor, draculin (an inhibitor of acti-
Wounds should be thoroughly cleaned with soap and water as vated factors X and IX), and a plasminogen activator which is being
soon as possible; suitable antiseptics include iodine and alcohol so- developed as a thrombolytic drug.
lutions. Prophylactic antimicrobials such as amoxicillin/​clavulanic The slow loris Nycticebus coucang (Primates; Lorisidae) possesses
acid, doxycycline, or erythromycin have proved effective in dog-​ brachial glands whose secretion contains toxic protein very similar
and cat-​bite wounds and are indicated for multiple or severe wounds in structure to Fel d 1 cat allergen, which the lorises lick up and can
and bites on the face and hands. For other bites, use penicillin, an inject when they bite. In humans, slow loris bites may be damaging,
aminoglycoside and metronidazole and for marine or aquatic infective, or toxic, causing pain, swelling, and even anaphylaxis.
wounds, to cover unusual bacteria such as Vibrio and Aeromonas
spp., doxycycline or co-​trimoxazole or, in severe cases, a combin-
ation of tetracycline with an aminoglycoside (e.g. gentamicin) and Venomous snakes
cefotaxime, or tetracycline with aminoglycoside and a fluoroquino-
lone. Specific infections, such as tetanus, rabies, and Herpes simiae Fewer than 200 species of venomous snake (families Colubridae,
virus (from monkey bites) must be considered and treated or pre- Atractaspidinae, Elapidae, and Viperidae) have been responsible
vented appropriately. for severely envenoming humans, resulting in death or permanent
disability. Since it may be difficult to distinguish venomous from
nonvenomous species, unnecessary contact with all snakes should
Venomous animals be avoided, and patients bitten by any species should be assessed
carefully.
For predation or defence, some animals inject venoms through
fangs, chelicerae (venom jaws), stings, spines, hairs, nematocysts, Distribution
and other specialized venom organs. ‘Spitting’ snakes, scorpions, The Antarctic; most islands of the western Mediterranean, Atlantic,
and millipedes squirt venom on to absorbent mucous mem- Caribbean, and eastern Pacific (including Hawaii); Chile, Iceland,
branes. The flesh or skin of some animals contains poisons acquired Ireland, Madagascar, New Caledonia, and New Zealand are free
through the food chain. Allergic reactions to injected venoms (e.g. of from venomous snakes. Elsewhere, venomous snakes are widely
Hymenoptera and cnidarians) may cause more frequent and serious distributed up to altitudes of more than 4900 m in the Himalayas
medical problems than their direct toxic effects. (Gloydius himalayanus), within the Arctic Circle (Vipera berus), in
the Indian and Pacific oceans as far north as Siberia (Pelamis pla-
tura/​Hydrophis platurus), and in some freshwater lakes (Hydrophis
Venomous mammals semperi).

Male duck-​ billed platypuses (Ornithorhynchus anatinus) have Classification

erectile venomous spurs on their hind limbs. These aquatic, egg-​ Medically important species have one or more pairs of enlarged teeth
laying mammals of eastern Australia sting at least one person each (fangs) in their upper jaws, containing a groove or closed channel
year in Victoria, but only 17 cases have been reported since 1817. through which they inject venom into their prey.
1782 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Colubridae
The short, immobile fangs are at the back of the maxilla
(Fig. 10.4.2.2). Most of the familiar snakes regarded as non-​
venomous (e.g. the British grass snake Natrix natrix helvetica
and the smooth snake Coronella austriaca), belong to this large
family. However, many colubrid species have proved capable of
causing at least local envenoming and some have caused severe
envenoming or death, such as three African species—​the boomslang
Dispholidus typus and the vine, twig, bird, or tree snake or Voëlslang
(Thelotornis kirtlandii and T. capensis); the Japanese yamakagashi
Rhabdophis tigrinus; and the Southeast Asian red-​necked keel-
back R. subminiatus. (Fig. 10.4.2.2).

Atractaspidinae (family Lamprophiidae)

The African and Middle Eastern burrowing asps, stiletto snakes, or
burrowing or mole vipers or adders strike sideways, impaling their

(a)

Fig. 10.4.2.3 Slender burrowing asp Atractaspis aterrima, Nigeria,

showing fang.
Copyright D. A. Warrell.

victims on one of their two long front fangs, protruding through

the partially closed mouth (Fig. 10.4.2.3). Four species, Atractaspis
microlepidota, A. engaddensis, A. corpulenta and A. irregularis, have
proved capable of killing humans.

Elapidae
This family includes cobras (Fig. 10.4.2.4), kraits, mambas, shield-​
nose snakes, coral snakes (Fig. 10.4.2.5), garter snakes, all the
venomous Australasian snakes (Fig. 10.4.2.6), and sea snakes
(Fig. 10.4.2.7). The short front fangs are immobile (10.4.2.4a
and Fig. 10.4.2.7). Several African and Asian species (rinkhals
and spitting cobras) can eject venom from the tips of their fangs
(b) (Fig. 10.4.2.3) as a fine spray for a distance of a few metres into the
eyes of a perceived aggressor.

Viperidae
The front fangs are long, curved, and capable of a wide range of
movement (Fig. 10.4.2.8). The subfamily Crotalinae comprises the
American rattlesnakes (Fig. 10.4.2.9), moccasins, lance-​headed vi-
pers, and Asian pit vipers, which possess a heat-​sensitive pit organ
behind the nostril (Fig. 10.4.2.10). The Old World vipers and adders
(subfamily Viperinae) lack this pit organ.

Incidence of snakebite and medically

important species
Snakebite is a frequent medical emergency in rural areas of many
Fig. 10.4.2.2 Back-​fanged Colubroid snakes. (a) Back fangs of red-​ tropical countries; its incidence is seriously underestimated by
necked keelback (Rhabdophis subminiatus), a Southeast Asian colubrid
snake (family Natricinae), capable of causing severe envenoming. hospital returns, because many victims seek the help of trad-
(b) Baron’s green racer (Philodryas baroni), a South American colubrid itional healers rather than western-​style doctors. In Kilifi District,
snake (family Dispsadidae), capable of causing mild local envenoming. Kenya, where snakebites cause 6.7 deaths per 100 000 per year
Copyright D. A. Warrell. (0.7% of all deaths), 68% of the victims had sought treatment from
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1783

(a)

(b) (c)

Fig. 10.4.2.4 Common Indian cobra Naja naja: (a) short front fang, (b) and (c) showing
defensive posture with open hood with ‘spectacle’ marking (specimen in Sri Lanka).
Copyright D. A. Warrell.

Fig. 10.4.2.6 Papua New Guinean taipan Oxyuranus scutellatus

Fig. 10.4.2.5 Painted coral snake Micrurus corallinus, Brazil. showing the distinctive dorsal red stripe.
Copyright D. A. Warrell. Copyright D. A. Warrell.
1784 SECTION 10 Environmental medicine, occupational medicine, and poisoning

120 9

110
8
100
7
90

Snakebite deaths in the study

Average rainfall (in mm)

80 6

70
5
60
4
50

40 Study deaths (n = 562) 3

30
2
20
1
10
Average rainfall
0 0

Month Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

Fig. 10.4.2.7 Monthly snakebite deaths in randomly selected study areas of India in 2005
(solid line) and average rainfall (dashed line), showing peak mortality during the monsoon.
From Mohapatra B, et al. (2011). Snakebite mortality in India: a nationally representative mortality survey.
PLoS Negl Trop Dis, 5(4), e1018.

traditional healers. In Africa, the saw-​scaled or carpet viper Echis In the Amami and Ryukyu islands of Japan, the habu, Protobothrops
spp., puff adder Bitis arietans, and spitting cobras (Naja nigricollis, flavoviridis, inflicted an average of 610 bites with 5.6 deaths per
N. mossambica, and so on) are the species of greatest medical im- year during the 1960s. In the United Kingdom, the adder or
portance. In the Benue Valley of north-​east Nigeria, E. ocellatus viper Vipera berus is the only venomous species (Fig. 10.4.2.12).
(Fig. 10.4.2.11) causes 500 bites per 100 000 population per More than 100 people are bitten each year, but only 14 deaths
year, with a 12% mortality. Vipers of the genus Echis, whose geo- have been reported since 1876, the last in 1975. Scandinavia has
graphical range extends through Africa north of the equator, the hundreds of adder bites each year, but very few deaths. V. aspis
Middle East, and eastern Asia to India, are responsible for many causes most bites in France, while V. ammodytes is important in
bites and deaths. In India, the most important species are cobras Eastern Europe.
Naja naja, N. kaouthia (Fig. 10.4.2.4), common krait Bungarus In Australia, there are about 1000 bites (4.76/​100 000 popula-
caeruleus, Russell’s viper Daboia russelii (Fig. 10.4.2.8), and the tion) and 2–​5 deaths (0.1–​0.2/​100 000) per year. Recently, almost
saw-​scaled viper E. carinatus. A well-​designed, nationwide study all fatalities have been attributed to brown snakes Pseudonaja
in India established that 46 000 people were killed by snakes in spp. Other important species are tiger snakes (Notechis scuta-
2005. In children aged 5–​14 years, snakebites caused 3% of all tus, and so on), taipan Oxyuranus scutellatus (Fig. 10.4.2.6),
deaths. Among fatalities, 97% died in rural areas, only 23% of and death adders Acanthophis spp. There are several 100 deaths
them in hospitals. In Bangladesh, a community-​based study es- each year in New Guinea, mostly caused by taipans. The highest
timated 600 000 bites and 6000 deaths each year. In Southeast snakebite mortalities, up to 24% of all adult deaths, are recorded
Asia, the Malayan pit viper Calloselasma rhodostoma, D. siamen- among hunter–​gatherer tribes of Brazil (Kashinawa), Venezuela
sis, green pit vipers (e.g. Trimeresurus T. albolabris), and cobras (Yanomamo), Ecuador (Waorani), Tanzania (Hadza), and Papua
N. kaouthia and N. siamensis cause most bites and deaths. In New Guinea.
Myanmar, Russell’s viper bite is a common cause of acute kidney
injury and is responsible for most of the estimated 1000 snakebite Epidemiology
deaths each year. In the United States of America, there are about Most snakebites are inflicted on the lower limbs of farmers, plan-
7000–​8000 bites each year with about five deaths. Rattlesnakes, tation workers, herdsmen, and hunters in rural areas of tropical
especially Crotalus adamanteus, C. atrox, C. horridus, C. oreganus, developing countries. The snake is usually trodden on at night or
C. scutulatus, C. viridis and Sistrurus miliaris, are the most dan- in undergrowth. Some species such as the Asian kraits Bungarus
gerous species. In Mexico there are about 27 000 bites each year. In spp. and African spitting cobras N. nigricollis enter human dwell-
Central and South America, medically important species include ings at night in search of their natural prey and may bite people
rattlesnakes (e.g. Crotalus simus, C. durissus) (Fig. 10.4.2.9) and who roll over on to them while sleeping on the floor or in response
the lance-​headed vipers Bothrops atrox (‘barba amarilla’), B. asper to human odour or warmth. Snakes strike if inadvertently trodden
(‘terciopelo’), B. bilineatus (‘papagaio’) and B. jararaca (‘jararaca’). upon or touched. In Europe, North America, and Australia, exotic
There are an estimated 4000 bites each year in Central America, venomous snakes are increasingly popular pets: their owners are
fewer than 100 in the Caribbean, and 45 000 in South America. sometimes bitten on their hands, especially when inebriated. In
 1785
(a) (b)

(c)

Fig. 10.4.2.8 Eastern Russell’s viper Daboia siamensis, Ban Mi, Thailand: (a) showing ‘chain’ pattern (scale in cm);
(b) showing long, hinged front fangs (reserve fang on the left side) in dental sheath; (c) dissection of venom apparatus.
Copyright D. A. Warrell.

Fig. 10.4.2.10 Southeast Asian white-​lipped green pit viper

Fig. 10.4.2.9 South American tropical rattlesnake or cascabel Crotalus Trimeresurus (Trimeresurus) albolabris showing heat-​sensitive pit organ
durissus cascavella. Specimen from Brazil. between eye and nostril.
Copyright D. A. Warrell. Copyright D. A. Warrell.
1786 SECTION 10 Environmental medicine, occupational medicine, and poisoning

(a)

(b)

Fig. 10.4.2.12 European adder or viper Vipera berus, the only

venomous British snake (specimen from Wales).
Copyright D. A. Warrell.

venomous snakes, severe flooding that concentrates the human and

snake populations in decreasing areas of dry land (e.g. Bangladesh,
Pakistan, India, Nepal, Myanmar, Vietnam, and Colombia) and
clearing of primary forests during construction of new highways
and irrigation and hydroelectric schemes (e.g. Brazil, Sri Lanka).
Snakebite or injection of snake venom has been employed for sui-
cide and homicide.

Venom apparatus
Venom glands of Elapidae and Viperidae are situated behind the eye,
(c) surrounded by compressor muscles (Fig. 10.4.2.8c). A venom duct
leads to the base of the fang in which venom is conducted along a
groove or through a closed canal. In Colubridae, or more broadly,
Colubroid snakes, venom secreted by Duvernoy’s gland tracks down
grooves in the anterior surfaces of fangs at the posterior end of the
maxilla (Fig. 10.4.2.2). The average dry weight of venom injected
at a strike is approximately for N. naja 60 mg, E. carinatus 13 mg,
D. russelii 63 mg, and Daboia palaestinae 32 mg. The amount in-
jected when a snakebites a human is highly variable. In a proportion
of bites there is negligible envenoming (‘dry bites’): more than 50%
of those bitten by Malayan pit vipers C. rhodostoma or Russell’s vi-
pers; less than 10% bitten by Echis spp.; but more than 75% bitten by
common brown snakes (Pseudonaja spp.) in Australia. The Palestine
Fig. 10.4.2.11 Saw-​scaled or carpet vipers-genus Echis. (a) Echis
ocellatus from West Africa. (Specimen from Nigeria). (b) Echis pyramidum
viper Daboia palaestinae expends only about one-​tenth of the cap-
from East Africa (specimen from Kenya). (c) Echis carinatus sochureki from acity of its venom gland at each consecutive strike, whereas Daboia
the Middle East and South Asia (specimen from Oman). siamensis exhausts more than three-​quarters of its reservoir at the
Copyright D. A. Warrell. first strike. The popular belief that snakes are less dangerous after
they have eaten is incorrect.

the United States, 25% of bites result from snakes being attacked Prevention of snakebite
or handled. Serious bites by back-​fanged (colubrid) snakes usu- To reduce the risk of bites, snakes should never be disturbed,
ally occur under these circumstances. Seasonal peaks in the inci- attacked, cornered, or handled, even if they are thought to be a
dence of snakebite are associated with agricultural activities, such harmless species or appear to be dead. Venomous species should
as ploughing before the annual rains in the West African Sahel and never be kept as pets or as performing animals. In snake-​infested
the rice harvest in Southeast Asia. In India, most snakebite deaths areas, boots, socks, and long trousers should be worn for walks in
occur during the May to October monsoon season (Fig. 10.4.2.7). undergrowth or deep sand, and gloves for exploring foliage. A light
Other factors are fluctuations in the activity or population density of should always be carried at night together with a stick for prodding
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1787

the ground ahead. Lightweight boots that were resistant to Russell’s permeability leading to oedema, blistering, and bruising, and
viper strikes were developed in Burma and proved acceptable to rice to necrosis. Venom l-​ amino acid oxidases are homodimeric
farmers for use during the high risk harvesting season. Collecting flavoenzymes that catalyse the oxidative deamination of an l-​
firewood; dislodging logs and boulders with bare hands; pushing amino acid substrate to an α-​keto acid, ammonia, and hydrogen
sticks or fingers into burrows, holes, and crevices; climbing rocks peroxide. They are widely distributed in venoms of Viperidae and
and trees covered with dense foliage; and swimming in overgrown Elapidae. Their reported biological activities include induction of
lakes and rivers are particularly hazardous activities. Unlit paths apoptosis, oedema, and haemolysis, antibacterial function, and
and gutters are especially dangerous after heavy rains. Sleeping platelet activation or inhibition.
on the ground carries a risk of nocturnal krait bites in South Asia
and of spitting cobra bites in Africa, but well tucked-​in mosquito Polypeptide toxins (neurotoxins)
nets are protective. To prevent sea-​snakebites, fishermen should Postsynaptic (α) neurotoxins such as α-​bungarotoxin and cobrotoxin
not touch these animals when they are caught in nets or on lines. contain about 60–​62 or 66–​74 amino acids. They bind to acetyl-
Swimmers and divers should not aggravate them and should avoid choline receptors at the motor endplate. Presynaptic (β) neuro-
wading in the sea, especially in muddy estuaries, in sand, or near toxins, such as β-​bungarotoxin, crotoxin, and taipoxin, contain
coral reefs. about 120–​140 amino acids and a phospholipase A subunit. These
It is futile and ecologically undesirable to attempt to exterminate release acetylcholine at the nerve endings at neuromuscular junc-
venomous snakes. Various substances toxic to snakes, such as in- tions and then damage the endings, preventing further release of
secticides and methylbromide, have been used to keep human transmitter.
dwellings free of these animals. However, no effective yet harmless
snake repellent has been discovered. Venom pharmacology
The smaller neurotoxins of the Elapidae are rapidly absorbed into
Immunization against envenoming the bloodstream, whereas the larger phospholipase A2 presynaptic
To be effective, high titres of a neutralizing antibody would have toxins and Viperidae toxins are taken up more slowly through the
to be circulating at the time of the bite. This has been achieved in lymphatics. Venoms of the spitting cobras and rinkhals can be ab-
animals used for antivenom production but only by frequent im- sorbed through the intact cornea, causing systemic envenoming and
munization, which would not be practicable even in the highest-​risk even death in animals. Envenoming after ingestion of snake venom
human populations. An accelerated (anamnestic) secondary rise in has not been reported in humans. Most venoms are concentrated
antibody levels, stimulated by envenoming, would be too slow to pre- and bound in the kidney, and some components are eliminated in
vent envenoming. An antirattlesnake vaccine for domestic dogs, of the urine. Crotaline venoms are selectively bound in the lungs, con-
dubious efficacy, is marketed in the United States and pre-​exposure centrated in the liver, and excreted in bile, while polypeptide neuro-
immunization of farmers in Japan, against habu (Protobothrops toxins, such as α-​bungarotoxin, are tightly bound at neuromuscular
flavoviridis) venom was ineffective. junctions. Most venom components do not cross the intact blood–​
brain barrier and so central nervous system effects of venom toxins
Properties of snake venoms are controversial.
More than 90% of the dry weight of venom consists of more than
100 different proteins: enzymes, non​enzymatic polypeptide toxins, Pathophysiology
and non​toxic proteins such as nerve growth factor. Enzymes consti- Swelling and bruising of the bitten limb result from increased
tute 80–​90% of viperid and 25–​70% of elapid venoms. They include vascular permeability induced by proteases, phospholipases,
digestive hydrolases, hyaluronidase, and activators or inactivators membrane-​damaging metalloproteinases (haemorrhagins), and
of physiological processes. Most venoms contain l-​amino acid endogenous autacoids released by the venom, such as hista-
oxidase, phosphomono-​and diesterases, 5′-​nucleotidase, mine, 5-​hydroxytryptamine, and kinins. Venoms of some of the
DNAase, NAD-​nucleosidase, phospholipase A2, and peptidases. North American rattlesnakes and viperine species cause a gen-
Elapid venoms also contain acetylcholine esterase, phospho- eralized increase in vascular permeability resulting in hypovol-
lipase B, and glycerophosphatase, while viperid venoms have aemia, haemoconcentration, hypoalbuminaemia, albuminuria,
metalloproteinases, endopeptidase, arginine ester hydrolase, serous effusions, pulmonary oedema, and, in the case of Burmese
kininogenase, as well as thrombin-​like, factor X, and prothrombin-​ D. siamensis, conjunctival and facial oedema (Fig. 10.4.2.13).
activating enzymes. Phospholipase A2 (lecithinase) is the most Tissue necrosis near the site of the bite is caused by myotoxic
widespread and extensively studied of all venom enzymes. It and cytolytic factors: in some cases, ischaemia resulting from
damages mitochondria, red blood cells, leucocytes, platelets, per- thrombosis, intracompartmental syndrome, or a tight tourni-
ipheral nerve endings, skeletal muscle, vascular endothelium, quet may contribute. Causes of hypotension and shock include
and other membranes, produces presynaptic neurotoxic activity, hypovolaemia, vasodilatation, and myocardial dysfunction. Some
opiate-​like sedative effects, the autopharmacological release of venoms release vasodilating autacoids such as histamine and ki-
histamine, and may be anticoagulant. The acetylcholinesterase nins. Venom of the Brazilian jararaca B. jararaca was found to
found in most elapid venoms does not contribute to their neuro- activate bradykinin and, through a bradykinin-​potentiating pep-
toxicity. Hyaluronidase promotes the spread of venom through tide, to prolong its hypotensive effect by inactivating the peptidyl
tissues. Proteolytic enzymes (metalloproteinases, endopeptidases, dipeptidase responsible both for destroying bradykinin and for
or hydrolases) are responsible for local changes in vascular converting angiotensin I to angiotensin II. This observation led
1788 SECTION 10 Environmental medicine, occupational medicine, and poisoning

important Colubridae. Many venoms are haemolytic in vitro,

but clinically significant intravascular haemolysis, apart from
the microangiopathic haemolysis associated with disseminated
intravascular coagulation described in victims of viperine and
Australian brown snake Pseudonaja bites, is seen only after bites
by D. russelii (Sri Lanka and India), and some Bothrops and colu-
brid species. Acute renal tubular necrosis may be caused by severe
hypotension, disseminated intravascular coagulation (D. russelii,
D. siamensis), a direct nephrotoxic effect of the venom (D. siamen-
Fig. 10.4.2.13 Gross bilateral conjunctival oedema (chemosis) in a
Burmese rice farmer 48 h after being bitten by a Russell’s viper (Daboia sis), and myoglobinuria secondary to generalized rhabdomyolysis
siamensis). (sea snakes, D. russelii in Sri Lanka and India, and tropical rattle-
Copyright D. A. Warrell. snakes). Neurotoxic polypeptides and phospholipases block
neuromuscular transmission causing death through bulbar or re-
spiratory paralysis.
to the synthesis of angiotensin-​converting enzyme (ACE) in-
hibitors. Bradykinin-​potentiating and ACE-​inhibiting peptides Clinical features
have also been found in several other crotaline venoms (genera Fear, effects of treatment, and the venom contribute to the symp-
Bothrops and Agkistrodon). Four sarafotoxins have been isolated toms and signs of snakebite. Even patients who are not envenomed
from the venom of the Israeli burrowing asp Atractaspis engad- may feel flushed, dizzy, and breathless, and may notice constriction
densis (Fig. 10.4.2.3). They show 60% sequence homology with of the chest, palpitations, sweating, and acroparaesthesiae. Tight
the endothelins, which are also 21-​ amino acid polypeptides. tourniquets may produce swollen and ischaemic limbs; local inci-
Sarafotoxins and endothelins are potent vasoconstrictors of cor- sions at the site of the bite may cause bleeding and sensory loss and
onary and other arteries, delay atrioventricular conduction, and herbal medicines often induce vomiting. The earliest symptoms dir-
are positively inotropic. ectly attributable to the bite are local pain and bleeding from the
Snake venoms can cause haemostatic defects in several different fang punctures, followed by pain, tenderness, swelling, and bruising
ways. Venom procoagulant enzymes, many of them serine pro- extending up the limb, lymphangitis, and tender enlargement of re-
teases, activate the blood clotting cascade at various sites. Some gional lymph nodes. An anaphylaxis-​like syndrome of early syncope,
Viperidae venoms contain thrombin-​like fibrinogenases, which vomiting, colic, diarrhoea, angio-​oedema, and wheezing may follow
remove fibrinopeptides from fibrinogen directly. Others acti- bites by European Vipera, Russell’s vipers, Bothrops spp., Australian
vate endogenous plasminogen. Venoms may induce or inhibit elapids, and Atractaspis engaddensis. Nausea and vomiting are
platelet aggregation. Spontaneous systemic bleeding is caused by common early symptom of systemic envenoming.
haemorrhagins, metalloendopeptidases, some with disintegrin-​
like and other domains, which damage vascular endothelium Bites by Colubridae (back-​fanged snakes)
(Fig. 10.4.2.14). The combination of consumptive coagulopathy, Severe envenoming causes repeated vomiting, colicky abdom-
thrombocytopenia, and vessel wall damage can result in mas- inal pain, headache, systemic bleeding with widespread ecchym-
sively incontinent bleeding, a common cause of death after oses and the risk of intracerebral haemorrhage, incoagulable
bites by Viperidae, Australasian Elapidae, and the few medically blood, intravascular haemolysis, and acute kidney injury. Local
swelling and bruising may be the only results of envenoming. The
first symptoms of envenoming may be delayed for 24–​72 h after
the bite.

Bites by Atractaspidinae (burrowing asps or stiletto snakes)

Local effects include pain, swelling, blistering, necrosis, and tender
enlargement of local lymph nodes. Violent gastrointestinal symp-
toms (nausea, vomiting, and diarrhoea), anaphylaxis (dyspnoea,
respiratory failure), and electrocardiographic (ECG) changes
(atrioventricular block, ST, T-​wave changes) have been described
in patients envenomed by A. engaddensis and A. microlepidota
andersoni.

Bites by Elapidae (cobras, kraits, mambas, African garter

snakes, coral snakes, Australasian snakes, and sea snakes)
Bites by kraits, mambas, coral snakes, and some cobras (e.g.
N. haje, N. nivea, and N. philippinensis) produce minimal local
Fig. 10.4.2.14 Haemorrhagin activity revealed clinically as gingival
haemorrhage in a patient bitten by a saw-​scaled or carpet viper Echis effects, but the venoms of African spitting cobras (N. nigri-
ocellatus in Nigeria. collis, N. mossambica, and so on) and Asian cobras (N. naja,
Copyright D. A. Warrell. N. kaouthia, N. sumatrana, and so on) cause tender local swelling,
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1789

Fig. 10.4.2.17 Neurotoxic envenoming. Ptosis, external

ophthalmoplegia, and facial paralysis in a Sri Lankan patient
envenomed by a common krait Bungarus caeruleus.
Copyright D. A. Warrell.

‘heaviness’ of the eyelids, blurred vision, paraesthesiae around the

mouth, hyperacusis, headache, dizziness, vertigo, hypersalivation,
congested conjunctivae, and ‘gooseflesh’. Paralysis is first detect-
Fig. 10.4.2.15 Extensive necrosis of skin and subcutaneous tissues in a able as ptosis and external ophthalmoplegia appearing as early as
Nigerian girl bitten nine days previously on the elbow by a black-​necked 15 min after the bite, but sometimes it is delayed for 10 h or even
or spitting cobra Naja nigricollis.
more than 24 h. Later the face, palate, jaws, tongue, vocal cords,
Copyright D. A. Warrell.
neck muscles, and muscles of deglutition may become paralysed
(Fig. 10.4.2.17). The pupils are dilated. Respiratory failure may
blistering, and superficial necrosis, which may be extensive be precipitated by airway obstruction at this stage, or later after
(Fig. 10.4.2.15). ‘Skip’ lesions, separated by apparently normal paralysis of intercostal muscles and the diaphragm. Neurotoxic
areas of skin, may occur (Fig. 10.4.2.16). However, elapid venoms effects are completely reversible, either acutely in response to
are best known for their neurotoxic effects. Early symptoms, be- antivenom or anticholinesterases—​for example, following bites
fore there are objective neurological signs, include vomiting, by Asian cobras, some Latin American coral snakes Micrurus
spp., and Australasian death adders Acanthophis spp.—​or they
may wear off spontaneously in 1 to 7 days. Excruciating pain and
paraesthesiae radiating up the bitten limb have been described
with bites by coral snakes (Micrurus tener and M. lemniscatus),
explained by specific activation of acid-​sensing ion channels by a
venom toxin (MitTx). Severe, non​colicky, crescendo abdominal
pain, attributable to the smooth muscle stimulating effects of an
AVIT toxin, is often the most striking initial symptom in victims
of krait bites (Bungarus caeruleus).
Envenoming by terrestrial Australasian elapids produces four
main groups of symptoms: neurotoxicity (Fig. 10.4.2.18), haemo-
static disturbances and, rarely, generalized rhabdomyolysis, and
acute kidney injury. Painful regional lymph nodes are a useful sign
Fig. 10.4.2.16 Zimbabwean girl showing ‘skip lesions’ separated by of impending systemic envenoming, but local signs are usually mild,
areas of intact skin after envenoming by a Mozambique spitting cobra except after bites by the king brown or Mulga snake Pseudechis aus-
Naja mossambica. tralis. Early symptoms include vomiting, headache, and syncopal
By courtesy of the late Revd Dr Robbie McCabe. attacks.
1790 SECTION 10 Environmental medicine, occupational medicine, and poisoning

(a)

Fig. 10.4.2.18 Mozambique spitting cobra (Naja mossambica) in the

act of ejecting venom from the tips of its fangs.
Courtesy Dr David J. Williams.
(b)

Patients ‘spat’ at by spitting elapids may develop venom

ophthalmia. There is intense pain in the eye, blepharospasm, pal-
pebral oedema, and leucorrhoea (Fig. 10.4.2.19a). Corneal ero-
sions can be seen by slit-​lamp or fluorescein examination in more
than half of patients spat at by N. nigricollis. Rarely, venom is ab-
sorbed into the anterior chamber causing hypopyon and anterior
uveitis. Secondary infection of corneal abrasions may lead to per-
manent blinding opacities or panophthalmitis (Fig. 10.4.2.19b).

Bites by sea snakes and sea kraits

Patients envenomed by sea snakes notice headache, a thick feeling
of the tongue, thirst, sweating, and vomiting. Between 30 min and
3.5 h after the bite, there is generalized aching, stiffness, and ten- Fig. 10.4.2.19 Venom ophthalmia caused by the black-​necked spitting
derness of the muscles. Trismus is common. Later there is gener- cobra Naja nigricollis: (a) Acute venom ophthalmia showing intense
alized flaccid paralysis. Myoglobinuria appears 3–​8 h after the bite. painful inflammation and discharge. (b) Neglected cobra spit ophthalmia
Myoglobin and potassium released from damaged skeletal muscles complicated by corneal erosion and pan ophthalmitis requiring
enucleation to prevent sympathetic ophthalmia of the other eye.
can cause acute kidney injury, while hyperkalaemia may precipi- Copyright D. A. Warrell.
tate cardiac arrest.

Bites by Viperidae (vipers, adders, rattlesnakes, lance-​headed However, fatal envenoming by a few species can occur in the ab-
vipers, moccasins, and pit vipers) sence of local signs (e.g. C. d. terrificus, C. scutulatus, and Burmese
Viper venoms usually produce more severe local effects than do Russell’s viper). Haemostatic abnormalities are characteristic of
those of other snakes. Swelling may become detectable within envenoming by Viperidae. Persistent bleeding from fang punc-
15 min and usually by 2 hours, but is sometimes delayed for sev- ture wounds, venepuncture, or injection sites, other new and par-
eral hours. It spreads rapidly with bruising, sometimes involving tially healed wounds, and postpartum, indicates that the blood is
the whole limb, adjacent trunk and, in children, the whole incoagulable. Spontaneous systemic haemorrhage is most often
body (Fig. 10.4.2.25). There is associated pain and tenderness detected in the gingival sulci. Epistaxis, haematemesis, cutaneous
in regional lymph nodes, with bruising of overlying tissues and ecchymoses, haemoptysis, and subconjunctival, retroperitoneal,
lymphangitic lines. Blistering, and necrosis may appear during and intracranial haemorrhages (Fig. 10.4.2.22) are also seen.
the next few days (Fig. 10.4.2.20). Necrosis can be severe fol- Patients envenomed by Burmese and Indian/​SriLankan Russell’s
lowing bites by some rattlesnakes, lance-​headed vipers Bothrops vipers may suffer haemorrhagic infarction of the anterior pitu-
spp., Asian pit vipers, and the large African Bitis species. When itary, resulting in acute or chronic pituitary/​adrenal insufficiency
the envenomed tissue is contained in a tight fascial compartment (Sheehan’s-​ like syndrome) (Fig. 10.4.2.23). Hypotension and
such as the pulp space of digits or the anterior tibial compart- shock are common in patients bitten by North American rattle-
ment, ischaemia may result (Fig. 10.4.2.21). Absence of swelling snakes (e.g. C. adamanteus, C. atrox, and C. scutulatus), Bothrops,
2 h after a viper bite suggests that there has been no envenoming. Daboia, and Vipera species (e.g. D. palaestinae and V. berus). The
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1791

Fig. 10.4.2.22 CT scan showing intracranial haemorrhage in a child

bitten by a common lancehead Bothrops atrox in Ecuador. The fluid level in
Fig. 10.4.2.20 Swelling, blistering, and necrosis that required
the larger collection of blood indicates that the blood was incoagulable.
amputation in a Thai woman bitten on the hand four days earlier by
Copyright D. A. Warrell.
a Malayan pit viper Calloselasma rhodostoma. There are widespread
ecchymoses.
Copyright D. A. Warrell.
of the bite and complain of loin pain, suggesting renal ischaemia
at a time when their plasma renin activity is high. Neurotoxicity,
central venous pressure is usually low and the pulse rate rapid, resembling that seen in patients bitten by Elapidae, is a feature
suggesting hypovolaemia resulting from extravasation of fluid of envenoming by a few species of Viperidae (e.g. C. d. terrificus,
into the bitten limb. Patients envenomed by Russell’s vipers show Gloydius spp., berg adder Bitis atropos and other small Bitis spe-
evidence of generally increased vascular permeability. Direct cies, and Sri Lankan D. russelii) (Fig. 10.4.2.24). There is evidence
myocardial involvement is suggested by an abnormal ECG or car- of generalized rhabdomyolysis (Fig. 10.4.2.24), but progression to
diac arrhythmia and reduced ejection fraction detected by echo- respiratory or generalized paralysis is unusual.
cardiography. Patients envenomed by some species of the genera
Daboia, Vipera, Crotalus, Bothrops, and Australasian elapids may
experience early transient and recurrent syncopal attacks, associ-
ated with features of an autopharmacological or anaphylactic re-
action, such as vomiting, sweating, colic, diarrhoea, shock, and
angio-​oedema. These symptoms may appear as early as 5 min
or as late as many hours after the bite. Early collapse after bites
by Australian brown snakes (Pseudonaja spp.) and tiger snakes
(Notechis spp.) has been attributed to coronary and pulmonary
thromboembolism but this seems unlikely. Acute kidney injury
is a common mode of death in patients envenomed by Viperidae.
Victims of Russell’s viper may become oliguric within a few hours

Fig. 10.4.2.21 Extensive necrosis of skin and muscle including the Fig. 10.4.2.23 Haemorrhagic infarction of the anterior pituitary in a
contents of the anterior tibial compartment in a patient bitten by a Burmese patient who died after being bitten by a Russell’s viper Daboia
lancehead Bothrops marajoensis in Brazil 27 days earlier. siamensis.
Copyright D. A. Warrell. By courtesy of Dr U Hla Mon, Yangon, Myanmar.
1792 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Fig. 10.4.2.25 Generalized swelling and bruising in a 4-​year-​old child

bitten by a European adder Vipera berus in Sweden.
Fig. 10.4.2.24 Brazilian girl bitten 24 h earlier by a tropical rattlesnake Courtesy of Dr H Persson.
Crotalus durissus terrificus. She has bilateral ptosis, paralysis of the
facial muscles, and gross myoglobinuria resulting from generalized
rhabdomyolysis.
Copyright D. A. Warrell. cavities and retroperitoneally can occur. The risk of bleeding
is greatly increased by misguided treatment with heparin. Fatal
haemothorax, massive haematemesis and melaena, haematuria,
Envenoming by European vipers and intrauterine fetal death are rare tragedies. Acute kidney
The common viper or adder V. berus (Fig. 10.4.2.12), the only injury is not uncommon in children. Increased capillary per-
venomous snake found in the United Kingdom, occurs in meability is reflected by the local and sometimes generalized
England, Wales, Scotland, and northern Europe, extending into oedema, as well as the more focal angio-​oedema that can lead
the Arctic Circle and through Asia as far east as Sakhalin island to fatal occlusion of the upper airway, and pulmonary, and cere-
and south to northern Korea. There are four other vipers that bral oedema. Coma and seizures are attributable to hypoten-
are widely distributed in mainland Europe: the nose-​horned sion, cerebral oedema, hyponatraemia, hypoalbuminaemia, or
or sand viper V. ammodytes in the Balkans, Italy, Austria, and hypoxaemia secondary to respiratory distress. Cardiac arrest,
Romania; the asp viper V. aspis in France (south of Paris), Spain, acute gastric dilatation, paralytic ileus, and acute pancreatitis
Germany, Switzerland, and Italy; Lataste’s viper V. latastei in are other reported complications. Classic mild neurotoxicity
Spain and Portugal, and Orsini’s viper V. ursinii in southeastern (ptosis, external ophthalmoplegia) has been reported after
France, central Italy, and Eastern Europe. The Montpellier snake bites by several species of European Vipera, including V. aspis,
Malpolon monspessulanus is a large back-​fanged colubrid snake V. berus, and V. ammodytes in certain geographical areas.
whose bite can cause transient mild local symptoms and rarely • Laboratory findings: neutrophil leucocytosis is common. Serum
neurotoxicity. creatine kinase (CK), transaminases, urea, and creatinine con-
centrations may be raised, and bicarbonate may be reduced.
Clinical features of European viper bite Thrombocytopenia and mild coagulopathy; reflected by pro-
• Local envenoming: immediate sharp pain is followed by spreading longed prothrombin time, activated partial thromboplastin
pain, tenderness, and tender enlargement of regional lymph time, hypofibrinogenaemia, and raised fibrin degradation prod-
nodes within hours. Reddish lymphangitic lines and bruising ucts or D-​dimer; is sometimes detected. Severe coagulopathy is
appear, and the whole limb may become swollen and bruised uncommon. Electrocardiographic changes include tachy-​and
within 24 h with involvement of the trunk and, in children, the bradyarrhythmias, atrial fibrillation, flattening or inversion of T-​
whole body (Fig. 10.4.2.25). Intracompartmental syndromes waves, ST elevation or depression, second-​degree heart block, and
and necrosis are rare. frank myocardial infarction.
• Systemic envenoming: dramatic anaphylactic symptoms may • Prognosis: most adder bites cause only trivial symptoms, but pa-
appear between 5 min and many hours after the bite: nausea, tients must be assessed individually and deaths have occurred
retching, vomiting, abdominal colic, diarrhoea, incontinence between 6 and 60 (average 34) h after the bite. Children may be
of urine and faeces, sweating, fever, vasoconstriction, tachy- severely envenomed: in a French series, there were three deaths
cardia, lightheadedness, shock with loss of consciousness, in a group of seven children aged between 2.5 and 10 years. The
angio-​oedema of the face, lips, gums, tongue, throat, and epi- dangers of adder bite should not be underestimated. The anti-
glottis, urticaria, and bronchospasm. These symptoms may venom treatment of adder bite is discussed in the following
persist or fluctuate for as long as 48 h in the absence of treat- paragraphs.
ment. Hypotension is a dangerous sign that usually develops
within 2 h and may resolve spontaneously, persist, recur, or Laboratory investigations
progress fatally. Clinical features of a bleeding diathesis are The peripheral neutrophil count may be raised to 20 000 cells/​µl
unusual, but bleeding from the gums and nose and into the or more in severely envenomed patients. The blood film
lungs, gastrointestinal and genitourinary tracts, and serosal may show evidence of microangiopathic haemolysis. Initial
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1793

haemocon­ centration, resulting from extravasation of plasma retrospective diagnosis, including forensic cases, tissue around
(Crotalus species and Burmese D. siamensis), is followed by anaemia the fang punctures, wound and blister aspirate, serum, and urine
caused by bleeding or, more rarely, haemolysis. Thrombocytopenia should be stored for EIA immunodiagnosis. Polymerase chain re-
is common following bites by pit vipers (e.g. Calloselasma rho- action (PCR) to detect venom gland RNA or snake DNA in the
dostoma, Crotalus oreganus helleri) and some Viperidae (e.g. Bitis bite wound are under development.
arietans and Russell’s vipers), but is unusual after bites by Echis
species. Management of snakebite
20-​ minute whole blood clotting test (20WBCT): this is a First aid
simple bedside test for venom-​ induced defibrinogenation or
The patient should be reassured and moved to the nearest hospital
anticoagulation. A few millilitres of venous blood are placed in
or dispensary as quickly, comfortably, and passively as possible. The
a new, clean, dry, glass vessel, left undisturbed for 20 min, and
whole patient should be immobilized, especially the bitten limb,
then tipped once to see if it has clotted or not. Positive 20WBCT
using a splint or sling.
(incoagulable blood) indicates systemic envenoming, either con-
Most traditional first aid methods are potentially harmful and
sumptive coagulopathy (plasma fibrinogen concentration below
should not be used. Local incisions and suction do not remove
0.5 g/​litre) or effects of an anticogulant toxin (e.g. envenoming by
venom effectively and may introduce infection, damage tissues, and
Australian black snake, Pseudechis spp.). It may be diagnostic of a
cause persistent bleeding. Vacuum extractors, potassium perman-
particular species (e.g. Echis spp. in Africa north of the equator).
ganate, and ice packs may potentiate local necrosis. Electric shocks
The only equipment required for the test is a new glass tube, but this
are dangerous and have not been proved beneficial. Tourniquets
may be difficult to find in modern hospitals where glass has been
and compression bands are potentially dangerous as they can cause
replaced by plastics. Glass is essential to contact-​activate Hageman
gangrene, increased fibrinolysis, and bleeding in the occluded limb,
factor (factor XII) which initiates the ‘intrinsic’ coagulation pathway.
peripheral nerve palsies, compartmental ischaemia, and intensifica-
Glass washed with soap or detergent may lose this property. A posi-
tion of local signs of envenoming.
tive 20WBCT had a positive predictive value of 89.7%, negative pre-
dictive value of 93.5%, sensitivity of 92.9%, and specificity of 90.6% Pressure-​immobilization (P-​I) methods
for plasma fibrinogen concentrations of less than 0.5 g/​litre. Point of
In animal studies, compressing superficial veins and lymph-
care INR coagulometers and D-​dimer tests are not reliable in snake-​
atics in the bitten limb delayed the spread of larger molecular
envenomed patients.
weight toxins such as the presynaptic phospholipase A2 toxins of
Laboratory tests of blood coagulation (prothrombin time, ac-
Australian elapid venoms. This delay might prevent development
tivated partial thromboplastin time, fibrinogen concentration)
of life-​threatening respiratory paralysis before the victim has had
and fibrinolysis (fibrin/​ fibrinogen degradation products, D-​
time to reach medical care. P-​I is, therefore, indicated after bites by
dimer) are more sensitive but take much longer and are more
neurotoxic elapids but also, in cases of bites by unknown species,
demanding in equipment than the simple 20WBCT. Patients with
P-​I should be applied immediately unless a bite by a neurotoxic
generalized rhabdomyolysis show a steep rise in serum creatine
elapid can, with confidence, be excluded.
kinase, myoglobin, and potassium levels. Black or brown urine
suggests generalized rhabdomyolysis and/​or intravascular haem- 1 Anker’s (Monash) pressure-​ pad immobilization method
olysis; in both cases, positive urine sticks tests will not distinguish (Fig. 10.4.2.26a). A pad of any available material, approximately
between blood, haemoglobin, and myoglobin. Concentrations 5 × 5 × 3 cm, is applied directly over the bite wound, at a pres-
of serum enzymes, such as CK and aspartate aminotransferase, sure of about 70 mm Hg, and the limb is splinted. This delayed
are moderately raised in patients with severe local envenoming, systemic envenoming, as assessed by measurements of venom
due to muscle damage at the site of the bite. High concentra- antigenemia, in a preliminary field trial in Burmese Russell’s
tions (CK >2000 U/​litre) suggest generalized rhabdomyolysis. viper bite victims.
Urine should be examined for blood/​haemoglobin, myoglobin, 2 Sutherland’s original pressure-​bandage immobilization method
and protein, and for microscopic haematuria and red cell casts. (Fig. 10.4.2.26b) involves bandaging the bitten limb with a series
Electrocardiographic abnormalities such as sinus bradycardia, of long, 10-​cm-​wide elastic bandages, ‘as firmly as for a sprained
ST–​T changes, various degrees of atrioventricular block, and ankle’ (about 55 mm Hg), starting distal to the bite site, continuing
hyperkalaemic changes may be seen. up to the groin or axilla and incorporating a splint. Although
never subjected to formal clinical trials, the method was con-
Immunodiagnosis sidered effective, based on anecdotal reports of delayed systemic
Specific snake venom antigens have been detected in wound swabs, envenoming and rapid deterioration after release of the bandage,
aspirates or biopsies, serum, urine, cerebrospinal fluid, and other in some cases supported by measurements of venom antigenemia.
body fluids. Venom antigenaemia can be quantitated using en- However, in practice, the technique has proved difficult to apply,
zyme immunoassay (EIA), providing the most accurate prognosis. even in Australia, and it is demanding on equipment and training.
Under ideal conditions, relatively high venom antigen concentra- External compression increases intracompartmental pressure and
tions (wound swabs or aspirates) may be detected quickly enough might accentuate the local effects of some necrotic snake venoms,
(15–​30 min) to allow the selection of the appropriate monospe- but animal studies found little evidence that this was deleterious
cific antivenom. A commercial venom detection kit for Australian and confirmed the life-​saving effects of lymphatic and venous
elapids is produced by Seqirus (formerly CSL), Melbourne. For compression.
1794 SECTION 10 Environmental medicine, occupational medicine, and poisoning

(a)

(b)

Fig. 10.4.2.26 Pressure-​immobilization methods. (a) Pressure-​pad immobilization. A pad of whatever material is
immediately available is placed directly over the bite wound and bound on very firmly with an inelastic bandage. The
whole limb is then splinted to prevent movement at any of its joints. (b) Pressure-​bandage immobilization. The bitten
limb is firmly bound with long, wide (4 cm) elastic bandages, starting distal to the bite site and ending at the armpit or
groin. A splint is incorporated.
Courtesy of Dr David J Williams.
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1795

Inhibition of the intrinsic lymphatic pump envenoming. There is abundant evidence that in patients with se-
A study of lymphatic flow in human volunteers and in rats showed vere envenoming, the benefits of this treatment outweigh the risks
that nitric oxide (NO)–​donating drugs, such as glyceryl trinitrate of antivenom reactions (see following paragraphs). Antivenom has
(GTN), applied topically to the bitten limb, substantially slowed reduced the mortality of systemic envenoming by Echis ocellatus in
lymphatic flow, despite movement of the limb. Topical application of Nigeria from 20% to 3% and by C. d. terrificus in Brazil from 74%
NO-​donating drugs might prove a useful adjunct to pressure-​pad or to 12%. Antivenoms are effective in reversing hypotension caused
pressure-​bandage first-​aid methods. by V. berus envenoming and coagulopathies caused by Bothrops
Pursuing and killing the snake is not recommended, but if the species, Russell’s vipers, C. rhodostoma, Trimeresurus T. albolabris,
snake has been killed, it should be taken with the patient to hospital. and Oxyuranus scutellatus. Antivenom, also known as antivenin,
It must not be handled as even a severed head can inject venom. antivenene, antisnakebite serum, and anti-snakevenom (ASV) is
Patients being transported to hospital should lie on their left side the partially purified immunoglobulin (whole IgG, F(ab′)2, or Fab
in the recovery position to prevent aspiration of vomit. Persistent fragments) of horses or sheep that have been hyperimmunized with
vomiting can be treated with chlorpromazine by intramuscular in- venom. Antivenoms are in short supply in sub-​Saharan Africa and
jection (25–​50 mg in adults, 1 mg/​kg in children; intravenous injec- New Guinea; elsewhere, they are of variable efficacy and safety and
tion risks hypotension), or chlorpromazine or prochlorperazine by are often used inappropriately.
intrarectal suppository. Syncope, shock, angio-​oedema, and other Indications for antivenom
autonomic symptoms can be treated with 0.1% adrenaline by intra-
Antivenom is indicated if there are signs of systemic envenoming
muscular injection (0.5 ml for adults, 0.01 ml/​kg for children) and
such as:
an antihistamine such as chlorphenamine maleate by intravenous
injection (10 mg for adults, 0.2 mg/​kg for children). Patients with • haemostatic abnormalities: spontaneous systemic bleeding,
incoagulable blood will develop haematomas after intramuscular incoagulable blood, or thrombocytopenia
and subcutaneous injections, and so the intravenous route should be • neurotoxicity: descending paralysis starting with ptosis and ex-
used whenever possible except in the case of adrenaline. Respiratory ternal ophthalmoplegia
distress and cyanosis should be treated by clearing the airway, giving • hypotension and shock, abnormal ECG, or other evidence of
oxygen, and, if necessary, assisted ventilation. If the patient is uncon- severe cardiovascular dysfunction
scious and no femoral or carotid pulses can be detected, cardiopul- • generalized rhabdomyolysis or massive intravascular haemolysis:
monary resuscitation must be started immediately. black urine
Hospital treatment Supporting evidence of severe envenoming is a neutrophil leuco-
Clinical assessment cytosis, elevated serum enzymes such as CK and aminotransferases,
haemoconcentration, severe anaemia, myoglobinuria, haemo-
In most cases of snakebite, uncertainties about the species and the globinuria, methaemoglobinuria, hypoxaemia, and acidosis.
quantity and composition of venom injected can be resolved only by In the absence of systemic envenoming, local swelling involving
admitting the patient to hospital for at least 24 h of observation. Local more than half the bitten limb, extensive blistering or bruising, bites
swelling is usually detectable within 15 min of pit viper envenoming on digits, and rapid progression of swelling are indications for anti-
and within 2 h of envenoming by most other vipers, but may not de- venom, especially in patients bitten by species whose venoms are
velop in patients bitten by some vipers, colubrids, and elapids such known to cause local necrosis (e.g. Viperidae, Asian cobras, and
as kraits, coral snakes, and sea snakes. Fang marks are sometimes African spitting cobras).
invisible. Tender enlargement of regional lymph nodes draining the Patients bitten by European Vipera spp. who show any evidence
bitten area is an early sign of envenoming by Viperidae and some of envenoming should be admitted to hospital for observation for at
Elapidae, notably Australasian elapids. All the tooth sockets should least 24 h. Antivenom should be given whenever there is evidence of
be examined meticulously as this is usually the first site of spontan- systemic envenoming (see earlier), even if its appearance is delayed
eous bleeding: other common sites are the nose, conjunctiva, skin, and for several days after the bite.
gastrointestinal tract. Persistent bleeding from venepuncture sites and
other wounds implies incoagulable blood. Hypotension and shock are Prediction of antivenom reactions
important signs of hypovolaemia, vasodilatation, or cardiotoxicity, Hypersensitivity testing by intradermal or subcutaneous injection
seen particularly in patients bitten by North American rattlesnakes or intraconjunctival instillation of diluted antivenom was widely
and some Viperinae (e.g. V. berus, Russell’s vipers, D. palaestinae). practised in the past. However, these tests delay the start of anti-
Ptosis is the earliest sign of neurotoxic envenoming (Fig. 10.4.2.17). venom treatment, are not without risk, and have no predictive value
Respiratory muscle power should be assessed objectively and repeat- for early (anaphylactic) or late (serum sickness-​type) antivenom
edly, for example, by measuring vital capacity. Trismus and general- reactions, because they are not usually the result of acquired
ized myalgia with muscle tenderness suggest rhabdomyolysis (sea IgE-​mediated type I hypersensitivity
snakes). If a procoagulant venom is suspected, the coagulability of
whole blood should be checked at the bedside using the 20WBCT. Prevention of early antivenom reactions
Prophylactic antihistamines (anti-​H1 and anti-​H2), corticosteroids,
Antivenom treatment and adrenaline have been widely used, singly or in combination,
In managing cases of snakebite, the most important decision is without convincing evidence of effectiveness. However, premedica-
whether or not to give antivenom, the only specific antidote for tion of 1007 Sri Lankan snakebite victims with promethazine,
1796 SECTION 10 Environmental medicine, occupational medicine, and poisoning

hydrocortisone, and adrenaline in a subcutaneous adult dose of 1 VIAL Fab ANTIVENOM I.VI. COMPARED WITH 1 VIAL I.M.I.
(9 PATIENTS VIA EACH ROUTE)
0.25 ml of 1:1000 was compared, each alone and in various com- 0.5
binations. Compared with placebo, adrenaline significantly reduced Fab AV I.V. Fab AV I.M.
severe reactions to antivenom by 43% (95% CI, 25–67) at 1 hour
0.4
and by 38% (95% CI, 26–49) up to and at 48 hours after antivenom
administration. Hydrocortisone and promethazine were ineffective,

Fab antivenom (ul/ml)

and addition of hydrocortisone negated the benefit of adrenaline. 0.3
Routine prophylaxis with low-​ dose subcutaneous epinephrine
(adult dose, 0.25 mg of 1: 1000 solution), given before starting anti-
venom infusion, should now be generally recommended based on 0.2
this convincing evidence.
0.1
Contraindications to antivenom
Atopic patients and those who have reacted previously to equine
antiserum are at increased risk of developing severe antivenom re- 0
0 1 3 6 12 24 48
actions. In such cases, antivenom should be given only if there is
definite systemic envenoming. Reactions may be prevented or Time after antivenom (hr)
ameliorated by pretreatment with subcutaneous adrenaline (see Fig. 10.4.2.27 Serum therapeutic antivenom concentrations in two
earlier). There is no time for rapid desensitization. groups of patients with mild envenoming given the same dose of a Fab
fragment antivenom by intramuscular or slow intravenous injection.
Selection and administration of antivenom Intramuscular administration resulted in delayed peak concentrations
Antivenom should be given only if its stated range of specificity in- (at 24 h) sixfold less than by intravenous injection.
Theakston RDG, Warrell DA, unpublished data.
cludes the species thought to be responsible for the bite. Whatever
the stated expiry date on the ampoule, opaque solutions should be
discarded, as precipitation of protein indicates loss of activity and and scoring systems are in use to guide choice of the initial dose of anti-
an increased risk of reactions. However, expiry dates quoted on venom but none has been tested for its prognostic significance. The
ampoules are often unnecessarily short, for commercial reasons; patient’s condition may deteriorate suddenly, making these rigid and
provided that the antivenom has been kept refrigerated and the so- unproven prescriptions unreliable. Many hospitals in the rural tropics
lution is clear, a high proportion of its original activity is retained give a standard dose of 1 to 2 ampoules to every patient who claims to
for 5 years or more. Monospecific (monovalent) antivenom is ideal have been bitten, irrespective of clinical severity. This practice squan-
if the biting species is known. Polyspecific (polyvalent) antivenoms ders scarce, expensive antivenom, and exposes non-​envenomed pa-
are used in many countries because of the difficulty in identifying tients to the risk of reactions. Some suggested initial doses are given in
the species responsible for bites. Polyspecific and monospecific anti- Table 10.4.2.1. Children must be given the same dose as adults.
venoms can be equally effective. Antivenoms may exhibit a range
of paraspecific neutralizing activity. For example, the South African Response to antivenom
Vaccine Producer’s (formerly SAIMR) ‘polyvalent antivenom’, which Often, there is marked symptomatic improvement soon after anti-
is raised against the venoms of 10 species, has paraspecific activity venom has been injected. In shocked patients, the blood pressure
against a further five species. may rise and consciousness returns (C. rhodostoma, V. berus, Bitis
It is almost never too late to give antivenom while signs of sys- arietans). Neurotoxic signs may improve within 30 min (Acanthophis
temic envenoming persist, but, ideally, it should be given as soon spp., N. kaouthia), but the response usually take several hours.
as it is indicated. Antivenom has proved effective up to 2 days after Spontaneous systemic bleeding usually stops within 15 to 30 min
sea snake bites and, in patients still defibrinogenated, weeks after and blood coagulability is restored within a median time of 6 h after
bites by Viperidae. In contrast, local envenoming is probably not antivenom treatment, provided a neutralizing dose has been given.
amenable unless antivenom is given within a few hours of the bite. More antivenom should be given if severe signs of envenoming persist
The intravenous route is far more effective than intramuscular after 1 to 2 h, or if blood coagulability is not restored within about 6 h.
(Fig. 10.4.2.27). An infusion of antivenom diluted in approxi- Systemic envenoming may recur hours or days after an initially good
mately 5 ml of isotonic fluid/​kg body weight may be easier to con- response to antivenom. This is explained by the continuing absorption
trol than an intravenous ‘push’ injection of undiluted antivenom of venom from the injection site after clearance of antivenom from
given at the rate of about 4 ml/​min. However, there is no evidence the bloodstream or redistribution of venom from the tissues into the
that dilution, or slower administration of antivenom within the vascular compartment. The apparent serum half-​lives of antivenoms
range 10–​120 minutes, affects the incidence or severity of early in envenomed patients range from 26 to 95 h. Envenomed patients
antivenom reactions. should therefore be assessed daily for at least 3 or 4 days.

Dose of antivenom Antivenom reactions

Manufacturers’ recommendations are based on mouse protection Early (anaphylactic) reactions These reactions develop within
tests and may be very misleading. Few clinical trials have been per- 10 to 180 min of starting antivenom in between 3% and 84%
formed to establish appropriate initial doses, and in most coun- of patients, depending on which antivenom is used. The inci-
tries this is judged empirically. Many clinical severity grading dence increases with dose and is lowest in antivenoms lacking
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1797

Table 10.4.2.1 Guide to initial dosage of selected important antivenoms (key to abbreviations at foot of table)

Species
Latin name Common name Manufacturer, antivenom Initial dose (approximate)
Acanthophis spp. Death adders CSL,a monospecific 1–​3 vials
Agkistrodon piscivorus, Copperhead and cottonmouth BTGg ‘CroFab’, Laboratorio Silanes (Mexico) 4–​6 vials
A. contortrix moccasins Antivipmyn
Bitis arietans Puff adder SAVPb polyspecific, ICPc EchiTAb-​plus-​ICP 80 ml
Bothrops asper Terciopelo ICPc polyvalent, Laboratorio Silanes (Mexico) 50–​100 ml
Antivipmyn TRI
Bothrops atrox Common lancehead Butantan, FEDd Antibotropico 20 ml
Bothrops (Bothriopsis) bilineatus Papagaio Butantan Antibotropico 20 ml
d
Bothrops jararaca Jararaca Instituto Butantan, FED Antibotropico 20 ml
Bothrops lanceolatus and Lesser Antillean fer de lance Sanofi-​Pasteur BothroFav 2–​6 vials
B. caribbaeus
Bungarus caeruleus Common krait Indian manufacturerse, polyvalent 100 ml
Calloselasma (Agkistrodon) Malayan pit viper Thai Red Cross monovalent or 100 ml
rhodostoma haemato-​polyvalent
Thai Government Pharmaceutical 50 ml
Organization monovalent
Cerastes spp. Desert (horned) vipers NAVPCf polyvalent 30–​50 ml
Vacsera AntiViper or polyvalent 30–​50 ml
g
Crotalus adamanteus Eastern diamondback rattlesnake BCG ‘CroFab’, Laboratorio Silanes (Mexico) 7–​15 vials
Antivipmyn
C. atrox Western diamondback BTGg ‘CroFab’, Laboratorio Silanes (Mexico) 7–​15 vials
rattlesnake Antivipmyn
C. oreganus and C. viridis sspp. Western rattlesnakes BTGg ‘CroFab’ or Laboratorio Silanes (Mexico) 7–​15 vials
Antivipmyn
C. simus and C. durissus sspp. Central and Southern American ICPc or Laboratorio Silanes polyvalent 5–​15 vial
rattlesnakes
Butantan, FEDd Anticrotalico, or 5–​20 vials
Antibotropico-​crotalico
Daboia (Vipera). Palaestinae Palestine viper Rogoff Medical Research Institute, Tel Aviv, 50–​80 ml
Palestine, viper-​monospecific
Daboia (Vipera) russelii Western Russell’s viper Indian manufacturerse polyspecific 100 ml
D. siamensis Eastern Russell’s viper Thai Red Cross monovalent or 50 ml
haemato-​polyvalent
Myanmar Pharmaceutical Factory monovalent 80 ml
Dendroaspis spp. Mambas SAVPb Dendroaspis or polyvalent 50–​100 ml
b
Echis ocellatus, E. leucogaster, African saw-​scaled or carpet SAVP Echis monovalent ICP, EchiTAb-​plus-​ICP, 20 ml, 3 vials, 1 vial
E. pyramidum (Africa) vipers MicroPharm EchiTAb-​G
Echis carinatus sspp. Asian saw-​scaled viper Indian manufacturerse, polyvalent 50 ml
f
Echis spp. Middle East Middle Eastern saw-​scaled vipers NAVPC Polyvalent Snake Antivenom Vacsera 50 ml
Polyvalent and Anti-​Viper Venom Antiserum
Hydrophiinae Sea snakes CSLa sea snake antivenom 1–​10 vials
c d
Lachesis spp. Bushmasters ICP polyspecific, FED Antibotropico laquetico, 10–​20 vials
Butantan Antiophidico
Micrurus spp. Central American and Brazilian ICPc monovalent 1–​5 vials
coral snakes
Butantan Antielapidico 1–​5 vials
Naja kaouthia Monocellate Thai cobra Thai Red Cross cobra monovalent or 100 ml
neuro-​polyvalent
N. naja Indian cobra Indian manufacturers,e polyvalent 100 ml
b c
N. nigricollis, N. mossambica, African spitting cobras SAVP polyvalent, ICP EchiTAb-​plus-​ICP 100 ml
and so on
Notechis scutatus Tiger snake CSL,a monospecific 1–​3 vials

(continued)
1798 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Table 10.4.2.1 Continued

Species
Latin name Common name Manufacturer, antivenom Initial dose (approximate)
Oxyuranus scutellatus Australian and New Papuan CSL,a monospecific 1–​6 vials
Taipan
Pseudonaja textilis Eastern brown snake CSL,a monospecific 1–​3 vials
Trimeresurus (Trimeresurus) White-​lipped and large-​eyed Thai Red Cross monovalent or 100 ml
albolabris, T. (T.) macrops green pit viper haemato-​polyvalent
Vipera berus and other European adder and other MicroPharm ‘ViperaTAb’, Sanofi-​Pasteur 100–​200 mg, 4 ml
European Vipera vipers ViperFav
a
CSL, Commonwealth Serum Laboratories, Australia; b SAVP, South African Vaccine Producers (formerly SAIMR: South African Institute for Medical Research); c ICP, Instituto
Clodomiro Picado, Costa Rica; dFED, Fundação Ezequiel Dias, Brazil; eIndian manufacturers (Vins, Bharat, Premium Serums and Vaccines, and so on); f NAVCP, National Antivenom
and Vaccine Production Center, KSA; g BTG (formerly Protherics).

complement-​activating aggregates. Fewer reactions occur when antihistamine such as chlorphenamine (2 mg every 6 h for adults;
administration is by intramuscular rather than intravenous injec- 0.25 mg/​kg per day in divided doses for children) or to oral prednis-
tion. The symptoms are itching, urticaria, cough, nausea, vomiting, olone (5 mg every 6 h for 5 to 7 days for adults; 0.7 mg/​kg per day in
other autonomic manifestations, fever, and tachycardia. Up to divided doses for children).
40% of patients with early reactions develop systemic anaphyl-
axis: hypotension, bronchospasm, and angio-​oedema. Deaths are Supportive treatment
rare, but individual cases, such as the asthmatic boy who died from
Neurotoxic envenoming
anaphylactic shock after receiving Pasteur antivenom in England
in 1957, have been widely publicized and have led to an unreason- Bulbar and respiratory paralysis may lead to death from aspiration,
able rejection of antivenom treatment. Early antivenom reactions airway obstruction, or respiratory failure. A clear airway must be
are unlikely to be type I, IgE-​mediated hypersensitivity reactions maintained and, if bulbar muscle weakness results in pooling of
to equine serum protein. They result from complement activation secretions, or respiratory distress develops, a cuffed endotracheal
by immune complexes or aggregates of IgG. tube, laryngeal mask airwayor i-​gel supraglottal airway should
be inserted or a tracheostomy performed. Provided they are ad-
Pyrogenic reactions Pyrogenic reactions result from contam-
equately ventilated, patients with neurotoxic envenoming remain
ination of the antivenom with endotoxin-​like compounds. Fever,
fully conscious with intact sensation and can respond to spoken
rigors, vasodilatation, and a fall in blood pressure develop 1 to 2 h
questions by flexing a finger or toe. Lifting their paralysed eyelids
after treatment. In children, febrile convulsions may be precipitated.
so that they can see is very reassuring. Patients have been effectively
Late serum sickness-​type reactions Late reactions of serum sickness ventilated manually (by Ambu bag or anaesthetic bag), as in the
type may develop between 5 and 24 (mean 7) days after antivenom 1952 poliomyelitis epidemic in Copenhagen, for 30 days and have
therapy. The incidence of these reactions and the speed of their de- recovered after 10 weeks of mechanical ventilation. Although artifi-
velopment increases with the dose of antivenom. Clinical features cial ventilation was first suggested for neurotoxic envenoming more
include fever, itching, urticaria, arthralgia (sometimes involving the than 100 years ago, patients continue to die because they are denied
temporomandibular joint), lymphadenopathy, periarticular swell- this simple procedure.
ings, mononeuritis multiplex, albuminuria, and rarely, encephalop- Anticholinesterases have a variable but potentially useful ef-
athy. This is a classic immune complex disease. fect in patients with neurotoxic envenoming, especially when
postsynaptic neurotoxins are involved. However, recent media
Treatment of antivenom reactions claims that intranasal neostigmine might provide a universal first-​
Adrenaline is the effective treatment for early reactions; 0.5 to 1.0 ml aid method for snakebite victims are unsubstantiated, misleading,
of 0.1% (1 in 1000, 1 mg/​ml) is given by intramuscular injection into and fanciful. The ‘Tensilon test’ should be performed in all cases
the lateral thigh to adults (children 0.01 ml/​kg) at the first signs of a of severe neurotoxic envenoming, as with suspected myasthenia
reaction. The dose may be repeated if the reaction is not controlled. gravis. Atropine sulphate (0.6 mg for adults; 50 µg/​kg for children)
Patients with profound hypotension, severe bronchospasm, or la- or glycopyrronium is given by intravenous injection followed by
ryngeal oedema may be given adrenaline by slow intravenous in- edrophonium chloride (Tensilon) by slow intravenous injection in
jection (0.5 mg diluted in 20 ml of isotonic saline over 10–​15 min). an adult dose of 10 mg, or 0.25 mg/​kg for children or neostigmine
For bronchospasm, a β2 agonist such as salbutamol should be given bromide or methylsulphate (Prostigmin) by intramuscular injec-
by inhaler or nebulizer, together with oxygen. A histamine anti-​H1 tion (0.02 mg/​kg for adults, 0.04 mg/​kg for children). The ‘ice test’
blocker, such as chlorphenamine maleate (10 mg for adults; 0.2 mg/​ is a possible alternative to the Tensilon test. In myasthenia gravis,
kg for children) can be given by intravenous injection to combat application of an ice-​filled plastic glove to one eye for 2 minutes
the effects of histamine release during the reaction, but this is less results in improvement in ptosis on that side, due to inhibition
urgent. Pyrogenic reactions are treated by physically cooling the of anticholinesterase. Patients who respond convincingly can be
patient and giving antipyretics. Late reactions respond to an oral maintained on neostigmine methylsulphate, 0.5 to 2.5 mg every
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1799

1 to 3 h up to 10 mg/​24 h maximum for adults or 0.01 to 0.04 mg/​kg may cause ischaemia that adds to the risk of venom-​induced ne-
every 2 to 4 h for children by intramuscular, intravenous, or sub- crosis. This may explain why digital bites are so often necrotic. The
cutaneous injection. classic signs of ‘compartment syndrome’ are excessive pain, weak-
ness and tenderness of the compartmental muscles, and pain when
Hypotension and shock they are passively stretched, hypoaesthesia of skin supplied by
If the central venous pressure is low or there is other clinical nerves running through the compartment, and obvious tenseness
evidence of hypovolaemia, isotonic saline should be infused. If of the compartment. Misleadingly, these signs are frequently pre-
there is evidence of increased capillary permeability (e.g. facial sent in snakebitten limbs in which intracompartmental pressures
and conjunctival oedema, serous effusions, haemoconcentration, are normal. Recent studies in the United States failed to demon-
hypoalbuminaemia, and so on) it may be safer in the long term to strate any benefit of fasciotomy in snakebite victims. In any case,
rely on a selective vasoconstrictor such as dopamine (starting dose fasciotomy is absolutely contraindicated until blood coagulability
2.5–​5 µg/​kg per min by intravenous infusion). Delayed hypotension has been fully restored (by adequate doses of antivenom followed
that develops about 1 week after bites by Burmese D. siamensis is a by clotting factors). Surgery must be justified by demonstrating
consequence of acute pituitary-​adrenal insufficiency (Sheehan’s-​like that intracompartmental pressure is consistently raised to less than
syndrome) responds to intravenous hydrocortisone. 30 mm Hg below mean arterial pressure, or it exceeds 45 mm Hg
in adults or 30 mm Hg in children, when measured directly with a
Oliguria and acute kidney injury Stryker transducer.
Urine output, serum creatinine, urea, and electrolytes should be
measured each day in patients with severe envenoming, and in those Haemostatic disturbances
bitten by species known to cause acute kidney injury (e.g. Russell’s Once specific antivenom has been given to neutralize venom pro-
vipers, hump-​nosed pit viper (Hypnale hypnale), C.d. terrificus, coagulants, restoration of coagulability and platelet function may
Bothrops spp., sea snakes). If urine output drops below 400 ml in be accelerated by giving (reliably screened) fresh whole blood, fresh
24 h, urethral and central venous catheters should be inserted. If frozen plasma, cryoprecipitates (containing fibrinogen, factor VIII,
urine flow fails to increase after cautious rehydration, patient should fibronectin, and some factors V and XIII), or platelet concentrates.
be placed on strict fluid balance. Dopamine (2.5 µg/​kg per min by Heparin has been used to treat a variety of snakebites, usually with
intravenous infusion) has proved effective in some patients bitten disastrous results. Heparin did not prove beneficial in patients
by Russell’s vipers, although its use has been largely abandoned by envenomed by Echis ocellatus.
nephrologists. Renal replacement therapy (peritoneal or haemo-
dialysis or haemofiltration) will usually be required. In Rangoon, Other drugs
Burma, the mortality of acute kidney injury following D. siamensis Corticosteroids, antifibrinolytic agents (aprotinin and ε-​aminocaproic
envenoming has been reduced to less than 30% by using peritoneal acid), antihistamines, trypsin, and a variety of traditional herbal rem-
dialysis, usually for only 72 h. edies have all been used, but none has proved effective and most are
potentially harmful.
Local infection at the site of the bite
After bites by some species (e.g. Bothrops spp., C. rhodostoma), Treatment of snake venom ophthalmia caused
local infections caused by unusual bacteria derived from the by spitting cobras and rinkhals
snake’s venom or fangs develop in 10% or more cases. A booster First-​aid treatment involves urgent decontamination of the af-
dose of tetanus toxoid should be given, but prophylactic antibiotics fected eye(s) using large volumes of water or any other available
are not indicated unless the wound has been incised or tampered bland fluid (even urine!). A single topical administration of local
with in any way or if there is necrosis with the associated risk of anaesthetic drops such as 0.4% oxybuprocaine hydrochloride, 4%
Clostridium tetani and other anaerobes. If a local abscess develops, lidocaine hydrochloride, or tetracaine hydrochloride drops cures
it should be drained and the pus cultured. Penicillin, chloram- the agonizing pain. Adrenaline (0.1%) drops are also effective.
phenicol, or erythromycin are usually effective. An aminoglycoside Corneal abrasions must be excluded by fluorescein staining and/​
such as gentamicin should be given for 48 h if there is evidence of or slit-​lamp examination. A prophylactic topical antibiotic
local necrosis. such as tetracycline, chloramphenicol, soframycin, ciprofloxacin,
or gatifloxacin should be instilled. Posterior synechiae, ciliary
Management of local envenoming spasm, and discomfort are prevented with 2% atropine, scopol-
Bullae are best left intact. The bitten limb should be nursed in the amine, or homatropine. In case of allergic keratoconjunctivitis
most comfortable position but not elevated excessively as this in- in someone previously spat at, topical antihistamines are used.
creases the risk of intracompartmental ischaemia. Once definite Topical or intravenous antivenom and topical corticosteroids are
signs of necrosis have appeared (blackened anaesthetic area with contraindicated.
putrid odour or signs of sloughing), surgical debridement, imme-
diate split-​skin grafting, and broad-​spectrum antibiotic cover are Interval between bite and death
indicated. Exceptionally, patients may die ‘within a few minutes’ (reputedly
after a bite by the king cobra Ophiophagus hannah) or as long as
Intracompartmental syndrome and fasciotomy 41 days (Echis carinatus) after snakebite. However, most deaths
Swelling of envenomed tissues within tight fascial compartments occur about 8 h after cobra bites (N. naja), 18 h after krait bites
such as the digital pulp spaces and anterior tibial compartment (Bungarus caeruleus), 16 h after North American rattlesnake bites
1800 SECTION 10 Environmental medicine, occupational medicine, and poisoning

(Crotalus spp.), 3 days after Russell’s viper bites, and 5 days after hypotension, syncope, angio-​oedema, sweating, rigors, tinnitus,
Echis bites. nausea, and vomiting. There may be leucocytosis, coagulopathy,
electrocardiographic changes, myocardial infarction, and acute
kidney injury. No fatal cases have reliably been reported. Specific
Venomous lizards antivenom is not generally available. A powerful analgesic may be
required. Hypotension should be treated with fluids, adrenaline,
Two species of venomous lizard (genus Heloderma) have proved or a pressor agent such as dopamine.
capable of envenoming humans. Venom from submandibular Recently, venomous salivary secretion have been demonstrated
glands pools in labial gutters in the lower jaw and is conducted in other groups of lizards such as iguanas (Iguanidae), glass/​alli-
along grooves in the lower teeth. The Gila monster H. suspec- gator lizards (Anguidae), and monitors (Varanidae), notably the
tum (Fig. 10.4.2.28), which is striped with a short thick tail and Komodo dragon Varanus komodoensis that has been responsible for
grows to 55 cm in length, occurs in the south-​western United human fatalities that were attributed to trauma of infection of the
States and adjacent areas of Mexico. The Mexican beaded lizard bite wounds.
or escorpión H. horridum, which is spotted with a relatively long
thin tail and reaches 1 m in length, is found in western Mexico
south to Guatemala. Heloderma venoms contain lethal glycopro-
tein toxins, Gila, and horridum toxins, phospholipase A2, and 5 Poisonous amphibians and birds
bioactive peptides of great interest, including helospectin (a vaso-
active intestinal peptide analogue) and exendins-​3 and -​4, which Poisonous amphibians
are glucagon-​like peptide-​1 (GLP-​1) homologues that stimulate The moist skin of amphibians such as frogs, toads, newts, and sala-
insulin secretion and inhibit glucagon secretion. A synthetic manders is an accessory respiratory organ, which is protected from
homologue of exendin-​4, exenatide, is a high affinity GLP-​1 re- microorganisms by highly toxic secretions containing amines,
ceptor agonist which has been developed for treatment of type peptides, proteins, steroids, and alkaloids. Some compounds are
2 diabetes mellitus. Bites are rare and are usually inflicted on the synthesized de novo, while others are sequestered from prey such
fingers, hands, and forearms of inebriated young men who are as ants, beetles, and millipedes. The bitter flavour and lethal effects
handling or trying to catch the lizards. The lizard hangs on with of these secretions and the vivid warning colouration of many spe-
its powerful jaws and is difficulty to disengage. Expert opinion cies defend them against predators. The skin of ‘poison-​dart’ frogs
currently favours levering the jaws apart with a screw driver, run- (Dendrobatidae) of Central and South America secrete lipophilic
ning the cold tap over the attached lizard, placing its four feet on alkaloids such as batrachotoxins (Phyllobates spp.), which activate
the ground or introducing some alcohol into its mouth. There is sodium channels; histrionico toxins (Dendrobates histrionicus)
immediate severe throbbing or burning local pain that radiates (Fig. 10.4.2.29), which block nicotinic receptors; pumiliotoxins
up the limb with tender swelling and regional lymphadenopathy. (D. pumilio), which affect sodium channels; and epibatidine
Systemic symptoms include weakness, dizziness, tachycardia, (Epipedobates tricolor), a powerful analgesic and nicotinic receptor

Fig. 10.4.2.29 Poison frog Dendrobates histrionicus (Dendrobatidae)

Bahia Solauo, Colombia. Its skin secretion contains potent nicotinic
Fig. 10.4.2.28 Gila monster Heloderma suspectum. receptor antagonists, histrionicotoxins.
Copyright D. A. Warrell. Copyright D. A. Warrell.
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1801

agonist. Two Colombian tribes, the Embará and Noanamá Chocó,

Venomous fish
use the skin poisons of three species of Phyllobates to coat the tips
of their blow-​gun darts. Some toads can squirt from their parotid
About 200 species of fish inhabiting temperate and tropical seas
glands venom containing bufadienolides which affect membrane
possess a defensive venom-​injecting apparatus that can inflict
Na+, K+-​ATPase. When licked or put in the mouth by dogs or chil-
dangerous stings, but more than 1200 species are now thought to
dren, or when ingested as Chinese traditional medicines such as
be venomous. Fatal stings have been reported from cartilagenous
Kyushin, Yixin Wan, or the topical aphrodisiac Ch’an-​Su, the poi-
fish (class Chondrichthyes), such as sharks and dogfish (order
sons can cause fatal digoxin-​like poisoning. Symptoms include
Squaliformes) and stingrays and mantas (order Rajiformes),
hypersalivation, cyanosis, cardiac arrhythmias, and generalized
and from bony fish (superclass Osteichthyes), such as ray-​finned
convulsions. Antidigoxin antibodies (‘Digibind’, ‘DigiTAb’) have
fish (class Actinopterygii) of the orders Siluriformes (catfish),
some therapeutic effect.
Perciformes (families Trachinidae (weever fish), Uranoscopidae
The skin of three species of newts, genus Taricha, from the
(stargazers or stone-​ lifters), and others) and Scorpaeniformes
western United States, contains tarichatoxins identical to tetro-
(scorpion fish, stonefish, lion fish Synanceja/​Synanceia spp.)
dotoxin, which also occurs in some toads, frogs, fish, crustaceans,
(Fig. 10.4.2.31). Two species of lion fish have been introduced
and octopuses (see following paragraphs). Tetrodotoxin can be
into the Atlantic ocean and now occupy the SE coast of the United
absorbed through the gastric mucosa, explaining the death of a
States and the Caribbean, posing an ecological threat to the
man who swallowed a 20-​cm long Oregon rough-​skinned newt
region. The Indo-​Pacific region and other tropical waters have the
Taricha granulosa. He developed paraesthesia of the lips, pro-
richest venomous fish fauna, but dangerous species such as sharks,
gressing to more generalized numbness and weakness, and had a
chimaeras, and weevers also occur in temperate northern waters,
cardiopulmonary arrest about 2 h after swallowing the newt.
and several large rivers in South American, West Africa, and
Poisonous birds Southeast Asia are inhabited by freshwater stingrays Potamotrygon
spp. (Fig. 10.4.2.32). Venom glands are embedded in grooves in
The feathers, skin, and breast muscles of five species of pitohui
the spines or, in the case of stingrays, lie beneath a membrane
or thickhead, passerine birds from New Guinea (genus Pitohui;
covering the long barbed precaudal spine.
Pachycephalidae) and the blue-​capped ifrita or ifrit (Ifrita kow-
aldi; Cinclosomatidae) contain homobatrachotoxin, a potent Incidence and epidemiology
steroidal alkaloid that activates sodium channels and was ori-
Weever fish are common around the coast of the British Isles,
ginally isolated from the skin of South American poison-​dart
especially off Cornwall. Hundreds of stings occur in some years,
frogs (Phyllobates—​see earlier paragraphs). The birds may ac-
with a peak incidence in August and September. It has been esti-
quire the poison by eating melyrid beetles (Choresine spp.).
mated that there are 1500 stings by rays and 300 stings by scorpion
Poisonous pitohuis have an unpleasant peppery odour, and
fish in the United States each year. Stings by venomous freshwater
their skin has a bitter flavour. Contact with their feathers causes
rays (Potamotrygon hystrix, P. motoro) are common in the Amazon
numbness and burning of the tongue, lip or skin wounds, and
region of Brazil. Ornate, but aggressive and venomous members
sneezing. This may be a protective mechanism, and the striking
of the genera Pterois and Dendrochirus (lion, zebra, tiger, turkey,
‘warning’ colouration of the hooded pitohui (P. dichrous) (Fig.
or red fire fish) (Fig. 10.4.2.31), which are popular aquarium
10.4.2.30) may be the subject of Müllerian mimicry by less
pets, often sting their owners on the fingers. Most fish stings are
poisonous species.
inflicted on the soles of the feet of people wading near the shore

Fig. 10.4.2.30 Hooded pitohui Pitohui dichrous. Varararta National

Park near Port Moresby, Papua New Guinea. Fig. 10.4.2.31 Lion fish Pterois volitans (Scorpionidae).
By courtesy of Dr Ian Burrows. Copyright D. A. Warrell.
1802 SECTION 10 Environmental medicine, occupational medicine, and poisoning

catecholamines. Pharmacological effects include local necrosis,

direct actions on cardiac, skeletal, and smooth muscle, resulting in
ECG changes, hypotension, paralysis, and central nervous system
depression.

Clinical features
Immediate sharp, agonizing pain is the dominant symptom. Hot,
erythematous swelling extends up the stung limb and may per-
sist with pain for several days and be complicated by necrosis
(Fig. 10.4.2.33) and secondary infection by marine Vibrio spp.
(such as V. vulnificus), freshwater species (such as Aeromonas
Fig. 10.4.2.32 Fresh water stingray Potamotrygon sp. hydrophila), and other unusual bacteria, particularly if the spine
Copyright D. A. Warrell. remains embedded in the wound. Stingray spines, which are up to
30 cm long, can cause severe lacerating injuries, especially to the
lower legs, but if the victim inadvertently lies on the ray or falls on
or in the vicinity of coral reefs. Venomous fish are effectively cam- to it, the spine may penetrate the thoracic or abdominal cavities
ouflaged (Synanceja spp.) or lie partly covered by sand. Stingrays with fatal results.
lash their tails at the intruding limb and usually impale the ankle Systemic effects are uncommon after weever stings (Trachinidae),
(Fig. 10.4.2.33). Fatal fish stings are very rarely reported. but people stung by rays or Scorpaenidae (scorpion-​and stonefish)
Prevention may develop nausea, vomiting, signs of autonomic nervous system
stimulation; such as diarrhoea, sweating, and hypersalivation; car-
Fish stings can be prevented by employing a shuffling gait when diac arrhythmias, hypotension, respiratory distress, neurological
wading, by avoiding handling living or dead fish, and by keeping signs, and generalized convulsions. Patients have died within 1 h of
clear of fish in the water, especially in the vicinity of tropical reefs. being stung by Synanceja verrucosa.
Footwear protects against most species except stingrays.
Treatment
Venom composition
Pain is alleviated by immersing the stung limb in water, which is
The instability of most fish venoms at normal ambient temperat- uncomfortably hot yet not scalding (<45°C; the 50°C recommended
ures has made them difficult to study. Stingray and weeverfish by some authorities will cause a full thickness scald!). Temperature
venoms contain peptides, enzymes, and a variety of vasoactive can be assessed with the unstung limb. Addition of magnesium sul-
compounds such as kinins, 5-​hydroxytryptamine, histamine, and phate is unnecessary. Injection of a local anaesthetic is less effective
even when applied as a ring block in the case of stung digits, but
a local nerve block with 0.5% of plain bupivacaine is effective. The
venomous spine (which may be barbed), fragments of membrane,
and other foreign material should be removed as soon as possible.
Systemic effects must be treated symptomatically. An adequate
airway should be established, and cardiopulmonary resuscitation
may be needed. Severe hypotension may respond to adrenaline,
bradycardia to atropine. Seqirus (formerly CSL) in Australia manu-
facture an antivenom specific for Synanceja trachynis, S. verrucosa,
and S. horridus. This has paraspecific activity against the venoms of
the North American scorpion fish (Scorpaena guttata) and some
other members of the Scorpaenidae. One ampoule (2 ml or 2000
units) is given intravenously for each two puncture marks found
at the site of the sting. The dose is increased for patients with se-
vere symptoms. Antibiotic treatment for secondary infections
should take into account the range of possible marine pathogens.
Doxycycline or co-​trimoxazole covers Vibrio and Aeromonas spp.

Poisoning by ingestion of aquatic animals

Acute gastrointestinal symptoms (‘food poisoning’) after eating sea-

food are usually caused by bacterial or viral infections such as Vibrio
parahaemolyticus (crustaceans, especially shrimps), V. cholerae
Fig. 10.4.2.33 Necrotic and secondarily infected wound at the site of a (crabs and molluscs), non-​O group 1 V. cholerae (oysters), V. vulnifi-
sting by a freshwater ray Potamotrygon hystrix in a Brazilian patient. cus (oysters), Aeromonas hydrophila (frozen oysters), Plesiomonas
By courtesy of Dr João Luiz Costa Cardoso. shigelloides (oysters, mussels, mackerel, cuttlefish), Shigella spp.
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1803

(molluscs), Campylobacter jejuni (clams), Salmonella typhi (mol- no gastrointestinal symptoms. Neurotoxic symptoms character-
luscs), hepatitis A virus (molluscs, especially clams, and oysters), ized by rapid onset, within 10–​45 minutes, of weakness, dizziness,
Norwalk virus (clams and oysters), and astro-​and calici-​viruses paraesthesiae of the lips, tongue, throat and, later, the limbs. Pallor,
(cockles and other molluscs). Botulism has been caused by eating sweating, and increased salivation may be present. Tachycardia,
smoked fish and canned salmon; and in Japan and elsewhere, fish hypotension, difficulty breathing, and flaccid ascending paralysis
and molluscs became contaminated with methyl mercury from in- may lead to respiratory paralysis; death usually occurs 2–​6 hours
dustrial waste, causing severe neurological damage and fetal abnor- after eating the fish. Usually, consciousness is retained throughout,
malities (‘Minamata disease’). although victims may appear comatose. Development of fixed di-
Natural toxins acquired in the food chain, originally from bac- lated pupils and brain stem areflexia suggests brain death, but com-
teria can contaminate the tissues of a variety of fish, shellfish (bivalve plete recovery is possible with mechanical ventilation. Freshwater
molluscs) and other marine animals, giving rise to the several dis- puffer fish poisoning in northern Thailand has been attributed to
tinctive syndromes of seafood poisoning. saxitoxin.

Ciguatera fish poisoning Histamine-​like syndrome (scombrotoxic poisoning)

Symptoms develop between 1 and 6 h (extreme range, min to 30 h) The dark red flesh of scrombroid fish (tuna, mackerel, bonito, skip-
after eating fish such as groupers, snappers, parrot fish, mackerel, jack) and of canned non​scrombroid fish (sardines, pilchards) may be
moray eels, barracudas, and jacks. These are warm-​water shore or decomposed by the action of bacteria, such as Proteus morgani and
reef fish. The global incidence is thought to exceed 50 000 cases per Klebsiella pneumoniae, which decarboxylate muscle histidine into
year. Up to 2% of the population may be affected each year (e.g. in saurine, histamine, cadaverine, and other unidentified toxins: 100 g
Kiribati, Tokelau, and Tuvalu in the Pacific region) with a case fatality of spoiled fish may contain almost 1 g of histamine. Histamine ab-
of 0.1%. The toxins responsible are polyethers such as ciguatoxin sorbed from the gut is normally broken down by N-​methyl trans-
(activates Na+ channels), maitotoxin (activates Ca2+ channels), and ferase and diamine oxidase (histaminase), but if the histamine
scaritoxin, ultimately derived along the food chain from benthic concentration is very high, or the patient is taking a diamine oxi-
dinoflagellates such as Gambierdiscus toxicus. They are concentrated dase inhibitor such as isoniazid (as antituberculosis chemotherapy),
in the liver, viscera, and gonads, especially of large carnivorous fish. scombrotoxic poisoning may result. Toxic fish may produce a tin-
The increasing market for exotic fish from the Caribbean and else- gling or smarting sensation in the mouth when eaten. Within min-
where has led to cases of ciguatera in the United Kingdom. utes or up to a few hours after ingestion, flushing, burning, sweating,
Acute gastrointestinal symptoms—​nausea, vomiting, diarrhoea, urticaria, and pruritis may develop with headache, abdominal colic,
abdominal pain and cramps, and a metallic taste in the mouth—​ nausea, vomiting, diarrhoea, bronchial asthma, giddiness, and
are followed by neurological symptoms—​paraesthesiae around the hypotension.
mouth and extremities, reversed hot-​cold sensation (dysesthesia),
increased salivation, dilatation of the pupils, strabismus, ptosis, Poisoning by ingesting carp gallbladder
weakness, and ataxia, usually resolve within a few hours, but paraes- In parts of East Asia, the raw bile and gallbladder of various spe-
thesiae and myalgia may persist for a week, or even months. Pruritus cies of freshwater carp (e.g. the grass carp Ctenopharyngodon idel-
of the soles and palms and rashes may occur. Cardiovascular fea- lus, ‘plaa yeesok’ Probarbus jullienii) are believed to have medicinal
tures include braycardia, hypotension, and hypovolemia. Similar properties. Patients in China, Taiwan, Hong Kong, Japan, Thailand,
symptoms (chelonitoxication) may follow ingestion of marine tur- and elsewhere have developed acute abdominal pain, vomiting, and
tles in the Indo-​Pacific area, with a much higher case fatality. watery diarrhoea 2 to 18 h after drinking the raw bile or eating the
raw gallbladder of these fish. One patient developed flushing and
Tetrodotoxin poisoning dizziness. Hepatic and renal damage may develop, progressing to
Scaleless fish, such as porcupine, sun, puffer, and toad fish (order oliguric or non​oliguric acute kidney injury (acute tubular necrosis).
Tetraodonitiformes) may become highly poisonous at certain The hepatonephrotoxin has not been identified, but is heat stable
seasons, such as May to June, the spawning season in Japan. and may be derived from the carp’s diet.
Tetrodotoxin, an aminoperhydroquinazoline, is one of the most
potent non​protein toxins known. It produces neurotoxic and Paralytic shellfish poisoning
cardiotoxic effects by blocking voltage-​gated sodium ion chan- Five main clinical syndromes of shellfish poisoning are recognized.
nels. It is found concentrated in the ovaries, viscera, and skin of Many of the causal toxins, derived from dinoflagellates and diatom
tetraodontiform fish; in the skin of newts (genus Taricha), frogs, algae, have been identified but no specific antidotes have been
and toads (genera Colostethus, Atelopus, Bracycephalus), and discovered.
salamanders; in the saliva of octopuses; in the digestive glands Diarrhoeal shellfish poisoning: Symptoms indistinguish-
of several species of gastropod molluscs; in a starfish, flatworm able from acute infective gastroenteritis evolve usually within
Planorbis spp., and nemertine worms in Japan; and is produced 30 minutes to 12 hours of eating the contaminated shellfish—​
by some bacteria (Pseudomonas, Pseudoalteromonas, Vibrio spp., diarrhoea, nausea, vomiting, and abdominal colic with recovery
and so on). over a few days. The toxins responsible include okadaic acid and
Puffer fish (‘fugu’) is particularly popular in Japan where, des- other dinophysis toxins, pectenotoxins, and yessotoxins, many
pite stringent regulations, there are still cases of tetrodotoxin poi- of which are protein phosphatase inhibitors. They occur in mus-
soning, with about four deaths each year. Nausea and abdominal sels, cockles, scallops, oysters, whelks, and green crabs in Japan,
pain occur but usually no vomiting or diarrhoea, or there may be Europe, and Africa.
1804 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Neurotoxic shellfish poisoning: Milder gastrointestinal and fish should be regarded as potentially tetrodotoxic, and very large
neurotoxic symptoms without paralysis develop 1–​3 hours after fish carry an increased risk of being ciguatera toxic. Moray eels and
ingestion of molluscs contaminated by brevetoxins from Karenia parrot fish (Scaridae) should never be eaten because of the high
brevis (formerly known as Gymnodinium breve or G. brevis) dino- risk of unusually rapid and severe ciguatera and scaritoxic fish poi-
flagellates which can also cause ‘red tides’. Neurotoxic symptoms, soning. Scrombroid poisoning can be prevented by eating fish fresh
reminiscent of ciguatera fish poisoning, include paraesthesiae, cold or by freezing fish as soon as possible after they are caught. Shellfish
allodynia (pain or hyperaesthesia on touching cold objects), my- should not be eaten during the dangerous seasons and when there
algia, vertigo, and ataxia. In the United Kingdom there have been are red tides.
several outbreaks of neurotoxic red-​whelk (Neptunea antiqua) poi-
soning attributable to tetramine.
Paralytic shellfish poisoning: Bivalve molluscs, such as mussels, Venomous marine invertebrates
clams, oysters, cockles, and scallops (and also xanthid, coconut, and
horseshoe crabs) may acquire tetrahydropurine neurotoxins such as Cnidarians (Coelenterata)
saxitoxin and gonyautoxins from dinoflagellates (Alexandrium spp., These include jellyfish, cubomedusoids, sea wasps, Portuguese-​men-​
Pyrodinium bahamense var. compressum and Gymnodinium catena- o’-​war, or bluebottles, hydroids, stinging corals, and sea anemones.
tum). These may be sufficiently abundant between latitudes 30 ºN Their tentacles are armed with millions of nematocysts (stinging
and 30 ºS during the warmer months of May to October to produce capsules). When triggered by contact or chemicals, stinging hairs
a ‘red tide’. The dangerous season is signalled by the deaths of large are everted at enormous acceleration and force, penetrating the
numbers of fish and sea birds. Symptoms develop within 30 min of skin as far as the epidermo-​dermal junction and producing lines of
ingestion. Descending paralysis may progress to fatal respiratory painful irritant weals. Cnidarian venoms contain peptides and other
paralysis within 12 h in 8% of cases. vasoactive substances such as 5-​hydroxyhistamine, histamine, pros-
Amnesic shellfish poisoning: Develops after ingestion of mussels taglandins, and kinins, which cause immediate excruciating pain,
and other molluscs contaminated with domoic acid from diatoms inflammation, and urticaria.
(Pseudonitzschia spp.). Gastroenteritis starts within 24 h of exposure
and, in in about half the cases, neurotoxic symptoms develop within Epidemiology
48 h. Severe headache and short-​term memory loss are common. The most dangerous species, the box jellyfish, cubomedusoid, sea
Amnesia is sometimes permanent. Severe symptoms include agi- wasp, or indringa Chironex fleckeri of northern Australia, has caused
tation, seizures, coma, profuse respiratory secretions, circulatory more than 70 deaths since 1883. Most stings occur in December
instability, and death. Elderly patients and those with underlying and January. Chiropsalmus quadrumanus and C. quadrigatus have
illnesses were most vulnerable. caused fatal jellyfish stings in the Indo-​Pacific region. Portuguese
Azaspricid poisoning: Acute gastrointestinal symptoms develop men-​o’-​war (Physalia spp.), Chinese jellyfish (Stomolophus nomu-
within 6–​18 hours of Ingestion and last up to 5 days. rai) and tiny cubomedusoids (Carukia barnesi) responsible for many
‘Irukandji stings’ in northern Queensland, Florida, and Guadeloupe
Diagnosis and treatment of seafood poisoning in the Caribbean, have also caused fatalities. Pelagia noctiluca may
The differential diagnosis includes bacterial and viral food poi- swarm in vast numbers off the northern Adriatic coast, stinging
soning and allergic reactions. many swimmers. The North American sea nettle (Chrysaora quin-
No specific treatments or antidotes are available, but gastrointes- quecirrha) is widely distributed throughout the Atlantic and Indo-​
tinal contents should be eliminated by emetics and purges if this can Pacific oceans and is especially abundant in Chesapeake Bay on
be achieved safely and within 1 to 2 h of ingestion. Activated char- the Maryland coast. There are millions of stings each year but no
coal adsorbs saxitoxin and other shellfish toxins. Atropine is said fatalities
to improve gastrointestinal symptoms and sinus bradycardia in
patients with gastrointestinal and neurotoxic poisoning. Calcium Prevention
gluconate may relieve mild neuromuscular symptoms. Oximes Bathers, especially children, should keep out of the sea at times of
and anticholinesterases appear ineffective in ciguatera and tetrodo- the year when dangerous cnidarians are prevalent, especially when
toxin poisoning, respectively. Mannitol has been advocated for early warning notices are displayed; or they should bathe in ‘stinger-​
treatment of ciguatera poisoning. In cases of paralytic poisoning, resistant’ enclosures, although these do not exclude Irukandji.
endotracheal intubation and mechanical ventilation and cardiac re- Wetsuits or Lycra garments, nylon stockings, and other clothing will
suscitation have proved life-​saving. The symptoms of scrombrotoxic protect against nematocyst stings.
poisoning can be alleviated with antihistamines and bronchodilators.
Clinical features
Prevention of poisoning by ingestion of aquatic animals Immediate severe pain is the commonest symptom. Nematocyst
Ciguatera toxin, tetrodotoxin, scombrotoxins, and most other stings may leave a diagnostic pattern on the skin: C. fleckeri produces
marine toxins are heat stable, so cooking does not prevent poi- wide, striated brownish-​ purple weals (Fig. 10.4.2.34), whereas
soning. Some toxins are fairly water soluble and may be leached Carukia barnesi causes a transient erythematous macule, and the
out by soaking. Therefore, water in which fish are cooked should Portuguese man-​o’-​war (genus Physalia) produces chains of oval
not be drunk. In tropical areas, the flesh of fish should be separ- weals surrounded by erythema. Chirodropids (genera Chironex
ated as soon as possible from the head, skin, intestines, gonads, and Chiropsalmus) cause the most severe systemic symptoms—​
and other viscera, in which toxins are concentrated. All scaleless respiratory arrest, generalized convulsions, pulmonary oedema,
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1805

Starfish and sea urchins (Echinodermata)

These animals are protected by hard exoskeletons with numerous
long, sharp projecting spines (Fig. 10.4.2.35) and grapples
(globiferous pedicellariae), which can release venom and a violet-​
coloured liquid when embedded in the skin. Severe pain and local
swelling may result, and sometimes systemic effects such as syn-
cope, numbness, generalized paralysis, aphonia, respiratory dis-
tress, cardiac arrhythmias, and even death. Embedded fragments
of spines may penetrate bones and joints and lead to secondary
infection and chronic granulomas.

Treatment
Hot water (see earlier paragraphs) may relieve the pain. Skin
penetrated by the spines, usually the soles of the feet, should be
softened with 2% salicylic acid ointment or acetone. An attempt
should then be made to squeeze out the spines or removed them
surgically but this may prove difficult. No antivenoms are avail-
able. There is a risk of marine bacterial infections (see earlier
paragraphs).
Fig. 10.4.2.34 Extensive weals from contact with the stinging tentacles
of the box jellyfish Chironex fleckeri in an Australian stung in Darwin. Cone shells and octopuses (Mollusca)
By courtesy of Drs B. Currie and P. Nitschke. The 500 species of cone shells (genus Conus) are carnivorous
marine snails that harpoon their prey (fish, polychaete worms, and
and cardiac arrest within minutes of the accident. Other systemic other molluscs), implanting a radular tooth charged with venom
effects include cough, nausea, vomiting, abdominal colic, diar- containing a mixture of small (10–​30 amino acid) peptide toxins
rhoea, rigors, severe musculoskeletal pains, and profuse sweating. (Fig. 10.4.2.36), conotoxins, that block acetylcholine recep-
‘Irukandji syndrome’ consists of severe musculoskeletal pain, anx- tors and voltage-​ sensitive calcium and sodium ion channels.
iety, trembling, headache, piloerection, sweating, tachycardia, Cone shells are attractive and valuable collectors’ items, but col-
hypertension, and pulmonary oedema starting about 30 min after lectors may be stung. Symptoms of envenoming include nausea,
a sting by C. barnesi (and by other species of tiny cubomedusoids) vomiting, paraesthesia, and numbness of the lips and site of sting,
and persisting for hours. Physalia species can also cause severe sys- numbness, dizziness, ptosis, diplopia, dysarthria, dyspnoea, and
temic envenoming, including intravascular haemolysis, peripheral loss of consciousness. In a series of 35 cases mostly stung by Conus
gangrene, and acute kidney injury. geographus reported in Japan (1896–​1996), 10 died within 2 to 5 h
of the sting.
Treatment
Several species of small octopus found in the Australian and
Victims of box jellyfish stings may die within minutes and so first aid West Pacific region (blue-​ ringed octopuses, Hapalochlaena spp.)
is urgent. The victim is taken out of the water to prevent drowning,
adherent tentacles are washed off with sea water or removed by
shaving the skin and hot water is applied to relieve pain as for fish
stings (see earlier). Undischarged nematocysts in adherent tentacles
should be inhibited. For Chironex and other cubozoans, including
Irukandji, commercial vinegar or 3–​10% aqueous acetic acid may
inhibit further nematocysts discharge, although this has become
controversial, but is not recommended for stings by Physalia or
Stomolophus. For Chrysaora stings, baking soda and water (50% w/​
v) is used. In vitro, several popular remedies, such as alcohol (in sun
lotion), ammonia, acetic acid, and meat tenderizer, caused massive
discharge of Chrysaora quinquecirrha and Physalia physalis tent-
acles. However, 5–​15% lignocaine hydrochloride prevented dis-
charge and relieved the pain of Chiropsalmus quadrumanus and
Chrysaora quinquecirrha stings, in proportion to the concentra-
tion applied. Pressure-​immobilization with a crepe bandage may
increase the amount of venom injected and is not recommended.
Cardiopulmonary resuscitation has proved life-​saving in several
Australian patients stung by C. fleckeri who became cyanosed, co-
matose, and pulseless. A specific ‘sea wasp’ antivenom for C. fleckeri Fig. 10.4.2.35 Black long-​spined sea urchin Diadema setosum
is manufactured in Australia but its efficacy is being questioned. (Diadematidae) with spines 35 cm long, Madang, Papua New Guinea.
Treatment with verapamil is not recommended. Copyright D. A. Warrell.
1806 SECTION 10 Environmental medicine, occupational medicine, and poisoning

(a)
Venomous arthropods

Bees, wasps, yellowjackets, hornets,

and ants (Hymenoptera)
The most frequent and severe hymenoptera stings are inflicted
by members of the families Apidae (honey bees Apis mellifera,
A. cerania, A. dorsata, and so on, and bumble bees Bombus spp.),
Vespidae (wasps, yellow jackets, white-​faced ‘hornets’, paper wasps
genera Vespula, Dolichovespula, Polistes, and true hornets genus
Vespa) (Fig. 10.4.2.38), and Formicidae (American fire ants genus
Solenopsis, Australian bull or bulldog ants genus Myrmecia). Allergic
reactions to single stings from hymenoptera are common, whereas
envenoming resulting from many stings is rare. Venom allergens in-
clude phospholipases A, hyaluronidase, acid phosphomonoesterases,
(b) and polypeptide neurotoxins such as apamin and melittin (A. mel-
lifera). Non​allergenic compounds include vasoactive amines, such
as histamine, 5-​ hydroxytryptamine, catecholamines and kinins,
cholinesterase (in the venom of Vespula germanica), pheromones,
2-​methylpiperidine alkaloids (in venoms Solenopsis), and anti-​
inflammatory peptides from honey bee venom.

Epidemiology
Each year, fewer than five people die from identified hymenopteran
sting anaphylaxis in England and Wales, 2–​3 per year in Australia,
and 40–​50 in the United States. The incidence of systemic reactions
Fig. 10.4.2.36 Cone shell Conus bullatus harpooning and then to stings by hymenoptera has been reported as 0.4 to 0.8% in chil-
ingesting a small fish. dren. In one adult population in the United States, the prevalence
Copyright D. A. Warrell. of systemic allergic sting reactions was found to be 4%; 20% of this
population showed evidence of venom hypersensitivity (skin tests
(Fig. 10.4.2.37) inject salivary tetrodotoxin when they bite swimmers or radioallergosorbent test, RAST). In the United Kingdom, most
with their powerful beaks. Bites are painful and cause local bleeding, patients allergic to bee venom are beekeepers or their relatives.
swelling, and inflammation. Severe neurotoxic symptoms, and even Since the escape of swarms of African honey bees A. m. scutellata in
fatal generalized paralysis, may develop within 15 min of the bite. Brazil, in 1957, this aggressive strain has spread throughout Latin
America and north as far as Las Vegas in the United States. About
Treatment
30 deaths from mass attacks by these bees have been reported each
No antivenoms are available. Cardiopulmonary resuscitation and year. Two species of fire ants, Solenopsis richteri and S. invicta, were
mechanical ventilation may be required. imported into the United States from South America in 1918 and
have now spread to 13 southern states where an estimated 2.5 million
people are stung each month. The incidence of systemic allergic re-
actions is about 4 per 100 000 population per year, and there have

Fig. 10.4.2.37 Southern/​lesser blue-​ringed octopus Hapalochlaena

maculosa, Point York, Southern Australia. Fig. 10.4.2.38 Stinger of European wasp Vespula vulgaris.
Copyright D. A. Warrell. Copyright D. A. Warrell.
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1807

been fatalities. In Tasmania and southern Australia, the jack jumper Allergic effects: Systemic anaphylaxis
ant Myrmecia pilosula causes 90% of all ant stings. About 2–​3% of Clinical suspicion of dangerous venom hypersensitivity arises
the population are hypersensitive, and there have been deaths when systemic symptoms follow a sting. Systemic symptoms in-
from anaphylaxis. clude tingling scalp; itching, initially of the palms, soles, axillae,
Prevention and perineum, becoming generalized; flushing; dizziness; syncope;
wheezing; abdominal colic (uterine colic in women), violent diar-
Patients who have a history of systemic anaphylaxis following rhoea, incontinence of urine and faeces; tachycardia and visual dis-
a sting and who have evidence of hypersensitivity to the venom turbances; all developing within a few minutes of the sting. Over
of the same family of hymenoptera (venom-​specific IgE detect- the next 15–​20 min, urticaria, angio-​oedema of the lips, gums, and
able in the serum or a positive skin test) should be considered tongue, a generalized redness of the skin with swelling, oedema
for desensitization with purified venoms. This treatment proved of the glottis, profound hypotension, and coma may develop. The
significantly more effective than placebo or the previously used median time to first cardiac arrest is 10–​20 min after the sting but
whole-​body extracts of hymenoptera in preventing anaphylactic deaths have occurred after only 2 min. A few patients develop serum
reactions to sting challenge. Desensitization usually involves sickness a week or more after the sting. Some patients with sting
weekly visits to hospital for at least 8 weeks for the administra- allergy have other evidence of an atopic disposition. Reactions are
tion of gradually increasing doses of venom. When protection enhanced by β-​blockers.
has been demonstrated by the patient’s ability to tolerate 100 µg of Severe local reactions to stings: a separate subset of patients who
venom (equivalent to two stings) they are ready for maintenance become allergic to hymenoptera venoms develop delayed and some-
therapy, usually 100 µg of venom every 4–​8 weeks. A period of times massive and persistent local swelling hours or days after the
2–​5 years of maintenance desensitization is recommended, after sting without showing any systemic features of anaphylaxis. Such
which more than 90% of subjects will remain protected against reactions, which may be progressively more severe after successive
systemic reactions after stopping treatment. Desensitization is stings, do not predict increased risk of anaphylaxis.
complicated by systemic reactions in 5–​15% of patients and by
local reactions in 50%. Diagnosis of anaphylaxis and venom hypersensitivity
Wasps are attracted by sweet things and meat in kitchens, green- Detection of a raised mast-​cell tryptase concentration is useful
grocers’ shops, orchards, vineyards, brightly coloured floral pat- in confirming the diagnosis of anaphylaxis and excluding panic
terns, and perfumes. Hornets are attracted by light. Some hornets attacks and other causes of collapse. Serum/​plasma concentrations
(e.g. Asian Vespa mandarina) are so aggressive that their nests peak 0.5–​1.5 h after the attack, but persist for 6–​8 h. Type I hyper-
must be eradicated before the area can be farmed. The risk of sensitivity is confirmed by detecting venom-​specific (Vespidae,
mass attacks by apids and vespids can be reduced by vigilance. Apidae, Formicidae) IgE in the serum using RAST or by prick-​skin
Observing increasing numbers of vespids can lead to discovery tests. Among hymenoptera venoms, there is strong cross reactivity
and destruction of their nests. Attacks on farm animals and a ten- between bumble bee and honey bee venoms and between wasp,
dency for bees to pursue apiarists walking away from the hives are yellow-​jacket, and true hornet venoms, but not between venoms
signs of an increasingly aggressive colony, prompting replacement of Apidae and Vespidae. Patients who have suffered a systemic re-
of the queens. action have a 50–​60% risk of a reaction to their next sting. Local
Clinical features reactions, even massive ones involving persistent swelling of the
whole stung limb, in the absence of systemic symptoms, do not pre-
Toxic effects dict a systemic reaction following subsequent stings. Children who
In non​sensitized people, a sting, which, in the case of Vespidae and have generalized urticaria after a sting have only a 10% chance of
Apidae, introduces about 50 µg of venom, will rapidly produce a hot, a systemic reaction when restung. Hypersensitivity to venom may
red, painful swelling and weal a few centimetres in diameter, which be lost spontaneously in some children and young adults but this is
persists for no more than a few hours. These effects are dangerous unpredictable and unreliable. In some countries, live insect-​sting
only if the airway is obstructed, following stings on the tongue. As challenge is used to assess hypersensitivity and response to im-
few as 30 stings can cause fatal systemic envenoming in children, munotherapy. The RAST test can be used for a post-​mortem diag-
but children and adults have survived more than 1 000 stings by nosis of hymenoptera sting anaphylaxis.
A. mellifera. Symptoms suggest histamine toxicity—​vasodilatation,
hypotension, vomiting, diarrhoea, throbbing headache, coma, and Treatment
bronchoconstriction. In Latin America, victims of mass attacks by The barbed stings of Apidae remain embedded at the site of the sting
A. m. scutellata develop generalized rhabdomyolysis (grossly ele- and continue to inject venom, so they should be removed immedi-
vated serum CK, aminotransferases, and myoglobin), intravascular ately by any means possible. Vespids can withdraw their stings and
haemolysis, hypercatecholaminaemia (hypertension, pulmonary sting repeatedly. Wasp stings may become infected because some
oedema, myocardial damage), bleeding, hepatic dysfunction, and species feed on rotting meat. Domestic meat tenderizer (papain) di-
acute kidney injury. In non​ sensitized individuals, stings from luted roughly 1:5 with tap water is said to produce immediate relief of
Solenopsis and Myrmecia spp. produce pain, itching, swelling, pain. Ice packs and aspirin are also effective. Systemic but not topical
and erythema around a central weal, which last a few hours, and antihistamines can be used for more severe local reactions. Massive
later vesicles or pustules. In an unsensitized patient, an estimated local reactions may require aspirin, non​steroidal anti-​inflammatory
10 000 S. invicta stings caused no systemic envenoming. agents, or even corticosteroids.
1808 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Systemic anaphylaxis
First, the patient must be laid down and kept flat, ideally in the re-
covery position. Immediate cardiopulmonary resuscitation may
be needed. Adrenaline should be given as soon as possible: 0.1%
(1:1000) (0.5–​1 ml for adults; 0.01 mg/​kg for children) given by
intramuscular injection into the anterolateral thigh, or, if the patient
is unconscious or pulseless, diluted 1:100 000, by slow intravenous
injection. In rare cases, blood pressure fails to respond to even re-
peated doses of adrenaline and fluid resuscitation. These patients
should be given cardiopulmonary resuscitation, selective bron-
chodilators such as salbutamol, pressor agents such as dopamine,
and intravenous histamine H1 blockers such as chlorphenamine
maleate (10 mg for adults; 0.2 mg/​kg for children). Corticosteroids
probably have no effect in acute anaphylaxis, but may prevent re-
lapses a few hours later. Patients who know that they are hypersen-
sitive should wear an identifying tag or bracelet (such as provided
by Medic-​Alert or Medi-​Tag in Britain) as they may be discovered
unconscious after being stung. They should be trained to give them- Fig. 10.4.2.39 Lesions caused by urticating abdominal hairs of female
selves adrenaline using an ‘EpiPen’ or similar apparatus, but a high moths Hylesia spp. in Brazil.
Copyright D. A. Warrell.
proportion of those who carry these kits are unable to use them
effectively through lack of training. Shock and upper-​or lower-​
airway obstruction are the main modes of death following insect-​ include local burning, erythema, swelling, inflammation, head-
sting anaphylaxis. ache, nausea, vomiting, malaise, bleeding from nose, gums, gut,
Severe envenoming from multiple stings by hymenoptera should genitourinary tract, and partly healed scars, polyarthralgia, and
be treated with adrenaline, intravenous antihistamines (doses as acute renal failure. Laboratory findings in envenomed patients are
mentioned earlier), and corticosteroids. Intensive care is essential. decreased plasma fibrinogen, factor V, factor XIII, and plasminogen
Intravenous fluids may protect the kidneys from the damaging ef- concentrations, as well as increased fibrin/​fibrinogen degradation
fects of myoglobinuria and haemoglobinaemia (‘pigment neph- products and fibrinolytic activity but a normal platelet count. An
ropathy’), as in patients with the crush syndrome. Experimental effective antivenom (‘Soro antilonômico’) is produced by Instituto
antivenoms have been produced but are not yet commercially avail- Butantan, São Paulo, Brazil.
able. Exchange transfusion or plasmapheresis might be considered
to remove venom in severe cases. Renal dialysis is often needed. Beetles (Coleoptera)
The most notorious vesicating beetle is ‘Spanish fly’ Lytta vesicato-
Butterflies and moths (Lepidoptera) ria (Meloidae—​blister beetles) whose venom contains cantharidin,
The stinging hairs of some species of adult moths can cause con- which causes blistering 2–​3 h after application to the skin. ‘Nairobi
tact dermatitis and urticaria (‘lepidopterism’), while caterpillars eye’ and similar blistering conditions in Australia and Southeast
can produce local or even systemic effects (‘erucism’). Venomous Asia are caused by Paederus (Staphylinidae) species 5–​10 mm in
lepidoptera are found in all parts of the world, but most cases of length (Fig. 10.4.2.40). The typical skin lesions (dermatitis linearis),
lepidopterism are reported from Middle and Southern America. whose appearance may be delayed 12–​96 h after contact, consist of
Severe cutaneous urticating eruptions can be caused by cater- erythema, itching, and blistering caused by inadvertently crushing
pillars of oak processionary moths Thaumetopoea processionea and smearing the beetle. Systemic symptoms such as fever, arth-
(Thaumetopoeidae) in central/​southern Europe and of the genus ralgia, and vomiting may arise in severe cases. The active principle
Megalopyge (Megalopygidae—​ called ‘puss caterpillars’ in the
southern United States) and by adult female moths of the genus
Hylesia (Saturniidae), which have barbed setae (‘flechettes’) on
their abdomens (Fig. 10.4.2.39). Epidemics of stings by these moths
have been described, especially from coastal areas of Brazil, Mexico,
Peru, and Venezuela. In Brazil, Colombia, Guyana, Paraguay, Peru,
and Venezuela, caterpillars of atlas or emperor moths (Lonomia
obliqua, L. achelous; Saturniidae) cause thousands of stings each
year. A tourist died of Lonomia envenoming died a few days after
returning to Canada from Peru where she had trodden on some
of these caterpillars. Venom injected through their bristles con-
tains fibrinolytic (factor XIII activator); anticoagulant; procoagu-
lant (activators of prothrombin, factor X, factor V), kallikrein-​like,
metalloproteinase, and phospholipase A2 activities resulting in Fig. 10.4.2.40 Vesicating beetle Paederus crebripunctatus (Staphylinidae)
defibrinogenation and spontaneous bleeding. The case fatality of responsible for causing ‘Nairobi eye’.
about 2% is usually attributable to cerebral haemorrhage. Symptoms Courtesy of Dr John Paul.
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1809

pederin is the most complex non​proteinaceous insect toxin known.

Treatment is palliative. The toxin is easily spread to other sites such
as the eye by fingers.

Scorpions (Scorpiones, Buthidae, Hemiscorpiidae)

Species capable of inflicting fatal stings occur in North Africa and the
Middle East (Androctonus, Buthus, Hemiscorpius (Fig. 10.4.2.41),
Leiurus spp.) South Africa (Parabuthus spp.); India, Sri Lanka,
and Nepal (Hottentotta (formerly Mesobuthus) tamulus); North,
Central and South America, Trinidad and Tobago (Centruroides
(Fig. 10.4.2.42), Tityus (Fig. 10.4.2.43) spp.). Scorpion toxins target
Na+, K+, Ca2+, and Cl-​ ion channels causing direct effects and the re-
lease of neurotransmitters such as acetylcholine and catecholamines.

Epidemiology
In Mexico, 250 000 stings with 70 deaths are reported each year,
attributed to Centruroides limpidus, C. noxius, C. suffusus, and so
on. Brazil recorded 91 000 scorpion stings and 121 deaths in 2016,
more for snake-bites. In Khuzestan Province, Iran, 25 000 stings
(Hemiscorpius lepturus, Androctonus spp., and Buthus spp.) are Fig. 10.4.2.42 Arizona bark scorpion Centruroides (Sculpturatus)
treated each year and are the fourth major cause of death. Algeria exilicauda.
and Tunisia report tens of thousands of stings and hundreds of Copyright D. A. Warrell.
deaths. In the United States 15 000 stings, mainly by Centruroides
exilicauda (Fig. 10.4.2.42) are reported in Arizona each year but stings by Hemiscorpius lepturus (Iran, Iraq, Pakistan, and Yemen)
deaths are rare. In Brazil, the important species are Tityus serru- are relatively painless. Systemic symptoms usually develop within
latus (Fig. 10.4.2.43) and other Tityus spp. In 2005, among 36 558 minutes but may be delayed for as much as 24 h. They vary, ac-
reported stings, there were only 50 deaths (case fatality 0.14%). In cording to the species of scorpion involved. Most scorpion venoms
India, many people are stung by the red scorpion Hottentotta (for- stimulate the release of acetylcholine and catecholamines, often re-
merly Mesobuthus) tamulus with fatalities in adults and children. sulting in initial cholinergic and later adrenergic symptoms. Early
Prevention symptoms include vomiting, profuse sweating, piloerection, alter-
nating brady-​and tachycardia, abdominal colic, diarrhoea, loss of
Scorpions can be excluded from houses by incorporating a row of sphincter control, and priapism. Later, severe life-​threatening car-
ceramic tiles into the base of the outside wall, making the doorsteps diorespiratory effects may appear: hypertension, shock, tachy-​and
at least 20 cm high, and using residual insecticides, such as carba- bradyarrhythmias, ECG changes, and pulmonary oedema with or
mate or organophosphate sprays or dusts indoors. without evidence of myocardial dysfunction. Severe cardiovascular
Clinical features complications are particularly associated with stings by Androctonus
Intense local pain is the commonest symptom. There may be slight
local oedema and tender enlargement of regional lymph nodes, but

Fig. 10.4.2.43 Brazilian yellow scorpion Tityus serrulatus, São Paulo,

Fig. 10.4.2.41 Hemiscorpius lepturus (Hemiscorpiidae), Iran. Brazil. Scale in cm.
Courtesy of Dr M. Radmanesh. Copyright D. A. Warrell.
1810 SECTION 10 Environmental medicine, occupational medicine, and poisoning

(a) (b)

Fig. 10.4.2.44 Twenty-​six-​day-​old child stung on right axilla by a

Brazilian yellow scorpion (Tityus serrulatus) in urban São Paulo: showing
agitation and pulmonary oedema.
Copyright D. A. Warrell.

Fig. 10.4.2.45 (a) Local swelling, blistering, and ‘purpuric plaque’

spp., Leiurus quinquestriatus, Hottentotta tamulus, and Tityus spp. caused by the sting of Hemiscorpius lepturus in Iran. (b) Progressing to
(Fig. 10.4.2.44). Neurotoxic effects such as erratic eye movements, necrosis with granulation tissue.
fasciculation, and muscle spasms, which can be misinterpreted as Courtesy of Dr M Radmanesh.
tonic-​clonic convulsive movements, and respiratory distress are a
particular feature of stings by Centruroides (sculpturatus) exilicauda
in Arizona. Parabuthus transvaalicus envenoming in southern addition of a new antivenom raised against H. tamulus concanensis
Africa is more likely to cause ptosis and dysphagia with death from venom produced more rapid recovery than prazosin alone. Antivenom
respiratory paralysis. Hemiplegia and other neurological lesions should be administered intravenously as soon as possible in patients
have been attributed to fibrin deposition resulting from dissem- with systemic envenoming and in young children stung by dangerous
inated intravascular coagulation, for example, after stings by Nebo species, even before the development of these symptoms. For patients
hierichonticus in the Middle East. with cardiovascular symptoms (hypertension, bradycardia, and early
Hypercatecholaminaemia could explain hyperglycaemia and pulmonary oedema), vasodilators such as the α1-​blocker prazosin are
glycosuria but in the case of stings by the black scorpion of Trinidad recommended. Patients who develop left ventricular failure despite
(Tityus trinitatis) there is severe abdominal pain with nausea, early prazosin therapy benefit from dobutamine. The use of atropine
vomiting, and haematemesis, hyperglycaemia, and biochemical evi- (except in cases of life-​threatening sinus bradycardia), cardiac glyco-
dence of acute pancreatitis attributable to simultaneous spasm of the sides and β-​blockers is not recommended.
sphincter of Oddi and pancreatic exocrine hypersecretion.
In Iran and Iraq, stings by Hemiscorpius lepturus (Hemiscorpiidae) Spiders (Araneae)
produce a unique clinical syndrome. The sting is painless but macular All but one family of this enormous order are venomous, but only
erythema, pupura, and bullae develop at the site with induration in about 20 species have proved dangerous to humans. Many others
39% of cases, swelling and necrosis that requires surgery in 20% of have been wrongly accused of inflicting harmful bites. Spiders bite
cases (Fig. 10.4.2.45). Systemic symptoms include dry mouth, thirst, with a pair of small fangs, the chelicerae, to which the venom glands
dizziness, nausea, vomiting, fever, cardiac arrhythmias, ST depres- are connected. Medically important genera include Loxosceles,
sion on ECG, hypoglycaemia, confusion and convulsions, leucocyt- causing necrotic araneism, and Latrodectus, Phoneutria, Atrax,
osis, thrombocytopenia, coagulopathy, haemolytic anaemia with Hadronyche, and Missulena spp., causing neurotoxic araneism.
haemoglobinuria, proteinuria, and acute kidney injury. Twenty per
cent (20%) of paediatric cases required dialysis. Early treatment with Epidemiology
Rhazi Institute antivenom proved effective. Spider bites are common in some parts of the world but there are
now few fatalities. In Brazil in 2016 there were 29 000 spider bites
Treatment with 22 fatalities. In Central and South America, Loxosceles spp.
Pain responds to local infiltration or ring block with local anaes- such as L. laeta and L. gaucho (Fig. 10.4.2.46) are widely distributed
thetic. Parenteral opiate analgesics, such as pethidine or morphine, and cause many bites. In Chile, the case fatality of loxoscelism ranges
may be required, but are said to be dangerous in victims of C. exil- from 1 to 17%. In the southern and south-​central United States,
icauda (sculpturatus). the brown recluse spider L. reclusa caused at least 200 bites and six
Antivenom is recommended. In a recent trial in children stung deaths during the last century. Bites by L. rufescens have been re-
by C. sculpturatus in Arizona, antivenom treatment was associated ported in the Mediterranean region, North Africa, and Israel. Most
with more rapid resolution of symptoms and less requirement for bites from Loxosceles spp. occur in bedrooms while people are asleep
midazolam sedation than placebo. In India, two studies found that or dressing.
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1811

Fig. 10.4.2.48 Curaçao black widow spider Latrodectus curacaviensis,

Brazil.
Copyright D. A. Warrell.

Highly dangerous funnel web spiders Atrax spp. are restricted

to south-​eastern Australia and Tasmania. The Sydney funnel web
Fig. 10.4.2.46 South American recluse spider Loxosceles laeta, Brazil. spider (A. robustus) is found only within a 160-​mile (256-​km) ra-
Copyright D. A. Warrell. dius of Sydney. The aggressive males caused at least 13 deaths be-
tween 1927 and 1980. Members of the related genera Hadronyche
and Missulena may be equally dangerous.
Black and brown widow spiders are cosmopolitan in distribu-
In England, mild neurotoxic araneism has been described after
tion. Latrodectus tredecemguttatus (sometimes referred to, loosely,
bites by Steatoda nobilis and S. grossa (Theridiidae) and the wood-
as ‘tarantula’) lives in fields in Mediterranean countries and has
louse spider Dysdera crocata.
been responsible for epidemics of bites. The Australian redback
spider (L. hasselti) (Fig. 10.4.2.47) causes up to 340 bites each year Necrotic araneism
in Australia; 20 deaths have been reported. It has colonized parts
Skin lesions, varying in severity from mild localized erythema and blis-
of Japan, New Zealand, UAE, and New Caledonia. In the United
tering to extensive granulomas and tissue necrosis, have been falsely
States, L. mactans was responsible for 63 deaths between 1950
attributed to a large variety of familiar peridomestic species, such as the
and 1959. Several species of Latrodectus occur in Latin America
Australian white-​tailed spider Lampona cylindrata, North American
(Fig. 10.4.2.48).
hobo spider Tegenaria agrestis, European and South American wolf
Wandering, armed, or banana spiders Phoneutria spp. (Fig.
spiders Lycosa spp. (including the Italian ‘tarantula’ L. terentula), and
10.4.2.49), cause bites and a few deaths in Latin American coun-
cosmopolitan sac spiders Cheiracanthium spp. However, only mem-
tries. They have been imported into temperate countries in bunches
bers of the genus Loxosceles have proved capable of causing ‘necrotic
of bananas, causing a few bites and deaths.

Fig. 10.4.2.47 Australian redback spider Latrodectus hasselti, Fig. 10.4.2.49 Brazilian armed, wandering, or banana spider
Adelaide, showing the dorsal red hourglass marking. Phoneutria nigriventer.
Copyright D. A. Warrell. Copyright D. A. Warrell.
1812 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Fig. 10.4.2.52 Intense local sweating and piloerection at the site of a

Fig. 10.4.2.50 ‘Red-​white-​and-​blue’ sign developing 18 h after a bite Brazilian banana spider bite Phoneutria nigriventer 30 min earlier.
by the Brazilian recluse spider Loxosceles gaucho. Copyright D. A. Warrell.
Copyright D. A. Warrell.
Neurotoxic araneism
arachnidism/​araneism’. Venom sphingomyelinase D is implicated in
The bite is very painful immediately, but local signs are minimal
the pathogenesis of dermonecrosis. Neutrophils adhere to the endo-
(L. mactans) or moderate (L. hasselti). After about 30 min, there is
thelium of cutaneous capillaries and degranulate. The bite itself is
painful regional lymphadenopathy, then headache, nausea, vomiting,
usually painless and unnoticed. Burning develops over several hours
and local sweating with piloerection (‘gooseflesh’, ‘goose bumps’),
at the site of the bite, with swelling and development of a character-
a sign highly suggestive of neurotoxic araneism (Fig. 10.4.2.52).
istic macular lesion, the red-​white-​and-​blue sign (Fig. 10.4.2.50)
Envenoming by L. mactans and L. tredecemguttatus, causes profuse
showing areas of red vasodilatation, white vasoconstriction, and blue
generalized sweating and fever with painful muscle spasms, tremors,
prenecrotic cyanosis. A blackened eschar develops, which sloughs in a
and rigidity. This may be sufficiently severe to embarrass respiration.
few weeks, leaving a full thickness necrotic ulcer. Sometimes an entire
The classic ‘facies latrodectismica’ is an agonized grimace, caused by
limb or area of the face is involved. Facial bites cause much swelling.
facial spasm and trismus, associated with swollen eyelids, congested
Some 13% of cases have systemic symptoms such as fever, headaches,
conjunctivae, flushing, and sweating (Fig. 10.4.2.53). Abdominal
scarlatiniform rash (Fig. 10.4.2.51), jaundice, methaemoglobinaemia,
rigidity may simulate an acute abdomen and prompt laparotomy.
and haemoglobinuria resulting from intravascular haemolysis. Renal
failure may ensue. The average case fatality is about 5%.

Fig. 10.4.2.51 Blanching generalized scarlatiniform rash appearing Fig. 10.4.2.53 ‘Facies latrodectismica’ with profuse sweating and
3 days after a bite above the left hip by a Brazilian recluse spider painful muscle spasms, persisting 24 h after a bite by Latrodectus mactans
Loxosceles gaucho. (‘viuda negra’, black widow) near Cusco, Peru.
By courtesy of Dr João Luiz Costa Cardoso. Copyright D. A. Warrell.
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1813

Other features include tachycardia, hypertension, restlessness, irrit- be weak or ataxic. Paralysis increases over the next few days: death
ability, psychosis, priapism, and rhabdomyolysis. A localized or dif- results from bulbar and respiratory paralysis and aspiration of
fuse rash may appear several days later. Envenoming by Phoneutria stomach contents. Vomiting is a feature of the more acute course of
and Atrax spp. produces similar features. Ixodes holocyclus envenoming.
This clinical picture has often been misinterpreted as poliomyel-
Treatment itis. Other neurological conditions, including Guillain–​Barré syn-
First aid drome, paralytic rabies, Eaton–​Lambert syndrome, myasthenia gravis,
In Australia, pressure-​immobilization (see Fig. 10.4.2.26) is recom- or botulism, may also be suspected. Diagnosis and cure depends on
mended for bites by A. robustus and Hadronyche species. finding the tick, which is likely to be concealed in a crevice, orifice,
or hairy area of the body. The scalp is the commonest place. Fatal tick
Specific treatment paralysis has been caused by a tick attached to the tympanic membrane.
Antivenoms for envenoming by Latrodectus spp. are made in Australia, Treatment
Mexico, South Africa, Brazil, and some other South American coun-
tries; for Atrax spp. in Australia; for Loxosceles spp. in Argentina, Brazil, The tick must be discovered and detached without being squeezed.
and Peru; and for Phoneutria spp. in Brazil. Despite decades of use, It can be painted with ether, chloroform, paraffin, petrol, or turpen-
there is no decisive evidence for the efficacy of Loxosceles antivenoms, tine, or prised out between the partially separated tips of a pair of
but neurotoxic araneism is more obviously responsive to antivenom. small, curved forceps. Following removal of the tick there is usu-
ally a rapid and complete recovery; but in Australia, patients have
Supportive treatment died even after the tick had been detached. The antivenoms, raised
Oral dapsone (100 mg twice daily) is said to reduce the extent of in dogs and rabbits in Australia, are no longer produced.
necrotic lesions by inhibiting neutrophil degranulation and calcium Centipedes and millipedes (subphylum Myriapoda)
gluconate (10 ml of a 10% solution, given by slow intravenous in-
jection) is said to relieve the pain of muscle spasms caused by the Centipedes (class Chilopoda)
venom of Latrodectus spp. rapidly and more effectively than muscle Epimorph centipedes have 15–​191 pairs of legs and move rapidly
relaxants such as diazepam or methocarbamol. Evidence for the and distractedly. They occur in most parts of the world including the
efficacy of these drugs is lacking. Antihistamines, corticosteroids, Arctic Circle. The largest, Scolopendra gigantea of South America,
α-​blockers, and atropine have also been advocated. For necrotic can grow to more than 30 cm in length. Many species can inflict
araneism caused by Loxosceles spp., early surgical debridement, painful stings through a pair of modified claws (forcipules) on the
corticosteroids, antihistamines, and hyperbaric oxygen all have postcephalic segment (Fig. 10.4.2.54). More than 3000 stings are
their advocates, but there is no basis for recommending their use.

Ticks (Acari) (a)

Taxonomy and epidemiology

Ticks, with mites, form the order Acari of the class Arachnida. Adult
females of about 34 species of hard tick (family Ixodidae) and imma-
ture specimens of nine species of soft ticks (family Argasidae) have
been implicated in human tick paralysis. The tick’s saliva contains
a neurotoxin, which causes presynaptic neuromuscular block and
decreased nerve-​conduction velocity. The tick embeds itself in the
skin with its barbed hypostome introducing the salivary toxin while
it engorges with blood.
Although tick paralysis has been reported from all continents,
including Europe, most cases occur in western North America
(Dermacentor andersoni), eastern United States (D. variabilis), (b)
and eastern Australia from north Queensland to Victoria (Ixodes
holocyclus—​known as the bush-​, scrub-​, paralysis-​, or dog-​tick). In
British Columbia there were 305 cases with a 10% case fatality be-
tween 1900 and 1968. About 120 cases have been reported in the
United States, and in New South Wales there were at least 20 deaths
between 1900 and 1945.

Clinical features
Ticks are picked up in the countryside or from domestic animals,
particularly dogs, in the home. Aalmost all fatal cases are children.
After the tick has been attached for about 5 or 6 days a progressive
ascending lower motor neurone paralysis develops with paraesthe- Fig. 10.4.2.54 (a) Thai centipede (Scolopendra dehaani) (b) showing
siae. Often a child, who may have been irritable for the previous 24 h, venom ‘claws’ or forcipules which are modified limbs.
falls on getting out of bed first thing in the morning and is found to Copyright D. A. Warrell.
1814 SECTION 10 Environmental medicine, occupational medicine, and poisoning

reported each year in Brazil. Venoms contain serotonin, histamine, (a)

lipids, polysaccharides, proteases, and peptides that are neurotoxic
to insects. Stings cause intense radiating pain, swelling, inflamma-
tion, erythema, and lymphangitis, and sometimes local necrosis.
Systemic effects such as vomiting, sweating, headache, cardiac ar-
rhythmias, myocardial ischaemia, rhabdomyolysis, proteinuria,
acute renal failure, and convulsions are extremely rare. The risk of
mortality was probably greatly exaggerated in the older literature.
Hypersensitivity may have played a role in these reactions. Reports
of documented fatalities remain elusive but are said to occur on some
Indian Ocean islands. The most important genus is Scolopendra
which is distributed throughout tropical countries. Local treatment
is the same as for scorpion stings. No antivenom is available.

Millipedes (class Diplopida)

Millipedes are widely distributed. They may exceed 35 cm in length,
have hundreds of legs (not a thousand, despite their name), move
sluggishly, and tend to coil into a ball. Most species possess glands in
each of their body segments which secrete, and in some cases squirt
out, irritant liquids for defence. These contain hydrogen cyanide and
a variety of aldehydes, esters, phenols, and quinonoids. Members of
at least eight genera of millipedes have proved injurious to humans,
including Rhinocricus (Caribbean), Spirobolus (Tanzania and Papua (b)
New Guinea), Spirostreptus and Iulus (Indonesia), and Polyceroconas
(Salpidobolus) (Papua New Guinea). Children are at risk when they
handle or try to eat these large arthropods. When venom is squirted
into the eye, intense conjunctivitis results, and there may be corneal
ulceration and, allegedly, blindness. Skin lesions initially stain brown
(‘mahogany stains’) or purple, blister after a few days, and then peel
(Fig. 10.4.2.55). They have been mistaken for signs of child abuse.
First aid is generous irrigation with water. Eye injuries should be
treated as for snake venom ophthalmia (see earlier in this chapter).

Leeches (phylum Annelida, class Hirudinea)

Leeches are bloodsucking, hermaphroditic, egg-​ laying annelids,

which have elongated annulated bodies. They attach themselves to
leaves, rocks, or the host by a posterior sucker. To feed, the leech Fig. 10.4.2.55 Skin and mucosal lesions (a) caused by application of
giant Papua New Guinea millipede (b) (Spirobolus vogesi).
applies its anterior sucker containing the mouth armed with three
Copyright Dr Bernie Hudson.
radially arranged jaws which make a Y-​shaped incision. Blood
is sucked out by the action of the muscular pharynx. To prevent
blood clotting, the saliva contains a histamine-​like vasodilator and can sense their prey with amazing efficiency. They drop on to the prey
anticoagulants, such as: hirudin from the medicinal leech Hirudo or pursue it with a looping or lashing motion. Leeches usually attach
medicinalis, which inhibits thrombin and factor IXa; hementin from themselves to the lower legs or ankles and are adept at penetrating
Haementeria ghilianii, which is directly fibrinolytic; and hementerin clothing, even long trousers tucked into socks and lace-​up boots. The
from H. depressa (= H. lutzi), a plasminogen activator. Other en- bite is usually painless and infested individuals may not realize what
zymes include esterases, antitrypsin, antiplasmin, and antielastase. has happened until they hear a squelching sound, notice that their feet
Recombinant hirudin is now produced as a therapeutic anticoagu- are warm and wet, and see blood welling over the tops of their boots.
lant. The medicinal leech is still used by plastic surgeons to reduce Land leeches ingest about 1 ml of blood in 1 h and then drop off, but
haematomas under skin grafts; the wound may become infected with the wound continues to bleed for some time and forms a fragile clot.
Aeromonas hydrophila, which lives symbiotically in the leech’s gut.
Two groups of leeches cause human morbidity and even mortality Aquatic leeches
in tropical countries. These species may be swallowed by individuals who drink stagnant
water or even mountain stream water, or they may attack bathers,
Land leeches entering the mouth, nostrils, eyes, vulva, vagina, urethra, or anus.
Species of the genera Haemadipsa and Phyrobdella are 1–​8 cm long. Hirudo medicinalis can ingest 5–​15 ml of blood, increasing its initial
They infest, often in enormous numbers, the damp leaf litter and low weight up to 10 times. The enormous brightly coloured buffalo leech
vegetation of rainforests, choosing game trails and watering places. By Hirudinaria manillensis of Southeast Asia, is up to 16 cm long and
standing on the posterior sucker and waving the anterior sucker, they can ingest 1 ml of blood in 10 min. Limnatis nilotica occurs around
 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals 1815

the Mediterranean, Middle East, and North Africa. Myxobdella af-

ricana occurs in East Africa. Dinobdella ferox (5 cm long) is found FURTHER READING
in Asia. Some aquatic leeches are very slow feeders and may remain Mechanical injuries caused by animals
attached for days or even weeks. L. nilotica and D. ferox have been Auerbach PS (ed) (2016). Wilderness medicine, 7th edition. Mosby
implicated in ‘halzoun’. However, in Lebanon, leech infestation con- Elsevier, Philadelphia, PA.
tracted from spring water (‘alack’) is distinguished from ‘halzoun’ Packer C, et al. (2011). Fear of darkness, the full moon and the noc-
following ingestion of raw offal (see Section 7 Infectious Diseases). turnal ecology of African lions. Plos One, 6, e22285.
Spotte S (2002). Candirú: life and legend of the bloodsucking catfish.
Prevention Creative Arts Books Company, Berkeley, CA.
Woodroffe R, Thirgood S, Rabinowitz A (eds) (2005). People and wild-
Leech intrusion can be reduced by impregnating clothing, especially
life: conflict or coexistence? Cambridge University Press, Cambridge.
the bottoms of trousers and socks, with repellents such as dibutyl
phthalate and diethyl toluamide and applying them to the skin and Websites
the inside and outside of footwear. If these compounds are not avail- Polar bears: http://​kho.unis.no/​doc/​Polar_​bears_​Svalbard.pdf
able, invasion of footwear during jungle walks can be prevented, ra- Shark attacks: http://​www.flmnh.ufl.edu/​fish/​Sharks/​ISAF/​ISAF.htm
ther messily, by rolling a rope of tobacco in the tops of the socks Venomous mammals
and keeping the feet well soaked with water or using an aqueous ex- Madani G, Nekaris KA (2014). Anaphylactic shock following the bite
tract of tobacco leaves. Women’s pantyhose are said to prevent leech of a wild Kayan slow loris (Nycticebus kayan): implications for slow
attachment, but may be damaged by DEET-​containing repellents. loris conservation. J Venom Anim Toxins Incl Trop Dis, 20, 43.
Effective leech-​proof light cotton socks are available commercially. Whittington CM, et al. (2008). Defensins and the convergent evolution
Children should be discouraged from bathing in leech-​infested of platypus and reptile venom genes. Genome Res, 18, 986–​94.
waters and all drinking water should be boiled or filtered. Venomous snakes
de Silva HA, et al. (2011). Low-​dose adrenaline, promethazine, and
Clinical features hydrocortisone in the prevention of acute adverse reactions to anti-
The main effect is blood loss, but other symptoms include pain caused venom following snakebite: a randomised, double-​blind, placebo-​
by the bite, secondary infection, a residual itching, and phobia. Ingested controlled trial. PLoS Med, 8, e1000435.
aquatic leeches usually attach to the pharynx but may penetrate the Gutiérrez JM, et al. (2017). Snakebite envenoming. Nat Rev Dis
Primers, 3, 17063.
bronchi or oesophagus. H. manillensis entering via the anus can reach
Meier J, White J (eds) (1995). Handbook of clinical toxicology of animal
the rectosigmoid junction of the bowel causing perforation and periton-
venoms and poisons. CRC Press, Boca Raton, FL.
itis. Patients with a leech in the pharynx often have a feeling of movement
Mohapatra B, et al. (2011). Snakebite mortality in India: a
at the back of the throat with cough, hoarseness, stridor, breathlessness, nationally representative mortality survey. PLoS Negl Trop Dis,
epistaxis, haemoptysis, and haematemesis. Fatal upper airway obstruc- 5, e1018.
tion may result. The leech Limnatis nilotica is no longer thought to be a Sutherland SK, Tibballs J (2001). Australian animal toxins: the crea-
cause of ‘halzoun’ (Lebanon) or ‘marrara’ (Sudan) (see Chapter 8.13 on tures, their toxins and care of the poisoned patient, 2nd edition.
pentastomiasis) but aquatic leech infestation could be a differential diag- Oxford University Press, Melbourne.
nosis of those dramatic syndromes of pharyngeal obstruction. Bleeding Warrell DA (2004). Epidemiology, clinical features and
may persist for up to a week after the leech has dropped off. In rural management of snakebites in Central and South America. In:
Thailand, vaginal bleeding in girls who have swum in ponds or canals Campbell J, Lamar WW, Greene H (eds) Venomous reptiles of
is often attributable to infestation by aquatic leeches. Sexual abuse may the Americas, 2nd edition, pp. 709–​61. Cornell University Press,
be wrongly inferred if this diagnosis is not considered. Transmission of Ithaca, NY.
rinderpest and other viruses, leptospirosis, and Trypanosoma cruzi has Warrell DA (2010). Snake bite. Lancet, 375, 77–​88.
Weinstein SA, et al. (eds) (2011). ‘Venomous’ bites from non-​venomous
been suggested but not proved. Secondary infection of medicinal leech
snakes: a critical analysis of risk and management of ‘colubrid’ snake
bites by Aeromonas hydrophila has been described.
bites. Elsevier, London.
Treatment White J (2013). A clinician’s guide to Australian venomous bites and
stings. CSL, Parkville.
Leeches are best scraped off with a fingernail. Traditional methods
such as applying a grain of salt, a lighted match or a cigarette, al- Websites
cohol, turpentine, or vinegar make the leech regurgitate into the Antivenoms
wound, creating a risk of infection. Local bleeding can be stopped World Health Organization (WHO) 2018 Guidelines: http:// ​www.who.
by applying a styptic, such as silver nitrate or a firm dressing. int/​bloodproducts/​snake_​antivenoms/​snakeantivenomguide/​en/​
Aquatic leeches that have penetrated the respiratory, upper gastro- Envenoming worldwide
intestinal, genitourinary tracts, or rectum must be removed by http://​www.toxinology.com/​
endoscope. Spraying with 30% cocaine, 10% tartaric acid, or di- http://​www.vapaguide.info/​
lute (1:10 000) adrenaline makes the leech detach from the naso- Snakebite in South and South East Asia (WHO SEARO 2016 Guidelines),
pharynx, larynx, trachea, or oesophagus, while irrigation with a 2nd edition: http://apps.who.int/iris/handle/10665/249547
concentrated salt solution may be effective in the genitourinary Snakebite in Africa (WHO AFRO 2010 Guidelines): http://apps.who.
tract and rectum. Leeches should not be pulled off so roughly that int/medicinedocs/en/d/Js17810en/
the mouth parts are left in the wound as this will lead to a chronic
Venomous lizards
infection. Antimicrobial treatment of secondary bacterial infec-
Beck DD (2005). Biology of Gila monster and beaded lizards. University
tions (e.g. of Aeromonas hydrophila with cefuroxime or a quin-
of California Press, Berkeley.
olone) may be required.
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Poisonous amphibians Kelen EMA, Picarelli ZP, Duarte AC (1995). Hemorrhagic syn-
Daly JW, Spande TF, Garraffo HM (2005). Alkaloids from amphibian skin: drome induced by contact with caterpillars of the genus Lonomia
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Myers CW, Daly JW, Malkin B (1978). A dangerously toxic new frog Coleoptera
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Nat History, 161(Art 2), 307–​66. Aoun O, et al. (2018). Mind the eye-squirter! An Anthia sexmaculata
Poisonous birds sexmaculata-related necrotic burn. J Travel Med, 25(1).
Dumbacher JP, et al. (1992). Homobatracho-​ toxin in the genus Eisner T, et al. (1990). Systemic retention of ingested cantharidin by
Pitohui: chemical defense in birds? Science, 258, 799–​800. frogs. Chemoecol, 1, 57–​62.
Dumbacher JP, et al. (2004). Melyrid beetles (Choresine): a putative Frank JH, Kanamitsu K (1987). Paederus sensu lato (Coleoptera:
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and toxic passerine birds. Proc Natl Acad Sci U S A, 101, 15857–​60. Entomol, 24, 1555–​91.
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Halstead BW (1988). Poisonous and venomous marine animals of the Scorpions
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 10.4.3 Poisonous fungi 1817

Karunaratne AH, et al. (2015). A Rare Case of Vaginal Bleeding in a fatality 10–​20%). Amatoxins block RNA polymerases, inhibiting
Child Due to a Leech Bite and Review of the Literature. Wilderness protein synthesis and damaging intestinal mucosa, kidneys
Environ Med, 26, 579–84. and especially liver. After an ominously long latent period of
Keegan HL (1963). Leeches as pests of man in the Pacific region. 8–​24 (mean 12) h, intense GI symptoms followed by transient
In: Keegan HL, McFarlane WR (eds) Venomous and poisonous ani- improvement and inexorably fulminant hepatic failure may de-
mals and noxious plants of the Pacific region, pp. 99–​104. Pergamon velop. Attempted decontamination employs multidose activated
Press, Oxford.
charcoal. Silibinin, high-​dose benzyl penicillin, and N-​acetyl cyst-
Sawyer RT (1986). Leech biology and behaviour. Oxford University
eine have been tried and polymyxin B suggested. Liver transplant-
Press, Oxford.
ation is life-​saving.
1B—​early primary nephrotoxicity (aminohexadienoic acid poi-
soning): Amanita smithiana and some other Amanita species cause
acute gastrointestinal symptoms followed a few days later by acute
kidney injury.
10.4.3 Poisonous fungi 1C—​ late primary nephrotoxicity (orellanine poisoning): two
Cortinarius species can cause insidious poisoning with acute kidney
Hans Persson and David A. Warrell injury, 4–​15 (mean 8) days after ingestion.
Group 2—​Neurotoxic mushroom poisoning
ESSENTIALS 2A—​ hallucinogenic mushrooms (‘magic mushrooms’) (psilocybin
poisoning): Psilocybe, Panaeolus, Conocybe, and other species con-
Phylum Ascomycota includes ergot and aflatoxin-​ producing taining potent hallucinogens cause LSD-​like euphoria, hallucinations,
Aspergillus; phylum Basidiomycota includes the larger umbrella-​ depersonalization, and anxiety within 10–​60 minutes. Treatment is
shaped gilled mushroom/​toadstools (order Agaricales). with diazepam.
Epidemiology—​most fungi are non​toxic and most fungal pois- 2B—​ autonomic-​ toxicity mushrooms (muscarinic poisoning):
onings are not severe, but morbidity and mortality remain high in some Inocybe, Clitocybe, Mycena, and Rubinoboletus species contain
Eastern and Central European countries and the Far East and may muscarine causing parasympathetic stimulation after 15 minutes to
be increasing worldwide with globalization of exotic species. Fungal 2 h. Treatment is with atropine.
poisoning usually results from mistaking poisonous mushrooms for 2C—​ central nervous system-​ neuroexcitatory mushrooms
edible ones, it may be accidental in children, or intentional for hallu- (ibotenic acid/​muscimol poisoning): fly agaric (A. muscaria) and
cinogenic effects, suicide, or even homicide. some other Amanita species contain GABA agonists causing exhil-
Prevention—​ educational campaigns should emphasize risks of aration and euphoria alternating with anxiety, agitation, and hallu-
careless harvesting and eating. Diagnosis: morphology and habitat cinations within 0.5–​1.5 h, sometimes with cholinergic symptoms.
of the ingested fungi (and residue in vomitus) and nature and timing Treatment is with diazepam.
of symptoms are informative. Poison information centres may be 2D—​Morel neurological syndrome: inadequately cooked ‘morels’
consulted. Laboratory methods can detect amatoxins, aflatoxins, and (Morchella species), popular ‘edible’ mushrooms, cause GI symp-
ergot alkaloids. toms, while M. esculenta and M. conica can cause severe neurological
Ergot (Claviceps purpurea poisoning)—​results from ingestion of symptoms (tremor, ataxia, visual disturbances, and so on), even if
contaminated grains, cereals, and foods (bread). Toxic sclerotia de- cooked.
velop in ovaries of parasitized grass flowers. Ergot alkaloids cause
uterine contraction and vasoconstriction, employed therapeutically Group 3—​Myotoxic mushroom poisoning
in migraine and obstetrics. Lysergic acid derivatives are psychedelic. 3A—​early myotoxicity (cycloprop-​2-​ene carboxylic acid poisoning):
Chronic ingestion causes gastrointestinal and neurological symp- Russula subnigricans causes gastrointestinal symptoms followed a
toms, peripheral vasocontriction, burning pain (‘St Anthony’s fire’) few h later by generalized myalgia and rhabdomyolysis.
and peripheral gangrene. Larger doses cause acute gastrointestinal 3B—​ late myotoxicity (saponaceolide B and M poisoning):
symptoms, paraesthesiae, hallucinations, convulsions, and death. large/​repeated meals of Tricholoma equestre/​ flavovirens, a popular
Treatment involves vasodilator drugs and anticoagulants. ‘edible’ mushroom, cause generalized rhabdomyolysis 1–​3 days after
Aspergillus aflatoxin poisoning—​ aflotoxins from saprophytic ingestion.
Aspergillus flavus contaminate peanuts, maize, and other grains,
Group 4—​Metabolic toxicity mushroom poisoning
seeds, and spices, especially in tropical countries. Outbreaks of
aflatoxicosis-​induced hepatitis leading to fatal hepatic necrosis 4A—​GABA-​blocking mushroom poisoning (gyromitrin poisoning):
and portal hypertension occur in undernourished rural popula- inadequately cooked ‘false morel’ (Gyromitra esculenta) and other
tions and, in areas of hepatitis B endemicity, cause hepatocellular Gyromitra species contain gyromitrin that impairs central ner-
carcinoma. vous system GABA synthesis. After 5—​8 h gastrointestinal symp-
Mushroom poisonings—​classification is based on toxic effects and toms, cerebellar disturbances, seizures, coma, hepatic damage,
related symptoms. haemolysis, and hypoglycaemia may ensue. Treatment is with
pyridoxine.
Group 1—​Cytotoxic mushroom poisoning 4B—​disulfiram-​
like mushroom poisoning (coprine poisoning):
1A—​primary hepatotoxicity (amatoxin poisoning) is caused by antabuse syndrome occurs when alcohol is drunk up to a week after
Amanita, Lepiota, and Galerina species, notably death cap Amanita eating Coprinus atramentarius, and some other Coprinus, Clitocybe
phalloides, responsible for 90% of mushroom fatalities (case Boletus species.
1818 SECTION 10 Environmental medicine, occupational medicine, and poisoning

fruiting bodies of these fungi which are typically umbrella-​shaped

4C—​polyporic mushroom poisoning (polyporic acid poisoning):
with a cap (pileus) with spore-​bearing gills (lamellae) on its under-
ingestion of the bracket mushroom Hapalopilus rutilans causes
side, on top of a stalk (stipe), with or without a ring and a volva at its
gastrointestinal symptoms, neurological effects, acute kidney injury,
base. Poisonous species must be distinguished from field (Agaricus
and passage of purple urine 12 h later.
campestris) and cultivated (A. bisporus) mushrooms and from the
4D—​ trichothecene mushroom poisoning (trichothecene poi-
many other mushrooms that are considered to be delicious and are
soning): Podostroma cornudamae ingestion has caused fatal multi­
passionately sought after by mycophiles worldwide.
system poisoning with peeling skin in Japan and Korea.
4E—​ hypoglycaemic mushroom poisoning: ‘Yunnan Sudden
Unexplained Death’ has been explained by ‘little white mushroom’
(Trogia venenata) poisoning. History
4F—​ hyperprocalcitoninaemic mushroom poisoning is caused
by ‘Satan’s bolete’ (Rubroboletus satanas) associated increased cir- Assyrian and pharaonic references to dangerous outgrowths in ears
culating procalcitonin and C-​reactive protein causing GI symptoms of grain date from 600 to 400 BC. In Europe, epidemics of gangrenous
and fever. (‘St Anthony’s fire’) and convulsive (‘St Vitus’s dance’) ergotism, ini-
4G—​pancytopenic mushroom poisoning: has been caused by tially killing tens of thousands, have occurred between the 9th and
Ganoderma neojaponicum, a popular herbal medicine in Asia. early 20th centuries AD. These followed the introduction of rye, a
host of ergot, as a major food crop for impoverished rural popula-
Group 5—​Gastrointestinal irritant mushroom poisoning tions. The poisonous properties of mushrooms/​toadstools have been
This common type of poisoning can follow ingestion of many genera recognized since ancient Greek and Roman times. Among famous
of mushrooms (Agaricus, Boletus, Entoloma, and so on) including fatalities, homicidal, accidental, or mythical, attributed to poisonous
many popular, ‘edible’ mushrooms. They cause gastrointestinal mushrooms, were Siddhartha Gautama (the Buddha), the Roman
symptoms alone, starting within a few hours and usually self-​limiting. Emperor Claudius, Pope Clement VII, the Holy Roman Emperor
Fluid and electrolyte replacement may be necessary, especially Charles VI, the Russian Tsar Alexis and his wife, and the 18th-​
in children and older people. In North America and Hawai’i, ‘false century German composer Johann Schobert.
parasol’ (Chlorophyllum/​Lepiota molybdites) and ‘Morgan’s mush-
room’ cause gastrointestinal symptoms and cholinergic effects within
30 min to 4 h. Aetiology
Group 6—​Miscellaneous adverse reactions to mushrooms
The most common cause of fungal poisoning is confusing poisonous
6A—​ shiitake mushroom dermatitis (lentinan poisoning): inad-
mushrooms with edible ones. Safe mushroom hunting requires skill
equately cooked shiitake mushrooms (Lentinola edodes) can cause a
and experience, as there are many possible sources of dangerous
generalized, linear prurigo 24 h after ingestion.
confusion. Too many people harvest, cook, and eat mushrooms
6B—​erythromelalgic mushroom poisoning (acromelic acid poi-
whose identity is uncertain. Toddlers may accidentally try mush-
soning): Clitocybe acromelalgia/​amoenolens can cause acromelalgia.
rooms and serious poisoning may occur, but this is fortunately un-
6C—​paxillus syndrome: severe gastrointestinal symptoms, haem-
common. Intentional ingestion of toxic fungi is mostly related to
olysis, and acute kidney injury can follow repeated ingestion of
abuse of hallucinogenic fungi. Suicidal ingestion is rare.
Paxillus involutus.
Illness after eating mushrooms is not necessarily related to poi-
6D—​encephalopathic syndrome Pleurocybella gyrometrinporrigens,
soning. Large mushroom fragments or raw mushrooms may prove
Pleurotus eryngii and some other popular ‘edible’ mushrooms have
hard to digest, there may be anxiety that toxic mushrooms might
caused encephalopathy in elderly people suffering from chronic
have been ingested, bacterial toxins may be present in mushrooms
renal or hepatic disease. Cyanide is implicated.
that have been stored for too long and fungi may be contaminated
with toxic heavy metals.
There are individual differences in sensibility to some fungal
Introduction toxins. One example is false morels Gyromitra spp. Toxin contents
may also vary between mushrooms of the same species.
This chapter covers poisoning by members of the fungal sub-
kingdom Dikarya that includes most of the ‘higher fungi’. The
phylum Ascomycota contains the medically important toxic fungi Epidemiology
Claviceps purpurea, the cause of ergotism, Aspergillus flavus, a source
of hepatotoxic and carcinogenic aflatoxins, the edible but potentially The incidence of fungal poisoning varies greatly worldwide.
toxic morel mushrooms (Morchella species), Gyromitra species, and Availability of fungi, depending on climate and geographical con-
Podostroma cornudamae that has caused multisystem symptoms ditions, economics, and lifestyle determine different local traditions
and signs. The phylum Basidiomycota includes the order Agaricales for harvesting and eating mushrooms. In some parts of the world
(gilled mushrooms/​toadstools or agarics) to which most of the med- mushrooms are part of the normal diet, but more commonly they
ically important larger fungi belong. ‘Mushroom’ and ‘toadstool’ are eaten as a delicacy. In most places, mushrooms cannot be con-
may suggest ‘edible’ and ‘poisonous’ respectively, but these terms are sidered indispensable for nutrition and so it remains an unaccept-
not strictly applied. They refer to the visible, above-​ground, fleshy, able paradox that self-​harvested mushrooms, enjoyed as a delicacy,
 10.4.3 Poisonous fungi 1819

still kill people in the 21st century. Most fungi are non​toxic and
Specific types of fungal poisoning
most fungal poisonings are not severe. However, in certain regions
such as Russia and other Eastern and Central European countries,
Ergotism (ergot Claviceps poisoning)
morbidity and mortality is high. Recent publications suggest an
increasing incidence of poisoning worldwide, or at least increased Ergotism results from ingestion of uncleaned grains and cereals, or
recognition and reporting. As in other branches of medicine, there their products such as bread, contaminated with Claviceps species,
is globalization, such that exotic fungi are being eaten across ex- an Ascomycota fungus. Ideal climatic conditions exist when a warm
panding geographical areas and being introduced into places where wet spring and summer follow a cold winter. Claviceps purpurea, the
their effects are unfamiliar. most important species, parasitises grasses and cereals, notably rye
but also wheat; C. fusiformis pearl millet in Africa and East Asia; and
C. africana sorghum in Africa. Claviceps spores infect the ovaries
of flowering grasses from which the poisonous ‘ergot’ or sclerotium
Prevention develops. It protrudes from the seed head, an odoriforous, hard,
curved, blackish-​purple body about 4 cm long shaped like a rooster’s
With a few exceptions, fungal poisoning is accidental. Many people spur (Fig. 10.4.3.1).
develop severe and life-​threatening illness after mushroom meals. There are three groups of ergot alkaloids: amines (e.g. ergonovine/​
Some die; others suffer chronic, irreversible organ damage requiring ergometrine); aminoacids (ergopeptides) (e.g. ergotamine); and semi­
transplantation. synthetic dehydrogenated compounds (e.g. dihydroergametrine).
Since mushrooms are eaten mostly as a delicacy and not as Ergonovine/​ergometrine causes powerful uterine contraction; er-
a basic nutritional requirement, it is a paradox that poisoning is gotamine causes vasoconstriction, uterine contraction, α-​adrenergic
so common. The solution is prevention. Educational campaigns blockade, and central emesis; while dihydroergotamine causes vaso-
should be launched to improve knowledge about mushrooms and constriction, α-​adrenergic blockade, and emesis. Beneficial effects
raise awareness of the risks involved in careless harvesting and of vascular and uterine smooth muscle contraction have been im-
eating. To many people mushroom hunting is an adventure, al- plemented for treatment of migraine and to promote delivery of the
most a game, but this easy-​going attitude must be changed. Because placenta and prevent post-​partum haemorrhage. Psychedelic lysergic
the geographical distribution and appearance of certain fungi are acid diethylamide (LSD) was first synthesized from ergotamine. The
variable, people who are not familiar with the local area tend to be ergot alkaloid ergine (d-​lysergic acid amide—​LSA), also found in
overrepresented as victims of fungal poisoning. Educational mater- seeds of the flowers of ‘morning glory’ (Ipomoea tricolor, Rivea/​
ials should therefore be multilingual and specifically addressed to Turbina corymbosa), has similar effects.
immigrants.
Clinical features
Ingestion of relatively small amounts of C. purpurea ergot over long
Diagnosis periods causes chronic drowsiness, vomiting, diarrhoea, muscle
twitching, ataxia, and hallucinations. Eventually, the vasocon-
Diagnosis may be difficult, as the circumstances are often con- strictive effects of ergot alkaloids cause ischaemia and gangrene of
fusing. It is important to consider any disease that may mimic the feet. The associated burning (ischaemic) pain led to the name
fungal poisoning. ‘St Anthony’s fire’ (not to be confused with erysipelas known as
The history is crucial. Attention should be paid to the appearance ‘the rose’).
of mushrooms ingested and the habitat where they were harvested. Larger doses cause acute vertigo, tinnitus, headache, high fever,
The speed of onset of symptoms and their character, intensity, and nausea, vomiting, other gastrointestinal disturbances, uterine con-
duration are often informative. tractions, paraesthesiae, hallucinations, behavioural abnormalities,
Some fungal poisonings may present with characteristic symp- weakness, convulsions, and death.
toms, for example, those caused by muscarine, psychotropic toxins, Claviceps fusiformis poisoning causes self-​limiting acute gastro-
and amatoxins (see following paragraphs). Careful observation and enteritis and drowsiness.
evaluation of evolving clinical features may, in combination with the A similar range of symptoms is described in patients who took
history, allow a diagnosis. excessive doses of therapeutic ergot alkaloids.
In difficult cases where a dangerous poisoning cannot be excluded,
macro-​and microscopic examination of the fungi (using online keys Treatment
and apps), including fragments recovered from vomitus, may prove For peripheral ischaemia, parenteral nitroprusside or nitrogly-
diagnostic. In many countries, poison information centres may as- cerin, oral prazosin, or ACE-​
inhibitors and anticoagulants are
sist, either by identifying the mushrooms themselves or by obtaining recommended.
advice from external experts.
Laboratory methods: DNA-​based macroarrays have been used to Prevention
identify mushroom fragments. α-​amanitin is detectable in serum by Selection of less susceptible strains, development of ergot-​resistant
high-​performance liquid chromatography (HPLC), and amatoxins crops, improved crop husbandry through minimizing ergot-​
by RIA, EIA, EPLC, LC/​MS/​MS and mass LC/​MS in urine. Aflatoxins susceptible grass weeds (e.g. black grass), azole-​treatment of grains,
are detected by thin-​layer chromatography and HPLC (EIA is too in- surveillance of milling, and use of food processing and baking
sensitive) and ergot alkaloids by HPLC and HPLC-​MS/​MS. reduce the risk of ergotism.
1820 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Fig. 10.4.3.1 Ergot (Claviceps purpurea) showing development of the sclerotium in the ovary of
the host grass flower (3–​5), and fruiting bodies (6–​8).
Reprinted from P. Esser (1910). Die Giftpflanzen Deutschlands. Braunschweig, Friedrich Vieweg und Sohn.
Copyright © 1910, Springer Fachmedien Wiesbaden, with permission from Springer.

Aspergillus aflatoxin poisoning A. nomius; and AFG1 and AFG2, produced by A. parasiticus and
Apergillus species are conidial Ascomycota fungi that are ubiqui- A. nomius. AFM1 and AFM2 in milk or urine of poisoned humans or
tous saprophytes of soil and vegetation, including agricultural crops. animals results from 4-​hydroxylation of AFB1 and AFB2 in the liver.
Aspergillus flavus is the most widespread species. About 30% of its Foodstuffs that are commonly contaminated with aflatoxins include
strains produce aflatoxins. These were first recognized, isolated, and ground (peanuts) and tree nuts, maize, corn, and other grains, seeds,
characterized in 1960, after the death of more than 100 000 turkeys cassava, dried fish, chilli peppers and other spices, especially in
from ‘turkey X disease’, attributed to consumption of Aspergillus-​ India, the Far East, and South America.
contaminated peanut meal. Among at least 14 of these naturally
occurring thermostable mycotoxins, the most important are the Clinical features
difurocoumarocyclopentenones: aflatoxins B1 (AFB1, the most dan- Outbreaks of aflatoxicosis-​
induced hepatitis have occurred in
gerous) and AFB2, produced by Aspergillus flavus, A. parasiticus and undernourished rural populations in tropical countries such as
 10.4.3 Poisonous fungi 1821

India (maize diet) and Kenya (corn diet). Jaundice, ascites, portal are intestinal mucosa, liver, and kidneys. Hepatotoxicity deter-
hypertension, and fatal portal variceal haemorrhage were features mines prognosis.
of these epidemics. High doses of aflatoxins B1 and G1 cause prolif-
eration of bile duct epithelium, fatty infiltration, and centrilobular Clinical features
necrosis. In areas of hepatitis B endemicity, aflatoxicosis is a co-​ After a latent period of 8–​24 (mean 12) h after ingestion, gastro-
carcinogen for hepatocellular carcinoma. AFB1 is the most potent intestinal symptoms start violently with intense, watery diarrhoea,
naturally occurring carcinogen. It is metabolized in the liver to a and vomiting and persist for 36 h. This latency has great diagnostic
reactive epoxide, which forms DNA adducts at some guanine res- significance. Patients become rapidly dehydrated and develop oli-
idues. The epoxide adduct catalyses a G → T mutation in the p53 guria, hypoglycaemia, hypokalaemia, and metabolic acidosis. After
tumour suppressor protein gene, causing a missense mutation that apparent improvement, biochemical signs of liver damage appear
inactivates its product. Treatment is supportive. after 36–​48 h and progress over the next few days. Fulminant hepatic
failure may develop. Initial disturbances of renal function will re-
Prevention solve after rehydration, but within another 3–​4 days, renal function
Risk of aflatoxicosis can be reduced by improving agricultural prac- may again deteriorate because of toxic kidney damage, a sign of poor
tices, including storage, and surveillance of AF levels in key crops prognosis.
and foodstuffs.
Treatment
Decontamination Forced emesis or gastric lavage is performed if
Classification of mushroom poisonings the patient is admitted within 4–​6 h and this can be accomplished
(mycetismus, mycetism, mycotoxicosis) safely. Multidose activated charcoal is always given.
Toxin removal
Fungal toxins are a heterogeneous group, chemically and toxi- • Multiple-​dose activated charcoal is administered for 3 days after
cologically. In clinical practice, the most relevant approach is a ingestion (20–​40 g every 3–​4 h or 50 g every 6 h).
classification based on toxic effects and related symptoms (see
• Diuresis of about 200 ml/​h (adults) is maintained for the first 24–​
Table 10.4.3.1). The scheme adopted here is the new classification
48 h after ingestion.
recently proposed by White, Weinstein, De Haro, Bédry, Schaper,
• Haemoperfusion or haemodialysis is not indicated unless the pa-
Rumack and Zilker (2016). These authors have also developed a
tient has pre-​existing renal disease or is admitted very early and in
useful diagnostic algorithm that is colour-​coded for key clinical
the asymptomatic period (very rare).
features of poisoning.
Reduction of hepatic toxin uptake Silibinin (a component of
Group 1—​Cytotoxic mushroom poisoning
silymarin from milk thistle—​Silybum marianum) (Legalon® SIL) is
1A—​Primary hepatotoxicity (amatoxin poisoning) a free radical scavenger, an anti-​inflammatory agent that stimulates
The highly poisonous amatoxins occur in species of the families protein synthesis and inhibits amatoxin uptake by hepatocytes. 5 mg/​
Amanitaceae (genus Amanita), Agaricaceae (genus Lepiota), and kg is given by intravenous infusion over 1 h, followed by 20 mg/​kg/​
Cortinariaceae (genus Galerina). 24 h as a continuous infusion for 3 days after ingestion. The effective-
The death cap Amanita phalloides (Fig. 10.4.3.2), destroying angel ness of this treatment is not entirely established. Parenteral silibinin
A. virosa (Fig. 10.4.3.3), eastern North American destroying angel is not always available, even in Western countries. High-​dose benzyl
A. bisporigera, Western North American destroying angel A. ocre- penicillin (600 mg or 1 megaU/​kg/​day is an alternative. Recently,
ata, Guangzhou destroying angel A. exitialis, and fool’s mushroom evidence has been produced that polymyxin B, which, prevents α-​
A. verna are the most commonly involved in human poisoning. amanitin from binding to RNA polymerase II, might be a promising
Galerina species such as L. marginata and Lepiota species such as new treatment.
L. helveola may also be implicated. Symptomatic and supportive care
• Symptomatic care is crucial and includes cautious monitoring,
Epidemiology
fluid replacement, and correction of metabolic disturbances.
Amatoxin poisonings are reported from all continents, but are most Hepatic and renal support may be required.
frequent in Europe, accounting for more than 90% of mushroom • There is some experimental, theoretical, and clinical support for
fatalities (case-​fatalities 18–​22% in adults, 33–​51% in children in the the use of N-​acetylcysteine (300 mg/​kg as a continuous IV infu-
1970s and 1980s). Case fatality has declined in Western countries sion over 21 h) as a liver-​protective agent.
but remains alarmingly high in other parts of the world.
• If fulminant hepatic failure is pending, a liver unit should be
Pathogenesis consulted for advice on treatment and with a view to possible
transplantation.
The eight amatoxins, of which α-​amanitin is the most toxic,
are cyclic octapeptides that inhibit transcription of DNA to Prognosis and comments The prognosis is related to toxic dose
mRNA by blocking nuclear RNA polymerases II and III ac- and start of treatment. Case fatality is high after heavy exposure.
tivity. This results in defective protein synthesis and cell death. Vigorous symptomatic and supportive care, maintenance of an ad-
Amatoxins also act with endogenous cytokines to induce apop- equate diuresis, and multiple-​dose activated charcoal are accepted
tosis, and there is glutathione depletion. The main target organs treatments. Silibinin may modify toxicity to some extent through
1822 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Table 10.4.3.1 Classification of mushroom poisoning according to principal clinical features of poisoning and causative toxin(s)
where known

Group Toxin Commonly implicated species Clinical effect Time of onset

1—​Cytotoxic poisoning
1A—​1° hepatotoxic Amatoxins Amanita phalloides, A. virosa, Intense gastroenteritis after 8–​24 h, 8–​12 h
A. bisporigera, A. ocreata, liver and kidney damage
A. exitialis, A. verna, Galerina
marginata, Lepiota helveola
1B—​1° early nephrotoxic Aminohexadienoic A. smithiana, A. proxima Gastroenteritis, headache, fatigue, 1–​12 h
acid myalgias, rash, AKI, cardiotoxicity
1C—​1° late nephrotoxic Orellanine Cortinarius orellanus, C. rubellus Gastroenteritis, headache, drowsiness, 4–​15 days
(speciosissimus) sweating, rash, AKI
2—​Neurotoxic poisoning
2A—​Hallucinogenic Psilocybins, psilocins, Psilocybe semilanceata, Euphoria, anxiety, agitation, aggression, 10–​60 minutes
‘magic mushrooms’ gymnopilins Panaeolus, Conocybe, hallucinations, depersonalization,
Gymnopilus, Copelandia, Pluteus, tachycardia, flushing
Stropharia species
2B—​Autonomic Muscarine Inocybe patouillardii, Clitocybe Nausea, diarrhoea, sweating, 15–​120
dealbata, C. rivulosa), Mycena, salivation, miosis, bradycardia, minutes
Rubinoboletus species hypotension, lacrimation, chills,
tremor, bronchospasm, and so on
2C—​CNS toxic Isoxazoles (ibotenic acid, A. muscaria, A. pantherina, Inebriation, euphoria, confusion, Minutes—​3 h
muscimol, muscazone) A. strobiliformis, A. regalis agitation, anxiety, delusions,
hallucinations, violent behaviour,
seizures, tachycardia, mydriasis,
urinary retention,
2D—​Morel neurological ? Morchella Gastroenteritis, dizziness, ataxia, visual 12 h
syndrome disturbances, headache, paraesthesiae,
trismus, muscle spasms, drowsiness/​
confusion, dysarthria
3—​Myotoxic poisoning
3A—​Early myotoxic Cycloprop-​2-​ene Russula subnigrans Gastroenteritis, rhabdomyplysis, 2+ h
carboxylic acid 2° AKI, collapse
3B—​Late myotoxic Saponaceolides B & M Tricholoma equestre/​flavovirens Fatigue, myalgia, weakness, 1–​3 days
rhabdomyolysis, sweating, AKI,
collapse
4—​Metabolic toxicity poisoning
4A—​GABA-​blocking Gyromitrins/​ Gyromitra esculenta Neurological, gastrointestinal, and 6–​12 h
monomethylhydrazine hepatic symptoms; haemolysis
4B—​Disulfiram-​like Coprines Coprinus atramentarius, Clitocybe Antabuse-​like reaction after alcohol
clavipes, Boletus luridus
4C—​Polyporic Polyporic acid Hapalopilus rutilans Gastroenteritis then neurotoxic 12 h
effects, purple urine, AKI, increased
aminopeptidases
4D—​Trichothecene Trichothecenes Podostroma cornudamae Gastroenteritis, hypertension, Hours–​days
oliguria, pancytopenia, skin peeling,
alopecia
4E—​Hypoglycaemic γ-​guanidinobutyric acid, Troiga venenata Profound hypoglycaemia (severe), 2h
2R-​amino-​4S-​hydroxy-​5-​ dizziness, SOB, syncope
hexynoic acid, 2R-​amino-​5-​
hexynoic acid
4F—H
​ yperprocalcitoninaemic ? Boletus satanas Gastroenteritis, low grade fever, 2h
increased plasma procalcitonin,
C-​reactive protein
4G—​Pancytopenic ? Ganoderma Fever, pancytopenia ?
neojaponicum
5—​Gastrointestinal irritant Many different and Agaricus, Entoloma, Boletus, Gastrointestinal symptoms 1–​3 h
poisoning unidentified Hebeloma, Tricholoma,
Russula, Lactarius, Ramaria,
Chlorophyllum/​Lepiota molybdites,
Macrolepiota/​Lepiota morganii

(continued)
 10.4.3 Poisonous fungi 1823

Table 10.4.3.1 Continued

Group Toxin Commonly implicated species Clinical effect Time of onset

6—​Miscellaneous reactions
6A—​Shiitake dermatitis Lentinans Lentinola edodes Linear prurigo 1–​2 days
6B—​Erythromelalgic Acromelic acid Clitocybe acromelalgia/​ Acromelalgia Hours–​days
amoenolens
6C—​Paxillus syndrome ? Paxillus involutus Collapse, gastroenteritis, 1–​2 h
autoimmune haemolysis, AKI, DIC
6D—​Encephalopathic Cyanide Pleurocybella Cramps, coma (in elderly patients with Days–​weeks
syndrome porrigens chronic renal/​hepatic disease)

Based on the new classification by White J, Weinstein SA, De Haro L, Bédry R, Schaper A, Rumack BH, Zilker T. (2016).

other Amanita species can cause acute kidney injury (AKI). Initial
gastrointestinal and other symptoms develop between 20 minutes
and 12 h after ingestion, followed by AKI a few days later. This was
reported from North America after ingestion of A. smithiana, mis-
taken for Tricholoma magnivelare, and in southern France, in pa-
tients who had eaten A. proxima, mistaken for A. ovoidea as part
of ‘proximien syndrome’. ‘Proximien syndrome’ consists of gastro-
intestinal symptoms starting 8–​14 h after ingestion, followed after
4 days by AKI with evidence of transient liver damage and severe
cardiotoxicity in some cases.

1C—​Late primary nephrotoxicity (orellanine poisoning)

Orellanine is a potent nephrotoxin present in certain species of
the family Cortinariaceae, genus Cortinarius. C. orellanus and
C. rubellus (speciosissimus) (‘cortinar’ or webcap”) (Figs. 10.4.3.4
Fig. 10.4.3.2 Death cap Amanita phalloides. and 10.4.3.5) are responsible for most poisonings. Orellanine is a
Courtesy of Hans Marklund. bipyridine N-​oxide that may interfere with protein synthesis in the
kidneys causing interstitial nephritis, tubular cell damage, basal cell
membrane rupture and, eventually, irreversible fibrosis.
reduction of the hepatic uptake of amatoxin. In some cases, liver
transplantation may be the ultimate way of saving the patient. Clinical features

1B—​Early primary nephrotoxicity Orellanine poisoning is the most insidious of all mushroom poison-
(aminohexadienoic acid poisoning) ings. Occasionally, there may be some mild gastrointestinal symp-
toms within a couple of days after the meal, but as these symptoms
Allenic norleucine (aminohexadienoic acid) and chlorocrotylglycine
in Amanita smithiana, A. pseudoporphyria, A. proxima, and some

Fig. 10.4.3.3 Destroying angel Amanita virosa. Fig. 10.4.3.4 Cortinarius rubellus (speciosissimus).
Courtesy of Hans Marklund. Courtesy of Astrid Holmgren.
1824 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Fig. 10.4.3.5 A common cause of poisoning by nephrotoxic Cortinarius Fig. 10.4.3.6 Liberty cap/​‘magic mushroom’ Psilocybe semilanceata.
spp. is confusion of Cortinarius rubellus (the lower three fungi in this Courtesy of Hans Marklund.
picture) and funnel chanterelle Cantharellus tubaeformis.
Courtesy of Astrid Holmgren.
gymnopilins—​ are tryptamine derivatives that increase sero-
tonin levels in the central nervous system and act as potent hal-
are both discrete and inconsistent they are easily overlooked. lucinogens. The effects mimic those of LSD. Ingestion is almost
However, usually symptoms do not appear until 4–​ 15 (mean invariably related to abuse as these fungi are sought out for their
8) days after the mushroom meal, and, by then, reflect established hallucinogenic properties and can be purchased legally in some
kidney damage. Symptoms evolve insidiously and are difficult for countries.
the patient to interpret—​headache, fatigue, intense thirst, chills,
muscular discomfort, abdominal, lumbar, and flank pain. After a Clinical features
polyuric phase, oliguria and anuria may follow. Laboratory tests on Within 10–​60 min, the patient will experience altered sense of time
admission reveal elevated serum creatinine and urea, proteinuria, and space, euphoria, hallucinations, and depersonalization. Less
haematuria, and—​characteristically—​pyuria. The AKI may resolve pleasurable symptoms are anxiety, agitation, aggression, bizarre
or become chronic. and terrifying hallucinations, tachycardia, mydriasis, headache,
Treatment and flushing. Symptoms peak at around 2 h after ingestion and start
vanishing after 4–​6 h. However, symptoms may persist and there
Since patients are normally admitted late, therapeutic interven- may be flashbacks after weeks or months.
tions can neither prevent nor reduce toxic damage. Renal function Organic psychosis is a differential diagnosis. A reliable history
is monitored. Therapy is symptomatic with support of renal func- may be available only after recovery.
tion and treatment of uraemia, including dialysis while waiting for
the kidneys to recover. In case of persistent renal insufficiency, the Treatment
options are chronic dialysis or transplantation. However, transplant- The patient should rest in a quiet environment and be sedated
ation should not be performed too early, as renal recovery may be (e.g. with diazepam). If this is inadequate, haloperidol or chlorpro-
considerably delayed. mazine can be added.
Very early suspicion of orellanine poisoning should prompt meas-
ures to prevent absorption and promote elimination. 2B—​Autonomic-​toxicity mushrooms (muscarinic poisoning)

Prognosis and comments Toxic amounts of muscarine occur particularly in certain Inocybe
species (e.g. I. patouillardii), Clitocybe species (e.g. C. dealbata,
End-​stage renal failure was observed in 11% of Polish, 17% of French, C. rivulosa), Mycena species, and Rubinoboletus species. Muscarine
and 40% of Swedish patients. It should be emphasized that treatment has also been detected in small, mostly insignificant amounts in
measures discussed above are theoretically based and there is so far other genera. Muscarine stimulates cholinergic receptors in the
no clinical support for a rational treatment strategy of this ghostly autonomic nervous system.
poisoning, apart from supportive and symptomatic care.
Clinical features
Group 2—​Neurotoxic mushroom poisoning
Symptoms of parasympathetic stimulation start within 15 minutes to
2A—​Hallucinogenic mushrooms (‘magic mushrooms’) 2 h. Nausea, diarrhoea, diaphoresis, hypersalivation, miosis, brady-
(psilocybin poisoning) cardia, and hypotension are common and rhinorrhoea, lacrimation,
Psilocybin and related toxins occur particularly in Psilocybe spe- chills, tremor, central nervous system depression, bronchorrhoea,
cies, for example, liberty cap Psilocybe semilanceata (Fig. 10.4.3.6), bronchospasm, and painful micturition have been reported. The pa-
and Panaeolus, Conocybe, Gymnopilus, Copelandia, Pluteus, tient is often pale and feels sick and miserable. The clinical features
and Stropharia species. The toxins—​psilocybins, psilocins, and are fairly diagnostic.
 10.4.3 Poisonous fungi 1825

Fig. 10.4.3.9 Panther cap Amanita pantherina.

Courtesy of Hans Marklund.

Clinical features
Symptoms start within 0.5–​1.5 h, peak at around 3 h, and vanish
gradually over the next 24 h. The symptoms are unpredictable:
Fig. 10.4.3.7 Fly agaric Amanita muscaria. exhilaration, euphoria, drowsiness, and confusion alternate
Courtesy of Ole Högberg. with anxiety, agitation, delusions, illusions, and hallucinations.
Extreme agitation and violent behaviour may ensue. Occasionally
Treatment myoclonic jerks, muscle fasciculations, and seizures are ob-
served. Tachycardia, mydriasis, and urinary retention may occur.
Intravenous atropine (adults 1–​ 2 mg, children 0.02–​
0.05 mg/​
kg)
Cholinergic symptoms are attributable to trace amounts of mus-
effectively counteracts the cholinergic symptoms. Repeated doses
carine in some specimens. Panther cap more often causes central
may be required. Symptomatic treatment is given as required.
nervous system depression, whereas fly agaric is more likely to
2C—​CNS-​neuroexcitatory mushrooms trigger excitation and bizarre behaviour.
(ibotenic acid/​muscimol poisoning) History and symptoms are often diagnostic. However, the his-
tory is often obscure until patients are fit enough to tell their story.
Isoxazoles (ibotenic acid, muscimol, and muscazone) occur in certain
Differential diagnoses include organic psychosis and central ner-
Amanita species, for example, fly agaric A. muscaria (Figs. 10.4.3.7
vous system infections.
and 10.4.3.8), panther cap A. pantherina (Fig. 10.4.3.9), A. strobili-
formis, and A. regalis. The toxins act as GABA agonists. Treatment
Treatment is symptomatic and supportive. Intravenous diazepam
(adults 5–​10 mg, children 0.1–​0.2 mg/​kg) is given and repeated
for sedation. Haloperidol or chlorpromazine may be useful as a
complement in delirious and agitated patients.

2D—​Morel neurological syndrome (toxin unknown)

‘Morel’ (Morchella species) are highly relished edible mushrooms, but
they contain toxic thermolabile hydrazine haemolysins. Ingestion of
un/​inadequately cooked morels causes acute gastroenteritis (nausea,
vomiting, abdominal pain, diarrhoea) after about 5 h.
In France and Bavaria, people who ingested morels such as Morchella
esculenta and M. conica, even cooked ones, developed neurological
symptoms about 12 h later: tremor, dizziness/​inebriation, unsteadi-
ness/​ataxia, visual disturbances, headache, paraesthesiae, trismus or
muscle spasms, drowsiness/​confusion, and dysarthria.

Group 3—​Myotoxic mushroom poisoning

3A—​Early myotoxicity (cycloprop-​2-​ene carboxylic
acid poisoning)
Fig. 10.4.3.8 Variations in appearance of fly agaric Amanita
muscaria—​may result in confusion with edible mushrooms. Generalized rhabdomyolysis following ingestion of Russula sub-
Courtesy of Ole Högberg. nigricans (order Russalales), a mushroom that stains red when
1826 SECTION 10 Environmental medicine, occupational medicine, and poisoning

damaged. It was first described in Taiwan in 2001 and subsequently is not immediately available, diazepam is given initially. It is wise to
in China, Japan, and Korea. Toxicity is attributable to unstable have a glucose infusion running and maintain an adequate diuresis.
cycloprop-​2-​ene carboxylic acid. Poisoning causes self-​limiting
nausea, vomiting, diarrhoea, and agitation about 2 h after ingestion 4B—​Disulfiram-​like mushroom poisoning (coprine poisoning)
in most victims, followed a few h later in a minority by generalized Antabuse syndrome
myalgia and rhabdomyolysis (serum creatine kinase concentration An ‘antabuse syndrome’ may be induced by ‘common ink cap’ or
>20 000 U/​litre), with or without hyperkalaemia, hypocalcaemia, ‘inky cap’ (Coprinus atramentarius), a few other Coprinus species,
respiratory failure, AKI, pulmonary oedema, hypertension, ven- Clitocybe clavipes, and Boletus luridus.
tricular tachycardia, and circulatory shock. The toxin (coprine) acts like disulfiram, blocking acetaldehyde
3B—​Late myotoxicity (saponaceolide B and M poisoning) dehydrogenase. Consequently, drinking ethanol after eating these
mushrooms will cause an antabuse syndrome—​flushing, sweating,
Rhabdomyolysis has been reported in France and Poland, after nausea, anxiety, tachycardia, hypotension, and dyspnoea. The risk
ingestion of large or repeated meals of ‘man on horseback’ or persists for about 1 week after the mushroom ingestion.
‘yellow knight’ (Tricholoma equestre/​flavovirens) that grow under If the mistake is discovered early, decontamination and adminis-
conifers. These puzzling observations, implicating a popular tration of activated charcoal may be useful. Otherwise symptomatic
mushroom, have caused considerable attention and concern. and supportive care is given.
Toxic saponaceolides B and M have been found in the related and
widely-​consumed ‘grey knight’ or ‘dirty tricholoma’ (T. terreum) 4C—​Polyporic mushroom poisoning (polyporic acid
but not in T. equestre. poisoning)

Clinical features An epiphytic bracket mushroom, ‘tender nesting polypore’, ‘purple

dye polypore’, or ‘cinnamon bracket’ (Hapalopilus rutilans) con-
Progressive fatigue, muscle weakness, myalgia especially in the tains polyporic acid that can cause gastrointestinal and neuro-
thighs, nausea, sweating, facial erythema, and evidence of generalize logical effects about 12 h after ingestion, followed in severe cases
rhabdomyolysis develop 1–​3 days after the last meal of T. equestre. by AKI, mild hepatotoxicity, proteinuria, pyuria, and diagnostic
In severe cases there is progression to fatal acute respiratory failure, purple/​violet coloured urine.
cardiac arrhythmias, and cardiovascular collapse. The case fatality
in Poland was 20%. Severity correlated with the amount of ingested 4D—​Trichothecene mushroom poisoning
mushroom. (trichothecene poisoning)

Group 4—​Metabolic toxicity mushroom poisoning Podostroma cornudamae ingestion has caused fatal multisystem
poisoning, including AKI, pancytopenia, peeling skin, and alopecia
4A—​GABA-​blocking mushroom poisoning in Japan and Korea attributable to trichothecenes.
(gyromitrin poisoning)
Gyromitrin occurs in fungi of the family Helvellaceae, genus 4E—​Hypoglycaemic mushroom poisoning
Gyromitra. Most poisonings are caused by the ‘false morel’ or Deaths of some 400 villagers in Yunnan Province, China over
‘Lorchel’ (Gyromitra esculenta), but the toxin is found also in other 35 years (‘Yunnan Sudden Unexplained Death’) have been attrib-
Gyromitra species. Gyromitrin decomposes in the stomach to uted to a previously undescribed species of ‘little white mushroom’,
form monomethylhydrazine. This reduces central nervous system Trogia venenata. It contains γ-​guanidinobutyric acid, 2R-​amino-​
pyridoxine and, hence, GABA synthesis. Glutathione depletion in 4S-​hydroxy-​5-​hexynoic acid, 2R-​amino-​5-​hexynoic acid which
erythrocytes and damage to hepatic macromolecules has also been cause profound hypoglycaemia (like hypogycin from ackee fruit
postulated. Gyromitrin is water-​soluble and volatile, and so can be below). Inhibition of β-​oxidation prevents generation of glucose by
partly removed from the fungus by drying or boiling. gluconeogenesis from lipid substrate.

Clinical features 4F—​Hyperprocalcitoninaemic mushroom poisoning

Systemic symptoms may follow inhalation of vapour, which also (toxin unknown)
irritates eyes and airways. Most common, however, is poisoning Poisoning by Satan’s bolete (Rubroboletus/​Boletus satanas) in France,
by ingestion of false morels that have not been properly pre- associated with high plasma concentrations of procalcitonin and
pared. Symptoms are delayed 5–​8 h. Vomiting and diarrhoea may C-​reactive protein, caused self-​limiting gastrointestinal symptoms
occur, but more typical features are vertigo, ataxia, nystagmus, and fever.
diplopia, balance disturbances, diaphoresis, slurred speech, and
drowsiness. Rare symptoms are delirium, seizures, and coma. 4G—​Pancytopenic mushroom poisoning (toxin unknown)
Moderate hepatic damage, haemolysis, and hypoglycaemia have Self-​limiting pancytopenia has been described in people taking
been observed. Ganoderma neojaponicum, a common constituent of herbal medi-
cines in China, NE, and SE Asia.
Treatment
If neurological symptoms prevail, it is relevant to give pyridoxine Group 5—​Gastrointestinal irritant mushroom poisoning.
25 mg/​kg as an intravenous bolus infusion over 30 min. Repeated Fungi solely causing gastroenteritis form the largest subgroup,
doses may be required. If the patient is convulsing and pyridoxine comprising species from many genera (e.g. Agaricus, Boletus,
 10.4.3 Poisonous fungi 1827

Entoloma, Hebeloma, Lactarius, Ramaria, Russula, and Tricholoma). gastroenteritis, haemolysis, and subsequent renal impairment. High
Many of these genera include delicious, popular, and edible mush- plasma concentrations of bilirubin and aminotransferases due to
rooms, increasing the risk of confusion. haemolysis may suggest amatoxin poisoning.
Few toxins in this group are chemically identified. They cause Symptomatic and supportive care includes fluid replacement,
non​specific irritation of the gastrointestinal mucosae. maintenance of adequate diuresis, and blood transfusions.

Clinical features 6D—​Encephalopathic syndrome (possibly cyanide poisoning)

Vomiting and diarrhoea start within a few hours and generally ‘Angel wing’ (Pleurocybella gyrometrinporrigens), ‘king trumpet
resolve quickly. Intensity and duration may, however, vary. For ex- mushroom’ (Pleurotus eryngii) and several other species of mush-
ample, ‘leaden entoloma’ (Entoloma sinuatum) may cause intense rooms long considered safe for eating have been responsible
and long-​lasting symptoms. Depending on length and duration of for delayed encephalopathic poisoning in Japan in elderly people
symptoms, fluid and electrolyte imbalance may ensue. often with chronic renal or hepatic disease. Cyanide has been
Gastrointestinal infection must be considered as a differential implicated.
diagnosis, together with effects of gorging on large amounts of indi-
gestible mushrooms (the death of the Roman Emperor Jovian was
attributed to ‘a surfeit of mushrooms’). Delayed onset of intense FURTHER READING
symptoms until 8 to 24 h after the mushroom meal suggests poten-
Bédry R, et al. (2001). Wild-​mushroom intoxication as a cause of
tially dangerous poisoning by amatoxin-​containing fungi (see fol-
rhabdomyolysis. N Engl J Med, 345, 798–​802.
lowing paragraphs).
Bresinsky A, Besl H (1990). A colour atlas of poisonous fungi. A hand-
Treatment book for pharmacists, doctors, and biologists. Wolfe Publishing,
London.
Admission to hospital is seldom necessary, but if symptoms are more Cooper MR, Johnson AW (1998). Poisonous plants and fungi in
intense fluid and electrolyte replacement may be necessary, espe- Britain. Animal and human poisoning, 2nd edition. The Stationery
cially in children and older people. Office, London.
The ‘false parasol’ or ‘green-​spored parasol’ (Chlorophyllum molyb- Dinis-​Oliveira RJ, et al. (2016). Human and experimental toxicology of
dites or Lepiota molybdites; also Morgan’s mushroom, Macrolepiota orellanine. Hum Exp Toxicol, 35, 1016–​29.
or Lepiota morganii) is the most commonly ingested poisonous Enjalbert F, et al. (2002). Treatment of amatoxin poisoning: 20-​year
mushroom in North America and Hawai’i. The toxin is irritant and retrospective analysis. J Toxicol Clin Toxicol, 40, 715–​57.
also exerts α-​adrenergic blockade and cholinergic effects. Garcia J, et al. (2015). A breakthrough on Amanita phalloides poi-
Within 30 min to 2 (–​4) h, intense, watery, and sometimes bloody soning: an effective antidotal effect by polymyxin B. Arch Toxicol,
diarrhoea begins (also a feature of ‘tsukiyotake’ —​Omphalotus japon- 89, 2305–​23.
Garcia J, et al. (2015). Amanita phalloides poisoning: mechanisms of
icas/​guepiniformis—​ingestion mistakenly for shiitake mushrooms in
toxicity and treatment. Food Chem Toxicol, 86, 41–​55.
Japan). This may result in dehydration, electrolyte imbalance, shock,
Graeme KA (2014). Mycetism: a review of the recent literature. J Med
and renal impairment. Occasionally miosis, pallor, diaphoresis, and Toxicol, 10, 173–​89.
hypotension are observed. Holmdahl J, Blohmé I (1995). Renal transplantation after Cortinarius
Fluid replacement and other symptomatic and supportive care are speciosissimus poisoning. Nephrol Dial Transplant, 10, 1920–​2.
given as required. Atropine is given in case of cholinergic symptoms. Karlson-​Stiber C, Persson H (2003). Cytotoxic fungi—​an overview.
Toxicon, 42, 339–​49.
Group 6—​Miscellaneous adverse reactions Lee PT, et al. (2001). Rhabdomyolysis: an unusual feature with mush-
to mushrooms room poisoning. Am J Kidney Dis, 38, E17.
6A—​Shiitake mushroom dermatitis (lentinan poisoning) Saviuc P, et al. (2010). Can morels (Morchella sp.) induce a toxic neuro-
logical syndrome? Clin Toxicol (Phila), 48, 365–​72.
Inadequately cooked shiitake mushrooms (Lentinola edodes) that Wasson RG (1972). The death of Claudius or mushrooms for
are cultivated in the Far East, can cause ‘shiitake dermatitis’, a gener- murderers. Botanical Museum Leaflets Harvard University, 23,
alized, light-​sensitive, erythematous, micro-​papular, linear, pruritic, 101–​28.
urticarial rash that appears 24 hours after ingestion and that persists White J, et al. (2016). Mushroom poisoning: a proposed new
for 3–​21 days. It is attributed to the thermolabile polysaccharide, clinical classification. (in press). Presented at The 18th World
lentina. Congress of the International Society on Toxinology, Oxford, UK,
25–​30 September 2015: abstract 143. Toxicon 103 Supplement
6B—​Erythromelalgic mushroom poisoning (acromelic acid (2015), 85–​6.
poisoning) Yin X, et al. (2014). Chemical and toxicological investigations of a pre-
Consumption of ‘paralysis funnel’ or ‘poison dwarf bamboo mush- viously unknown poisonous European mushroom Tricholoma ter-
room’ (Clitocybe acromelalgia/​amoenolens) can cause persisting reum. Chemistry, 20, 7001–​9.1
acromelalgia, attributed to acromelic acid. Zhou ZY, et al. (2012). Evidence for the natural toxins from the
mushroom Trogia venenata as a cause of sudden unexpected
6C—​Paxillus syndrome (toxin unknown) death in Yunnan Province, China. Angew Chem Int Ed Engl, 51,
2368–​70.
After repeated ingestion of the ‘roll-​rim cap’ or ‘poison pax’ (Paxillus Mushroom identification app: http://​rogersmushroomsapp.com/​
involutus), its antigens may induce a Paxillus syndrome: severe
1828 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Table 10.4.4.1 Classification of the main plant toxins

10.4.4 Poisonous plants Neurotoxins Anticholinergic alkaloids
Michael Eddleston and Hans Persson Hallucinogenic toxins
Convulsants
Nicotinic agonists
ESSENTIALS Cardiotoxins Aconitine
Many plants contain toxic substances—​heterogeneous in chemical Grayanotoxins
composition and diverse in toxic effects. When classifying plant pois- Cardiac glycosides
onings, a pragmatic approach is to look at the main clinical effects,
Taxanes
but it should be emphasized that few plant toxins produce just one
type of symptom and that symptomatology is often multiple, with Cytotoxic agents Colchicine
some features predominating. Toxalbumins
Ingestion of, or contact with, poisonous plants is common but ser- Cyanogenic glycosides
ious plant poisoning is rare worldwide because most plant exposures Diterpenoid glucosides
are accidental: the majority occur in small children, the ingested dose Epidemic dropsy alkaloids
is usually small, and no treatment is required.
Hepatotoxins Pyrrolizidine alkaloids
Globally, severe plant poisoning usually results from intentional
exposure. Toxic plants are ingested for self-​harm in certain regions Senna occidentalis toxins
(e.g. in Sri Lanka and India), where cardiac glycosides in yellow ole- Hypoglycin
ander Cascabela thevetia and odollam Cerbera manghas and diphyllin Nephrotoxins Aristolochic acid
glycosides in oduvan Cleisthanthus collinis are responsible for much Diphyllin glycosides
morbidity and mortality. Other intentional and serious poisonings
Terpenes
occur with, for example, Aconitum and Colchicum spp.. Plants with
Antraquinone glycosides
psychotropic and hallucinogenic effects, for example, Datura and
Cannabis spp., are abused as recreational drugs or used in food or Oxalic acid
drinks to render travellers unconscious for robbery. Gastrointestinal irritants Calcium oxalate
Severe unintentional poisoning has resulted from the use of herbal Oxalic acid
medicines or foods containing, or contaminated by, plant toxins Diterpene esters
(e.g. aconitine in China, cyanide (cassava) in Africa, and aristolochic
Dermatotoxins Calcium oxalate
acid (Aristolochia spp.) in Europe). Food insecurity in lower in-
Oxalic acid
come countries results in outbreaks of poisoning, often in children
(e.g. with pyrrolizidine alkaloids in Heliotrope species, mitochondrial Phototoxic psoralens
toxins in Xanthium strumarium, a hepatotoxin in Blighia sapida, and
cyanogenic glycosides in toxic Detarium senegalense).
Treatment of severe plant poisoning includes careful de- Neurotoxic plants
contamination and symptomatic and supportive care. Specific
antidotes are only available for poisoning by plants containing Anticholinergic toxins
belladonna alkaloids (physostigmine), cardiac glycosides (digoxin-​
Belladonna alkaloids (atropine, hyoscyamine, scopolamine) occur
specific Fab fragments), and cyanogenic agents (dicobalt edetate,
in a variety of plants, including deadly nightshade Atropa bella-
hydroxocobalamin).
donna, henbane Hyoscyamus niger, thorn apple/​jimson weed Datura
stramonium, and angels’ trumpets Brugmansia suaveolens. These al-
kaloids are muscarinic acetylcholine receptor antagonists, causing
Aetiology and epidemiology central and peripheral anticholinergic effects. Poisoning can occur
unintentionally in children or, in some localities, as part of drugging
The most common exposure to toxic plants, particularly in the West, a person for robbery; most commonly, toxicity occurs after recre-
is in young children as they explore their environment. Few of these ational use in young people ingesting Datura or Brugmansia spp.
exposures result in serious harm. In other parts of the world, par- The anticholinergic toxidrome includes tachycardia, fever, agita-
ticularly Asia, the most common plant exposures are from self-​harm tion, flushing, mydriasis, delirium, hallucinations, and urinary re-
in adolescents and adults, sometimes with fatal outcome. Deaths also tention. The latter can make confused patients even more distressed
occur after children (although rarely adults) eat poisonous plants and should be actively sought. Rarely, seizures and coma ensue.
as food, especially where there is food insecurity. Herbal medicines Differential diagnoses include sympathomimetic or serotinergic
containing toxic principles cause accidental plant poisoning, while toxidromes, common after poisoning with amphetamines and other
recreational ingestion or smoking of psychoactive plants is popular central nervous system stimulants, and central nervous system
in industrialized countries. infection.
A clinically oriented overview of the main plant toxins is given in Nurse in a quiet calm environment; diazepam may be required
Table 10.4.4.1. for sedation. Physostigmine given by slow intravenous push (adults
 10.4.4 Poisonous plants 1829

1–​2 mg, children 0.02–​ 0.04 mg/​kg) can reverse marked central latter. Their unpleasant taste should reduce the risk of poisoning by
anticholinergic toxicity that is not settling with time and diazepam. ingestion; nevertheless, they are sporadically confused with herbs and
The dose may be repeated as required. Physostigmine should be eaten in salads. Early symptoms are vertigo, agitation, thirst, tachy-
withheld if cardiotoxic agents have been co-​ingested, if the pa- cardia, hypertension, salivation, diaphoresis, vomiting, and diarrhoea.
tient has a bradycardia, or if there are signs of cardiac conduction Muscle fasciculation, convulsions, hypotension, bradydysrhythmias,
abnormalities. ascending weakness, paralysis, and coma may follow. Careful symp-
Unilateral mydriasis may occur in people (often gardeners, tomatic and supportive care, including assisted ventilation, may be
hence ‘gardeners’ mydriasis’) who handle plants of this type and required.
happen to rub their eye. This has caused confusion on presentation Cytisine in Laburnum spp. (e.g. golden chain) and lobeline in
to hospital and unnecessary, expensive investigations. Lobelia spp. cause mild nicotine-​like effects. However, the most
common symptoms after ingestion are vomiting and diarrhoea.
Hallucinogenic toxins Childhood exposures are frequent and symptoms mostly mild or
Some plant toxins are particularly popular among abusers because of moderate. Treatment is symptomatic.
their hallucinogenic properties. Examples are tetrahydrocannabinols
in cannabis Cannabis sativa, alkaloids in khat Catha edulis, mes- Other neurotoxins
caline in peyote Lophophora williamsii, and myristicin in nutmeg Toxins in fruit of the buckthorn or tullidora bush, Karwinskia hum-
Myristica fragrans. Ayahuasca is a hallucinogenic brew made from boldtiana, in Central America produce a flaccid, symmetric, ascending
Banisteriopsis caapi vine and Psychotria viridis leaves in South paralysis of the lower limbs. The dimeric hydroxyanthracenone
America. After absorption, the usual first pass breakdown of peroxisomicine A1 appears to be cytotoxic but the precise mechanism
dimethyltryptamine from P. viridis is inhibited by monoamine oxi- of the peripheral neuropathy is not yet known. Buckthorn poisoning
dase inhibitors in B caapi, markedly potentiating the effect of the can easily be mistaken for Guillain-​Barré syndrome unless there is a
former. Treatment is symptomatic, with a calm environment and history of fruit ingestion. Treatment is supportive until the peripheral
benzodiazepines as necessary. neuropathy resolves, with careful monitoring for impending ventila-
Convulsants tory failure.
Gelsemine in lemuan Gelsemium elegans in China and yellow
The γ-​ aminobutyric acid (GABA) antagonists, cicutoxin and jessamine G sempervirens in North America is a glycine agonist.
oenanthotoxin, are some of the most potent convulsants known. Patients present with dizziness and eye manifestations (blurred vi-
Cicutoxin occurs in cowbane Cicuta virosa, water hemlock C mac- sion, diplopia, nystagmus, ptosis), progressing to coma, seizures,
ulata, and western water hemlock C douglasii, while oenanthotoxin and respiratory failure requiring mechanical ventilation. Treatment
occurs in hemlock water dropwort Oenanthe crocata. requires supportive and intensive care.
Severe poisoning has occurred in adults eating one of these
plants after mistaking it for an edible plant. Typical symptoms
include gastrointestinal upset, increased salivation, diaphoresis,
and violent, recurrent, and long-​lasting tonic–​clonic convulsions. Cardiotoxic plants
These may result in hypoxia, severe metabolic acidosis, coma, cir-
culatory instability, rhabdomyolysis, joint dislocations, and rectal Aconitine
prolapse. Aconitine is one of the most potent plant toxins known, occurring
Diagnosis is typically based on the presence of recurrent seiz- in multiple Aconitum spp. (e.g. monkshood, A napellus) native to
ures together with the history of plant ingestion. Treatment re- mountainous parts of the northern hemisphere and now grown
quires careful symptomatic and intensive care, with emphasis on widely in gardens. The toxin binds to voltage-​gated sodium chan-
combating convulsions with benzodiazepines, barbiturates, and nels causing persistent sodium influx and depolarization of cardiac
general anaesthesia, correction of acidosis, and maintenance of and neurological tissue. Serious poisoning results from intentional
urinary output. ingestion of the plant, homicidal administration of aconitine in
Other toxins reported to cause coma and/​or seizures include food, and from unintentional overdose of Asian herbal medica-
coriamyrtin in Coriaria myrtifolia in the Western Mediterranean, tions. It is also used in arrow poisons (e.g. Bikh in Nepal).
terpenes in chinaberry Melia azedarach in South East Asia, the Ingestion results in rapid onset of burning and tingling in the
alkaloid dauricine in moonseed Menispermum canadense and lips, mouth, and pharynx, followed by numbness and paraesthesia
podophylloresin in may apple Podophyllum peltatum, both in of the limbs, hypersalivation, and gastrointestinal symptoms in
North America, strychnine in the nux vomica or strychnine tree particular severe and protracted vomiting. Many kinds of dys-
(Strychnos nux-​vomica) in South and South East Asia, and un- rhythmias occur, but particularly ventricular ectopy leading to
known toxins in Urobotrya siamensis Hiepko in South East Asia ventricular tachycardia and fibrillation that may be refractory to
and star fruit Averrhoa carambola in patients with chronic kidney treatment. Cardiac failure and shock often develop; coma, mus-
disease in East Asia. Treatment is symptomatic and supportive. cular weakness, neuromuscular failure, and seizures also occur.
Considering the extreme toxicity of this plant, gastrointestinal
Nicotinic agonists decontamination should be performed. Treatment includes optimal
The tobacco plant Nicotiana tabacum and hemlock Conium macula- symptomatic and supportive care, directed at dysrhythmias and
tum contain multiple alkaloids with nicotinic receptor agonist effects, cardiac failure, including magnesium, flecainide, or lidocaine, and
particularly nicotine in the former and coniine and γ-​coniceine in the extracorporeal membrane oxygenation.
1830 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Grayanotoxins in hyperkalaemia, as well as raised intracellular sodium and then

Grayanotoxins occur in multiple Rhodedendron spp. Pollen from raised intracellular calcium concentration. Bradycardia with sinus
these plants are incorporated by bees into ‘mad’ honey particularly and AV blocks are common; death occurs in 5–​10% of patients,
around the Black Sea and Himalayas. The toxic dose is reported to likely due to catecholaminergic polymorphic ventricular tachy-
be 20–​200 g of honey, with a clear dose response. Similar to acon- cardia. Where available, digitalis-​specific antibodies (ovine Fab
itine, the toxin binds to and activates voltage-​gated sodium channels fragments) are highly effective (Fig. 10.4.4.1). Where not avail-
on nerve, muscle, and heart cells. Strong vagal effects cause brady- able, management focuses on symptomatic care and treatment of
cardia. Toxicity often lasts for 2–​3 days, with occurrence of car- hyperkalaemia.
diac dysrhythmias, dizziness, diplopia, reduced consciousness, and Taxanes
rarely respiratory failure. Treatment is supportive.
Grayanotoxins also occur in mountain laurel Kalmia latifolia, Taxin alkaloids in yew Taxus spp. block Na+ and Ca+ channels,
Menziesia spp., and Pieris spp. inducing QRS prolongation, atrioventricular block, ventricular fib-
rillation, and cardiac arrest. They also block Na+ channels and dis-
Cardiac glycosides rupt microtubule function, inhibiting cell division, causing central
Cardiac glycosides occur in multiple foxglove spp., including nervous system and gastrointestinal effects. Treatment involves
Digitalis purpurea and D lanata, common oleander Nerium ole- supportive care, with extracorporeal membrane oxygenation if
ander, yellow oleander Cascabela thevetia, sea mango or odollam available.
tree Cerbera manghas, lily of the valley Convallaria majalis, and red Other cardiotoxins
squill Urginea maritima. Cardiac glycoside poisoning is particularly
common in South Asia where C. thevetia and C. manghas are com- Other cardiotoxins include veratrine in Veratrum and Zigadenus
monly used for self-​harm, resulting in hundreds of deaths each year; spp. and phoratoxin in American mistletoes Phoradendron spp.
poisoning with other cardiac glycoside containing plants is more
usually unintentional.
Ingestion results in severe gastrointestinal features, with ab- Cytotoxic plants
dominal pain, profuse vomiting, and diarrhoea common. The
toxins’ inhibition of the Na+/​K+ ATPase on cardiomyocytes results Colchicine
Colchicine occurs in autumn crocus/​meadow saffron Colchicum
Baseline autumnale and glory lily Gloriosa superba. It binds to β-​tubulin,
producing antimitotic effects on cells with high metabolism
(e.g. gut and bone marrow), but also direct toxicity on heart, liver,
and kidneys. Intentional exposures may result in severe poisoning.
t = 30 min The clinical course has different phases. After an initial delay—​
sometimes of many hours—​there is onset of intense gastrointestinal
symptoms, followed by dysrhythmias, circulatory failure, seizures,
central nervous system depression, and muscular weakness. There
may be signs of renal and hepatic damage and, after a few days, bone
t = 60 min
marrow depression. Patients who survive the acute phase may lose
their hair and develop a peripheral neuropathy.
Multiple-​dose activated charcoal may enhance elimination, but
intensive care is crucial together with measures to encourage bone
t=2h
marrow recovery. Anticolchicine Fab fragments have been studied
but are not yet available in clinical practice.

Toxalbumins
t=8h Ricin in the castor plant Ricinus communis and abrin in je-
quirity bean Abrus precatorius are water-​soluble proteins known
as toxalbumins. Ricin is so toxic that it has been placed on the
Chemical Weapons Convention List. These compounds block
t = 48 h protein synthesis by inhibiting ribosome function, causing cell
death, with the gut as the primary target organ. Intact beans are
not toxic as they pass through the gut without releasing toxin.
However, beans that have been chewed are highly toxic, with just
a few sufficient to cause severe poisoning. A few hours after inges-
Fig. 10.4.4.1 Resolution of atrioventricular conduction block after tion, severe gastroenteritis may occur with heavy fluid and elec-
treatment with 1200 mg of digoxin-​specific Fab fragments.
trolyte loss, resulting in renal failure, circulatory instability, and
Reprinted from The Lancet, Vol. 355, No. 9208, Eddleston M et al., Anti-​digoxin Fab
fragments in cardiotoxicity induced by ingestion of yellow oleander: a randomised hepatic damage. Treatment is symptomatic with vigorous fluid
controlled trial, pages 967–​72, Copyright © 2000, with permission from Elsevier. replacement.
 10.4.4 Poisonous plants 1831

Cyanogenic glycosides children when food is short. These toxins block the adenine nu-
Over 25 cyanogenic glycosides are known, occurring in more than cleotide translocator in mitochondria, inhibiting mitochondrial
2500 species of plants distributed across the world. They occur in oxidative phosphorylation. Patients develop vomiting, abdom-
kernels or fruits of Prunus spp. such as bitter almonds, apricots, inal pain, and diarrhoea, then headache, convulsions, coma, car-
cherries, and peaches as well as non-​Prunus spp. such as loquat diovascular collapse, and liver failure. The published case fatality
Eriobotrya japonica, cassava (Manihot spp.), elderberry Sambucus is high, with most deaths occurring within 24 hrs. Treatment is
nigra, and toxic fruits of the tallow tree Detarium senegalense. Even supportive.
apple pips Malus spp. contain small amounts of cyanogenic glyco- Epidemic dropsy alkaloids
sides, but large amounts are required to cause poisoning. After the
kernels are chewed and swallowed, barriers between the cyanogenic The alkaloids sanguinarine and dihydrosanguinarine in seeds of
glycoside and enzyme break down, resulting in enzymatic release the Mexican prickly poppy Argemone mexicana cause epidemic
of cyanide in the stomach. This is a slow process, and symptoms of dropsy in populations, particularly South Asian, that cook with
poisoning may be delayed for many hours. Cyanide poisoning from mustard oil Brassica nigra. Dropsy occurs when B nigra seeds
plants is unusual but, should it occur, treatment is as outlined else- become contaminated with A mexicana seeds, either acciden-
where for cyanide (see Chapter 10.4.1). tally due to A mexicana growing in or near B nigra cultivation or
Inappropriately prepared cassava M. esculenta represents a spe- due to intentional adulteration. The alkaloids damage capillaries,
cial, large-​scale problem of chronic cyanide exposure, producing leading to vascular protein loss and oedema. Patients present with
neurological disorders such as tropical ataxic neuropathy and diarrhoea, cough, and marked bilateral pitting oedema of the legs;
konzo. It was observed in Nigeria in the 1930s, and subsequently right sided congestive cardiac failure may occur. Treatment is
in other African countries. Food insecurity results in atypical ways symptomatic.
of preparing cassava, producing small outbreaks from time to time.

Diterpenoid glucosides Hepatotoxic plants

The diterpenoid glucosides, atractyloside and carboxyatractyloside,
have been identified in bird-​lime or blue thistle Atractylis gummif- Pyrrolizidine alkaloids
era in north Africa and in the cocklebur thistle Xanthium strumar- Hepatotoxicity most commonly occurs when people ingest plants
ium in Bangladesh (Fig. 10.4.4.2). These plants are usually eaten by containing pyrrolizidine alkaloids. These toxins cause veno-​occlusive
disease and occur in many Senecio, Crotalaria, Heliotropium, and
(a) Symphytum spp. Cases are reported from Afghanistan, countries of
the old USSR, India, and Jamaica; large epidemics have occurred in
west Asia when Heliotropium plants have contaminated grain fields
producing contamination of flour with pyrrolizidine-​containing
seeds. Outbreaks have also occurred when misidentification of
plants has resulted in them being incorporated into herbal medi-
cines. Treatment is supportive.

Senna occidentalis toxins

Epidemics of acute hepatomyoencephalopathy have been noted in
young children in India. Previously thought to be due to virus in-
fection, they are now recognized to be due to ingestion of beans
from Senna (prev Cassia) occidentalis. The plant contains a var-
iety of toxins (anthraquinones, emodin, glycosides, toxalbumins,
alkaloids). Previously healthy children present with vomiting, agi-
tation, and abnormal movements that rapidly progress to coma.
(b) H Blood tests show markedly raised alanine transaminase and cre-
O OH atine kinase. In a study of 55 children, 42 (76%) died. Treatment
S O H3C
CH2 is supportive.
HO O O
O O
O S O OH Hypoglycin
O
HO O
H Hypoglycin found in unripe fruit of the ackee Blighia sapida tree
CH3
COOH causes a reduction in liver fatty acid β oxidation, production of toxic
CH3 metabolites, and liver steatosis. Patients present with vomiting,
sometimes severe hypoglycaemia, coma, and convulsions. Many
Fig. 10.4.4.2 (a) Atractylis gummifera L. (chardon a glu, bird-​lime, or cases, including localized outbreaks, have been reported from West
blue thistle). (b) The plant’s toxin, atractyloside, which is a mitochondrial
adenine nucleotide translocator inhibitor.
Africa, Haiti, and Jamaica (where it is termed the Jamaican vomiting
(a) Courtesy of Luis Nunes Alberto, licensed under the Creative Commons disease). Treatment involves correction of hypoglycaemia and
Attribution-​Share Alike 3.0 Unported license. intensive care.
1832 SECTION 10 Environmental medicine, occupational medicine, and poisoning

reddening, blistering, and uncommonly, in very large expos-

Nephrotoxic plants
ures, nephritis. Dysphagia, vomiting, and diarrhoea may follow.
Treatment is rinsing of the mouth and oral fluids for dilution.
Aristolochic acid
Balkan endemic nephropathy is due to dietary exposure to seeds
of the European birthwort Aristolochia clematitis, which grows Dermatotoxic plants
intermingled with the wheat used for bread. During the early
1990s, hundreds of patients in Belgium and the United Kingdom Euphorbia and Dieffenbachia spp. damage skin as described earlier
developed renal failure after Aristolochia fangchi was mistakenly for mucous membranes. Hypersensitivity to plant allergens may
incorporated into a herbal weight loss treatment instead of also cause impressive skin reactions. Examples are poison ivy Rhus
Stephania tetrandra. The mechanism of aristolochic acid induced radicans, western poison oak Toxicodendron diversilobum, Primula
nephropathy is not known. Treatment is supportive. obconica, and citrus plants and fruit. Treatment involves rinsing
with water and symptomatic care.
Diphyllin glycosides The giant hogweed and other Heracleum spp., rue Ruta graveo-
Self-​p oisoning with leaves of the oduvan Cleistanthus colli- lens, and gas plant Dictamnus albus contain phototoxic psoralens.
nus tree in south India is responsible for perhaps hundreds of Contact with sap and subsequent solar radiation can provoke in-
deaths each year. The plant contains the diphyllin glycosides tense phototoxic reactions with eczematous skin lesions and large,
cleistanthins A and B which cause severe hypokalaemia (via painful bullae. The best treatment is to rinse the skin directly after
kaliuresis) and metabolic acidosis (due to renal tubular acid- exposure and avoid sunlight. When skin damage is already estab-
osis), acute respiratory distress syndrome, cardiovascular shock, lished, treatment is the same as for chemical burns.
rhabdomyolysis, and neuromuscular weakness that may require
ventilation. Deaths occur from cardiac dysrhythmias; the prog-
nosis is worse when water from boiled leaves is drunk. There FURTHER READING
is no antidote although K+ replacement & acetylcysteine have Chan TY (2009). Aconite poisoning. Clinical Toxicology, 47, 279–​85.
been tried. Chauvin P, Dillon JC, Moren A (1994). Sante, 4, 263–​68.
Chrispal A (2012). Cleistanthus collinus poisoning. J Emerg Trauma
Other nephrotoxins Shock, 5, 160–​6.
Spurge laurel Daphne laureda, mezereon Daphne mezereum, and Eddleston M, et al. (2000). Anti-​digoxin fab fragments in cardiotoxicity
induced by ingestion of yellow oleander: a randomised controlled
savin Juniperus sabina contain terpenes that cause intense irritation
trial. Lancet, 355, 967–​72.
and blistering in the mouth and gastrointestinal tract, but also renal
Eddleston M, Persson H (2003). Acute plant poisoning and antitoxin
inflammation with haematuria and proteinuria. Anthraquinone antibodies. J Toxicol Clin Toxicol, 41, 309–​15.
glycosides and oxalic acid in rhubarb Rheum rhabarbarum cause Gokmen MR, et al. (2013). The epidemiology, diagnosis, and manage-
irritation in the mouth and gastrointestinal tract; transient renal ment of aristolochic acid nephropathy: a narrative review. Ann Int
impairment and metabolic acidosis may follow ingestion of large Med, 158, 469–​77.
amounts of raw leaves or stems. Rumex spp. (docks and sorrels) also Gurley ES, et al. (2010). Fatal outbreak from consuming Xanthium
contain oxalates; food based on these plants may result in similar strumarium seedlings during time of food scarcity in northeastern
toxic effects. Bangladesh. PLoS One, 5, e9756.
Islam MN, et al. (2014). Toxic compounds in honey. J Appl Toxicol, 34,
733–​42.
Gastrointestinal irritants Krenzelok EP (2010). Aspects of datura poisoning and treatment.
Clinical Toxicology, 48, 104–​10.
Meda HA, et al. (1999). Epidemic of fatal encephalopathy in preschool
Popular plants with sap containing calcium oxalate and oxalic acid
children in Burkino Faso and consumption of unripe ackee (Blighia
are elephant’s ear Philodendron spp., cuckoo pint Arum maculatum,
sapida) fruit. Lancet, 353, 536–​40.
and dumb cane Dieffenbachia spp. The needle-​shaped calcium ox-
Tourdjman M, et al. (2009). Plant poisoning outbreak in the western
alate crystals damage mucous membranes mechanically. Euphorbia area of Cambodia, 2005. Transactions of the Royal Society of Tropical
and Daphne spp. contain irritating diterpene esters that cause Medicine and Hygiene, 103, 949–​51.
pain, burning sensations in the mouth and pharynx, salivation,
10.5
Podoconiosis (non​filarial elephantiasis)
Gail Davey

loci and podoconiosis, suggesting that the disease may be a T-​cell-​

ESSENTIALS mediated inflammatory disease.
Podoconiosis is the lesser-​known of the two major forms of trop- The best evidence to date suggests that podoconiosis is the re-
ical lymphoedema. The disease affects genetically susceptible indi- sult of an abnormal inflammatory reaction to mineral particles that
viduals who go barefoot and whose feet and legs are exposed long penetrate the skin and accumulate in the lower leg. Colloid-​sized
term to red clay soils. It is found focally across tropical Africa, Central particles of elements common in irritant clays (aluminium, silicon,
America, and North India where such soils coexist with high altitude, magnesium, and iron) have been demonstrated in the lower limb
high rainfall, and low-​income populations. Prodromal symptoms lymph node macrophages of both patients and non​patients living
include itching and a burning sensation in the foot; early changes barefoot on the clays. Electron microscopy of lymph nodes shows
include spreading or ‘splaying’ of the forefoot and leakage of col- evidence of follicular hyperplasia, with an increased number of pro-
ourless ‘lymph’ fluid’. Later stages are manifested by lymphoedema, liferative germinal centres. An exaggerated lymphocyte population
which is usually bilateral and limited to below the knee. Early stage (predominantly CD4+ T lymphocytes) is seen in the paracortex
disease is reversible through good foot hygiene and use of socks and sinuses of some of the nodes.
shoes. Late-​stage disease, which results in considerable economic
and social difficulties, is treated with foot hygiene, bandaging, socks
and shoes, elevation, and (if necessary) nodulectomy. The disease’s Epidemiology
later stages result in considerable economic and social hardship and,
despite treatment, may never fully resolve. Podoconiosis has been reported from highland areas of tropical
Africa, Central America, and north-​west India (Fig. 10.5.1). Africa
appears to be the most endemic World Health Organization (WHO)
region: high prevalence areas have been confirmed in Ethiopia,
Aetiology and pathogenesis Cameroon, Rwanda, Uganda and Kenya, and were previously re-
ported in Tanzania, Equatorial Guinea, the islands of Bioko, São
Spatial analysis has been used to link environmental factors with Tomé, and Principe, and Cabo Verde. Recent nationwide mapping
occurrence of podoconiosis. These include altitude (between of podoconiosis in Ethiopia, the most heavily endemic country in
1000 and 2500 metres above sea level), annual precipitation the world, suggests that 1.54 million individuals, or 4% of the adult
(>1250 mm), higher vegetation index, and population density. population, live with podoconiosis, and almost half the population
Similar approaches have been used on a smaller scale to investi- (47.8%) live in areas environmentally suitable for the development
gate associations between specific mineral constituents of soil and of podoconiosis. The condition has been reported in the Central
disease, with phyllosilicate materials (smectite clays and mica), American highlands from Mexico, south to Ecuador, but recent
quartz, iron oxide, and zirconium associated with podoconiosis work suggests very few new cases in these areas. Podoconiosis has
prevalence. also been reported in north-​west India, Sri Lanka, and Indonesia.
Not everyone exposed to these soils develops podoconiosis, but Large-​scale population studies in Ethiopia indicate that being fe-
family clustering has long been observed. Recent genetic studies male, older, unmarried, washing the feet less frequently than daily,
demonstrated high heritability of the trait and segregation analysis and being semi-​skilled or unemployed are all associated with in-
suggests the presence of an autosomal codominant major gene con- creased risk of podoconiosis. All major community-​based studies
ferring susceptibility to podoconiosis. A genome-​wide association have shown onset in the first or second decade and a progressive
study demonstrated association between variants in HLA class II increase in prevalence up to the sixth decade.
1834 SECTION 10 Environmental medicine, occupational medicine, and poisoning

Average Prevalence (%) based on available data

0.21–0.30 1.00–2.51 Case report Not reporting
0.31–0.99 2.52–4.62 Reported Presence

Fig. 10.5.1 Geographical distribution of prevalence of podoconiosis—dots represent island nations.

Source data from Deribe K, et al. (2015). The feasibility of elimination of podoconiosis. Bull WHO, 93, 712–18.

exacerbation of symptoms when they try to walk long distances or

Clinical, economic, and social burdens
do hard physical work.
Early changes include spreading or ‘splaying’ of the forefoot,
Studies have documented that 77.4% to 97% of patients have experi-
swelling of the sole of the foot, leakage of colourless ‘lymph’ fluid
enced ‘acute attacks’ (acute dermatolymphangioadenitis or ADLA)
from the foot, and changes in the skin so that it looks like moss
at least once per year. These are episodes of inflammatory swelling
or velvet (Fig. 10.5.2). The affected person may report limb aches,
of lymphoedematous legs that may be triggered by bacterial, viral,
heaviness of the lower leg and foot, and odour from the lymph leak,
or fungal superinfection. They are characterized by hot, painful, and
which may attract flies.
reddened swelling and lead to loss of productivity.
As the lymphoedema progresses, both legs and feet will be af-
According to a study in southern Ethiopia in an area with 1.7 mil-
fected, though one is usually more severely affected than the other.
lion residents, the annual economic cost of podoconiosis was more
than 16 million USD per year, which when extrapolated to the country
as a whole, suggests cost of more than 200 million USD per annum
for Ethiopia. People with podoconiosis were found to be half as pro-
ductive as those without podoconiosis but with the same occupations.
The social impact of podoconiosis is also significant. Qualitative
studies in southern Ethiopia have shown that widespread miscon-
ceptions about the causes, prevention, and treatment of podoconiosis
have contributed to it being considered the most stigmatizing health
problem in endemic areas. This is manifested in patients being ex-
cluded from school, denied participation in local meetings, churches
and mosques, and excluded from marrying unaffected individuals.
Affected individuals report lower quality of life, higher levels of mental
distress, and higher levels of depression than their healthy neighbours.

Clinical features

The disease process is usually described in three phases: prodromal,

early, and advanced. Prodromal symptoms include itching of the Fig. 10.5.2 Early changes—​oedema, block toes, changes in skin colour
skin of the forefoot, a burning sensation in the foot and lower leg, (here related to the pattern of the open sandal worn), lymph ooze, and
‘chills’, or generalized joint pains. The affected person may describe early mossy changes around interdigital clefts.
 10.5 Podoconiosis (nonfilarial elephantiasis) 1835

In advanced disease, the swelling may be soft and fluid swelling

(‘water-​bag’ type, Fig. 10.5.3), hard and fibrotic swelling (‘leathery’
type, Fig. 10.5.4), or a mix of these two.

Differential diagnosis

Podoconiosis must be distinguished from lymphoedema caused

by filariasis (see Table 10.5.1), leprosy, onchocerciasis, rheumatic
heart disease, pelvic surgery, and Milroy’s disease.

Clinical investigation

In the community, diagnosis is usually based on the features given

in Table 10.5.1. A more comprehensive algorithm that excludes
lymphatic filariasis through antigen and antibody testing has been
Fig. 10.5.3 ‘Water-​bag’ type swelling: patient in her early 20s.
developed for mapping studies. Each foot should be assessed for
mossy changes, interdigital maceration, wounds, and stage of dis-
ease according to the five-​level Tekola staging system.

Prevention

Evidence suggests that primary prevention should consist of

avoiding prolonged contact between the skin and irritant soils
through the regular wearing of closed shoes. Daily foot hygiene
is also important for prevention, as is covering mud floors of
traditional houses. ‘Community conversations’ have been suc-
cessfully used in endemic areas to provide information about the
causes of podoconiosis and to encourage preventive behavioural
changes.

Treatment

Treatment of podoconiosis lymphoedema is aimed at reducing

the frequency of acute attacks, restoration of the barrier function
of the skin, and reduction of exposure to irritant soil. A simple
Fig. 10.5.4 ‘Leathery’ type advanced podoconiosis in patient aged 14. package of self-​care measures including foot hygiene, ointment,

Table 10.5.1 Distinguishing podoconiosis from lymphatic filariasis

Characteristic LF Podoconiosis
Area of residence <1000 m above sea level >1500 m above sea level
Chief cause Mosquito-​borne parasite Genetic susceptibility plus long-​term
exposure to irritant highland soil
Diagnosis Field ‘ICT’ blood test Exclusion of other cause of leg swelling
Site of first symptom Any part of limb except foot Toes and foot
Lymph node ‘attacks’ Precede swelling of limb Follow swelling of limb
Chief site of swelling Above and below knee Below knee
Prevention Mosquito nets Protective footwear
Mass Drug Administration (MDA) Floor coverings
Foot washing
Treatment 2 drugs (albendazole + DEC) Foot hygiene, bandages, exercises, socks
Foot hygiene and shoes
1836 SECTION 10 Environmental medicine, occupational medicine, and poisoning

bandages, elevation, exercises, and use of socks and shoes has re- levels. Together with non​government partners, Footwork has coord-
cently been shown to reduce the incidence and duration of acute inated training of health workers in podoconiosis management in
attacks. Charles’s operation (removal of skin, subcutaneous tissue, Cameroon and Uganda and will provide similar training in Rwanda
and deep fascia to lay the muscles and tendons bare, followed by and Burundi.
grafting of healthy skin), is no longer recommended, as long-​term
results are disappointing. Nodulectomy may be required if one or
two nodules prevent use of footwear, and follow-​up has shown skin Likely research developments
healing postnodulectomy to be good.
The Global Atlas of Podoconiosis project was launched in 2017
to further understanding of the geographical distribution and
Prognosis spatial epidemiology of the disease. Studies examining host im-
munological and inflammatory responses are currently underway.
Recent follow-​up during a community-​based trial suggests excess A range of devices to enable better diagnosis and volume meas-
mortality associated with podoconiosis. Untreated patients have urement are being developed and tested, while a trial examining
severely reduced mobility and work capacity by their mid-​40s, the effectiveness of doxycycline has recently been launched in
chiefly due to episodes of acute dermatolymphangioadenitis. Cameroon. Implementation research exploring optimal integration
of podoconiosis care into existing health systems is also underway.

Global awareness
FURTHER READING
Podoconiosis was included in the WHO list of ‘Other Neglected Deribe K, Cano J, Trueba ML, Newport MJ, Davey G. (2018). Global
Tropical Conditions’ in February 2011, and is currently addressed epidemiology of podoconiosis: a systematic review. PLoS Negl Trop
under the lymphatic filariasis programme of the Department for Dis, 12(3), e0006324.
Control of Neglected Tropical Diseases (NTDs). Elimination Deribe K, et al. (2015). The feasibility of elimination of podoconiosis.
of podoconiosis as a public health problem is achievable be- Bull WHO, 93, 712–​18.
cause no biological agent or vector involved in podoconiosis has Negussie H, et al. (2018). Lymphoedema management to prevent
been identified, the global scale of the problem is relatively acute dermatolymphangioadenitis in podoconiosis in northern
small, and the strategies for podoconiosis prevention and control Ethiopia (GoLBet): a pragmatic randomised controlled trial. The
Lancet Global Health, 6(7), e795–​e803.
are safe.
Tekola F, et al. (2006). Economic costs of podoconiosis (endemic
A national network, the National Podoconiosis Action Network,
non-​filarial elephantiasis) in Wolaita Zone, Ethiopia. Trop Med Int
and a global initiative, Footwork, the International Podoconiosis Health, 11, 1136–​44.
Initiative (https://​podo.org), were launched in 2012. These aim Tekola F, et al. (2012). The HLA class II locus confers susceptibility to
to advocate for and coordinate integration of podoconiosis inter- podoconiosis. N Engl J Med, 388, 1200–​8.
ventions into NTD control strategies at national and international
SECTION 11
Nutrition
Section editor: Katherine Younger

11.1 Nutrition: Macronutrient metabolism 1839 11.5 Diseases of affluent societies and the need
Keith N. Frayn and Rhys D. Evans for dietary change 1891
J.I. Mann and A.S. Truswell
11.2 Vitamins 1855
Tom R. Hill and David A. Bender 11.6 Obesity 1903
I. Sadaf Farooqi
11.3 Minerals and trace elements 1871
Katherine Younger 11.7 Artificial nutrition support 1914
Jeremy Woodward
11.4 Severe malnutrition 1880
Alan A. Jackson
11.1
Nutrition: Macronutrient metabolism
Keith N. Frayn and Rhys D. Evans

intermediary reduction-​oxidation molecules which carry the energy

ESSENTIALS to a common pathway of oxidation linked to the phosphorylation
Food intake is sporadic and, in many cultures, occurs in three daily of ADP to ATP. Hence, the energy is used to synthesize ATP, the
boluses. At the same time, energy expenditure is continuous and can common energy carrier to which most energy-​requiring biological
vary to a large extent independently of the pattern of energy intake, processes are linked. At a whole-​body level, this process is termed
although fixed or predictable demands (e.g. through occupation) ‘catabolism’. Conversely, in energy-​rich states when energy intake
means that in most persons food intake and energy expenditure are exceeds expenditure, these metabolic pathways can be reversed,
soon balanced. whereby ingested nutrients from all three groups are assembled into
The body has developed complex systems that direct excess large storage macromolecules (‘anabolism’) (Fig. 11.1.1).
nutrients into storage pools; as they are needed, they also regu- Lipids (fats) are the most energy-​dense metabolic fuels (c.37 kJ/​g).
late the mobilization of nutrients from these pools. Analogous to The storage form of lipids for energy provision is triacylglycerol
the fuel tank of a car and the throttle that regulates fuel oxida- (TAG), which comprises three fatty acids esterified to a glycerol
tion, supply and need are closely linked, except that in the vehicle backbone. Being highly hydrophobic and reduced, TAGs are very
there is just one fuel and just one engine. In contrast, in humans energy dense and a highly efficient energy store. However, TAGs
there are three major nutrients and a variety of tissues and organs, are relatively slow to mobilize, must be oxidized to yield energy and
each of which may have its own preferences for fuels that vary cannot provide energy anaerobically, and the non​esterified fatty
with time. Carbohydrate, lipid, and protein (the latter a source of acids (NEFAs) from which they are assembled are amphipathic
amino acids) are the three types of energy supply that are stored (detergent-​like) and hence potentially toxic in high concentra-
variably and assimilated from food each day. That we can carry tions. Furthermore, fatty acids cannot be converted into carbohy-
on our daily lives without thinking about whether to store or mo- drates or proteins, limiting their metabolic flexibility. Carbohydrates
bilize fuels, and which to use, attests to the remarkable efficiency such as glucose are less reduced and more soluble than lipids and
and refinement of these systems of metabolic control. hence ­contain only about half the energy density of fats (c.17 kJ/​g),
but they are non​toxic, quickly mobilized/​utilized, and can provide
some energy anaerobically. They are stored as the glucose polymer
glycogen. Glycogen, as a polar molecule, is stored with water (about
Overview of metabolism three times its own weight), so its low energy density makes this an
inefficient energy store, and only limited amounts are synthesized
The body requires energy for chemical and mechanical work in (Table 11.1.1).
order to maintain homeostasis; functions including maintenance of Carbohydrates are able to supply intermediary metabolites to
ionic gradients, transport, biosynthesis, heat generation, and loco- maintain pathway integrity (anaplerosis) in contrast to lipids, oxi-
motion. This energy is derived from three groups of energy-​rich dation of which leads to depletion of intermediary metabolites
substrates: carbohydrates, lipids, and amino acids. Multiple groups (cataplerosis): hence some carbohydrate is always required for me-
are utilized because they all have chemical and thermodynamic ad- tabolism to proceed efficiently (captured in the old aphorism ‘fat
vantages and disadvantages, and together they provide energy under burns in the fire of carbohydrate’). Proteins (polymers of amino
widely varying conditions and demands. All three nutrient groups acids) have similar energy content to carbohydrates (c.17 kJ/​g),
exist in large, energy-​rich macromolecular storage forms. The prin- but each protein has a specific function and they are not used as
cipal macronutrient stores are listed in Table 11.1.1 and are related dedicated energy stores. In catabolic states of carbohydrate deple-
to daily fluxes of energy substrates in the body. tion (e.g. starvation), however, proteins are broken down to their
For energy mobilization these are sequentially broken down into constituent amino acids for conversion into glucose for energy and
less energy-​rich metabolites, the energy liberated being captured by anaplerosis—​hence proteins constitute a virtual carbohydrate store.
1840 SECTION 11 Nutrition

Table 11.1.1 The principal macronutrient stores

Macronutrient Total amount in body Energy equivalent (MJ) Days’ supply if the only Daily intake (g) Daily intake as
energy source percentage of store
Carbohydrate 0.6 kg 8.5 <1 300 60
Free glucose 12 g
Liver glycogen 100 g
Muscle glycogen 500 g
Fat (triacylglycerol) 12–​18 kg 550 56 100 0.7
Circulating in plasma 5g
Stored in adipocytes 12–​18 kg
Protein and amino acids 12 kg 200 (20) 100 0.8
Free amino acids 100 g
Protein 12 kg

Note: These are very much typical rounded figures. Days’ supply is the length of time for which this store would last if it were the only fuel for oxidation at an energy expenditure of
10 MJ/​day: the figure for protein is given in parentheses since protein does not fulfil the role of an energy store in this way.

Whole body metabolic strategy therefore comprises breaking pathways is carried as a hydride (H-​) ion by NAD+ and FAD as their
down large macronutrient storage molecules (TAGs, glycogen, reduced forms, NADH and FADH2: these redox carriers are then
protein—​by lipolysis, glycogenolysis and proteolysis respectively) reoxidized by the electron transport chain, the energy derived being
into smaller energy-​rich substrates (NEFAs, glucose, amino acids) used to phosphorylate ADP to ATP (oxidative phosphorylation). By
with distinct characteristics and roles. In the next stage of metab- contrast, in anabolism these pathways are reversed, chemical energy
olism these small substrates are converted into a common fuel, being used to synthesize complex energy-​rich storage macromol-
acetyl-​CoA (by β-​oxidation, glycolysis, and amino acid metabolism, ecules from simple precursor substrates.
respectively). In the final stage of metabolism the acetyl-​CoA is fully Three key features of metabolism impact metabolic strategy and
oxidized by the tricarboxylic acid (TCA) cycle into carbon dioxide energy provision:
within the mitochondria. The step-​wise release of energy from these
• Most energy stored in the body is in the form of lipid (TAGs);
• This lipid cannot be converted to carbohydrate; and
• All tissues require some glucose for normal metabolic func-
Energy-rich Complex tioning, and some tissues (glycolytic, lacking mitochondria, such
substrates: molecules: as erythrocytes) have an absolute requirement for glucose, or
• Carbohydrates • Polysaccharides cannot utilize NEFAs (brain).
• Lipids • Lipids
Since very little carbohydrate is stored (c.100 g hepatic glycogen;
• Proteins • Nucleic acids
<1 day if sole fuel), in catabolic states glucose is rapidly depleted
• Proteins
and alternative mechanisms are required to provide or replace glu-
cose: under these conditions, breakdown of protein to amino acids,
CATABOLISM

ANABOLISM

chemical and then conversion of these to glucose by gluconeogenesis, becomes

energy an essential pathway. Indeed, the ability of the body to divert protein
• ATP from its primary (e.g. contractile) function to a secondary function
• NAD(P)H
of glucose provision has been the adaptation that has allowed such
limited stores of the energy density-​inefficient glycogen to be per-
Energy-poor Precursor mitted. Another mechanism is ketogenesis, whereby the liver con-
end-products: molecules: verts TAG-​derived NEFAs into small, soluble (non​amphipathic)
• CO2 • Amino acids ketone bodies, which can be utilized by many tissues, including
• H2O • Hexoses brain, hence acting as a ‘glucose-​sparing’ substrate.
• NH3 • Fatty acids Hence during conditions of energy repletion, energy in ex-
cess of current requirements is stored in a tissue-​specific manner
Fig. 11.1.1 Anabolism and catabolism. Anabolism refers to the (lipid as TAGs principally in adipose tissue; carbohydrate as
synthesis of complex molecules from simpler ones, and in the context glycogen in most tissues but specifically in liver for glucose re-
of metabolism refers to energy storage within carbohydrate, lipid lease to maintain blood glucose concentration; amino acids ‘vir-
and protein macromolecules; catabolism refers to the breakdown tually’ in labile proteins, e.g. muscle). In subsequent periods of
of molecules to smaller ones which contain less energy; the energy limited energy ingestion (postabsorptive, fasted) this substrate
difference is released and used for biological work (including providing
the energy for anabolism). Biological energy is carried in the form of resource can be mobilized in a regulated fashion and directed to
‘high energy’ phosphate groups (e.g. ATP) and as electrons (hydride specific tissues according to their metabolic requirement. These
ions, e.g. NADH). pathways are illustrated schematically in Fig. 11.1.2.
 11.1 Nutrition: Macronutrient metabolism 1841

TRIACYLGLYCEROL GLYCOGEN PROTEIN

5
1 2 3 4

nonesterified glucose (6C) glucogenic ketogenic

fatty acids amino acids amino acids
10 (≥3C) (≡2C)
5C-sugars
( x x 2C) NADPH
8 9
6 7
lactate pyruvate (3C)

CO2 PDH

acetyl-CoA(2C)

ketone bodies
CoA

NADH e-
O2 e- TCA
cycle
H 2O NAD+
ATP ADP
2CO2
WORK

Fig. 11.1.2 Stages of metabolism. Flux in a downward direction is catabolic (energy-​yielding) while
upward flux denotes energy storage, hence is anabolic. In the first stage of energy mobilization, large
storage macromolecules are broken down to smaller, energy-​rich, substrates (NEFAs, glucose, amino
acids). In the second stage, these small energy-​rich substrates are converted into the common ‘fuel’ for
oxidation, acetyl-​CoA. While these pathways can be reversed in order to store excess energy (anabolism),
in the case of carbohydrates the conversion of pyruvate to acetyl-​CoA by pyruvate dehydrogenase (PDH)
is essentially irreversible, therefore lipids (which are assemblies of two carbon groups themselves derived
from acetyl-​CoA) cannot be converted into pyruvate, and hence carbohydrates. In the third stage of
energy mobilization, the acetyl-​CoA is fully oxidized by the tricarboxylic acid (TCA) cycle; the energy
released is carried by electron transporters down the electron transport chain and converted into ATP by
oxidative phosphorylation. 1. esterification 2. lipolysis 3. glycogenesis 4. glycogenolysis 5. protein synthesis/​
proteolysis 6. lipogenesis 7. β-​oxidation 8. gluconeogenesis 9. glycolysis 10. pentose phosphate pathway.

amount of ATP is generated by so-​called substrate-​level phosphor-

Carbohydrate metabolism in the
ylation, as opposed to the oxidative phosphorylation pathway men-
postabsorptive and postprandial states
tioned earlier: indeed, this is a cytosolic pathway and can occur even
in cells that lack mitochondria. Pyruvate, as described next, may be
Pathways of glucose metabolism
reduced to lactate (C3H6O3, so exactly half a glucose molecule with
Glucose is a ubiquitous sugar which may be derived from dietary no redox changes). Pyruvate can also enter mitochondria where it
carbohydrate or synthesized in the body. As noted here already, it can be a substrate for the enzyme complex known as pyruvate de-
is stored in polymeric form as glycogen: this removes the osmotic hydrogenase (pyruvate dehydrogenase complex, PDC). PDC not
problems that would arise if it were stored in cells as free sugars. only further oxidizes pyruvate, but also removes one carbon, re-
Glucose, as a polar molecule, cannot cross membranes composed sulting in the formation of acetyl-​CoA which, as described earlier,
of phospholipid bilayers by diffusion, and a family of glucose trans- can be fully oxidized in the TCA cycle.
porter proteins, expressed in a tissue-​specific manner, facilitates The pathway of glucose synthesis, gluconeogenesis, occurs
its movement in and out of cells. Within cells, the first step of glu- primarily in liver cells and is basically a reversal of glycolysis al-
cose metabolism is always phosphorylation to glucose 6-​phosphate, though with some specific steps, circumventing energy-​yielding
brought about by a member of a family of enzymes (‘hexokinases’—​ and largely irreversible steps of glycolysis. The major substrate for
the form expressed in liver and pancreatic β-​ cells is generally gluconeogenesis under most conditions is lactate. Amino acids
known as glucokinase) again expressed in a tissue-​specific manner. whose carbon skeletons can be converted to lactate or pyruvate
Phosphorylation ensures that the molecule does not diffuse again out (discussed later) can also contribute, as can the glycerol released
of the cell. Glucose (molecular formula C6H12O6) is broken down by from lipolysis of TAGs in adipose tissue. Note that glucose may be
the pathway of glycolysis to pyruvate (C3H4O3, showing that H has broken down to lactate in red blood cells, for instance: the lactate
been lost relative to C and O; i.e. this is a partial oxidation). A small may be transferred via the bloodstream to the liver where it is used
1842 SECTION 11 Nutrition

to make new glucose. This cycle is sometimes called the Cori cycle. Lactate and ethanol metabolism
It does not result in irreversible loss of glucose from the body. That Glycolysis requires an electron acceptor, and NAD+ acts in this
occurs after the action of PDC, as acetyl-​CoA can no longer be re- role, becoming reduced to NADH; however, the NAD+ must be
converted to glucose. replenished for glycolysis to continue. In the aerobic state this is
Glycogen synthesis starts with glucose 6-​phosphate and involves achieved by oxidizing NADH back to NAD+ in the electron trans-
sequential polymerization of glucose units on a protein backbone port chain, with useful energy yield. However, in the absence of
(glycogenin). Glycogenolysis involves the reverse: sequential re- oxygen the electron transport chain is inhibited and the NADH is
moval of glucose units. In most tissues this will result in glucose reoxidized back to NAD+ by linking this to the reduction of pyru-
6-​phosphate that can enter the pathway of glycolysis. In the liver vate to lactate, as just described, by lactate dehydrogenase (LDH).
specifically (and to some extent in kidney, especially during star- Hence lactate (instead of pyruvate) accumulates but NADH does
vation) the enzyme glucose 6-​phosphatase may convert glucose 6-​ not, and NAD+ is replenished; glycolysis proceeds, providing
phosphate to glucose: thus, glucose released from glycogenolysis or limited ATP production by substrate-​ level phosphorylation
produced by gluconeogenesis may be released into the bloodstream (anaerobic metabolism) (Fig. 11.1.3). This is a true fermentation
to maintain blood glucose concentrations in the postabsorptive or pathway: ‘homolactic fermentation’.
the fasting state. Lactate is produced by tissues lacking mitochondria (and hence
Breakdown of glucose as far as acetyl-​CoA can also be part of a electron transport chains, e.g. red blood cells) and physiologically
synthetic process. Acetyl-​CoA produced from glucose is the starting by oxidative tissues in the presence of oxygen, where it likely rep-
point for the pathways of lipid synthesis: lipogenesis, which usu- resents a redox buffering mechanism, but excessive lactate produc-
ally refers to the synthesis of fatty acids from glucose, and choles- tion is associated with the hypoxic (and ischaemic) state. However,
terol synthesis. These pathways, like most biosynthetic pathways, the lactate contains considerable energy (more than pyruvate as it is
are cytosolic, and the acetyl-​CoA must be transferred out of the further reduced), and when oxygen availability is restored and oxi-
mitochondria. dative metabolism is again possible, it makes an excellent substrate,
One further pathway of glucose metabolism will be mentioned being converted back to pyruvate (LDH being near-​equilibrium)
briefly: the pentose phosphate pathway. This involves the metab- for subsequent oxidation via the TCA cycle (e.g. in myocardium).
olism of glucose 6-​phosphate through a complex series of reactions Furthermore, lactate is a principal substrate for gluconeogenesis as
that generate pentose sugars, used in nucleic acid synthesis, and also discussed above. This Cori cycle is constitutive (lactate being con-
reducing power in the form of NADPH. NADPH is used in many stantly produce by glycolytic tissues such as erythrocytes). However,
biosynthetic pathways such as lipogenesis. since the concentration of lactate in the blood is dependent not only

glucose

ADP ADP

ATP ATP
glycolysis

NAD+ NAD+

NADH NADH

2 3
lactate pyruvate acetaldehyde ethanol
CO2 NAD+
NAD+
CO2
1 4
NADH

acetyl-CoA acetate
Fig. 11.1.3 Fermentation reactions. Glucose is split to pyruvate by glycolysis, with small
amounts of ATP formed. In the absence of oxygen or a functioning TCA cycle, NAD+ must be
regenerated to allow glycolysis to continue. In humans (black lines) this is achieved by lactate
production; the lactate can be used to resynthesize glucose by gluconeogenesis or oxidized when
oxygen becomes available. In yeasts (orange lines), NAD+ regeneration is achieved by ethanol
formation. Metabolism of ethanol by humans alters the NAD+:NADH ratio with significant effects
on metabolism. Pyruvate dehydrogenase (red) common to both. 1. pyruvate dehydrogenase
2. lactate dehydrogenase 3. alcohol dehydrogenase 4. acetaldehyde dehydrogenase.
 11.1 Nutrition: Macronutrient metabolism 1843

on peripheral tissue production (e.g. hypoxic/​ischaemic muscle) while lipogenesis is increased (increased acetyl-​CoA), leading to
but also on hepatic disposal (uptake and gluconeogenesis), hep- hepatic lipid (TAG) accumulation and alcoholic fatty liver.
atic blood flow and liver function must both be considered when
interpreting hyperlactataemic states. Glucose metabolism in the postabsorptive
Certain organisms, such as yeasts, have an alternative strategy to state (overnight-​fasted)
regenerate NAD+ for glycolysis—​alcoholic fermentation. Here, the In the overnight-​fasted (postabsorptive) state, no glucose enters
pyruvate is decarboxylated to acetaldehyde with carbon dioxide the plasma from the small intestine. Glucose enters and leaves the
evolved, and acetaldehyde is then reduced to ethanol; the alcohol plasma at about 2 mg/​kg body weight per min (200 g/​24 h). About
dehydrogenase enzyme responsible is linked to the oxidation of one-​half of this will be consumed by the brain. Of the remainder, a
NADH, regenerating NAD+ and glycolysis continues. The ethanol considerable proportion will be utilized by blood cells and periph-
accumulates and inhibits competing microorganisms. When eral tissues by anaerobic glycolysis, thus returning lactate to the liver
ethanol is ingested by humans, its metabolism has multiple effects for reconversion to glucose (Fig. 11.1.4). This is the Cori cycle.
as a result of this link to the NAD+:NADH ratio (redox potential). Glucose is produced by hepatocytes from glycogen breakdown
Following absorption, ethanol is oxidized to acetaldehyde by alcohol and from gluconeogenesis. Net glycogen breakdown is stimulated
dehydrogenase, and acetaldehyde is further oxidized to acetate by by the relatively low insulin/​glucagon ratio after overnight fasting.
aldehyde dehydrogenase; both these enzymes are linked to NAD+ The major substrates for gluconeogenesis are pyruvate, derived from
and generate NADH (and potentially reactive oxygen species). The lactate (released from blood cells and peripheral tissues) and alanine
acetate is converted into acetyl-​CoA, providing an abundant energy (from proteolysis), and glycerol (from lipolysis). The pathway of
source. However, the high levels of NADH inhibit the oxidation of gluconeogenesis predominates over that of glycolysis, again because
lactate to pyruvate, limiting the availability of lactate as a precursor of the relatively low insulin/​glucagon ratio.
for gluconeogenesis (and causing a mild metabolic lactic acid-
osis). In addition, the NAD-​dependent malate shuttle is inhibited, Glucose metabolism after a meal
limiting availability of alanine also as a gluconeogenic substrate. The When a meal enters the system (the postprandial state), this pattern
result is decreased gluconeogenesis and potentially hypoglycaemia. of metabolism changes rapidly. About 12 g of free glucose are present
Furthermore, the TCA cycle and fatty acid β-​oxidation are inhibited, in the circulation and extravascular space. Typically, a single meal

Brain CO2
GLUT3

Muscle
Insulin
Glucose + Glycogen
+ Insulin
GLUT4
GLUT2 G6P
Insulin Insulin Pyruvate,
– +
Lactate
Glycogen G6P Pyruvate, CO2
Lactate
+ – CO2
Insulin Insulin
GLUT4
Lactate + Insulin
GLUT2
Liver
Adipose tissue
Insulin
+ Glucose
GLUT2
Glucose
Pancreas

GLUT2
Small intestine

Fig. 11.1.4 Overview of carbohydrate metabolism. Pathways in the liver shown as regulated
by insulin are probably controlled by the insulin/​glucagon ratio (high in the fed state, low in
fasting). In muscle, contraction is an important stimulus for glycogen breakdown and glycolysis.
Adrenaline also contributes. Not shown is the significant glucose uptake by red blood cells and
other glycolytic tissues, returning lactate to the liver (Cori cycle). GLUT2 is the high-​Km non-​
insulin-​regulated glucose transporter (i.e. the glucose flux is determined by concentration),
GLUT3 is the low-​Km brain glucose transporter (the glucose flux is relatively independent of
concentration within the normal range), and GLUT4 the insulin-​regulated glucose transporter
(insulin brings about movement of GLUT4 to the cell surface from intracellular vesicles). G6P is
glucose 6-​phosphate.
1844 SECTION 11 Nutrition

will provide about 100 g of glucose, entering the circulation over

perhaps 60 min. In order to minimize variations in plasma glucose
concentration, coordinated mechanisms come into play to suppress Liver
the production of endogenous glucose and to increase the rate of re-
NEFA
moval of glucose from the circulation.
- Insulin
Much of the incoming glucose may be taken up by hepatocytes
as described earlier, but some enters the systemic circulation and Ketone bodies Adipose tissue
stimulates pancreatic insulin secretion (and somewhat suppresses & CO2 HSL,
glucagon secretion). Insulin is liberated into the portal vein. Thus, VLDL ATGL
Insulin + - Insulin
TAG
the liver is exposed to high concentrations of glucose (from the small LPL + Catecholamines
intestine) and insulin. The net effect is to reverse glycogenolysis, so
that glycogen synthesis begins. In addition, gluconeogenesis is sup-
pressed and glycolysis favoured (Fig. 11.1.4). Hepatocyte glucose NEFA
Chylomicrons
output is therefore rapidly suppressed and converted to an uptake of (via lymphatics)
glucose. At the same time, utilization of glucose by insulin-​sensitive TAG
peripheral tissues such as skeletal muscle and adipose tissue is in- Insulin - LPL
Small intestine
creased. The main mechanism of this short-​term change is the re- FA
CO2
cruitment of the insulin-​regulated glucose transporter GLUT4 to Muscle,
the cell membrane (Fig. 11.1.4). However, the decrease in concen- myocardium
renal cortex
tration of plasma NEFAs (see following paragraphs) will also remove etc
inhibition of glucose uptake caused by fatty acid oxidation. Within
muscle, glycolysis and glycogen synthesis will be stimulated by in- Fig. 11.1.5 Overview of fat metabolism. Dietary triacylglycerols (TAGs)
enter the circulation in the form of chylomicrons. Fatty acids are taken
sulin. In adipose tissue, increased glucose uptake provides glycerol up by tissues through the action of the enzyme lipoprotein lipase (LPL).
3-​phosphate (formed from glycolysis) for esterification of fatty acids Adipose tissue is the major TAG store. TAGs are mobilized in times of
(see following paragraphs). Thus, insulin is the key regulator of the energy demand by the enzymes adipose triglyceride lipase (ATGL) and
rapid changes that occur in glucose metabolism in the postprandial hormone-​sensitive lipase (HSL; for more detail see Fig. 11.1.6), liberating
state: it brings about glucose storage as glycogen, and promotes the non​esterified fatty acids (NEFAs) into the circulation, from where they
may be taken up by several tissues and used for synthesis of new TAGs
utilization of glucose at the expense of fatty acids.
and for oxidation. Major points of hormonal regulation are shown (italic).

Lipid metabolism in the postabsorptive consume a low-​fat, high-​carbohydrate diet.) There is also the pos-
and postprandial states sibility of lipogenesis in the liver with export of TAG-​fatty acids to
adipose tissue. This pathway undoubtedly contributes to lipid storage
As discussed earlier, lipids are stored primarily as TAGs in adipo- but is small quantitatively under most conditions. The major path-
cytes. When energy is required in other tissues, TAGs are hydrolysed ways of fat metabolism are summarized in Fig. 11.1.5.
by enzymes (lipases) within adipocytes, and NEFAs are transported
through the circulation, bound to albumin as they are not in them- Triacylglycerols in the circulation
selves water-​soluble, to those tissues that can take them up and use TAGs are not water-​soluble—​this is one reason that they are such an
them (Fig. 11.1.2). This is the pathway of fat mobilization. However, efficient form of energy storage. However, this poses problems when
adipocyte TAG stores remain relatively constant in amount over they must be transported through the plasma. Evolution has solved
many years (if body weight is stable), showing that there must also this problem by the development of lipoproteins, submicroscopic
be matching pathways for deposition of TAGs in adipocytes (fat lipid droplets in which a core of neutral lipid (TAGs or cholesteryl
storage). In principle adipocyte TAGs could arise from direct uptake esters) is stabilized by a surface monolayer of amphipathic phospho-
of plasma NEFAs, by uptake of plasma TAGs, and by de novo syn- lipids. This is an oil-​in-​water emulsion and is highly analogous to the
thesis of fatty acids from glucose or amino acids within the adipo- stable lipid droplets in milk. Plasma lipoproteins are heterogeneous
cytes by the pathway of lipogenesis. The first of these pathways, direct and are usually classified by their density—​essentially, the greater
uptake of NEFAs, can be demonstrated by tracer methods but does the core lipid content per particle, the less dense the particle (lipid
not achieve net fat storage, as the NEFAs will have arisen from adipo- being less dense than water), and this enables different fractions to
cyte TAG stores. It has been suggested that this pathway may serve to be separated in an ultracentrifuge.
redistribute lipids between adipose depots. Uptake of fatty acids from The main lipoprotein carriers of TAGs in the circulation are
plasma TAGs (rather than uptake of the TAGs themselves) is, how- known as the TAG-​rich lipoproteins: chylomicrons, secreted from
ever, an important pathway, and indeed the predominant pathway the small intestine and transporting dietary lipid, and very low-​
for fat storage in humans. It will be considered further next. The last density lipoprotein (VLDL) particles secreted from the liver, trans-
of these options, de novo synthesis of glucose from glucose or amino porting endogenous TAGs (i.e. lipid from hepatocytes). In the
acids, can be demonstrated to occur, but much evidence points to postabsorptive state, chylomicron-​TAG secretion is virtually zero.
this being a very minor pathway for adipose tissue lipid deposition Secretion of VLDL is a means of exporting lipid from the liver to
in humans. (It may be more prominent in rodents, which typically peripheral tissues.
 11.1 Nutrition: Macronutrient metabolism 1845

Direct uptake of TAGs from plasma only occurs in small amounts

when whole lipoprotein particles are taken into cells by receptor-​
mediated pathways. No TAG transporter protein has been identi-
fied. Instead, the main route for cellular uptake of plasma TAGs is
TAG
hydrolysis within the capillaries to release fatty acids that may be
taken up by simple diffusion across the phospholipid bilayer, or by Perilipin
carrier-​mediated diffusion. As with glucose transport, there are sev-
eral fatty acid transport proteins, although rather more disparate CGI-58
than the GLUT family of glucose transporters.
Hydrolysis of lipoprotein TAGs in the capillaries of many tissues ATGL
FA
is mediated by the enzyme lipoprotein lipase, situated in the ca-
pillaries and bound to the capillary endothelial cells. This occurs DAG
in skeletal muscle and heart, adipose tissue, mammary glands, and
other tissues that use fatty acids, although not the liver. (In the liver HSL
there is a related enzyme, hepatic lipase.) Lipoprotein lipase acts on FA
the circulating TAG-​rich particles to liberate fatty acids which may
be taken up by the parenchymal cells (muscle fibres, adipocytes, MAG
and so on).
Adipose tissue lipoprotein lipase is upregulated by insulin, giving MGL
that tissue a special role in clearance of dietary lipid from the chylo- FA
microns in the postprandial state. In the postabsorptive state, muscle
lipoprotein lipase is likely to predominate as the site of removal of Glycerol
TAGs from the VLDL particles. Muscle lipoprotein lipase expression Fig. 11.1.6 Fat mobilization in adipocytes. The pathway of adipocyte
is upregulated in response to physical activity, and during fasting. lipolysis is mediated by a series of three enzymes which progressively
The fatty acids can then be used as an oxidative fuel by the muscle. In remove NEFAs from stored TAGs. Adipose triglyceride [triacylglycerol]
this process, VLDL particles lose their TAG core and become rela- lipase (ATGL) is active against TAGs, whereas hormone-​sensitive lipase
(HSL) is active mainly against diacylglycerols (DAGs), with some activity
tively enriched with cholesterol and phospholipids. After several
against TAGs also. Monoacylglycerol (MAG) lipase (MGL) acts to release
cycles through such capillary beds, they shrink to become simple free glycerol together with one NEFA. Free glycerol is exported from
particles with a core of cholesteryl ester and an outer phospholipid the adipocyte and will eventually be taken up by the liver. The pathway
shell: these are known as low density lipoprotein (LDL) particles, the of adipocyte lipolysis is highly regulated. HSL is activated on a very
main carrier of cholesterol in the circulation. short-​term basis by reversible phosphorylation by protein kinases
A and G, brought about by changes in the intracellular concentrations
Fat mobilization, non​esterified fatty acids and ‘energy of cyclic AMP and cyclic GMP. The regulation of ATGL is less direct.
transport’ from adipose to other tissues ATGL has an essential coactivator protein called CGI-​58 (comparative
gene identification member 58). There is additional regulation at the
Lipid is mobilized from adipose tissue stores in the form of NEFAs surface of the lipid droplets where these lipases act. The lipid droplet
(Fig. 11.1.2, Fig. 11.1.5). The adipocyte has a central droplet of is coated with specific proteins, a major one of which in the adipocyte
TAGs, which is hydrolysed by intracellular enzymes (Fig. 11.1.6), is perilipin 1. Perilipin 1 is itself subject to phosphorylation, under the
same conditions as HSL, and this appears to cause a conformational
releasing glycerol and NEFAs. Fat mobilization is stimulated by cat-
change that allows lipases to access the lipid droplet. CGI-​58 is bound
echolamines but powerfully suppressed by insulin (see Fig. 11.1.5). to perilipin in the unstimulated state, but released, and hence is free to
Thus, fat mobilization is active in the postabsorptive state when in- activate ATGL, upon perilipin phosphorylation. The figure shows a lipid
sulin levels are low, and there is a call upon the body’s fat stores. It is droplet surrounded by perilipin. Upon phosphorylation of perilipin,
also activated during exercise, mainly by catecholamine stimulation. and also of HSL, a conformational change in perilipin (i) allows the
Atrial natriuretic peptide (ANP), released from the heart during ex- lipases access to the lipid droplet and (ii) allows CGI-​58 to dissociate and
thus to activate ATGL. N.B. The lipases act much closer to the surface
ercise, also stimulates lipolysis. The turnover of NEFAs in the plasma of the lipid droplet than is shown here. Fatty acids (FA on diagram)
is rapid. They are the major oxidative fuel in muscle after overnight may be released from the cell for transport to other tissues, although
fast. In the liver, fatty acids are both a fuel for oxidation and a sub- a proportion is always re-​activated (thio-​esterified to CoA) and re-​
strate for synthesis of TAGs that will be exported as VLDL. A typical esterified to form TAGs.
concentration of non​esterified fatty acids in the plasma after over- Largely reproduced from Gurr MI, Harwood JL, Frayn KN, Murphy DJ, Michell RH.
Lipids: Biochemistry, Biotechnology and Health (Lipid Biochemistry: an Introduction,
night fast is 500 µmol/​litre, one-​tenth that of glucose, but because of 6th edn), 2016 (Wiley, Oxford).
their rapid turnover, their larger molecular mass and more reduced
state fatty acids account for about twice the energy turnover of glu-
cose in the circulation. present in the circulation. Therefore, as in the case of glucose, the
amount in a meal could overwhelm the system unless coordinated
Disposition of dietary fat mechanisms come into play to ensure its rapid dispersion.
Dietary fat is almost entirely (typically 95% or more) in the form Dietary TAG is digested in the stomach and small intestine and
of TAGs. A typical meal might contain 30 to 40 g of lipid. The typ- packaged by the enterocytes of the duodenum and proximal je-
ical plasma TAG concentration in a healthy subject is 1 mmol/​litre, junum into chylomicrons, which enter the circulation via the lymph-
confined to the vascular space; this means that about 3 g of TAGs is atics (Fig. 11.1.5). Therefore, unlike other nutrients absorbed from
1846 SECTION 11 Nutrition

the small intestine, they bypass the liver on first passage. The chylo- and heart muscle and in liver. In 1963, Philip Randle and colleagues
microns also carry other lipid constituents of food, including choles- described the glucose–​fatty acid cycle, which encompasses one
terol and fat-​soluble vitamins. In the circulation their fate is similar aspect of this mutual relationship between carbohydrate and lipid
to that of VLDL particles, although the tissue-​specific regulation oxidation. It is summarized in Fig. 11.1.7. The concept was based
of lipoprotein lipase ensures that adipose tissue (where lipoprotein upon observations that availability of fatty acids reduced the oxi-
lipase is upregulated by insulin) is a major site of clearance of their dation of glucose in skeletal and cardiac muscle. This basic obser-
TAGs. The pathway of TAG synthesis from fatty acids in adipocytes, vation has been confirmed many times both in vitro and in vivo.
as in the liver, is stimulated by insulin. Therefore, there is a short and The glucose–​fatty acid cycle describes both the normal interplay
energy-​efficient pathway for storage of dietary fatty acids in adipose between fat and carbohydrate oxidation, and also pathological situ-
tissue (Fig. 11.1.5). The half-​life of chylomicron-​TAGs in the circu- ations involving excess availability of lipids and insulin resistance
lation is about 5 min. After hydrolysis of most of the TAGs, the rem- (e.g. type 2 diabetes and obesity).
nant particles are removed by receptors in the liver and other tissues.
Thus dietary cholesterol, which remains in the remnant particles Glucose and the regulation of fatty acid oxidation
along with fat-​soluble vitamins, is transported mainly to the liver. An additional mechanism was first described in 1977 by Denis
Provided that a meal contains carbohydrate or protein, stimu- McGarry and Daniel Foster. They were following up a long-​standing
lation of insulin secretion will rapidly suppress the mobilization observation that the generation of ketone bodies by the liver was
of adipose tissue TAG stores, and concentrations of NEFAs in the suppressed by insulin. They showed that malonyl-​CoA, the first
plasma fall after a meal. Therefore, utilization of fatty acids by tis- committed intermediate in the pathway of de novo lipogenesis (pro-
sues such as skeletal muscle and liver will be decreased simply by duced by acetyl-​CoA carboxylase; see earlier), strongly inhibits fatty
lack of availability. This reduces competition for oxidation in muscle, acid oxidation. This inhibition is mediated via the enzyme carnitine
further increasing glucose utilization. In liver, the lack of NEFAs is palmitoyltransferase-​1 in the mitochondrial membrane. Carnitine
likely to decrease the secretion of VLDL-​TAGs. Within the liver, palmitoyltransferase-​1 is responsible for the transport of fatty acids
insulin powerfully stimulates esterification of fatty acids (for TAG from the cytoplasm to the mitochondrion for β-​oxidation. Acetyl-​
synthesis) at the expense of oxidation of fatty acids (see following CoA carboxylase is activated by insulin (both by increased gene
paragraphs). transcription and by reversible dephosphorylation). Hence, in a
carbohydrate-​replete state, malonyl-​CoA will be formed and fatty
acid oxidation inhibited (Fig. 11.1.7).
Interrelationships between carbohydrate This is now recognized as a widespread regulatory mechanism.
and lipid metabolism There are two isoforms of acetyl-​CoA carboxylase. Acetyl-​CoA
carboxylase 1, expressed in lipogenic tissues such as liver and adi-
Links between carbohydrates and lipids pose tissue, is involved in de novo fatty acid synthesis. Acetyl-​CoA
carboxylase 2 is expressed more in tissues oxidizing fatty acids such
Carbohydrates and lipids are our main energy fuels. Oxidation
as heart and skeletal muscle and is thought to produce malonyl-​CoA
of each of them is regulated by how much we ingest, our physical
for regulatory, rather than synthetic, purposes. Muscle carnitine
activity level and many other factors. However, it should not be
palmitoyltransferase-​1 is more sensitive to inhibition by malonyl-​
surprising that the metabolic fates of these two important fuels are
CoA than is the liver enzyme. The ability of glucose to inhibit the
also intertwined metabolically.
oxidation of fatty acids in muscle has been clearly demonstrated in
As noted earlier, in mammals lipids cannot be converted to
vivo, and has been termed the ‘reverse glucose–​fatty acid cycle’.
glucose in a net sense. Glucose can, however, be converted to
lipid. Acetyl-​CoA produced by PDC leaves the mitochondrion
(it is transported across the mitochondrial membrane as citrate),
and is then a substrate for the pathway of de novo lipogenesis, Protein and amino acid metabolism and
which begins with the enzyme acetyl-​CoA carboxylase, forming their regulation
malonyl-​CoA.
Principal among the way these fuels interact is carbohydrate-​ The body pools of protein and amino acids, and their turnover, are
induced insulin secretion. Insulin, as outlined earlier (Fig. 11.1.5), summarized in Fig. 11.1.8. Insulin exerts a net anabolic effect on
acutely suppresses the release of NEFAs from adipose tissue. body protein, mainly in skeletal muscle, whereas thyroid hormones
Therefore, when carbohydrate is readily available, lipid stores are and cortisol are generally catabolic. Anabolism is also stimulated
conserved. In the longer term, ingestion of a high-​carbohydrate diet by anabolic steroids, by physical training, and during growth by the
will induce enzymes of lipid synthesis and downregulate enzymes insulin-​like growth factors (IGF-​1; IGF-​2).
of fatty acid oxidation, through insulin-​and carbohydrate-​response Dietary protein, digested in the small intestine and absorbed
elements in the promoter regions of the relevant genes (see para- as free amino acids and short peptides, enters the portal vein.
graph on ‘Regulation of macronutrient flux’). Enterocytes of the small intestine remove some amino acids, espe-
cially glutamine, for use as an oxidative fuel. The remaining products
Glucose–​fatty acid cycle of digestion next enter the liver, where further preferential extrac-
Beyond this, there are specific cellular mechanisms that regulate the tion occurs. Amino acid oxidation is, under most circumstances,
relative oxidation of carbohydrate and lipid. These probably operate the major oxidative pathway in the liver—​about 60% of incoming
in several tissues, although they have been most studied in skeletal amino acids may be directed into immediate oxidation. The rate of
 11.1 Nutrition: Macronutrient metabolism 1847

Fig. 11.1.7 The glucose–​fatty acid cycle. When glucose and insulin concentrations are high, release of
non​esterified fatty acids (NEFAs) from adipose tissue is suppressed, and glucose utilization predominates
in insulin-​sensitive tissues such as skeletal muscle—​its uptake is stimulated by GLUT4. In addition, glucose
metabolism inhibits NEFA oxidation: stimulation of acetyl-​CoA carboxylase (ACC; 1 in image) produces
malonyl-​CoA which inhibits uptake of fatty acyl-​CoA (FA-​CoA) into the mitochondrion by inhibiting
carnitine palmitoyl-​transferase-​1 (CPT-​1; 2 in image), hence β-​oxidation of fatty acids is inhibited.
In the fasting state (glucose and insulin concentrations are low), insulin-​mediated inhibition of adipose
tissue lipolysis is decreased, and NEFA utilization predominates, reinforced by inhibitory effects of fatty
acids and their products of β-​oxidation on glucose uptake and oxidation. This may have pathological
significance, in that states in which NEFA concentrations tend to be high (e.g. type 2 diabetes mellitus) will
be associated with resistance of glucose utilization to insulin.

hepatic protein synthesis is also high, and since much of the pro- amino acids are metabolized principally in the liver, these essen-
tein is secreted (e.g. albumin), this represents a net loss of amino tial amino acids are metabolized in peripheral (non​hepatic) tissue,
acids from the liver (perhaps a further 20% of the incoming amino es­pecially skeletal muscle.
acids). The remaining mixture of amino acids, around 20% of those Amino acids must be synthesized, obtained from the diet or de-
absorbed, enters the systemic circulation. This mixture is enriched rived from proteolysis (although no dedicated protein exists whose
in the branched-​chain amino acids (BCAA) leucine, isoleucine, and sole function is to supply amino acids for energy). ‘Non​essential’
valine, which have a special role in muscle. BCAA make up approxi- amino acids can be synthesized from intermediary metabolites
mately one-​third of all amino acids in the body; while the other (or from other amino acids); ‘essential’ amino acids cannot be
synthesized by humans and therefore must be obtained from the
diet. ‘Conditionally essential’ amino acids can be synthesized in only
Protein 100 g/day limited amounts, and this must be supplemented by the diet in states
CO2 plus urea, NH3, of rapid protein synthesis (e.g. growth). Free amino acids (dietary,
equivalent to protein synthetic, proteolytic) constitute a soluble amino acid pool; this is
100 g/day quantitatively small, but dynamic. From this pool, amino acids are
used for biosynthetic functions as well as degradation for energy
production, their carbon skeletons entering the common metabolic
10 kg protein pool of intermediary metabolites shared with carbohydrate and lipid
300 g/day 300 g/day metabolism.
? 100 g amino acids
While amino acids are used to synthesize proteins, proteins are
Nucleotides, hormones etc broken down to amino acids, this constituting the protein turnover
Fig. 11.1.8 The body pools of protein and free amino acids and their rate (Fig. 11.1.8), which varies between individual proteins. For a
turnover. Numbers are approximate. protein to be useful as a source of amino acids for energy production,
1848 SECTION 11 Nutrition

amino acid Aminotransferases are widespread in most tissues and are

near-​equilibrium, hence readily reversible. Each is specific for a
deamination limited number of amino acids, but most utilize 2-​oxoglutarate (α-​
ketoglutarate) as the amino (N) acceptor, producing the carbon back-
carbon skeleton bone of the donor amino acid together with glutamate (amino acid +
NH3 (2-oxoacid) 2-​oxoglutarate → 2-​oxoacid + glutamate). Hence 2-​oxoglutarate and
glutamate are central to amino acid catabolism as these reactions
urea ‘funnel’ the various amino acids into glutamate (and note that 2-​
cycle
TCA intermediates
acetyl-CoA oxoglutarate is common to the TCA cycle, and its utilization by this
acetoacetyl-CoA
(≥ 3 C; glucogenic)
(≡2C; ketogenic) pathway depletes TCA intermediates—​cataplerosis).
urea 3 Alanine aminotransferase (ALT) transfers the amino group of ala-
1 2 nine to 2-​oxoglutarate, forming pyruvate and glutamate. Aspartate
aminotransferase (AST) transfers the amino group of aspartate to
ketone bodies
glucose
fatty acids
2-​oxoglutarate, forming oxaloacetate and glutamate—​however, this
enzyme usually works in the reverse direction, its function being
to convert glutamate (derived from amino acid funnelling, de-
CO2+ H2O + ATP
scribed earlier) into aspartate, which is required to donate a second
Fig. 11.1.9 Amino acid metabolism. In order to yield energy, amino urea N-​atom to the urea cycle. Since ALT and AST are both intra-
acids must have their α-​amino group removed (deamination). This is cellular enzymes and widespread, necrosis of many tissues causes
achieved by transamination and oxidative deamination (see Fig. 11.1.10). them to increase in plasma; they are commonly used to diagnose
The resulting ammonia is converted to urea (urea cycle) in order to hepatocellular damage.
decrease its toxicity. The remaining carbon skeleton (2-​oxoacid; ‘α-​keto
The second type of reaction responsible for amino acid de-
acid’) enters the common metabolic pool of intermediary metabolites
for immediate oxidation, or conversion into glucose (glucogenic amino amination is oxidative deamination. Since most amino acids have
acids; blue) or lipids (ketogenic amino acids; green) for subsequent been deaminated (funnelled) into glutamate by transamination,
oxidation. glutamate is the only amino acid that undergoes direct, oxida-
tive, deamination, by glutamate dehydrogenase, regenerating
2-​oxoglutarate and producing ammonia (NH3). Unusually for
its turnover rate must be relatively high, and there must be a rela- a highly regulated enzyme, glutamate dehydrogenase is revers-
tively large amount of it in the body. ible, and can use NAD+ or NADP+ as electron acceptors. In the
Dietary amino acids surplus to synthetic requirements (for ‘forward’ direction of deamination (catabolic, amino acid break-
proteins, nucleotides, hormones, neurotransmitters, creatine, down), it uses NAD+, but in the ‘reverse’ direction of amination
porphyrins, sphingolipids) are utilized directly for energy pro- of 2-​oxoglutarate to glutamate (anabolic, amino acid synthesis)
duction. Although many amino acids exist in vivo (20 ‘standard’ it uses NADPH, reflecting the different roles of these cofactors
amino acids are coded for in proteins, but there are others that as redox energy carriers in different metabolic states. Hence,
are not used for peptide bond formation), and some have indi- aminotransferases (transamination) and glutamate dehydrogenase
vidual amino acid metabolic pathways, most follow a common (oxidative deamination) work together to produce ammonia for
biochemical route to yield their energy. Amino acids comprise a detoxification to urea in the urea cycle, and carbon skeletons for
central (α-​) carbon bonded to a carboxyl, amino, hydrogen and further intermediary metabolism (Fig. 11.1.10).
side chain (‘R group’) group—​hence they contain C, H, O atoms, The urea cycle occurs in the liver (the pathway is partially pre-
like carbohydrates and lipids, but also a distinguishing N-​atom. sent in kidney, and also in the brain, but this is not a significant
The common feature of amino acid metabolism is removal of site of blood urea production.) Urea (CO(NH2)2) contains two ni-
the amino-​N group (deamination), which is excreted as urea or trogen atoms: one derives from ammonia (produced by oxidative
ammonia (or incorporated into certain biomolecules), followed deamination of glutamate, described earlier), the other derives from
by utilization of the remaining carbon skeleton (α-​keto acid; AST (also from glutamate; Fig. 11.1.10); the body excretes nitrogen
2-​oxoacid) (Fig. 11.1.9). The fate of the 2-​oxoacid carbon skeleton with minimal carbon (and energy) loss. Because urea is very water-​
depends on where it enters the common metabolic pool of inter- soluble, much nitrogen can be excreted for relatively little water loss,
mediary metabolism. an important adaptation in terrestrial animals. Urea lacks toxicity
at physiological concentrations; it is (neuro)toxic only in extremely
Nitrogen disposal high concentrations, for example those seen in untreated renal
Deamination of amino acids is achieved by two types of reaction failure, but considerably less so than ammonia.
which function in a complementary manner (Fig. 11.1.10). The first Besides urea formation, there is another route of ammonia excre-
is transamination, in which the amino group from one amino acid tion. In peripheral tissues (e.g. muscle) ammonia may be formed
is transferred to another 2-​oxoacid (carbon skeleton), forming its by the oxidative deamination of glutamate (by glutamate dehydro-
corresponding amino acid (i.e. amino acid-​1 + 2-​oxoacid-​2 ↔ 2-​ genase). This reaction, in combination with the aminotransferases,
oxoacid-​1 + amino acid-​2). The enzymes responsible for transamin- can be seen to capture amino nitrogen from several amino acids.
ation reactions are aminotransferases (transaminases), all of which However, blood ammonia concentrations are very low (it is highly
contain pyridoxal phosphate, a derivative of vitamin B6, in their ac- toxic) and instead it is exported by being fixed in the amido
tive centres. (side chain) group of glutamine by the enzyme glutamine
 11.1 Nutrition: Macronutrient metabolism 1849

oxidative
transamination urea cycle transamination
deamination

CO2
amino acid 2-oxoglutarate NH3 aspartate 2-oxoglutarate

glutamate aspartate
aminotransferase
dehydrogenase aminotransferase

carbon skeleton glutamate OAA glutamate

(2-oxoacid)

urea

intermediary
metabolism
Fig. 11.1.10 Amino acid deamination. Multiple amino acids are ‘funnelled’ into one amino acid, glutamate, which acts as
the universal donor of the α-​amino group. Transamination reactions, catalysed by aminotransferase enzymes (transaminases),
are responsible for the funnelling of most amino acids into glutamate; the remaining 2-​oxoacid (carbon skeleton) can then be
used for energy generation. These transamination reactions occur both in tissues of amino acid supply (e.g. muscle) and in the
site of urea synthesis (liver); alanine is used for amino acid transport and therefore an important aminotransferase is alanine
aminotransferase (ALT), yielding the 2-​oxoacid pyruvate. Aspartate aminotransferase (AST) also utilizes glutamate for deamination.
Glutamate provides both nitrogen atoms for the urea cycle (urea: CO(NH2)2) and is the only amino acid to undergo direct
(oxidative) deamination by glutamate dehydrogenase. OAA, oxaloacetate.

synthetase: hence glutamine is carrying two nitrogen atoms. In acids are derived from endogenous proteolysis in many peripheral
liver, the enzyme glutaminase removes the amido nitrogen of (non​hepatic) tissues. Amino acid transport from peripheral tissues
glutamine as ammonia for rapid incorporation into urea. In the to the liver for catabolism involves transport of both the N-​group
kidney, glutaminase also removes the amido group of glutamine (for deamination and excretion) and the carbon skeleton (for oxida-
to form ammonia (and glutamine; glutamate dehydrogenase then tion/​glucose synthesis) (Fig. 11.1.11).
deaminates this to form another ammonia), but here the resulting Hence, amino acids released from proteolysis in peripheral
ammonia is excreted directly into the urine as a urinary buffer. tissues must transfer their amino nitrogen to the liver. This re-
There is also a supply of ammonia from the small intestine. sults in considerable interaction between the pathways of amino
acid, carbohydrate, and fat metabolism. Measurements of arterio-
Metabolism of carbon skeleton venous differences across muscle and adipose tissue show that
Following amino acid deamination, the remaining 2-​oxoacid enters the release of the amino acids alanine and glutamine predomin-
the common metabolic pool. All amino acid carbon skeletons ultim- ates. Since glutamine carries two nitrogens it is, under most cir-
ately yield just seven products of intermediary metabolism: pyru- cumstances, the predominant nitrogen carrier. Arteriovenous
vate, 2-​ oxoglutarate, succinyl-​CoA, fumarate, oxaloacetate, difference measurements across the splanchnic bed (by cath-
acetyl-​CoA, and acetoacetyl-​CoA. The first five of these represent eterization of the hepatic vein) show an almost identical pattern
at least three carbons, hence amino acids producing these metab- for uptake: removal of alanine and glutamine far exceeds that of
olites can be used for glucose synthesis (‘glucogenic’). The acetyl-​ other amino acids. Therefore, amino acids in tissues including
CoA and acetoacetyl-​CoA, however, yield two carbon groups or muscle must transfer their amino nitrogen to alanine (by trans-
equivalent, and amino acids which produce them cannot be used amination with pyruvate) and glutamine (formed by glutamine
for gluconeogenesis (Fig. 11.1.9)—​they can be directly oxidized in synthetase from glutamate, itself arising by transamination with
the TCA cycle, undergo lipogenesis or be used to synthesize ketone 2-​oxoglutarate). It is important that the 2-​oxoacid acceptors,
bodies (‘ketogenic’). The glucogenic amino acids therefore confer pyruvate and 2-​oxoglutarate, are common metabolic intermedi-
on proteins the property of acting as a carbohydrate reserve in states ates and thus readily available.
such as starvation. All three BCAA are transaminated by a single branched-​chain
aminotransferase, and the resulting branched-​ chain 2-​ oxoacids
Intertissue amino acid flux undergo oxidative decarboxylation (branched-​chain α-​ketoacid de-
Considerable flux of amino acids occurs between tissues as part hydrogenase (BCKD) complex). Branched-​chain amino acids ab-
of intermediary metabolism. Liver is the site of both ureagenesis sorbed from the diet are not removed from the portal circulation
(amino-​N metabolism) and gluconeogenesis (carbon skeleton me- by the liver (therefore avoid the hepatic first pass effect of other
tabolism), and diet-​derived amino acids enter the liver through the amino acids) and appear in high concentration in the blood from
portal circulation for immediate processing. However, many amino the splanchnic bed; furthermore, branched-​chain amino acids may
1850 SECTION 11 Nutrition

Liver

glucose glucose

pyruvate
urea NH3 glucose
alanine alanine
CO2 + H2O
alanine pyruvate
AA
2-oxoglutarate
PROTEIN
2-oxoglutarate glutamate
AA BCAA
urea NH3
BCAA 2-oxoacid

2-oxoglutarate
PROTEIN
NH3
Intestine
glutamine
glutamate Muscle
NH3 Kidney

glutamine glutamine

urea
NH3

Fig. 11.1.11 Intertissue amino acid flux. Amino acids are provided from the diet and by amino acid
turnover from labile protein pools. In catabolic states where amino acids are required for energy (glucose)
provision, muscle proteolysis and transamination yield alanine and glutamine for export (muscle is the
major source of amino acids during starvation and is shown here for clarity). Alanine is transported to the
liver, where it is deaminated, and its carbon skeleton (pyruvate) used for gluconeogenesis; the glucose
produced is used by brain, or recycled to the muscle to facilitate further nitrogen transport (glucose-​alanine
cycle), while the nitrogen is converted to urea for renal excretion. Glutamine exported from peripheral
protein sources is transported to several tissues, including kidney, where it is deaminated to yield free
ammonia, an important urinary buffer. AA, amino acids; BCAA, branched-​chain amino acids.

also have a role as nutrient signals. Hence, branched-​chain-​amino be viewed on several levels. The simplest involves the effects of sub-
acids act as a major source of nitrogen in skeletal muscle to maintain strate concentration, and is dependent upon the kinetic properties
pools of glutamine, glutamate, and alanine (branched-​chain amino of enzymes and transport proteins.
acid transferase activity is significantly higher than BCKD activity). The next level involves more specific interaction of nutrients, or
Much of the alanine released from skeletal muscle comes from pathway intermediates, with enzymes, usually through allosteric
transamination of pyruvate formed in glycolysis. Within the liver, effects (binding of the effector alters the conformation of the en-
the amino group can be transferred further (e.g. to oxaloacetate, zyme and hence its catalytic properties). There are many examples
forming aspartate, which is one of the immediate donors of nitrogen in the metabolism of carbohydrate, fat, and protein. The enzyme
to the urea cycle). The pyruvate thus formed may be a substrate for 6-​phosphofructo-​1-​kinase in the glycolysis pathway is a good ex-
gluconeogenesis, producing glucose that can be recycled to periph- ample. This enzyme is subject to allosteric regulation by many com-
eral tissues. This metabolic cycle has been called the glucose-​alanine pounds that relate to the energy status of the cell. For instance, it
cycle. It closely parallels the Cori cycle (see Fig. 11.1.4). is activated by AMP (indicating energy shortage) and inhibited by
An important aspect of the large depot of muscle protein is that ATP. Such mechanisms undoubtedly provide important fine tuning
it represents a potential source of synthesis of new glucose during of flux along various pathways, entirely in accord with the modern
fasting. In that situation, while the brain continues to require glu- view that control of flux does not reside in certain rate-​limiting
cose for oxidation, and as glycogen reserves are depleted, new glu- steps but is distributed among many steps along a pathway. Related
cose can only be formed from glycerol, released in adipose tissue to this, the enzyme AMP-​activated protein kinase (AMPK) re-
lipolysis, and from amino acids. sponds to the cellular energy status and regulates several metabolic
pathways accordingly (see ‘Further reading’).
These mechanisms operate essentially within tissues. However,
Regulation of macronutrient flux the coordination of nutrient metabolism requires considerable
interaction between tissues and organs. This coordination is largely
The need for the coordinated control of nutrient storage, mobiliza- brought about by the hormonal and nervous systems. Certain hor-
tion, and flux between tissues and along the many metabolic path- mones play a particularly important role in regulation of macronu-
ways, is met by a complex series of control mechanisms. These may trient flux (Table 11.1.2). The role of the nervous system in metabolic
Table 11.1.2 Major hormonal effects on intermediary metabolism

Hormone Origin Target tissue Major metabolic effects Comments

Insulin Pancreatic islets (β-​cells) Liver Stimulation of glycogen synthesis/​suppression of glycogen Regulates glucose storage in liver
breakdown
Stimulation of glycolysis/​suppression of gluconeogenesis Regulates hepatic glucose output
Suppression of fatty acid oxidation/​ketogenesis Via malonyl-​CoA
Stimulation of triacylglycerol synthesis
Stimulation of cholesterol synthesis
Skeletal muscle Stimulation of glucose uptake Via recruitment of GLUT4 (see Fig. 11.1.4)
Stimulation of glycogen synthesis
Net protein anabolic effect Suppression of protein breakdown may be more important than
stimulation of protein synthesis
Adipose tissue Activation of triacylglycerol removal from plasma Via lipoprotein lipase
Suppression of fat mobilization Via intracellular lipases (see Fig. 11.1.6)
Glucagon Pancreatic islets (α-​cells) Liver Stimulation of glycogen breakdown/​suppression of In effect the regulation is via the insulin/​glucagon ratio
glycogen synthesis
Stimulation of gluconeogenesis/​suppression of glycolysis
Stimulation of fatty acid oxidation/​ketogenesis
Somatostatin δ-​Cells in pancreatic islets Cells secreting other Indirect, via inhibition of secretion of insulin, glucagon, Somatostatin or analogues are used to treat growth hormone excess
and in gastrointestinal tract; peptide hormones; growth hormone and other peptide hormones; and via
some neuroendocrine acid-​producing parietal inhibition of gastric acid secretion
neurons in brain cells of stomach
‘Incretins’ K and L cells in α-​ and β-​Cells of Indirect, via increasing the effect of ingested carbohydrate The name ‘incretins’ covers at least two peptide hormones,
gastrointestinal tract pancreatic islets on insulin secretion (hence the name ‘incretin’); and glucagon-​like peptide-​1 (GLP-​1) and gastric inhibitory peptide
reducing glucagon secretion (also known as: glucose-​dependent insulinotropic polypeptide
or GIP). Analogues, or small molecules that block the proteolytic
breakdown of incretins, now used in treatment of type 2 diabetes
Adrenaline Adrenal medulla Adipose tissue Stimulation of fat mobilization Via intracellular lipases (see Fig. 11.1.6)
Skeletal muscle Stimulation of glycogen breakdown Acts in concert with muscle contraction
Tri-​iodothyronine Thyroid All oxidative tissues Increase in basal metabolism
Cortisol Adrenal cortex Liver Stimulation of gluconeogenesis
Skeletal muscle Generally catabolic effect on protein
Adipose tissue Promotes site-​specific fat deposition (central depots) and
fat mobilization (peripheral depots)
Growth hormone Anterior pituitary Liver Stimulation of gluconeogenesis Direct effect: other effects are mediated indirectly via insulin-​like
growth factors
Adipose tissue Stimulation of fat mobilization This is an acute effect: chronically, growth hormone promotes
mobilization from central fat depots
Insulin-​like growth Liver (IGF-​I) and other Several Generally insulin-​like acute effects on metabolism Physiological role is probably longer-​term effects on growth
factors (IGF) I and II tissues (both)
Leptin Adipose tissue Hypothalamus Suppression of appetite; possibly stimulation of energy Latter effect prominent in rodents, may not occur in humans; low
expenditure leptin levels (signalling starvation) more important than high levels
signalling excess. Recombinant leptin has been used to treat the
rare genetic condition of leptin deficiency
11.1 Nutrition: Macronutrient metabolism

Reproductive system Signals sufficient fat stores for reproduction to be possible As with effects on hypothalamus, low leptin may be a signal of starvation
1851
1852 SECTION 11 Nutrition

regulation is often difficult to assess. Although the effects of adren- minutes), often brought about through reversible phosphorylation
aline are properly regarded as hormonal, liberation of noradrenaline or dephosphorylation of enzymes, and longer-​term effects (hours or
from sympathetic nerve endings in tissues may bring about iden- days), brought about by regulation of gene expression. The former
tical effects and can be difficult to distinguish. The somatic nervous are usually exerted through binding to cell surface receptors linked
system (motor neurons innervating skeletal muscle) has clear effects to a variety of second-​messenger systems, the latter through nuclear
(e.g. stimulation of breakdown of muscle glycogen linked to muscle receptors (e.g. for glucocorticoids and thyroid hormones; for more
contraction). The autonomic nervous system probably plays mul- details see Chapter 13.1). However, the distinction is not absolute
tiple roles, but some are indirect (e.g. regulation of blood flow and (e.g. insulin brings about both acute and longer-​term effects through
cardiac output), thus affecting delivery of substrate to tissues, and binding to the same cell surface receptor).
regulation of the secretion of pancreatic hormones. Until recently it was considered that there was a complete
The effects of hormones are mediated in many ways, but these distinction between hormones and substrates (or metabolites).
may be divided into acute effects (usually acting within seconds or One obvious distinction is in typical concentrations in plasma.

Table 11.1.3 Some G-​protein-​coupled receptors (GPCRs) that respond to nutrients and related metabolites

GPCR number Other names Gene name Ligand Tissue expression Physiological role and comments
(major tissues)
GPR40 FFA1, FFAR1 (free FFAR1 Long-​chain fatty Pancreatic β-​cells Potentiates glucose-​stimulated insulin
fatty acid receptor 1) acids (C12–​C16) secretion
GPR41 FFA3, FFAR3 FFAR3 Short-​chain fatty Adipose tissue, Stimulation of leptin production;
acids gastrointestinal (GI) tract stimulation of gut hormone secretion
(enteroendocrine cells)
GPR43 FFA2, FFAR2 FFAR2 Short-​chain fatty Adipose tissue, GI tract Adipogenesis, reduction of lipolysis;
acids (enteroendocrine cells) stimulation of gut hormone secretion
GPR70 Taste receptor 1, TAS1R1 L-​amino acids Taste cells, GI tract,
T1R1 pancreatic islets
GPR71 Taste receptor 2, TAS1R2 Sugars, artificial Taste cells, GI tract, TAS1R1 and TASR2 act as heterodimers
T1R2 sweeteners pancreatic islets with TASR3 to act as receptors for umami
and sweet tastes, respectively
Taste receptor 3, TAS1R3 See comments on Taste cells, GI tract,
T1R3 T1R1, T1R2 pancreatic islets
GPR81 HCAR1 Lactate Adipocytes System by which lactate reduces
(hydroxycarboxylic adipocyte lipolysis; may act as a paracrine
acid receptor 1) amplifier of insulin action on lipolysis
(since insulin increases adipocyte lactate
production)
GPR109A HM74A, NIACR1 HCAR2 Probably 3-​ Adipocytes Identified initially as the receptor for
(hydroxycarboxylic hydroxybutyrate nicotinic acid (a component of the B-​
acid receptor 2) (ketone body) vitamin niacin), used in large doses to
treat high triacylglycerol concentrations.
Only known metabolic function is to
suppress adipocyte lipolysis. Since
3-​hydroxybutyrate is a product of hepatic
fatty acid oxidation, this could provide a
feedback loop
GPR109B HCAR3 3-​hydroxyoctanoic Adipocytes Reducing lipolysis when fat oxidation
acid (intermediate of is already high (e.g. in pathological
fatty acid oxidation) situations)
GPR119 Oleoylethanolamide GPR119 Oleoylethanolamide Pancreatic β-​cells, GI Oleoylethanolamide has appetite-​
receptor and other lipids tract suppressing activity (although not
containing oleic entirely via GPR119). It is related to
acid, e.g. 2-​oleoyl the endogenous cannabinoids. 2-​
glycerol monoacylglycerol stimulation in the
GI tract may enhance GLP-​1 secretion
(together with GPR40)
GPR120 FFAR4 n-​3 Fatty acids Macrophages, GI tract, Has been suggested to modulate anti-​
adipose tissue, brain inflammatory effects of n-​3 fatty acids.
(hypothalamus) Human genetic variation associated with
obesity and insulin resistance
GPR131 GPBAR1 (G protein-​ GPBAR1 Bile acids Liver, adipose tissue, GI Regulates gall bladder filling with bile,
coupled bile acid tract, gall bladder gut motility, and secretion of GI tract
receptor 1), TGR5 hormones
 11.1 Nutrition: Macronutrient metabolism 1853

Table 11.1.4 Mechanisms by which nutrients regulate expression of genes involved in macronutrient metabolism

Stimulus Transcription factor Examples of proteins whose expression is Comments

regulated at the mRNA transcription level
Glucose Carbohydrate-​response Pyruvate kinase (liver isoform) (+)
element binding protein Acetyl-​CoA carboxylase 1 (+)
Fatty acid synthase (+)
SREBP-​1c (see next) (+)
Insulin (in the pancreatic β-​cell) (+)
Insulin Various, binding to a variety GLUT 1, 2, 3, 4 (glucose transporters) (+) Glycolysis and lipogenesis are activated, gluconeogenesis
of insulin response elements Hexokinase, glucokinase (+) suppressed; see ‘Further reading’ for more information
(see ‘Further reading’) Glyceraldehyde-​3-​phosphate
dehydrogenase (+)
Glucose-​6-​phosphatase (–​)
Acetyl-​CoA carboxylase 1 (+)
Fatty acid synthase (+)
SREBP-​1c (+)
Cholesterol Sterol regulatory element SREBP-​1c: The two major isoforms, SREBP-​1c and SREBP2 respectively,
(and insulin) binding proteins (SREBP) acetyl-​CoA carboxylase 1 (+) regulate lipogenesis (in response to glucose and insulin) and
Fatty acid synthase (+) cellular cholesterol homeostasis (in response to cellular sterol
Stearoyl CoA desaturase (+) levels; low sterol levels allow mature SREBP2 to migrate to the
SREBP2: nucleus)
LDL receptor (+)
HMG CoA synthase (+)
HMG CoA reductase (+)
Fatty acids Peroxisome proliferator-​ PPARs act as transcription factors as heterodimers with the
activated receptors (PPARs): retinoid-​X receptor; the endogenous ligand is unclear:
it might be a fatty acid (weak affinity) or a fatty acid derivate
(e.g. a prostaglandin) (higher affinity)
PPAR​α (Liver): Apolipoproteins; enzymes of Target for the fibrate lipid-​lowering drugs
peroxisomal fatty acid oxidation
PPAR​δa Enzymes of mitochondrial oxidation Effects have been documented in adipose tissue, skeletal
Adipocyte differentiation factors muscle, and heart; clinical use of agonists uncertain
PPAR​γ Adipose tissue FABP (also known as aP2) Target for the thiazolidinedione insulin-​sensitizing agents
Lipoprotein lipase
Adiponectin
Amino acids Mammalian (or mechanistic) IGFBP-​1 (–​) Induction of IGFBP-​1 (binds IGF-​1) when amino acid supply is
target of rapamycin (mTOR); Asparagine synthase (–​) restricted limits growth;
Activating transcription Amino acid transporters (–​) (especially neutral molecular mechanisms are described in ‘Further reading’
factor 4 (ATF4) amino acid transport system A; cationic amino
acid transporter CAT-​1)

Note: (+), indicates gene induction; (–​), gene suppression.

a
Also known as PPAR​β, NUC 1, FAAR (fatty-​acid activated receptor).
FABP, fatty acid binding protein; GLUT, glucose transporter; HMG, 3-​hydroxy-​3-​methylglutaryl; IGF, insulin-​like growth factor; IGFBP, IGF binding protein.

For instance, insulin is major regulator of glucose metabolism A further level of coordination is through the effects of nutri-
(see earlier) and yet insulin concentrations in plasma are typic- ents themselves, or important cellular components such as chol-
ally 10–​100 pmol/​l, whereas glucose concentrations might be esterol, upon gene expression (summarized in Table 11.1.4). This
5–​10 mmol/​litre (a difference of about eight orders of magnitude). can be seen as a longer-​term mechanism to ensure that metab-
However, in recent years it has been appreciated that many nutri- olism is appropriate to the diet being ingested and the lifestyle
ents and their metabolites also regulate metabolic pathways rap- followed.
idly by signalling through receptors that were once thought to A variety of nutrient response elements are known in the promoter
be receptors for hormones and neurotransmitters. In particular, regions of genes for enzymes concerned with substrate metabolism.
this applies to signalling through the G protein-​coupled receptors Particular examples are the carbohydrate-​response element (which
(GPCRs). A variety of compounds that we recognize as nutrients upregulates expression of genes for glucose metabolism such as
or related metabolites is now known to signal through specific pyruvate kinase in the glycolysis pathway, and lipogenic genes), the
GPCRs. This adds a further level of control of metabolic pathways sterol response element (by which insulin activates lipogenic gene
according to nutrient and metabolite availability. These actions expression, as in Table 11.1.4, and cellular sterols downregulate ex-
are usually rapid (many mediated via alteration of cellular cyclic pression of the low density lipoprotein receptor and the enzymes of
AMP concentrations) and so are complementary to the longer-​ cholesterol biosynthesis) and response elements for fatty acid de-
term effects of nutrients and metabolites exerted on gene expres- rivatives. Fatty acids affect gene expression through a family of tran-
sion, as discussed next. Some examples of nutrients and their scription factors known as the peroxisome proliferator-​activated
metabolites and the GPCRs through which they may act are given receptors, summarized in Table 11.1.4. The expression of many
in Table 11.1.3. genes is also regulated by insulin.
1854 SECTION 11 Nutrition

Long YC, Zierath JR (2006). AMP-​activated protein kinase signaling

FURTHER READING in metabolic regulation. J Clin Invest, 116, 1776–​83.
Blad CC, Tang C, Offermanns S (2012). G protein-​coupled receptors Nakamura MT, Yudell BE, Loor JJ (2014). Regulation of energy me-
for energy metabolites as new therapeutic targets. Nat Rev Drug tabolism by long-​chain fatty acids. Prog Lipid Res, 53, 124–​44.
Discov, 11, 603–​19. Newman JC, Verdin E (2014). Ketone bodies as signalling metabolites.
Feige JN, et al. (2006). From molecular action to physiological out- Trends Endocrinol Metab, 25, 42–​52.
puts: peroxisome proliferator-​activated receptors are nuclear recep- Poupeau A, Postic C (2011). Cross-​regulation of hepatic glucose me-
tors at the crossroads of key cellular functions. Prog Lipid Res, 45, tabolism via ChREBP and nuclear receptors. Biochim Biophys Acta,
120–​59. 1812, 995–​1006.
Frayn KN, Evans RD (2019). Human metabolism: a regulatory perspec- Rosenbaum DM, Rasmussen SGF, Kobilka BK (2009). The structure
tive, 4th edition. Wiley/​Blackwell, Oxford. and function of G-​protein-​coupled receptors. Nature, 459, 356–​63.
He W, et al. (2012). Mitochondrial sirtuins: regulators of protein acyl- Shimano H, Sato R (2017). SREBP-regulated lipid metabolism:
ation and metabolism. Trends Endocrinol Metab, 23, 467–​76. convergent physiology—divergent pathophysiology. Nat Rev
Howell JJ, Manning BD (2011). mTOR couples cellular nutrient Endocrinol, 13, 710–30.
sensing to organismal metabolic homeostasis. Trends Endocrinol Thorens B, Mueckler M (2010). Glucose transporters in the 21st cen-
Metab, 22, 94–​102. tury. Am J Physiol Endocrinol Metab, 298, E141–​5.
Jeon T-​I, Osborne TF (2012). SREBPs: metabolic integrators in physi- Uyeda K, Repa JJ (2006). Carbohydrate response element binding pro-
ology and metabolism. Trends Endocrinol Metab, 23, 65–​72. tein, ChREBP, a transcription factor coupling hepatic glucose util-
Kersten S (2014). Physiological regulation of lipoprotein lipase. ization and lipid synthesis. Cell Metabolism, 4, 107–​10.
Biochim Biophys Acta, 1841, 919–​33. Wang H, Eckel RH (2009). Lipoprotein lipase: from gene to obesity.
Krycer JR, et al. (2010). The Akt-​SREBP nexus: cell signaling meets Am J Physiol Endocrinol Metab, 297, E271–​88.
lipid metabolism. Trends Endocrinol Metab, 21, 268–​76. Wong RH, Sul HS (2010). Insulin signaling in fatty acid and fat
Lass A, et al. (2011). Lipolysis—​a highly regulated multi-​enzyme com- synthesis: a transcriptional perspective. Curr Opin Pharmacol, 10,
plex mediates the catabolism of cellular fat stores. Prog Lipid Res, 684–​91.
50, 14–​27. Wu G (2009). Amino acids: metabolism, functions, and nutrition.
Liu Z, Barrett EJ (2002). Human protein metabolism: its meas- Amino Acids, 37, 1–​17.
urement and regulation. Am J Physiol Endocrinol Metab, 283, Zechner R, et al. (2012). FAT SIGNALS—​lipases and lipolysis in lipid
E1105–​12. metabolism and signaling. Cell Metab, 15, 279–​91.
Li X, Sun K (2018). Regulation of lipolysis in adipose tissue and clin- Zhang BB, Zhou G, Li C (2009). AMPK: an emerging drug target for
ical significance. Adv Exp Med Biol, 1090, 199–210. diabetes and the metabolic syndrome. Cell Metab, 9, 407–​16.
11.2
Vitamins
Tom R. Hill and David A. Bender

The vitamins and their metabolic functions and deficiency signs are
ESSENTIALS shown in Table 11.2.1. In some cases, different chemical forms of the
The vitamins are a disparate group of organic compounds that are vitamin show the same biological activity—​in this case the different
required in small amounts (mg or µg per day) for the maintenance of compounds are referred to as vitamers, and a generic descriptor is
normal health and metabolic integrity. Four vitamins (A, D, E, and K) used to include all compounds that have the activity of the vitamin.
are lipid soluble, while the others are water-​soluble.
Requirements and reference intakes of vitamins
Determining how much of any particular vitamin is required for
health is not straightforward, a standard technique being to deprive In order to determine requirements, volunteers have been deprived
volunteers of the vitamin in question until there is detectable meta- of the vitamin in question until there is a detectable metabolic
bolic change and then replete with graded doses of the vitamin until change, then repleted with graded doses of the vitamin until normal
normal metabolism is restored, with the reference intake (recom- metabolism is restored. This provides an estimate of the average re-
mended daily intake or amount or recommended dietary allow- quirement of the population group under investigation. To allow for
ance) set at 2× standard deviation above the average requirement. individual variation in requirements, the reference intake is set at
Deficiency leads to more or less specific signs and symptoms, 2× standard deviation above the average requirement (Fig. 11.2.1).
and (assuming no bar to absorption or metabolism) restoring the Assuming a normal distribution of requirements, this is an intake
vitamin to the diet will cure the deficiency disease. Effects of defi- that is more than adequate to meet the requirements of 97.5% of
ciency can be catastrophic and can cause, for example, blindness the population. This reference intake is variously known as the re-
(vitamin A); rickets/​osteomalacia (vitamin D); beriberi and Wernicke’s commended daily intake or amount (RDI or RDA), the reference
encephalopathy (thiamine); pellagra (niacin); anaemia (vitamin B12 nutrient intake (RNI), or the population reference intake (PRI). For
and folate); and scurvy (vitamin C). Excess of some vitamins can also some vitamins deficiency is more or less unknown, and an accept-
cause disease. able intake (AI) based on average intakes, which are obviously (more
Several vitamins are used as effective and even life-saving therapies than) adequate, is used in place of a reference intake. An intake 2×
in inborn errors of metabolism, e.g. homocystinuria, methylmalonic standard deviation below the average requirement is adequate for
acidaemia, pyridoxal (phosphate) responsive epilepsy syndromes, only 2.5% of the population. Reference intakes of vitamins published
sideroblastic anaemia. They may overcome inherited defects in by the UK, EU, and US authorities, and the UN Food and Agriculture
transporter function or have an activator or stabilizing role as cofac- Organization, are shown in Online Tables 11.2.1–​11.2.4.
tors for a mutant enzyme. If an individual has an intake below the reference intake, this does
not imply deficiency. Indeed, if a population group has an average
intake below the reference intake, this does not imply a problem: it
is only when the average intake is below the average requirement
Introduction that deficiency is likely. The lower graph in Fig. 11.2.1 shows the
data plotted as the percentage of the population whose requirements
The vitamins are a disparate group of organic compounds that are have been met at any given level of intake, and therefore can be in-
required in small amounts (mg or µg per day) for the maintenance of terpreted as the probability that any given intake is adequate to meet
normal health and metabolic integrity. With two exceptions (vitamin an individual person’s requirement.
D and niacin) they cannot be made in the body but must be provided Many inborn, and acquired disorders os metabolism that are
in the diet. Deficiency leads to more or less specific signs and symp- ­responsive to specific pharmocological vitamin supplementation
toms, and (assuming no bar to absorption or metabolism) restoring are known. These may declare themselves for the first time in ado-
the vitamin to the diet will cure the deficiency disease. Four vitamins lescence or adult life; inborn errors of B vitamin matabolism and
(A, D, E, and K) are lipid soluble, while the others are water-​soluble. transport often require supraphysiological doses.
1856 SECTION 11 Nutrition

Table 11.2.1 The vitamins

Vitamin Functions Deficiency disease

A Retinol Visual pigments in the retina; regulation of gene expression and Night blindness, xerophthalmia; keratinization of skin
β-​carotene cell differentiation;
(β-​carotene is an antioxidant)
D Calciferol Maintenance of calcium balance; enhances intestinal Rickets = poor mineralization of bone;
absorption of Ca2+ and mobilizes bone mineral osteomalacia = bone demineralization
E Tocopherols Antioxidant, especially in cell membranes Extremely rare—​serious neurological dysfunction
tocotrienols
K Phylloquinone Coenzyme in formation of γ-​carboxy-​glutamate in proteins of Impaired blood clotting, haemorrhagic disease
menaquinones blood clotting and bone matrix
B1 Thiamin Coenzyme in pyruvate and α-​keto-​glutarate dehydrogenases, Peripheral nerve damage (beriberi) or central nervous
and transketolase; role in nerve conduction system lesions (Wernicke-​Korsakoff syndrome)
B2 Riboflavin Coenzyme in oxidation and reduction reactions; prosthetic Lesions of corner of mouth, lips, and tongue,
group of flavoproteins seborrhoeic dermatitis
B3 Niacin Coenzyme in oxidation and reduction reactions, functional part Pellagra—​photosensitive dermatitis, depressive psychosis
Nicotinic acid of NAD and NADP
nicotinamide
B5 Pantothenic acid Functional part of CoA and acyl carrier protein fatty acid Peripheral nerve damage (burning foot syndrome)
synthesis and metabolism
B6 Pyridoxine Coenzyme in transamination and decarboxylation of amino Disorders of amino acid metabolism, convulsions
pyridoxal acids and glycogen phosphorylase; role in steroid hormone
pyridoxamine action
B7 Biotin Coenzyme in carboxylation reactions in gluconeogenesis and Impaired fat and carbohydrate metabolism, dermatitis
fatty acid synthesis
B9 Folic acid Coenzyme in transfer of one-​carbon fragments Megaloblastic anaemia
B12 Cobalamin Coenzyme in transfer of one-​carbon fragments and metabolism Pernicious anaemia = megaloblastic anaemia with
of folate degeneration of the spinal cord.
C Ascorbic acid Coenzyme in hydroxylation of proline and lysine in collagen Scurvy—​impaired wound healing, loss of dental cement,
synthesis; antioxidant; enhances absorption of iron subcutaneous haemorrhage

Several of the vitamins are toxic in excess. For these, a toler- Functions
able upper level (TUL) of habitual intake is established from the Vitamin A, its analogues, and its metabolites function in vision
highest level of intake at which there is no detectable sign of tox- (Fig. 11.2.3), cell differentiation, embryogenesis, the immune re-
icity, with a safety factor to ensure that no-​one will receive an ex- sponse, reproduction, and growth. Carotenoids also have a variety
cessive intake. TULs published by the US Institute of Medicine of different actions, including possible antioxidant activity, immune-​
and the European Food Safety Authority are shown in Online enhancement, inhibition of mutagenesis and transformation, and
Table 11.2.5. reduced risk of age-​related macular degeneration and cataracts,
decreased risks of some cancers, and decreased risk of cardiovas-
cular events.
Vitamin A
Deficiency
Vitamin A is a generic term used to designate any compound Vitamin A deficiency is common in the developing world but is
possessing the biological activity of retinol (Fig. 11.2.2). The rare in developed countries, where severe deficiency associated
main dietary sources of retinols are liver, kidney, egg yolk and with malnutrition causes night blindness and xerophthalmia—​
butter; β-​carotene is mainly found in green leafy vegetables and Bitot’s spots, xerosis conjunctiva, and keratomalacia. At least
carrots. 50% of young children in sub-​Saharan Africa and South Asia
Until recently the term ‘retinol equivalents’ (Res) was used to are vitamin A deficient, with night blindness being just one of
convert all sources of preformed retinol and provitamin A caroten- the stages where vitamin A deficiency reduces the ability to see.
oids in the diet into a single unit: nutritionally, 1 μg RE = 1 μg of all-​ The other deficiency diseases are the result of abnormal func-
trans-​retinol = 2 μg of supplemental (in oil) all-​trans-​β-​carotene = 6 tioning of epithelial cell on surface of the eye. In resource-​r ich
μg of dietary all-​trans-​β-​carotene = 12 μg of other dietary pro- countries, vitamin A deficiency is mainly seen in patients with
vitamin A carotenoids. When defining RE it was assumed that the fat malabsorption.
efficiency of absorption of provitamin A carotenoids was rela- Other consequences of vitamin A deficiency include impaired
tively good. Recent studies document, however, that absorption of cell differentiation and development; replacement of mucus-​
carotenoids is much lower and appears to be quite variable secreting cells with keratin-​secreting cells; reduced immunity to
 11.2 Vitamins 1857

Average requirement

Frequency

Mean - 2 SD Mean + 2 SD
threshold intake reference intake

Intake to meet criterion of requirement

100

90

80
Mean + 2 SD
reference intake
Percentage of population

70
Average requirement
60

50

40

30
Mean - 2 SD
20 threshold intake

10

0
Intake to meet criterion of requirement

Fig. 11.2.1 The derivation of reference intakes of nutrients from the distribution around the
observed mean requirement; plotted here as a cumulative distribution curve, enabling estimation
of the probability that a given level of intake is adequate to meet an individual’s requirement.

viral infection; impaired reproduction (male and female); abnormal adequate body reserve in men more than 19 years is 625 µg RAE/​
growth; reduced ferritin synthesis; loss of appetite, reduced growth, day, and for women is 500 µg RAE/​day. The recommended dietary
severe weight loss, death. allowance (RDA) for vitamin A is set using a coefficient of variation
Meta-​analysis of trials of vitamin A supplementation given to pre- (CV) of 20% and the EAR for adequate stores of vitamin A.
school children in populations with endemic vitamin A deficiency
has shown a weighted average mortality reduction of 11%. Higher levels of intake
Several adverse effects have been reported at intakes of preformed
Requirements and criteria of adequacy vitamin A above the population reference intake. Acute toxicity can
Current estimates of vitamin A requirements are based on the in- cause nausea, vomiting, vertigo, drowsiness, and blurred vision.
take required to maintain a reserve concentration of at least 20 µg Chronic toxicity can manifest with bone and muscle pain, visual
retinol/​g of liver tissue. This concentration is adequate to main- impairment, headache (with increased cerebrospinal fluid pressure,
tain normal plasma concentrations of retinol and protect against a pseudotumour cerebri), ataxia, alopecia, yellowing (carotenaemia)
vitamin A deficiency for approximately 4 months while the person and peeling of the skin, hyperlipidaemia, and hepatotoxicity.
consumes a vitamin A-​deficient diet. The estimated average re- Based on hepatotoxicity (in all adults) and teratogenicity in
quirement (EAR) of preformed vitamin A required to achieve an women of childbearing age, the tolerable upper intake levels (UL)
1858 SECTION 11 Nutrition

across the intestine, such as phosphorus, zinc, and manganese and

enhances the net renal reabsorption of calcium and phosphorus.
1,25(OH)2D3 is thus a major regulator of calcium homeostasis,
and it also has important modulatory roles in other organ systems,
including the endocrine glands, the immune system, the cardiovas-
cular system, and the reproductive and nervous systems.
The biological actions of 1,25 (OH)2 D3 in target tissues are me-
diated either through, (i) a nuclear vitamin D receptor (VDR),
which once complexed with 1,25 (OH)2 D3 and retinoic acid recep-
tors (RXR) can regulate gene expression (genomic effects), or (ii)
intracellular signalling pathways activated through putative plasma
membrane receptors (non​genomic effects).

Deficiency
The serum or plasma concentration of 25(OH)D is considered to be
the best index of vitamin D nutritional status because it closely reflects
the amount produced in the skin and ingested in the diet, and meas-
urement of 25(OH)D is used routinely for the detection of vitamin D
deficiency. Vitamin D deficiency (defined by a 25(OH)D concentra-
tion <25 nmol/​litre) increases the risk of rickets in children and osteo-
malacia in adults, processes in which the bone matrix (osteoid) fails to
mineralize. Vitamin D deficiency can also result in immunosuppres-
sion and muscle weakness and may increase the risk of colon cancer.

Requirements and criteria of adequacy

Fig. 11.2.2 Vitamin A and the major provitamin A carotenoids. Establishing dietary requirements for vitamin D is difficult be-
cause sunlight makes a very significant contribution to vitamin D
status. Recent attempts to define vitamin D requirements have been
for preformed vitamin A (retinol and retinyl esters) has been set at based on the dose–​response relationship between oral vitamin D
3000 µg RE/​day for adults by both European Food Safety Authority and circulating 25(OH)D concentrations. Using both data from
(EFSA) and the Institute of Medicine (IOM), with correction for dif- epidemiological and intervention studies, the Institute of Medicine
ferences in basal metabolic rate compared to adults using scaling established a population 25(OH)D concentration of 40 nmol/​litre and
according to body surface area (body weight × 0.75) (Table 11.2.2). 50 nmol/​litre as the basis for setting an estimated average require-
All-trans retinoic acid is used parenterally to induce apoptosis and ment of 10 µg/​day and a recommended daily allowance (RDA) of
remission in promyelocytic leukaemia. Isotretinoin (13-cis-retinoic 15 µg/​day, respectively, in people aged 1–​70 years. In the United
acid) is widely used for severe acne and sometimes also to prevent Kingdom, the Scientific Advisory Committee on Nutrition es-
certain skin cancers, especially those ­related to sunlight exposure. tablished a reference nutrient intake (RNI) of 10 μg/day for the
majority of children and adults based on achieving a population
25(OH)D concentration of 25 nmol/litre.
Vitamin D
Higher levels of intake
The term ‘vitamin D’ was given during the early 1920s to a group Very high intakes of vitamin D from supplements lead to hyper­
of closely related secosteroids with antirachitic properties. The calcaemia and calcification of soft tissues. Sunlight exposure does
two main dietary forms of vitamin D in foods are cholecalciferol not lead to excessive formation of vitamin D. It has been suggested
(vitamin D3, derived from animals) and ergocalciferol (vitamin D2, that the concentration of previtamin D in the skin of Caucasians
derived from plants). Both chole-​and ergo-​calciferol are also formed reaches an equilibrium within 20 min of UVB exposure, with any
by photoirradiation from their precursors 7-​dehydrocholesterol in excess 7-​dehydrocholesterol being converted to inactive metabol-
vertebrates and ergosterol in some fungi. The chemical structures ites such as tachysterol and lumisterol, hence UVB exposure beyond
of vitamin D2 and vitamin D3 differ only in their side chain at C-​17, the minimal erythemal dose does not increase vitamin D produc-
which in vitamin D2 has a double bond and an additional methyl tion further.
group (Fig. 11.2.4).

Functions Vitamin E
As shown in Fig. 11.2.5, vitamin D undergoes 25-​hydroxylation in
the liver, then 1-​hydroxylation in the kidney to yield the active hor- The chemistry of vitamin E is complex because there are eight struc-
mone, calcitriol (1,25-​dihydroxy-​vitamin D). The main biological turally related forms—​four tocopherols (α-​, β-​, γ-​and δ-​) and four
role of 1,25(OH)2D3 is to promote intestinal calcium absorption. tocotrienols (α-​, β-​, γ-​and δ-​)—​that are produced at various levels
In addition, it increases the absorption of other essential minerals and in different combinations by all plant tissues and in some
 11.2 Vitamins 1859

CH3 CH3 CH3 H3C CH3 CH3

H3C
CH2OH

CH3 CH3 H3C

All-trans-retinol 11-cis-retinol CH2OH

H3C CH3 CH3

CH3 H3C
11-cis-retinaldehyde HC=O
+H C=O
3N

H3C CH3 CH3 NH

Lysine residue in opsin

CH3 H3C
C=O
Rhodopsin HC N
(visual purple)
NH

LIGHT 10-15 sec

H3C CH3 CH3 CH3

H C=O
C N
NH
CH3
Photorhodopsin
45 psec
Bathorhodopsin
30 nsec
Lumirhodopsin
75 μsec
Metarhodopsin I
10 msec GTP Transducin-GDP Pi

CH3 CH3 Metarhodopsin II GTPase

H3C CH3 H
C=O minutes GDP Transducin-GTP

Metarhodopsin III
CH3 Inactive Active
All-trans-retinaldehyde phosphodiesterase phosphodiesterase
Opsin
cGMP 5'GMP
Na+ channel open Na+ channel closed

Fig. 11.2.3 The role of retinaldehyde in the visual cycle.

Table 11.2.2 Tolerable upper levels of habitual intake of preformed retinol

Tolerable upper limit Reference intake Ratio

µg/​day µg/​day
Infants 900 350 2.6
1–​3 years 1800 400 4.5
4–​6 years 3000 500 6.0
6–​12 years 4500 500 9.0
13–​20 years 6000 600–​700 8.6–​10
Adult men 9000 700 12.9
Adult women 7500 600 12.5
Pregnant women 3000 700 4.3
 OH
LIGHT LIGHT

HO
7-Dehydrocholesterol CH3 Previtamin D H3C Tachysterol

Slow OH
thermal isomerization

CH2 CH2

HO HO
Vitamin D3 Vitamin D2
calciol (cholecalciferol) ercalciol (ergocalciferol)

Fig. 11.2.4 The synthesis of vitamin D in the skin. The structure of ergocalciferol (vitamin D2) is shown in the
yellow box.

OH OH

Calciol 25-hydroxylase Calcidiol 1-hydroxylase

CH2 CH2 CH2

HO HO HO OH
Calciol Calcidiol Calcitriol
(cholecalciferol) (25-hydroxycholecalciferol) (1 ,25-dihydroxycholecalciferol)

Calcidiol Calcidiol
24-hydroxylase OH 24-hydroxylase OH

OH OH

Calcidiol 1-hydroxylase

CH2 CH2

HO HO OH
24-Hydroxycalcidiol Calcitetrol

COO-

CH2

HO OH
Calcitroic acid
Fig. 11.2.5 The metabolism of vitamin D to yield its active metabolite calcitriol (1,25-​dihydroxy vitamin D) and
its inactivation.
 11.2 Vitamins 1861

CH3
HO α-Tocopherol H 3C α-Tocotrienol

H3C O H3C O
CH3 CH3
CH3 CH3
CH3 CH3
HO β-Tocopherol
HO β-Tocotrienol

O CH O CH3
3
CH3 CH3

HO γ-Tocopherol HO γ-Tocotrienol

H3C O H3C O
CH3 CH3
CH3 CH3

HO δ-Tocopherol HO δ-Tocotrienol

O CH3 O CH3
CH3 CH3

Fig. 11.2.6 The vitamin E vitamers.

cyanobacteria. The main dietary sources are oils (e.g. olive, sunflower), Clinical manifestations of vitamin E deficiency include neuro-
meat, eggs, and leafy vegetables. All forms of vitamin E are amphi- logical syndromes (ataxia, hyporeflexia, loss of proprioception,
pathic molecules with the general structures shown in Fig. 11.2.6. skeletal myopathy) and anaemia due to haemolysis.

Functions Requirements and criteria of adequacy

Vitamin E (as α-​tocopherol) is an indispensable component of There is little consensus as to the threshold concentration of
biological membranes with membrane-​ stabilizing properties plasma or serum α-​tocopherol at which people can be defined
and high antioxidant activity. The overall mechanisms of lipid as having either an inadequate or acceptable vitamin E status.
peroxidation and antioxidant protection in biological and food The Food and Nutrition Board (2000) set an EAR of 12 mg/​d of
systems have been extensively reviewed. The antioxidant activity α-​tocopherol for all adults aged over 19 years, with an RDA of
of chain-​breaking antioxidants is determined by how rapidly they 15 mg/​day, assuming a coefficient of variation of 10%. In Europe,
scavenge free radicals, the ease of hydrogen transfer from an anti- the Scientific Committee for Food (1993) did not set a PRI for
oxidant to a free radical and the difference in the standard one-​ vitamin E on the basis that there is no evidence of deficiency from
electron reduction potentials. Vitamin E, in addition to having a a low intake.
protective role in the oxidative modification of LDL, may affect
or limit the progression of atherosclerosis and several other con- Higher levels of intake
ditions in ways that are unrelated to its antioxidant activity. The The tolerable upper intake level (UL) is 1000 mg/​d, based on studies
other vitamers have lower biological activity than α-​tocopherol showing haemorrhagic toxicity in rats and in the absence of human
(see Online Table 11.2.6). dose–​response data. The Scientific Committee for Food (1993)
proposed that the intake should not exceed 2000 mg α-​tocopherol
Deficiency equivalents per day.
Vitamin E deficiency is seen rarely in clinical practice, but there
may be a risk of vitamin E deficiency in premature infants because
the placenta does not transfer α-​tocopherol to the fetus in adequate Vitamin K
amounts. When it occurs in older children and adults, it is usually a
result of lipoprotein deficiencies or a lipid malabsorption syndrome. The term ‘vitamin K’ describes several related compounds that have
These include patients with abetalipoproteinaemia or homozygous in common a 2-​methyl-​1,4-​naphthoquinone ring system, but differ
hypobetalipoproteinaemia, those with cholestatic disease, and pa- in the length and degree of saturation of their isoprenoid side chain
tients receiving total parenteral nutrition. There is also an extremely at the 3-​position. Three vitamin K compounds have biological ac-
rare autosomal recessive neurodegenerative disease (ataxia with tivity: phylloquinone, (vitamin K1), menaquinones (vitamin K2),
vitamin E deficiency, AVED) in which primary vitamin E deficiency and menadione (vitamin K3; see Fig. 11.2.7). Vitamin K1 is found
occurs in the absence of lipid malabsorption as a result of mutations mainly in green vegetables, with particularly high levels in broccoli,
in the gene for α-​tocopherol transfer protein (α-​TTP). Brussels sprouts, kale, and spinach.
1862 SECTION 11 Nutrition

O The resultant Gla residues increase the affinity of the vitamin K-​
CH3 dependent proteins for calcium ions. Prothrombin and other proteins
of the blood clotting system (Fig. 11.2.9), as well as certain bone matrix
proteins, contain Gla and thus require vitamin K for their synthesis.
O 3
Deficiency
Phylloquinone (vitamin K1)
Newborn infants are at serious risk of haemorrhage because of
O poor placental transfer of vitamin K, lack of intestinal bacteria, and
CH3 the low vitamin K content in breast milk. For this reason, vitamin
K is routinely administered prophylactically at birth in many coun-
tries. The risk of bleeding is greatest in prematurely born infants,
O n in breast-​fed infants, and in those with gastrointestinal conditions
CH3 that impair vitamin K absorption. In normal infants, plasma pro-
Menaquinone (vitamin K2)
C=O thrombin concentrations and those of the other vitamin K-​de-
OH O pendent factors are approximately 20% of adult values at birth.
CH3 CH3 Normal or near-​normal blood coagulation is usually maintained
in older children and adults and clinical deficiency is rare.
Several factors protect adults from a lack of vitamin K,
OH O including widespread distribution of vitamin K in plant and
animal tissues, the vitamin K cycle, which conserves the vitamin,
Menadiol (vitamin K3) C=O Menadiol diacetate
(acetomenaphthone) and the microbiological flora of the normal gut, which synthesizes
CH3
menaquinones. However, subclinical vitamin K deficiency in
Fig. 11.2.7 Vitamin K vitamers. Menadione and menadiol diacetate are extrahepatic tissues, particularly in bone, is not uncommon in the
synthetic compounds that are converted to menaquinone in the liver. adult population.

Functions Requirements and criteria of adequacy

Vitamin K acts as a cofactor for a carboxylation reaction that trans- A large review, including 11 different studies, reported that phyllo-
forms selective glutamate residues to γ-​carboxyglutamate (Gla) res- quinone intake ranged from 60 to 210 µg/​day with an average intake
idues in proteins. The reaction is catalysed by the microsomal enzyme of approximately 80 µg/​day for younger adults (<45 years) and ap-
vitamin K-​dependent γ-​glutamyl carboxylase, which in turn is linked proximately 150 µg/​day for older adults (>55 years). Healthy indi-
to a cyclic pathway known as the vitamin K epoxide cycle (Fig. 11.2.8). viduals with a phylloquinone intake of 80 µg/​day show no signs of

–
H2C—COO- HC—COO- -OOC—CH—COO-

CH2 O2 CH2 CO2 CH2

Glutamate
NH–HC–C=O carboxylase NH–HC–C=O HN–CHC=O

Glutamate residue Glutamate carbanion γ-Carboxyglutamate residue

OH O
CH3 CH3
O
R R
OH O
Vitamin K hydroquinone Vitamin K epoxide

NADP+ Disulfide Sulfydryl

Quinone Vitamin K quinone Vitamin K epoxide
reductase reductase reductase
NADPH Sulfydryl Disulfide
O
CH3

R
O
Vitamin K quinone
Fig. 11.2.8 The role of vitamin K in γ-​carboxyglutamate synthesis.
 11.2 Vitamins 1863

Surface adsorption or kallikrein

Injury
Factor XII Active factor XII

Thromboplastin
Factor XI Active factor XI +Factor VII

Factor IX Active factor IX

Factor VIII Active factor VIII

Factor X Active factor X

Factor V

Prothrombin Thrombin

Fibrinogen Fibrin

Fig. 11.2.9 The intrinsic and extrinsic clotting factor cascades.

deficiency, suggesting that this level is probably adequate for most of Functions
the adult population. The most recent guideline (AI) for vitamin K Thiamine has a central role in energy-​yielding metabolism. As thia-
intake in the United States for adults (aged 19 years and older) is 120 mine diphosphate (Fig. 11.2.10) it provides the coenzyme for three
µg/​day for men and 90 µg/​day for women. In Europe, the Scientific multienzyme complexes catalysing the oxidative decarboxylation of
Committee on Food (SCF) made no recommendation for a PRI for pyruvate, α-​ketoglutarate and branched-​chain keto-​acids derived
vitamin K but considered that an intake of 1 µg/​kg body weight/​day from the branched-​chain amino acids, as well as the coenzyme for
appears to be adequate and would be provided by a normal diet. transketolase in the pentose phosphate pathway of carbohydrate
metabolism. Thiamine triphosphate has a role in nerve conduction,
Higher levels of intake
acting to phosphorylate a membrane sodium ion transporter.
In a few human studies there is no evidence of adverse effects as-
sociated with supplementary intakes of vitamin K in the form of Deficiency
phylloquinone of up to 10 mg/​day (more than two orders of mag- Thiamine deficiency, most commonly found in populations where
nitude higher than AI) for limited periods of time. These limited the diet consists mainly of polished rice or milled white cereals,
data are supported by experimental animal studies in which no ad- leads to impaired carbohydrate metabolism and the develop-
verse effects were observed after daily administration of extremely ment of lactic and pyruvic acidosis. It can result in three distinct
high doses (2000 mg/​kg body weight) for 30 days. However, high conditions:
intakes of phylloquinone can negate the effects of the anticoagulant
warfarin. The synthetic form of vitamin K, menadione, can interfere 1. Beriberi, chronic peripheral neuritis, which may or may not be
with the function of glutathione, one of the body’s natural antioxi- associated with heart failure and oedema.
dants, resulting in oxidative damage to cell membranes. 2. Acute pernicious beriberi, in which heart failure and metabolic
abnormalities predominate, with little evidence of peripheral
neuritis.
Vitamin B1 (thiamine) 3. Wernicke’s encephalopathy with Korsakoff ’s psychosis, which is
associated especially with alcohol and narcotic abuse, and is due
Dietary thiamine is mainly found in legumes, brown rice, and cer- to central nervous system lesions.
eals made from whole grains. It is very low in white (polished) rice
or wheat flour, and denatured by the cooking, baking, and canning Treatment of beriberi and Wernicke’s is with parenteral (if the pa-
of foods. tient is critically ill) followed by oral thiamine

Thiamine Thiamine diphosphate

H3C N NH2 CH
3
H3C N NH2 CH
3 H2 O O
– ––

– ––

CH2 ·CH2OH CH2 ·C ·O—P—O—P—O-

N + N +
C—N C—N O- O-
H2 S H2 S

Fig. 11.2.10 Thiamine and the coenzyme thiamine diphosphate.

1864 SECTION 11 Nutrition

Requirements and criteria of adequacy Deficiency is characterized by lesions of the margin of the lips
The activation of erythrocyte transketolase by added thiamine di- (cheilosis) and corners of the mouth (angular stomatitis), painful des-
phosphate is the most widely used criterion of adequacy; an activa- quamation of the tongue, and seborrhoeic dermatitis with filiform ex-
tion coefficient of more than 1.25 is considered to reflect deficiency, crescences. There is resistance to malaria in deficiency, partly because of
and less than 1.15 adequate status. The reference intake is 100 µg/​MJ a high requirement of the parasite for riboflavin, and partly because in
(0.5 mg/​1000 kcal) energy intake. There is no evidence on which to deficiency erythrocyte membranes are inadequately protected against
set upper levels of thiamine intake. oxidative damage, leading to membrane fragility and exposure of vul-
nerable stages of parasite development to the host’s immune system.
Requirements and criteria of adequacy
Vitamin B2 (riboflavin)
The activation of erythrocyte glutathione reductase by FAD is the
Riboflavin is found in many foods including milk and eggs, meat most widely used criterion of adequacy; an activation coefficient of
and fish, green vegetables, and fortified bread and cereals. more than 1.7 indicated deficiency. Normal values of the activation
coefficient are seen in people whose intake is between 1.2–​1.5 mg/​day.
Functions There is no evidence on which to set upper levels of riboflavin intake.
Riboflavin provides the coenzyme of many enzymes involved in
­energy-​yielding metabolism, both as riboflavin itself and also as Vitamin B3 (niacin)
riboflavin monophosphate and flavin adenine dinucleotide (FAD,
see Fig. 11.2.11). The flavin coenzymes undergo either single-​ The generic descriptor niacin, which is found in many foods, is
electron reduction, forming a semiquinone radical, or a two-​electron used for two vitamers: nicotinic acid and nicotinamide, although
reduction (see Online Fig. 11.2.1). In the mitochondrial electron in the United States niacin is generally used to mean the acid, with
transport chain, they therefore provide a link between the obliga- niacinamide for the amide.
tory two-​electron reactions of nicotinamide adenine dinucleotide
(NAD) and the single-​electron reactions of cytochromes and non​ Functions
haem iron proteins. Niacin provides the nicotinamide ring of the coenzymes NAD and
NADP (nicotinamide adenine dinucleotide phosphate), which
Deficiency function as electron acceptors in a wide variety of oxidation and re-
Riboflavin deficiency is widespread in developing countries, but des- duction reactions (Fig. 11.2.12). In addition, NAD is the source of
pite its central role in metabolism, deficiency is rarely fatal. This is ADP-​ribose for ADP-​ribosylation of enzymes to modify their ac-
partly because the vitamin is widespread in foods, such that most tivity, and poly-​adenosylation of breakage points in DNA, initiating
diets will provide minimally adequate amounts, and also because in the DNA repair mechanism.
deficiency there is very efficient recycling of riboflavin released by the
turnover of enzymes; only a small amount is catabolized or excreted. CONH2 COOH
In resource-​rich countries riboflavin deficiency may be seen in an-
orexia nervosa, patients with malabsorption, and in rare inborn errors N N
of metabolism (e.g. glutaric acidaemia type 1, multiple acyl-​coenzyme
Nicotinamide Nicotinic acid
A dehydrogenase deficiency, riboflavin transporter deficiencies).

NH2
CONH2
O O N N
– ––

– ––

N CH2-O–P–O–P–O–CH2 N
O N
OH OH OH OH

OH OH
O
Nicotinamide adenine dinucleotide (NAD)
Phosphorylated
in NADP

XH2 X H H
CONH2 CONH2
+ H+
N N

Oxidized coenzyme Reduced coenzyme

(NAD+ or NADP+) (NADH or NADPH)
Fig. 11.2.12 Niacin vitamers and the nicotinamide nucleotide
Fig. 11.2.11 Riboflavin and the flavin coenzymes. coenzymes.
 11.2 Vitamins 1865

Vitamin B6

There are six vitamers of vitamin B6: pyridoxal, pyridoxine,

pyridoxamine, and their phosphates; all are converted to the active
coenzyme pyridoxal phosphate in the body (Fig. 11.2.14). They are
predominantly found in plant foods.

Functions
Pyridoxal phosphate has a major role in amino acid metabolism,
acting as the coenzyme for transamination and decarboxylation.
Decarboxylation products of amino acids include several neuro-
transmitters. Pyridoxal phosphate is also the coenzyme for glycogen
phosphorylase in liver and muscle, and has a role in modulating the
actions of steroid hormones, acting to release hormone-​receptor
Fig. 11.2.13 A pellagra-​like scaling, crusted dermatitis in a butterfly complexes from DNA binding.
distribution in a patient with Hartnup disease.
From Galadari E, Hadi S, Sabarinathan K (1993). Hartnup disease. Int J Dermatol, 32,
904, Copyright © 2007, John Wiley and Sons.
Deficiency
Acquired deficiency of vitamin B6 occurred when infants fed an
Deficiency overheated milk formula developed severe seizures responsive
Pellagra, due to dietary deficiency of niacin and tryptophan, can be to vitamin B6: liberated lysine reacted with endogenous vitamin,
seen in resource-​poor countries where the diet is based on untreated to generate pyridoxyllysine, which has antivitamin activity.
corn, and this was a major public health problem in the southern Deficiency of pyridoxal 5’-phosphate principally causes peripheral
United States during the first half of the 20th century for the same neuropathy in adults, most often due to drugs such as isoniazid,
reason. Treating corn with alkali, as is done in the preparation of hydralazine and penicillamine that form complexes with the active
tortillas, increases the bioavailability and absorption of niacin and B6 vitamer.
prevents pellagra. Enriching processed flour with niacin and other Several important inherited defects causing vitamin B6 defi-
B-​vitamins eradicated dietary pellagra in the United States. ciency are now known. These occur principally in infants and chil-
Pellagra can also occur in alcoholics, patients with anorexia dren in whom seizures and (sometimes) dystonia are dominant
nervosa or malabsorption, carcinoid syndrome (where tryptophan clinical features. These generally respond well to vitamin B6 (pyri-
is metabolized to 5-​OH tryptophan and serotonin instead of to nico- doxine hydrochloride), but some patients with particular defects of
tinic acid), with prolonged use of isoniazid (and some other drugs), B6 activation will require pyridoxal 5-phosphate supplementation,
and in rare inherited metabolic conditions (e.g. Hartnup disease). which must be given parenterally. Other effects of vitamin B6 de-
Pellagra is characterized by a sun-​ burn like dermatitis ficiency include white matter disease, sideroblastic anaemia, dis-
(Fig. 11.2.13), depressive psychosis, and diarrhoea, and (un- turbed amino acid profiles, hypoglycaemia and hypophosphatasia.
treated) it is commonly fatal.
Requirements and criteria of adequacy
Requirements and criteria of adequacy Two enzyme assays are widely used to assess vitamin B6 status; acti-
Niacin is not strictly a dietary essential since it can be formed from vation of erythrocyte aspartate and alanine transaminases by pyri-
the essential amino acid tryptophan, and it is likely that normal in- doxal phosphate. In addition, plasma concentrations of pyridoxal
takes of tryptophan can meet niacin requirements; 60 mg of trypto- phosphate and urinary excretion of the metabolite pyridoxic acid are
phan is equivalent to 1 mg of preformed niacin. The usual criterion used. The metabolism of two amino acids, tryptophan and methio-
of adequacy is measurement of urinary excretion of niacin metabol- nine, are also vitamin B6 dependent, and after a loading dose of 2–​5 g
ites, although the ratio of NAD:NADP in erythrocytes has also been of the amino acid, abnormal metabolites are excreted in the urine.
used. Neither is wholly satisfactory. Because NAD and NADP act as Because of the central role of vitamin B6 in amino acid metab-
cosubstrates and are not tightly bound to enzymes, there is no en- olism, requirements depend on protein intake; the average require-
zyme activation assay for niacin status. The average requirement is ment is 13 µg/​g dietary protein, and reference intakes are based on
1.3 mg niacin equivalents (mg preformed niacin + 1/​60 mg trypto- 15–​16 µg/​g protein.
phan)/​MJ energy intake, giving a reference intake of 1.6 mg/​MJ.
Upper levels of intake
Upper levels of intake Pyridoxine supplements have been widely recommended for the
High intakes of nicotinic acid can lead to vasodilatation and premenstrual syndrome and as an anti-emetic. Daily doses of sev-
flushing, and also (especially with sustained-​release preparations eral grams cause frank sensory neuropathy and injury may occur at
used to treat hyperlipidaemia) to liver damage. The European Food 50–200 mg. The Institute of Medicine set a daily maximum of 100 mg
Safety Authority has set an upper level of 10 mg nicotinic acid/​day. but the European Food Safety Authority has taken a more precau-
Nicotinamide does not cause flushing or liver damage. It has been tionary approach, and set an upper level of 25 mg/day. More generous
used in relatively high doses for prevention trials of type I diabetes supplements are recommended for individual inborn diseases such as
mellitus; EFSA has set an upper level of 12.5 mg/​kg body weight/​day, homocystinuria, sideroplastic anaemia and pyridoxine-sensitive seiz-
equivalent to c.900 mg/​day for an adult. ures (see further reading and Chapters 12.1 and 12.2).
1866 SECTION 11 Nutrition

H2 CH2OH O- H CH2OH
2

– –
HO–C OH Kinase O—P–O–C OH
O-
N CH3 Phosphatase N CH3
Pyridoxine Pyridoxine phosphate

Oxidase

COO- O-
H2 H2 HC O H2 HC O

– –
HO–C OH HO–C OH Kinase O—P–O–C OH
Oxidase O -

N CH3 N CH3 Phosphatase N CH3

4-Pyridoxic acid Pyridoxal Pyridoxal phosphate

Transaminases Oxidase

H2 H2C—NH2 O- CH2NH2
H2

– –
HO–C OH O—P–O–C OH
Kinase
O-
N CH3 Phosphatase N CH3
Pyridoxamine Pyridoxamine phosphate
Fig. 11.2.14 Interconversion of the vitamin B6 vitamers.

with oral intrinsic factor, whereas those who secrete anti-​intrinsic

Vitamin B12
factor antibodies require parenteral vitamin B12 (Chapter 22.6.6).
The structure of vitamin B12 is shown in Fig. 11.2.15. Several com- Requirements and criteria of adequacy
pounds related to vitamin B12 occur in plants, bacteria, and algae, but
The total body pool of vitamin B12 is around 2.5 mg, with a minimum
have no vitamin activity, and many have antivitamin activity. The only
desirable body pool of 1 mg, and about 0.1% of the body pool is lost
sources of true vitamin B12 are animal foods, although supplements
daily, giving an average requirement for replacement of 1–​2.5 µg/​day
prepared by bacterial fermentation are available for vegetarians.
and reference intakes of 1.4–​2.0 µg. A significant amount of vitamin
Functions B12 is secreted in the bile and re-​absorbed bound to intrinsic factor,
hence requirements for people who do not secrete intrinsic factor or
There are two vitamin B12-​dependent enzymes: methionine
secrete anti-​intrinsic factor antibodies are considerably higher.
synthetase and methylmalonyl CoA mutase. The methionine
The assessment of vitamin B12 status is by measurement of the
synthetase reaction is central to the function of folate, and vitamin
plasma concentration of the vitamin by radio-​ligand binding assay
B12 deficiency leads to secondary folate deficiency (see Online
using intrinsic factor as the binding protein. Urinary excretion of
Fig. 11.2.6 and Chapter 22.6.6). The reaction of methylmalonyl CoA
methylmalonic acid indicates deficiency. The absorption of the
mutase is shown in Online Fig. 11.2.2.
vitamin can be assessed by the Schilling test, in which an oral dose
Deficiency of radioactively labelled vitamin B12 is given together with paren-
Dietary deficiency of vitamin B12 occurs only in strict vegetarians teral administration of a flushing dose of 1 mg of non​radioactive
who eat no food of animal origin. Pernicious anaemia (megalo- vitamin to saturate body reserves. Urinary excretion of the radio-
blastic anaemia with spinal cord degeneration) occurs as a result of active vitamin is measured as an index of absorption.
failure to absorb the vitamin. The megaloblastic anaemia is due to There is no evidence on which to set upper levels of vitamin B12
secondary folate deficiency, and the irreversible nerve damage to intake.
lack of methionine in the central nervous system as a result of im-
paired activity of methionine synthetase (see Online Fig. 11.2.6).
Absorption of vitamin B12 from foods requires the action of gastric Folate (Vitamin B9)
acid to release the vitamin from protein binding, followed by binding to
intrinsic factor, a protein secreted by the gastric parietal cells. Binding The structure of folic acid (tetrahydrofolic acid) is shown in
to intrinsic factor is essential for absorption of the vitamin in the small Fig. 11.2.16. Many plant and animal foods, particularly leafy vegetables
intestine. Classical pernicious anaemia is an auto-​immune disease. and liver, contain a variety of one-​carbon substituted derivatives of folic
Patients who form antibodies against gastric parietal cells can be treated acid, collectively known as folates (see Online Fig. 11.2.3), and they may
 11.2 Vitamins 1867

Because of the role of folate in synthesis of purine and pyrimidine

nucleotides, folate antagonists are used in cancer chemotherapy.

Deficiency
Adults eating a normal diet in developed countries in which many
foods (typically cereals and grains) are routinely fortified with folic acid
rarely develop dietary folate deficiency. However, folate deficiency can
arise in those who consume a poor diet (e.g. chronic alcohol misuse,
anorexia nervosa), have malabsorption, take drugs that interfere with
folate metabolism (e.g. methotrexate, phenytoin), or have increased
folate requirements (e.g. pregnancy, lactation, chronic haemolytic an-
aemia, widespread exfoliative skin diseases, haemodialysis).
The most obvious clinical feature of folate deficiency is macrocytic
anaemia. Other manifestations include mouth ulcers and (possibly)
neurocognitive changes, although the latter are more commonly at-
tributed to vitamin B12 deficiency.

Requirements and criteria of adequacy

Depletion/​repletion studies using folic acid suggest an average re-
quirement of 80–​100 µg/​day, and studies of the excretion of folate
metabolites on a folate-​free diet suggest a requirement for replace-
ment of 80 µg/​day. Because of uncertainty over both the various
forms of folate in foods, and their relative biological availability
and activity, reference intakes allow a wide margin of safety and are
Fig. 11.2.15 Vitamin B12. Four coordination sites of the central cobalt based on an allowance of 3 µg/​kg body weight (and hence 210 µg/​
atom are chelated by the nitrogen atoms of the corrin ring, and one
day for a 70 kg adult).
by the nitrogen of the dimethylbenzimidazole nucleotide. The sixth
coordination site may be occupied by CN–​ (cyanocobalamin), OH Folate status can be assessed by measurement of serum or erythro-
(hydroxocobalamin), H2O (aquocobalamin), –​CH3 (methylcobalamin), or cyte folate, by either radio-​ligand binding or microbiological growth
5’deoxyadenosine (adenosylcobalamin). assays. Functional folate status can be assessed by measurement of
the urinary excretion of formiminoglutamate (FIGLU) after a test
dose of histidine: as shown in Online Fig. 11.2.5, FIGLU is an inter-
have up to seven additional glutamate residues. The extent to which the
mediate in histidine catabolism, and its onward metabolism to glu-
various folates in food are absorbed varies. In order to permit calcula-
tamate is folate-​dependent.
tion of folate intake the dietary folate equivalent (DFE) has been defined
Rapidly dividing cells can use either preformed thymidylate
as 1 µg mixed food folates or 0.6 µg folic acid. On this basis, total DFE
(TMP) for DNA synthesis, or can synthesize it de novo from dUMP
intake = µg mixed food folates + 1.7 x µg (synthetic) folic acid.
in a folate-​dependent reaction. Stimulated lymphocytes incubated
Functions with [3H]TMP will incorporate it into DNA, but if they have ad-
equate folate status and are provided with dUMP, they will form
Folate functions in the transfer of single carbon units in the catab-
non​radioactive TMP, so reducing the amount of radioactivity in-
olism of a variety of compounds and the synthesis of serine, me-
corporated into DNA.
thionine, thymidine monophosphate and purines (see Online
Aside from addressing any underlying cause, folate deficiency is
Fig. 11.2.4). Much folate is methylated during absorption, and me-
typically treated with oral folic acid (1–​5 mg daily), which is gener-
thyl folate is the main form of the vitamin in the circulation. The re-
ally adequate even in the presence of malabsorption.
duction of methylene folate to methyl folate is irreversible, and free
folate can only be released by the reaction of methionine synthetase, Supplementing Folate intake
which is vitamin B12-​dependent. Vitamin B12 deficiency therefore
Supplements of folic acid of 400 µg/​day started before concep-
leads to functional folate deficiency, since the vitamin is trapped as
tion reduce the incidence of spina bifida and other neural tube de-
unusable methyl folate. For further discussion see Chapter 22.6.6.
fects by at least 50%. Similar supplements also reduce the plasma
concentration of homocysteine, which is an independent risk
O factor for atherosclerosis and coronary heart disease (see Online
H H2 H H2 H COO
N C N C N CH Fig. 11.2.6).
HN In order to reduce the incidence of neural tube defects, some coun-
CH2
H2N N N Tetrahydrofolate (THF) CH2 tries have introduced mandatory fortification of flour with folic acid.
H
C=O However, intakes in excess of 1000 µg/​day may mask the megaloblastic
anaemia in people with vitamin B12 deficiency due to atrophic gastritis,
(Glu)n
and there is some evidence that high intakes of folate may accelerate the
Fig. 11.2.16 Folic acid (tetrahydrofolate). transformation of benign intestinal polyps to cancer. In addition, folic
1868 SECTION 11 Nutrition

acid antagonizes the action of some antiepileptic medication. An upper Deficiency

level of intake is set at 1000 µg of folic acid/​day for adults. Prisoners of war in the Far East in the 1940s showed, among other
deficiency diseases, a new condition of paraesthesia and severe pain
Biotin (vitamin B7) in the feet, which was tentatively ascribed to pantothenic acid defi-
ciency, although no specific trials of pantothenic acid were carried
Biotin (Fig. 11.2.17) is widely distributed on foods and also out—​they were repleted with yeast extract and other rich sources of
synthesized by intestinal flora, although it is not known to what ex- vitamins. Other than that, pantothenic acid deficiency has only been
tent this bacterial biotin is absorbed. observed in experimental studies using antivitamin antimetabolites
in which deficiency led to neuromotor defects and mental depres-
Functions sion (probably due to defective synthesis of acetylcholine), gastric
Biotin functions to transfer carbon dioxide in a few carboxylation re- disturbances, and impaired synthesis of steroids.
actions, forming protein-​bound carboxy-​biocytin (see Fig. 11.2.17). Requirements
It also has a role in regulating the cell cycle by biotinylation of his-
tones and other proteins. There is no evidence on which to base reference intakes for panto-
thenic acid. Average intakes are between 3 and 7 mg/​day, and these
Deficiency are obviously more than adequate to meet requirements. There is no
Because biotin is widely distributed in foods, deficiency is unknown evidence on which to base upper levels of intake.
except among people maintained on total parenteral nutrition for
prolonged periods, or people who eat abnormally large amounts of Vitamin C (ascorbic acid)
uncooked egg white, which contains the protein avidin that binds
biotin and renders it unavailable for absorption. Avidin is denatured Ascorbic acid (Fig. 11.2.19) is a vitamin for only a few vertebrates,
when eggs are cooked, and cooked eggs are a rich source of the including human beings and other primates: other species synthesize
vitamin. Deficiency leads to impaired fatty acid synthesis and fine it as an intermediate in the gulonolactone pathway of carbohydrate
scale dermatitis and alopecia. metabolism. Those species that require it in the diet have suffered
Requirements loss of the enzyme gulonolactone oxidase. Ascorbic acid and the oxi-
dized forms, monodehydroascorbate and dehydroascorbate, all have
There is no evidence on which to base reference intakes for biotin. vitamin activity. It is found in citrus fruits, tomatoes, potatoes, and a
Average intakes are between 10 and 200 µg/​day, and these are ob- range of other fruits and vegetables.
viously more than adequate to meet requirements. There is no evi-
dence on which to base upper levels of intake. Functions
Ascorbic acid has specific roles in two groups of enzymes:
Pantothenic acid (vitamin B5) a) Copper-​
containing hydroxylases, including dopamine
β-​hydroxylase in noradrenaline and adrenaline synthesis and
Pantothenic acid is widely distributed in foods—​indeed, the name peptidylglycine hydroxylase, which are involved in postsynthetic
means ‘from everywhere’. modification and activation of certain peptide hormones. In
Functions
(Cysteamine)
Pantothenic acid has a major role in energy-​yielding metabolism as
the functional moiety of coenzyme A (Fig. 11.2.18) and in the syn- H2 H2
O = C—NH—C ·C ·SH
(Pantothenic acid)

thesis of fatty acids as the prosthetic group of acyl carrier protein.

– – – – – – – –

CH2 -SH group forms thioesters

CH2 with fatty acids
NH
O O
C=O
HN NH HN NH CHOH
H3C–C–CH3 NH2
H C–—
—O
S C – O- S C –N CH2 N
– –

CH N
—
–—

Biotin
—
–—

O O
Biotinyl lysine (biocytin)
NH O O-
N
–

-O–P–O–P–O–CH O N
O 2
—
—
—
—

-OOC—
N NH O O

H C–— Coenzyme A (CoASH)

C –N —O O OH
S
– –

– –

CH –O
-O – P –
—
–—

Carboxybiocytin O NH
O-
Fig. 11.2.17 Biotin, biocytin (ε-​amino biotinyllysine) and Fig. 11.2.18 The role of pantothenic acid in the structure of
carboxy-​biocytin. coenzyme A.
 11.2 Vitamins 1869

CH2OH CH2OH CH2OH gives a reference intake of 40 mg/​day, as does measurement of the rate
HO–CH
O HO–CH O HO–CH O turnover of the whole-​body ascorbate pool during depletion using
O O O radioactive or stable isotopically labelled vitamin. However, the rate of
turnover decreases during depletion, and depends on the initial size
OH OH O OH O O of the body pool. Extrapolating back from depletion to normal status
Ascorbate Monodehydroascorbate Dehydroascorbate gives reference intakes of 60–​80 mg/​day. Saturation of neutrophils
(semidehydroascorbate) with vitamin C gives a reference intake of 90 mg/​day. Measurement of
Fig. 11.2.19 Vitamin C.
total leukocyte vitamin C cannot be used as an index of status without
a differential leukocyte count, since different classes of leukocytes are
these enzymes the copper is oxidized in the reaction, and ascor- saturated with the vitamin at different concentrations.
bate is specifically required to reduce it to restore activity.
Higher levels of intake
b) α-​Ketoglutarate-​linked iron-​containing hydroxylases, including pro-
line and lysine hydroxylases involved in collagen synthesis. In these At intakes above about 100 mg/​day, the body’s capacity to metabolize
enzymes the reactive iron undergoes accidental oxidation in some vitamin C is saturated and any further intake is excreted unchanged
reaction cycles as a result of binding and activating oxygen, and as- in the urine. However, the absorption of inorganic iron salts requires
corbate is specifically required to reduce it back to restore activity. reduction to Fe2+ in the intestinal lumen, and intakes of 25–​1000 mg
of vitamin C together with inorganic iron (be it in supplements or
Ascorbate also acts as a general antioxidant, acting non​enzymically foods) maximizes absorption. This is a potential hazard of high in-
to reduce reactive oxygen species and the tocopheroxyl radical takes of the vitamin by people with a genetic failure of the regulation
formed by oxidation of vitamin E. of iron absorption (haemochromatosis, Chapter 12.7.1). Similarly,
Deficiency relatively high intakes of vitamin C with meals reduces the non​
enzymic formation of nitrosamines from dietary amines and nitrite.
Historically, scurvy, due to vitamin C deficiency, occurred at the end There is, however, little evidence to support the use of high doses of
of winter when there was limited availability of fresh fruit and veget- vitamin C to prevent or cure the common cold, or other illnesses.
ables. In Britain it is most often seen in the isolated elderly poor. It is High concentrations of ascorbate can react with proteins, glycating
characterized by capillary fragility and subcutaneous petechial haem- them in the same way as occurs with glucose in poorly controlled
orrhages (Fig. 11.2.20). At a later stage there is bleeding of the gums diabetes mellitus, and there is some evidence of increased risk of car-
and loss of dental cement with tooth loss. Impaired collagen cross- diovascular disease in people with diabetes who consume high doses
linking leads to poor wound and fracture healing, bone pain with of vitamin C. Upper levels of intake for adults are set at 2000 mg/​day.
demineralisation and osteoporosis: scars are thin and weak and may
dehisce spontaneously. Scurvy with florid osteoporosis occurs in pa-
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errors of absorption and intracellular pathways. J Inherit Metab Dis, Standing Committee on the Scientific Evaluation of Dietary Reference
42, 686–705. Intakes, Food and Nutrition Board, Institute of Medicine (2001).
Institute of Medicine (2000). Dietary reference intakes for vitamin C, vitamin Dietary reference intakes for vitamin A, vitamin K, arsenic, boron,
E, selenium and carotenoids. National Academy Press, Washington, DC. chromium, copper, iodine, iron, manganese, molybdenum, nickel, sil-
Jiang Q, et al. (2001). γ-​Tocopherol, the major form of vitamin E in the icon, vanadium and zinc. National Academy Press, Washington, DC.
US diet, deserves move attention. Am J Clin Nutr, 74, 712–​22. Standing Committee on the Scientific Evaluation of Dietary Reference
Kril JJ (1996). Neuropathology of thiamine deficiency disorders. Intakes, Food and Nutrition Board, Institute of Medicine (2001).
Metab Brain Dis, 11, 9–​17. Dietary reference intakes for calcium and vitamin D. National
Lal H, Pandey R, Aggarwal SK (1999). Vitamin D: non-​skeletal actions Academy Press, Washington, DC.
and effects on growth. Nutr Res, 19, 1683–​718. Tahiliani AG, Beinlich CJ (1991). Pantothenic acid in health and dis-
Leon del-rio A (2019). Biotin in metabolism, gene exression and ease. Vitam Horm, 46, 165–​228.
human disease. J Inherit Metab Dis, 42, 647–54. Tucker JM, Townsend DM (2005). Alpha-​tocopheropl: roles in preven-
Marcé-Grau A, Martí-Sánchez L, Baide-Mairena H, Ortigoza-Escobar tion and therapy of human disease. Biomed Pharmacother, 59, 380–​7.
JD, Pérez-Dueñas B (2019). Genetic defects of thiamine transport Vallerand IA, Lewinson RT, Farris MS, et al. (2018). Efficiency and
and metabolism: A review of clinical phenotypes, genetics, and ­adverse events of oral isotretinoin for acne: a systematic review.
functional studies. J Inherit Metab Dis, 42, 581–97. Br J Dermatol, 178, 76–85.
Merrill AH, Jr., Henderson JM (1987). Diseases associated with defects Various authors (1999). Symposium proceedings: nutrition, biochem-
in vitamin B6 metabolism or utilization. Annu Rev Nutr, 7, 137–​56. istry and molecular biology of biotin. J Nutr, 129, 476s–​503s.
Morrissey P, Hill TR (2009). Fat soluble vitamins and vitamin C in milk Wagner KH, Kamal-​Eldin A, Elmadfa I (2004). Gamma-​tocopherol-​
and milk products. In: Fox PF, McSweeney P (eds) Advanced dairy an underestimated vitamin? Ann Nutr Metab, 48, 169–​88.
chemistry-​3. lactose, water, salts and minor constituents, pp. 527–​89. Wang S (2009). Epidemiology of vitamin D in health and disease. Nutr
Springer, New York. Res Rev, 22, 188–​203.
Neuzil J, Weber C, Kontush A (2001). The role of vitamin E in athero- Wang ZY, Chen Z (2000). Differentiation and apoptosis induction
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disease. Atherosclerosis, 157, 257–​83. 101–6.
O’Callaghan B, Bosch AM, Houlden H (2019). An update on the gen- Wilson MP, Plecko B, Mills PB, Clayton PT (2019). Diseases affecting
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flavin transporter deficiency. J Inherot Metab Inherit Dis, 42, 598–607. Ziegler M (2000). New functions of a long-​known molecule. Emerging
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11.3
Minerals and trace elements
Katherine Younger

bromine, cadmium, germanium, lead, nickel, rubidium, silicon,

ESSENTIALS tin, and vanadium. They would be required in amounts less than
The essential minerals, calcium, phosphorus, potassium, sulphur, so- 1 mg/​day and are therefore sometimes referred to as ultratrace
dium, chlorine, and magnesium (macrominerals) and trace elements elements.
chromium, copper, fluorine, iodine, magnesium, manganese, mo- Most of the other elements may be found in the human body, in
lybdenum, phosphorus, selenium, and zinc, have diverse and critical amounts that depend on the environment, but have no known func-
functions in human metabolism. tion and may be toxic (e.g. mercury).
Dietary sources and the intake requirements for macrominerals The essential trace elements function as part of enzyme reac-
and trace elements for optimal physiological well-​being have been tions, either as a constituent part of the enzyme, the metalloen-
established, and the upper range of intake has been also been set so zymes, or as activators of enzyme systems (where they are more
that unwanted or even toxic effects can be avoided. loosely bound). They have a structural and catalytic role in gene
Deficiency of certain trace elements contributes importantly to expression. Other functions include the storage and transport
the global burden of illness and mortality, especially in infants under of substrates as metalloproteins (e.g. zinc + insulin in secretory
the age of five years. Latterly also, especially in high-​and middle-​ vesicles in the β cells of the pancreas). Their essentiality arises from
income regions, there has been burgeoning public and commercial their individual chemistry, which determines their specific roles.
interest in the role of, and requirements for, minerals and trace elem- In general, the more soluble the mineral or trace element,
ents in health and disease. An up-​to-​date familiarity with the scien- the better it is absorbed in the gut. Uptake is usually controlled
tific basis of mineral and trace element physiology is therefore critical (i.e. via transport proteins), except when intakes are very high. All
for maintaining good standards of clinical practice and to inform the elements may be toxic in excess; intake may be via the gut, skin,
best standards of nutritional advice, especially in the treatment of or lungs.
severe illnesses associated with deficiency or toxic excess of one or Excretion is usually minimal when the element is present in the
more macrominerals or trace elements. body bound to protein(s), hence the risk of toxicity. Normal loss
of these elements is mainly via desquamation (and bile), though
chelating agents can be administered in the case of copper tox-
icity (e.g. in Wilson’s disease) in order to promote excretion in the
Introduction urine (and phlebotomy is used to deplete the body of excess iron in
hemochromatosis).
Around 4% of body weight is made up of mineral elements, of Primary deficiencies occur widely in the cases of iron and iodine,
which seven are required in larger amounts: calcium, phosphorus, and, in some groups, zinc and selenium. Secondary deficiencies
potassium, sulphur, sodium, chlorine, and magnesium. In health may occur due to excess losses from the body (urine, blood, diar-
these are required in amounts of g/​day and may be referred to as the rhoea), or due to malabsorption, gut surgery, alcohol abuse, and
macrominerals. They are present principally in body fluids (typic- other clinical conditions.
ally as electrolytes) and as structural components of tissues. It is possible that suboptimal status of minerals and trace elem-
The remaining element are required in amounts less than 100 ents could be involved in the development of degenerative diseases
mg/​day and are termed trace minerals/​elements: iron, zinc, copper, such as coronary heart disease, cancer, and osteoporosis. However,
iodine, manganese, molybdenum, selenium, and chromium. Cobalt it is currently difficult to investigate this due to the lack of good
is required only as preformed vitamin B12. Fluorine is not essential methods for assessing status and hence determining requirements
but is beneficial as fluoride. Lithium is used to treat bipolar disorder. of some minerals and trace elements, and the complex interactions
Some other elements may prove to be essential to humans (based possible between them and other minerals, nutrients, and non-​
on their role in other organisms): aluminium, arsenic, boron, nutrients in the diet.
1872 SECTION 11 Nutrition

particularly important in newborn babies (being 5–​10-​fold more

Chromium
concentrated than in adults), in order to provide copper for growth
while intakes are low. Preterm infants are therefore at risk of copper
Chromium exists in nature in several valence states, trivalent (re-
deficiency since their liver stores are inadequate, and cow’s milk is a
ducing) being the most stable in biological systems. Hexavalent
poor source of copper.
chromium is a strong oxidizing agent and is carcinogenic. Trivalent
In the plasma, more than 60% of copper is bound to caeruloplasmin,
chromium was established as an essential nutrient in 1977 when the
which functions as a ferroxidase enzyme. Iron crosses cell mem-
diabetic signs of a patient on TPN were reversed by supplemental
branes in the Fe 2+ (ferrous) form and is oxidized by caeruloplasmin
chromium. Chromium’s main role appears to be the regulation
to the Fe 3+ (ferric) form in order to bind to its transport protein,
of insulin, normalizing its secretion in both hyper-​and hypogly-
transferrin. Copper deficiency (rare) therefore causes hypochromic
caemia such that blood glucose concentrations are normalized,
anaemia; other symptoms include neutropenia and bone abnormal-
and having no effect where glucose tolerance is normal. Lipid pro-
ities (and in an inherited copper deficiency disease, Menkes syn-
files are also improved following normalization of insulin function.
drome, characteristic hypopigmentation, and pili torti). In adults,
Supplemental chromium increases insulin binding and increased
copper deficiency also causes myelopathy and hence spastic gait and
numbers of insulin receptors, and may be involved in the phosphor-
peripheral neuropathy similar to that seen in vitamin B12 deficiency
ylation and dephosphorylation of insulin receptor proteins.
(subacute combined degeneration of the spinal cord).
Deficiency in humans is rare; the clinical signs and symptoms
High levels of dietary zinc are known to adversely affect copper
include impaired plasma glucose utilization and increased insulin
absorption and bioavailability via the induction of the protein
requirements, weight loss, neuropathy, elevated plasma fatty acids,
metallothionein in the intestinal epithelial cells, which inhibits up-
and abnormalities in nitrogen metabolism.
take into the blood. Copper absorption may also be inhibited by
The richest dietary sources of chromium are brewer’s yeast, spices
dietary ferrous iron, sucrose, fructose, animal proteins, S-​amino
such as black pepper, mushrooms, prunes, raisins, nuts, asparagus,
acids, and histidine. High dietary amounts of ascorbic acid sup-
beer, and wine. Stainless steel vessels can contribute chromium to
plements, molybdenum, calcium, and/​ or phosphorus and cad-
acidic foods. Absorption of chromium is inversely related to dietary
mium have been shown to adversely affect copper absorption and
intake at normal intakes of 10–​40 µg/​day, via a saturable passive
bioavailability.
diffusion process in the small intestine; absorption is promoted by
The richest dietary sources of copper are organ meats, seafood,
ascorbic acid. It is transported in the blood mainly bound to trans-
nuts, seeds, and whole grains. Drinking water distributed via
ferring, and excreted mainly in the urine.
copper piping can add 1.0 mg/​day to intakes in acid and soft water
There is no satisfactory measure of chromium status, thus set-
areas. Absorption of copper depends on dietary intake, shown to
ting recommended dietary intakes is problematic. The UK dietary
range from 56% at low intakes (0.78 mg/​day) to 12% at high intakes
reference value (DRV) merely recommends safe and adequate in-
(7.53 mg/​day); on typical EU diets, average absorption is 30–​40%.
takes of more than 25 µg/​day for adults and 0.1–​0.2 µg/​kg/​day for
Copper balance can therefore be achieved over a broad range of
children and adolescents. The US Institute of Medicine (IOM) has
intakes, mainly by regulating excretion in bile (the major route of
set adequate intakes (AI) ranging from 0.2 µg/​day in infants up to
excretion).
35 µg/​day in adult men, 25 µg/​day in adult women, 35 and 45 µg/​
Recommended intakes for copper have been set: for adult males and
day in pregnant and lactating women, respectively. In contrast, the
females the UK DRV reference nutrient intake (RNI) is 1.2 mg/​day,
European Food Safety Authority (EFSA) has not set any recom-
and the IOM recommended daily allowance (RDA) is 900 µg/​day.
mendations due to lack of evidence. Similarly, there is insufficient
Chronic copper toxicity can arise due to high levels in drinking
evidence on which to base upper intake levels (UL), though there is
water, and causes liver, kidney, and brain damage, probably due to
World Health Organization (WHO) guidance that chromium sup-
oxidation. Acute copper toxicity causes gastrointestinal disturb-
plementation should not exceed 250 µg/​day.
ances. The IOM have set the UL for adults at 10 mg/​day, whereas the
EFSA figure is 5 mg/​day.
People with Wilson’s disease (an autosomal recessive disease
Copper of copper storage, incidence 1 in 30 000 worldwide), if untreated
(with a chelating agent), accumulate copper in the liver, the cornea
This essential transition metal can switch between redox states (cu- (Fig. 11.3.1) and the central nervous system, leading ultimately to
prous, Cu1+, and predominant cupric, Cu2+) forming a catalytic hepatic failure and death (Chapter 12.7.2).
centre in several enzymes, notably cytochrome oxidase in the inner There may also be a genetic component in many cases of Indian
mitochondrial membrane, dopamine β-​hydroxylase required for childhood cirrhosis, arising from consumption of milk that has been
the synthesis of noradrenaline, Cu/​Zn superoxide dismutase which boiled and stored in copper and brass containers.
protects cells from oxidative damage, and lysyl oxidase which hy- Neurodegenerative diseases such as Alzheimer’s and human prion
droxylates some of the ε-​amino groups of elastin thereby enabling disease have been associated with disruptions in copper metabolism.
crosslinking which is essential for the integrity of connective tissue. Mutations in the Cu/​Zn superoxide dismutase gene are seen in 20%
Copper is therefore required for infant growth, immune function, of familial cases of motor neurone disease, though it is not clear how
bone strength, red and white blood cell maturation, and iron, chol- this causes the progressive muscle weakness and atrophy; ditto in
esterol, and glucose metabolism. The human body contains be- Down’s syndrome, where there is an extra copy of this enzyme on
tween 50 and 150 mg, mostly bound to proteins. Liver stores are the extra chromosome 21.
 11.3 Minerals and trace elements 1873

and it should be noted that there is a narrow margin between bene-

ficial intakes and the levels that cause fluorosis.

Iodine

Iodine, I2, is a non​metallic blue-​black solid halogen that sublimes

to form a violet gas. Iodine can exist in various oxidation states, the
commonest being –​1 (iodide), +5 (iodates) and + 7 (periodates).
Iodine is the only mineral element that is an essential component
of hormones, that is, the thyroid hormones thyroxine (T4) and the
more active triiodothyronine (T3). These appear to bind to nu-
clear receptors in cells, affecting gene expression in brain cells, pi-
tuitary, liver, heart, and kidney cells, stimulating enzyme synthesis,
Fig. 11.3.1 Kayser–​Fleischer ring: deposit of copper (brown, golden, oxygen consumption, and hence metabolic rate overall. Heart rate,
or reddish-​green) in Descemet’s membrane of the cornea. respiratory rate, substrate mobilization, and oxidation, and other
Reproduced from Bloom S, Webster G, Marks D (2011). Oxford handbook of physiological activities are all involved. Hypothyroidism and hyper-
gastroenterology and hepatology, 2nd edition with permission from Oxford
University Press. thyroidism are the terms used to describe under-​and overproduc-
tion of thyroid hormones, respectively. Iodine probably also has
other functions since it is concentrated from the blood by the sal-
Fluorine ivary glands, the gastric mucosa, the choroid plexus (brain) and the
lactating mammary gland. Iodine is required for the development of
Fluorine, as the highly soluble fluoride ion, has gained notoriety in the nervous system during the first trimester of pregnancy. Iodine
recent years as a public health issue. It is beneficial in bones and teeth, may also have antibiotic and anticancer roles. Functional indicators
forming calcium fluorapatite, and in teeth also fluorhydroxyapatite, of iodine status are provided by serum levels of thyroid stimulating
which together with fluoride’s bacteriostatic effect, helps prevent hormone (TSH, most sensitive), T4, and T3.
dental caries. However, fluoride is toxic in excess, causing fluorosis, Iodine deficiency disorders (IDD) are some of the most preva-
hence public concern. Fluorosis is dose-​related, the effects ranging lent nutritional deficiencies worldwide. In the fetus it causes severe
from mere mottling of the teeth (endemic in areas such as parts of brain damage (cretinism: IQ as low as 20, hearing and speech de-
Africa, China, and India where fluoride levels in water are naturally fects, characteristic physical abnormalities) or hypothyroidism
high, i.e. over 10 mg/​litre; see Fig. 11.3.2), through to calcification of with less severe brain damage, both with stunted growth. In young
the ligaments and tendons causing crippling skeletal fluorosis (ex- children and adolescents, iodine deficiency causes hypothyroidism
tremely rare in the developed world, seen only when excess intakes, (high TSH with very low T3 and T4, causing lethargy, weakness,
i.e. over 10 mg/​day are consumed over at least 10 years, or in cases of weight gain, poor concentration, oedema, myalgia, myxoedema, de-
industrial poisoning; see Fig. 11.3.3). layed tendon reflexes, slow heart rate) and intellectual and growth
Both EFSA and IOM have derived an AI for fluoride. The EFSA AI retardation, while in adolescents and adults it causes goitre and
for adult males is 3.4 mg/​day and 2.9 mg/​day for adult females (with hypothyroidism. The hypothyroidism is also associated with other
a UL for adults of 0.12 mg/​kg body weight/​day); the corresponding mineral deficiencies: zinc, iron, copper, and the metabolic disrup-
IOM AIs are 4.0 and 3.0 mg/​day (UL 10 mg/​day). If fluoridated, the tion caused by IDDs affects the metabolism of many other nutrients,
public water supply is generally fluoridated at levels up to 1 mg/​litre, notably vitamin A.

(a) (b)

Fig. 11.3.2 Dental fluorosis: (a) mild and (b) severe.

(a) By Dozenist (CC BY-​SA 3.0, https://​creativecommons.org/​licenses/​by-​sa/​3.0).
1874 SECTION 11 Nutrition

Fig. 11.3.3 Skeletal fluorosis.

Reprinted from Indian Journal of Medical Specialties, Vol. 8, Gupta L, Zanwar A, Agarwal V, Skeletal fluorosis mimicking Diffuse Idiopathic Skeletal Hyperostosis, Pages 213–​4,
Copyright © 2017, with permission from Elsevier.

Goitre is an enlargement of the thyroid gland, due to hyperplasia is also associated with decreased fertility, increased rates of stillbirth
and an excess of colloid in the follicles (the gland is stimulated to and spontaneous abortion, perinatal and infant mortality.
grow by TSH in an attempt to extract iodide from the blood; see It has been estimated that over 1 billion live in iodine-​deficient
Fig. 11.3.4). Goitre is ultimately harmful since, if large enough, the areas, mostly in Africa and Asia. The WHO has identified iodine de-
thyroid gland presses on the windpipe and gullet. Iodine deficiency ficiency as the main cause of preventable brain damage worldwide.
Iodine supplementation in the form of iodized salt or iodized oil
injections can reverse many of the deficiency symptoms in adults
and older children, including goitre and mental deficiency (to some
extent) and hypothyroidism. However, cretinism is irreversible.
Goitrogens are another factor associated with iodine deficiency.
They are organic substances (glucosides) containing sulphur (thio-
cyanates, isothiocyanates) which interfere with the uptake of iodide
by the tissues, causing goitre. Active goitrogens may be released
from progoitrogens by plant enzymes, or in animal tissues. Foods
containing goitrogens or progoitrogens include cassava (a staple
in much of Africa, the progoitrogen hydrogen cyanide is removed
by soaking in water), bamboo shoots, maize, sweet potatoes, lima
beans, brassica vegetables (e.g. cabbage). Tobacco smoke contains
thiocyanate and other antithyroid compounds. In addition, the
amounts of Ca, F, Mg, and Mn ions in hard water may be goitrogenic.
The best sources of iodine are seafoods (fish, shellfish, seaweed);
milk is now a major source of iodine (though seasonal) since the
introduction of iodine-​supplemented cattle feed and salt licks, iod-
inated casein (a lactation promoter), and teat dip containing iodo-
phors (sterilization agents). Organic milk has been found to be lower
in iodine content than conventional milk due to the restrictions of
organic farming. The iodine content of cereals and grains is variable
as the level is dependent on the iodine content of the soil (iodine is
leached out of soil by high rainfall, glaciations, or soil erosion, hence
inland/​upland areas most deficient). In most European countries
and the United States and Canada, iodine intake is maintained by
Fig. 11.3.4 Goitre.
the use of iodized table salt; without it, low intakes are of concern,
From Wass JAH, Stewart PM, Amiel SA, Davies MJ (eds) (2011). Oxford textbook of
endocrinology and diabetes, 2nd edn. By permission of Oxford University Press. particularly among young women.
 11.3 Minerals and trace elements 1875

Iodine is usually present in food and water as iodide or iodate (sol- 20–​70%) and excretion via the kidney (the principal regulator).
uble), is rapidly absorbed in the intestine and circulates in the blood; Vitamin D may regulate absorption, phosphate (free and/​or phos-
excess is excreted in the urine (hence urinary levels are a useful in- phate groups in phytate) may inhibit absorption, and protein and
dicator of recent iodine intake). Approximately 80% of circulating fructose may enhance it.
iodide is taken up by the thyroid glands; depending on the activity of Frank magnesium deficiency only occurs secondary to other dis-
the gland. Here, the iodide is oxidized to iodine which is then bound eases (including endocrine disorders such as hyperparathyroidism
to tyrosine in thyroglobulin proteins to form monoiodotyrosine and and hyperthyroidism) which cause malabsorption or excess losses
diiodotyrosine, catalysed by thyroid peroxidase. These iodinated of Mg via muscle wasting, diarrhoea, vomiting, or urinary losses due
compounds are converted to triiodothyronine, T3, and thyroxine, to renal dysfunction. Prolonged fasting can also cause magnesium
T4 in the epithelial cells of the gland. T4, thyroxine, is then bound deficiency, as can proton pump inhibitors when used in combin-
to a globulin to form thyroglobulin, for storage in the follicles of ation with diuretics. Hypomagnesaemia is particularly common in
the gland until released into the blood (Chapter 13.3.1). Flavonoids patients with alcoholism admitted to hospital, with causes including
(from many plants) and phenol derivatives (from soil) inhibit thyroid poor dietary intake, diarrhoea, acute pancreatitis, and urinary
peroxidase and are therefore antithyroid. The enzymes responsible wasting due to tubular toxicity of alcohol.
for forming T3 from T4 (in the liver, kidney, muscle, and pituitary) There are several rare genetic abnormalities of Mg status which
are the selenium-​dependant deiodinases, and selenium and iodine lead to Mg deficiency, with features including reduced serum Mg2+
deficiencies overlap in various places (e.g. China, Tibet, Zaire). and red cell magnesium, hypocalcaemia, and hypocalciuria, hypo-
Recommended intakes have been set for iodine: for adult men and kalaemia caused by excess potassium excretion, neuromuscular
women the UK DRV RNI for adults is 140 µg/​day, the IOM RDA is dysfunction, muscle weakness, tachycardia, ventricular fibrillation,
150 µg/​day, rising to 220 µg/​day in pregnancy and the EFSA have set and death.
an AI for adults at 150 µg/​day, and 200 µg/​day in pregnancy. Suboptimal magnesium status has been associated with chronic
Excess iodine intakes (>2 mg/​day) can cause elevated TSH levels, diseases including cardiovascular disease, hypertension, eclampsia,
possibly leading to hypothyroidism (Chapter 13.3.1). Consequently, pre-​eclampsia, and osteoporosis, though this is controversial due
ULs have been set, at 600 µg/​day by the EFSA, 1.0 mg/​day in the partly to the lack of sensitive and reliable tools for assessing magne-
United Kingdom and 1.1 mg/​day by the IOM. In contrast, those sium status. However, there is concern that magnesium intakes (in
with IDDs can develop hyperthyroidism when exposed to moderate the United States and Europe) are suboptimal, thus the IOM have
doses of iodine. Some individuals are sensitive to iodine and may de- raised the RDA for magnesium for adult men and women to 420
velop mild skin symptoms (at relatively low doses), in severe cases, mg/​day and 320 mg/​day, respectively; the EFSA have set AIs of 320
leading to cardiovascular collapse, convulsions, and death. and 300 mg/​day for men and women, respectively, while the corres-
ponding UK DRV RNIs are 300 and 270 mg/​day.
Magnesium salts have a laxative effect, and ULs have been set for
Magnesium supplemental magnesium (only) at 250 mg/​day for adults by the
EFSA and 350 mg/​day by the IOM.
Magnesium is unusual among the minerals in that, because it is an
essential component of chlorophyll, the best dietary sources are
plant-​based (green vegetables, whole grains, and pulses). Processing Manganese
reduces the magnesium content, so highly refined diets are low in
magnesium. Fish and shellfish are intermediate sources and tap and Manganese is a transition element which can exist in 11 oxidation
bottled water also contribute (variable). states, Mn2+ being the predominant form in biological systems. The
The body contains approximately 25 g (1000 mmol) of magne- human body contains about 15 mg of manganese, 25% of which is
sium, mostly (50–​60%) in bone, in combination with phosphate and in the skeleton; relatively high concentrations are also present in
bicarbonate. The rest is in the soft tissues where it is mostly in com- the liver, pancreas, and intestine. Manganese is an essential cata-
bination with protein. Serum magnesium (Mg2+) is normally strictly lytic cofactor for mitochondrial superoxide dismutase, arginase,
maintained between 0.75 and 0.95 mmol/​litre; it is involved with and pyruvate carboxylase; it is also an activator of several other en-
acid/​base balance. Intracellular magnesium concentration is much zymes. It is therefore essential for amino acid, lipid, and carbohy-
higher, approximately 10 mmol/​litre (maintained against a con- drate metabolism.
centration gradient). Mg2+ plays a role as cofactor in over 300 en- Primary deficiency has not been reported in humans, probably
zymic steps in intermediary metabolism: ATP synthesis, Coenzyme due to the relative abundance of Mn in the food supply (whole-​
A, DNA replication, RNA transcription, protein synthesis, β-​ grain cereals, legumes, nuts, fruits, and dried tea are good sources,
oxidation, and glycolysis. Mg2+ is an integral part of mitochondrial depending on the soil, also crustaceans and molluscs, while animal
superoxide dismutase. Mg2+ is also involved with the maintenance products are less good). One case of an individual fed a purified
of the potential difference across the membranes of nerves and diet (accidentally) deficient in Mn has been reported, which caused
muscles. Parathyroid hormone (PTH) release requires Mg2+, hence weight loss, dermatitis, reduced growth of hair and nails, reddening
calcium homeostasis depends on it; also K and Na homeostasis. of black hair, and lowered blood lipids. However, it is possible that
Hypomagnesaemia is defined as a serum Mg2+ below 0.75 mmol/​ deficiency may occur more widely in infants since breast (and for-
litre and is often accompanied by hypocalcaemia. mula) milks are low in manganese.
Magnesium homeostasis is maintained by control (of the ac- Absorption (both active, hence regulated, and passive) occurs in
tive component) of absorption in the small intestine (efficiency is the small intestine and is relatively inefficient (<10%), and may be
1876 SECTION 11 Nutrition

inhibited by phytate, calcium, and phosphate; also non​haem iron acids (DNA, RNA) and phospholipids (membranes). It is involved in
due to competition for binding and absorption sites. Manganese is cell energy metabolism as the energy-​containing nucleotides ATP,
taken up from the blood by the liver and transported to extrahepatic ADP, AMP, GDP, GMP, and in the activation (by phosphorylation)
tissues by transferrin and possibly α​2-​macroglobulin and albumin. of many proteins. This phosphorus can be recycled. Phosphorus is
Excretion is mainly in the bile. therefore essential for cell metabolism.
Manganese status cannot be usefully assessed, so only AIs have Phosphorus homeostasis is determined by dietary intake, intes-
been set by the IOM, at 2.3 and 1.8 mg/day for adult men and women, tinal absorption, exchanges with bone and intracellular compart-
respectively, and the adult EFSA at 3.0 mg/day. Manganese neuro- ments and renal excretion (the main regulator); PTH and calcitonin
toxicity is caused by contaminated dust or fumes—‘manganic both increase phosphate excretion.
madness’. Oral manganese can also be neurotoxic, an effect en- Since phosphorus is a major constituent of all cells, all-​natural
hanced by ethanol. Manganese toxicity with Parkinsonian features foods of plant or animal origin contain it, particularly the foods rich
is a notorious complication of parenteral nutrition (Chapter 11.7): in protein (e.g. meats, especially organ meats, eggs, cheese, milk,
T1-weighted MR images show high-signal deposits in basal ganglia. fish, nuts, legumes, and whole grains which contain phytic acid).
ULs have been set by the IOM at 11 mg/day for adults; for lack of Fruit and vegetables are less good sources. Phosphates are also added
data, EFSA have not. Recessive defects in the SLC30A10 carrier dis- during food manufacture (e.g. polyphosphates) which are added
turb manganese homeostasis and cause hypermanganesaemia, dys- to processed meats (they retain water, increasing the weight of the
tonia, Parkinsonism, dementia, polycythaemia and later, cirrhosis. meat); phosphoric acid is also present in ‘cola’ and other soft drinks
Prompt use of parenteral calcium edetate can give effective relief. (it is an acidulant, hence the deleterious effect on teeth). Absorption
efficiency for inorganic phosphate ranges from 55 to 70% and appar-
ently does not adapt in response to low or high intakes or require-
Molybdenum ment (in contrast with calcium).
Primary phosphorus deficiency is unknown, except in star-
Molybdenum is a transition metal that has five oxidation sates, of which vation (Chapter 11.4). Inadequate phosphorus intake causes
Mo4+ and Mo6+ are the predominant species. In nature, it occurs only in hypophosphataemia and consequent cellular dysfunction, manifest
the combined state or as the molybdate anion in solution. Molybdenum as anorexia, muscle weakness, bone pain, rickets, osteomalacia, de-
is an essential cofactor for several iron-​and flavin-​containing enzymes bility, increased susceptibility to infection, paraesthesia, ataxia, con-
(e.g. xanthine oxidase/​hydrogenase and aldehyde oxidase). fusion, and ultimately death. Secondary deficiency can be caused by
Primary deficiency seems not to occur in humans, and there are chronic malabsorption. Also, in people consuming large amounts
no useful biomarkers of molybdenum status. A single case of possible of aluminium hydroxide antacids, or calcium carbonate; these bind
deficiency has been reported in a patient on total parenteral nutrition phosphate in the gut, so it cannot be absorbed. Phosphate metab-
lacking molybdenum for more than 12 months. Good dietary sources olism is also disrupted by diseases affecting the kidneys or bone.
include milk, beans, cereals (especially the germ); water also contrib- Several genetic diseases (of phosphate transport in the kidney) lead
utes to intakes. Absorption of molybdenum is efficient (40–​100%); it to phosphorus deficiency.
is widely distributed in the body fluids, and is mainly excreted in the Recommended intakes for phosphorus have been traditionally
urine and bile. tied to those for calcium (equimolar, e.g. the UK DRV PRIs for
The IOM has set an RDA for adults at 45 µg/​day (rising to 50 µg/​ adults). More recently, the IOM have set an RDA based on serum
day in pregnancy and lactation), and the EFSA have set an AI for all inorganic phosphate levels for all adults at 700 mg/​day, rising to 1200
adults at 65 µg/​day. mg/​day in pregnancy. The EFSA set an AI of 550 mg/​day for adults
Molybdenum supplementation depletes body levels of copper, based on the whole-​body calcium to phosphorus ratio.
useful in the case of Wilson’s disease where it has been used as a che- Excess phosphorus intake causes hyperphosphataemia, causing
lating agent. Based on adverse reproductive effects in animals, ULs secondary hyperparathyroidism, which leads to increased production
have been set by the IOM at 2 mg/​day for adults, and the EFSA at 0.01 of 1,25(OH)2D and consequent bone resorption to restore calcium
mg/​kg body weight/​day, equivalent to 0.6 mg/​person/​day for adults. homeostasis. Chronic secondary hyperparathyroidism eventually
reduces bone mineral density and can result in ectopic calcification.
However, this is only seen in patients with end-​stage renal disease.
Phosphorus As long as renal capacity is adequate, excess phosphate is excreted.
Nevertheless, high phosphorus dosages have been reported to cause
Phosphorus is non​metallic. It is highly reactive, so it is present in na- osmotic diarrhoea and mild gastrointestinal symptoms.
ture only in combined forms, predominantly with calcium in rock or There is concern that phosphate-​containing food additives may
bone. The commonest form of phosphorus in nature is as phosphate, induce secondary hyperparathyroidism and its consequent adverse
PO42-​. The body contains approximately 0.6–​1.1% phosphorus (total effects in those consuming a diet high in processed food. However,
600–​900 g)—​mostly (85%) as hydroxyapatite (mineral) in bones no ULs have been determined due to lack of data.
and teeth, the rest is in the soft tissues where it takes part in most
metabolic reactions. Half to two-​thirds of the phosphorus in blood
is in the erythrocytes. Fasting serum phosphate is normally 0.8–​ Selenium
1.4 mmol/​litre, the concentration is controlled via urinary excre-
tion. Serum PO42–​ ion has an important role in buffering (acid/​base Selenium is a stable, non​metallic element that occurs in four natural
balance). In cells, phosphorus is important in the structure of nucleic oxidation states (0, –​2, + 4 and + 6). It combines with other elements
 11.3 Minerals and trace elements 1877

to form selenides, selenites, and selenates, or with oxygen to form observed in response to Se supplementation. Vitamin E and Se de-
oxides and oxyacids. Selenium replaces sulphur to form many or- ficiencies are related; each ‘spares’ the requirement for the other,
ganic selenium compounds, especially selenocysteine (SeCys), though differently in different species.
also selenomethionine (SeMet) in selenoproteins (which may also Interestingly, Se deficiency appears to predispose to certain other
contain selenides). In populations, selenium nutritional status is diseases, notably viral infections (e.g. in Se-​deficient mice), the
strongly related to the Se content of soil; which is low in parts of normally harmless coxsackie virus becomes virulent, causing myo-
China and Russia, New Zealand, and Northern Europe, whereas carditis (virulence persists when virus then isolated and injected
parts of the United States, Canada, and Colombia have high Se soil into Se-​replete animals). Furthermore, a coxsackie virus has been
(causing toxicity in grazing animals). found in Keshan disease patients. Other retroviral diseases could
Selenium occurs in over 30 selenoproteins as selenocysteine, have developed under comparable circumstances (e.g. the crossing
which is the active site. An important selenoprotein is glutathione over from monkeys) and increased virulence of HIV in Se-​deficient
peroxidase (GPx, contains 4 atoms of Se acting as a redox centre) people in Zaire (and from them to other, healthy people), ditto
which is a major component of antioxidant defence. There are sev- new influenza strains in China. In addition, some human viruses
eral different forms of GPx, occurring in different locations in the (e.g. HIV, Coxsackie, hepatitis, measles) induce synthesis of viral
cell, and in different tissues, for example, cytosolic (GPx1), mem- selenoproteins, thus reducing Se availability for the host, which
brane (GPx4), extracellular (GPx3), and gastrointestinal (GPx2). could thus reduce the host’s defence.
They comprise about a third of total body Se. Other important Se en- The selenium content of food varies depending on the selenium
zymes include the iodothyronine deiodinases (three isoforms, in the content of the soil (e.g. cereals and grains <0.1 to >0.8 μg/​g).
liver) which control levels of active thyroid hormone T3, converted Selenium may be added to animal feed resulting in improved Se
from T4. Also, selenoprotein P in plasma protects endothelial cells content of animal-​derived products. Brazil nuts are a particularly
against peroxynitrite (a pro-​oxidant), and thioredoxin reductases rich source of Se, containing 18–​12 μg/​g. Fish, shellfish, and offal
(three isoforms) reduce nucleotides in DNA synthesis, regenerate are rich sources of Se, less rich are meat and eggs; however, the Se
antioxidant systems, maintain intracellular redox state, and regulate from animal sources is less bioavailable than that from plant sources.
DNA expression by redox control of binding of transcription factors Losses occur during refining and cooking.
to DNA. Se is absorbed mainly in the small intestine. Organic forms of Se
Se is therefore required for intra-​and extracellular antioxidant de- are more bioavailable than inorganic (e.g. from water, dietary sup-
fence, cell division, and gene expression, immunocompetence, thy- plements). Plant sources, (containing a higher proportion of organic
roid metabolism and reproduction (in the male). Epidemiological selenium compounds, especially SeMet) are better absorbed than
evidence suggests that good Se status may protect against cancer animal sources (which contain sulphides, selenites, SeCys, and some
(particularly prostate cancer), heart disease, and perhaps inflamma- SeMet). More than 90% of SeMet, the major dietary form of the
tory conditions such as rheumatoid arthritis, ulcerative colitis, and element, is absorbed by the same mechanism as methionine itself.
asthma (although evidence is less convincing). SeCys also appears to be well absorbed.
Selenium deficiency causes poor growth, liver necrosis, degener- In the blood, Se travels bound mainly to VLDL β-​lipoprotein;
ation of striated muscle, capillary fragility, and myocardial damage. smaller amounts are bound to albumin. The liver, kidney, heart, and
In China, Keshan disease, a cardiomyopathy seen in children and muscle are the main target organs.
women of childbearing age (often fatal, causing insufficiency of In cells, Se can be bound to selenium-​binding proteins, or it can
cardiac function, cardiac enlargement, and abnormal rhythm) is be used to form selenocysteine which can then be incorporated
associated with very low soil Se, low Se intakes (less than 12 µg/​ into polypeptides (via a tRNA specific for SeCys, the ‘21st amino
day), and poor Se status, and can be corrected by Se supplemen- acid’).
tation. However, other factors are probably involved since not all Methylation of selenium occurs in the liver prior to excretion
the features can be explained by Se deficiency and in (for example) by the kidneys, mainly as trimethylselenium ion. Se also leaves the
New Zealand or Finland where intakes are only 15–​40 µg/​day, no body in faeces (bile, intestinal secretions, unabsorbed dietary Se),
such disease is found. The same is true for Kashin–​Beck disease, as shed skin, and in the breath, as dimethylselenide (volatile, garlic
an osteoarthropathy (causing osteochondropathy, enlarged joints, odour).
shortened fingers/​toes and dwarfism) affecting mostly growing chil- In assessing Se status, dietary intake measurements using food
dren, which is seen in parts of Siberia and China. Some patients on tables are not useful due to variations in Se content of foods and
TPN develop symptoms similar to Keshan disease, which can be bioavailability. Plasma Se reflects recent dietary intake while
corrected by Se. erythrocyte Se reflects longer-​term intake. Whole blood, hair, and
Selenium deficiency may induce goitre (iodine deficiency) due to toenail Se can be used to assess changes in Se status. Functional
its role in deiodinases. Chronic low selenium intake reduces innate indices are most useful in assessing status, for example, plasma, or
immunity via the selenoproteins. An apparent hierarchical response (better) platelet GSx activity, together with thyroid and immune
to Se deficiency exists with the brain, endocrine, and reproductive function tests (since these reflect different levels of Se status, i.e.
organs preferentially provided with and retaining more Se compared optimal status may occur at Se intakes above what is required to
with other tissues. saturate GSx activity).
There may be genetic variation in metabolic requirements for Recommended intakes have been set for Se: for adult men and
Se, caused by polymorphisms in genes coding for selenoenzymes women the UK DRV RNIs are 75 and 60 µg/​day, respectively, the
(analogous to MTHFR variants in the case of folate). This would IOM RDA is 55 µg/​day for adults and the EFSA AI is 70 µg/​day for
explain the large individual variation in selenoenzyme activity adults.
1878 SECTION 11 Nutrition

Of concern is the observation that blood Se in the United Kingdom

has fallen by half in over the last 30 years, and current intakes are
only half of the RNI (due partly to a change in the source of wheat
for breadmaking from higher Se Canadian wheat to lower Se wheat).
It is therefore possible that there is widespread covert suboptimal Se
status in the United Kingdom (and elsewhere).
The margin between beneficial and toxic intakes of Se is narrow,
only 3-​or 4-​fold: the EFSA UL for adults is 300 µg Se/​day, and that
set by the IOM is 400 µg Se/​day. Intakes over 850–​900 µg/​day cause
chronic selenosis. The symptoms include brittle hair and nails, skin
lesions, mottled teeth, foul body odour and breath (dimethyl sel-
enide), and peripheral nerve changes. Selenite and SeCys are more
toxic than SeMet, and much more toxic than other organic forms.
Excess dietary Se interferes with the bioavailability of zinc, and may
ameliorate the toxicity of heavy metals (e.g. mercury and methyl
mercury in fish); conversely Se bioavailability is reduced by heavy
metals and a high-​sulphur diet. Excess Se also affects other nutrients
positively (copper stores in the heart, liver, kidneys), or negatively Fig. 11.3.5 Acrodermatitis enteropathica.
(iron stores). Reproduced from Lewis-​Jones S (ed) (2010). Paediatric dermatology (Oxford Specialist
Handbooks in Paediatrics) with permission from Oxford University Press.

Zinc including due to Crohn’s disease, or liver disease, are at risk of zinc
deficiency.
This essential transition metal exists in biology almost exclusively A recessively inherited defect in zinc absorption, Acrodermatitis
in the Zn2+ state and is a cofactor (often acting as an electron ac- enteropathica, causes acute zinc deficiency, which manifests as
ceptor) in more than 300 different enzymes in all branches of bullous dermatitis of the feet, hands, and around the orifices (see
metabolism; notably carbonic anhydrase in erythrocytes, Cu/​ Fig. 11.3.5), diarrhoea, failure to thrive, susceptibility to infection,
Zn superoxide dismutase, alcohol dehydrogenase, alkaline phos- and death in early life if not treated.
phatase, aldolase, carboxypeptidase, RNA polymerase, and DNA Most (60%) of the approximately 2–​4 g of zinc in the adult body
polymerase. In addition, zinc is a stabilizing structural component is in muscle, 30% in bone and the rest distributed among the other
of several proteins, including the insulin granules stored in the tissues. The choroid and retina of the eye and male reproductive
β cells of the pancreas, and the zinc ‘finger proteins’ involved in organs contain relatively high concentrations (semen concentra-
the regulation of gene transcription. It is also involved in recep- tion is 100× that in blood plasma). Less than 0.1% is in plasma
tors for thyroid hormones, steroid hormones, vitamins D and A, (mostly bound to albumin), thus plasma zinc is only of limited
mediating their interactions with promoter regions on DNA. Zinc use as a measure of current status (and is reduced in any condition
also functions as an antioxidant in vivo and it plays an important that affects plasma albumin levels). Zinc content of erythrocytes,
role in the immune system; it has long been regarded as beneficial leucocytes, and hair can be used as indicators of longer-​term
for wound healing. status, but are not sensitive to mild deficiency.
Because Zinc is required for all aspects of normal metabolism, High-​protein foods are the best dietary sources of zinc; the
deficiency causes diverse symptoms: growth cessation and sexual concentration in meat is in direct proportion to the darkness
and skeletal immaturity (in children and adolescents), a char- in colour and provides most of the zinc intake in the developed
acteristic bullous-​pustular dermatitis, alopecia, diarrhoea, in- world, along with milk, cheese, eggs, and whole-​grain cereals
creased susceptibility to infection, loss of taste and appetite, and (milling removes the zinc, but also the phytate which inhibits
neuropsychiatric disturbances. Chronic zinc deficiency was first absorption). Other metals (iron, copper, cadmium) may impair
reported in remote areas of Iran, caused by a diet of mostly un- zinc absorption by competing for uptake whereas dietary com-
leavened bread which is high in phytate, binding cations in the gut ponents that increase the solubility of zinc (organic acids, pro-
and preventing their absorption. Zinc deficiency is widespread in tein, histidine, cysteine) enhance absorption. Zinc absorption is
children, and is particularly prevalent in South Asia, sub-​Saharan a regulated, carrier-​mediated process (via metallothionein) and
Africa, and regions of Central and South America. Marginal zinc varies from 20–​40% on mixed Western diets to only 10–​15% on
deficiency is more difficult to diagnose and may be associated with unrefined vegetarian diets, most of which is excreted in the bile,
other micronutrient deficiencies, including iron. Zinc supple- there being no apparent specific storage in the body. When intakes
mentation may improve growth and development in infants and are raised, fractional absorption decreases and intestinal excre-
young children, and improve the immune response, hence redu- tion increases, while urinary losses remain constant. At very high
cing morbidity due to diarrhoea and respiratory infections in chil- intakes, the excess zinc is lost via the hair.
dren, particularly in developing countries. Low zinc status in poor Recommended intakes have been set for zinc: for adult men and
urban women has also been associated with low birth weight and women the UK DRV RNIs are 9.5 and 7.0 mg/​day, respectively, the
increased risk of preterm delivery. Because there is a major entero- IOM RDAs are 11.0 and 8.0 mg/​day, and the EFSA RDAs give ranges
hepatic circulation of zinc, patients suffering from malabsorption, of 9.4–​16.3 and 7.5–​12.7 mg/​day.
 11.3 Minerals and trace elements 1879

Zinc toxicity has been caused by consuming water or food stored

Institute of Medicine. http://​iom.nationalacademies.org/​Reports.aspx?
in galvanized containers, or by overconsuming supplements, and searchQuery=DRI
ULs have been set by the IOM at 40 mg/​day for adults, and by the Institute of Medicine. http://​nationalacademies.org/​hmd/​Activities/​
EFSA at 25 mg/​day. Consideration should be given to people with Nutrition/​SummaryDRIs/​DRI-​Tables.aspx
Menke’s disease (a rare genetic defect in the uptake of copper from Kumar N (2006). Copper deficiency myelopathy (Human Swayback).
gut cells into the blood) who are susceptible to excess zinc intake Mayo Clinic Proceedings, 81, 1371–84.
which may further limit copper absorption. Livingstone C (2018). Manganese provision in parenteral nutrition:
an update. Nutrition and Clinical Practice, 33, 404–8.
Panel on Dietary Reference Values of the Committee on Medical
FURTHER READING Aspects of Food Policy (1991). Report on Health and Social Subjects
Clayton PT (2017). Inherited disorders of transition metal metab- 41. Dietary reference values for food energy and nutrients for the
olism: an update. J. Inherit Metab Dis, 40, 519–29. United Kingdom. HMSO, London.
European Food Safety Authority (2017). Dietary Reference Values SACN updates and position statements. https://​www.gov.uk/​government/​
for Nutrients Summary report. https://www.efsa.europa.eu/en/ collections/​sacn-​reports-​and-​position-​statements
supporting/pub/e15121 Tuschl K, Clayton PT, Gospe SM Jr, Mills PB (2017). Dystonia/
Ferreira CR, Gahl WA (2017). Disorders of metal metabolism. Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic
Transl Sci Rare Dis, 2(3–4), 101–39. Liver Disease. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE,
Institute of Medicine (2006). Dietary Reference Intakes—​the essen- Bean LJH, Stephens K, Amemiya A (eds). GeneReviews® [Internet].
tial guide to nutrient requirements. The National Academies Press, Seattle (WA): University of Washington, Seattle.
Washington, DC. http://​iom.nationalacademies.org/​reports/​2006/​ Yao Y, Pei F, Kang P (2011). Selenium, iodine, and the relation with
dietary-​reference-​intakes-​essential-​guide-​nutrient-​requirements.aspx Kashin-Beck disease. Nutrition, 27(11-12), 1095–100.
11.4
Severe malnutrition
Alan A. Jackson

ESSENTIALS Severe acute malnutrition

Severe malnutrition results from the interaction of three distinct
Severe malnutrition is the consequence of systemic deficiency
but related processes: (1) reductive adaptation, which is a general
of energy and nutrients over a prolonged period: in children de-
response to preserve essential function that takes place when the
velopment is stunted and the individual is at risk of fatal (often
demands of the body for energy and nutrients are not adequately
clinically ‘silent’) infection and other illnesses. It is a medical and
met; (2) inflammatory/​immune responses and healing, which are
societal emergency: mortality is high, despite attempts to provide
impaired as a result of reductive adaptations; (3) specific nutrient
appropriate care.
deficiencies, when failure because of marginal diet to correct exces-
When severe malnutrition affects several individuals in a society, it
sive losses of nutrients (e.g. through diarrhoea and vomiting) leads
reflects a state in which basic needs and justice are not met. Severe
to major imbalances. These combine to put the child at risk of the
malnutrition may also result from clinical disorders affecting a single
deadly triad of infection, hypothermia, and hypoglycaemia, often
person with gastrointestinal disease, poor appetite, or reduced food
compounded by marked fluid and electrolyte disturbances.
intake for other reasons.
Sick malnourished individuals have no appetite for food, with
Classification loss of appetite being an important protective mechanism against
The World Health Organization has produced guidelines for facility-​ consuming food which is likely to stress the systems of the body.
based care of patients suffering severe malnutrition. Prompt clas- Attempts (well meaning) to force feed are dangerous: the poten-
sification into groups of differential risk assists in the identification tially fatal ‘recovery syndrome’ (manifest as heart failure, progressing
of those requiring the most immediate clinical care (severe acute to circulatory collapse, often with severe secretory diarrhoea) must
malnutrition, defined as weight for height more than three standard be avoided. Aside from the provision of a sympathetic and quiet
deviations below the reference mean, a mid upper-​arm circumfer- environment during treatment, key aspects of management in-
ence of less than 115 mm, or the presence of oedema of both feet) clude: (1) resuscitation—​management of infection, fluid, and electro-
and in monitoring the outcomes of intervention. Low height for lyte imbalances, and shock, also treatment of vitamin A deficiency;
age indicates long-​term malnutrition or poor health (stunting); low (2) stabilization—​give small frequent meals (every 3–​4 h throughout
weight for height or low mid upper-​arm circumference indicate re- 24 h; 100 kcal/​kg per day; 1–​1.5 g protein/​kg per day), add specific
cent or continuing severe weight loss (wasting); low weight for age nutrients to food to correct deficiency (potassium, magnesium, folic
implies stunting and/​or wasting. acid, zinc, copper, multivitamin), treat infections, transfuse for se-
vere anaemia, treat skin lesions, exclude tuberculosis; (3) weight gain
Prevention
(rapid catch-​up growth)—​ad libitum intake, continue with micronu-
Malnutrition is a preventable condition and the early identification trient supplements, add supplemental iron.
of those at risk (e.g. by regular weighing) and the implementation
of interventions (e.g. advice and demonstration of best practice in
child care and feeding) which correct underlying problems and pre-
vent further deterioration is central to strategies for effective care. Introduction
Childhood malnutrition is a clinical problem for the individual,
but also a symptom of ineffective public health policy. Aside from Severe malnutrition occurs in societies that are not able to meet
feeding, important aspects are to recognize and treat infection, basic needs for healthcare and survival. It is characterized by under-
immunize against infection, enhance the child-​rearing skills of the development, poverty and deprivation, an insanitary environment,
parents, and strengthen general hygienic practices, especially for frequent infections, and food that is poor in quality or limited in
water and sanitation. availability. A series of vicious cycles operate within individuals and
across generations, limiting the ability of vulnerable groups, families,
 11.4 Severe malnutrition 1881

Table 11.4.1 The case mortality for complicated severe malnutrition has failed to improve because of four major errors of management

1. The assumption that a low plasma albumin concentration is the basis of oedema and can be effectively treated with a high-​protein diet
2. The use of diuretics for the treatment of oedema
3. Early use of iron supplements to treat anaemia
4. Failing to differentiate that the acute illness should be managed before any attempts to correct weight loss

From Schofield C and Ashworth A (1996). Why have mortality rates for severe malnutrition remained so high? Bulletin of the World Health Organization, 74, 223–​9.

and individuals to cope with the harsh realities of a hostile environ- so an improvement in percentage terms does not necessarily mean
ment, either through the exigencies of nature or a human unwill- a decrease in the absolute numbers of malnourished people across
ingness to share the available resources with greater equity. Across the globe.
the globe, severe malnutrition is a common condition during child- Severe malnutrition is a late stage in a process where an individual
hood. It is most prevalent among the poorest in developing coun- has had inadequate access to sufficient energy and nutrients for a
tries, but it is also found with uncomfortable frequency among the period of time. During this time, the function of the body changes
most deprived of every society, including those in Europe and North until a point is reached where severely malnourished children are
America. It is a frequent aspect of clinical medicine in patients who, significantly different from normal children in their response to
for any reason, have a loss of appetite or a reduction in food intake. medical treatment. This stage differentiates those who might be
The same principles of management and care apply wherever the readily treated in a community setting from those who require
problem is found. more skilled care in a facility. If this group is treated in the same
Malnutrition at any age impairs the ability to perform and way as normal children, they will very likely die. Based upon best
function. Children with severe malnutrition are at risk of life-​ practice, mortality would be expected to be around 5 to 10%, but in
threatening diseases, which require urgent attention. More in- many centres, case mortality has remained unchanged for 50 years,
sidiously, malnutrition during childhood stunts development and around 40 to 50%. Sometimes, this can be attributed to poor case
leaves a scar that remains for the rest of that person’s life. This lost management, with four major errors in care occurring in about 80%
potential can express itself as an increased risk of ill health, as im- of centres (Table 11.4.1). However, frequently, the organization of
paired intellectual development leading to poor school perform- systems of care is poor or the availability of simple, basic resources
ance, or in limited physical development leading to poorer work are limited or insecure.
performance. Once part of an individual’s potential for develop- The World Health Organization (WHO) has produced guidelines
ment has been lost, the clinical and social implications tend to be for community and facility-​based care with effective facility-​based
cumulative. On a global scale, the sum total of the loss of indi- treatment using a 10-​step approach (Fig. 11.4.1). During the early
vidual capability represents a fundamental brake on aspirations for period of care, the order in which different aspects of treatment are
social and economic development. Most recent estimates indicate carried out is critical for a successful outcome. A central feature is
that globally, 45% of the disease burden for children under 5 years that, as a first step, the body’s cellular machinery has to be repaired
of age can be attributed directly or indirectly to malnutrition, at
least 3 million deaths and 6% of total global disability-​adjusted life
years (DALYs). This burden is not spread evenly between different
parts of the world. For the worst-​affected countries, as many as
Activity Initial treatment Rehabilitation Follow-up
50% of children under 5 have malnutrition, which is severe enough
days 1–2 days 3–7 weeks 2–6 weeks 7–26
to threaten life, with the highest prevalence in sub-​Saharan Africa
and the greatest numbers in Southeast Asia. This is representative Treat or prevent:
of the day-​to-​day situation, and is not a peculiarity of special emer- hypoglycaemia
hypothermia
gencies. There are at least 150 million children in the world for
dehydration
whom severe deprivation, indexed as stunting or survival on less Treat Infection
than $2/​day, has limited their potential for normal physical and
Correct electrolyte
neurocognitive development. imbalance
without iron with iron
Notwithstanding the large number of children with severe mal- Correct micronutrient
nutrition, over the past 20 years there has been a shift to the right of deficiencies
the curve for the distribution of the height and weight of children, Begin feeding

indicating a general success for specific interventions. Thus, change Increase feeding to
is possible, and when suitable measures are put in place sustained recover lost weight
(’catch-up growth’)
improvement can be achieved. However, there is absolutely no basis Stimulate emotional and
for complacency, as recent figures suggest a slowing down, or even a sensorial development
reversal, of this improvement. This may relate to an inability to con- Prepare for discharge
trol infections effectively, with tuberculosis, malaria, and diarrhoea
continuing to play a major role and the HIV epidemic making a sig- Fig. 11.4.1 WHO recommendations for the 10-​step approach to the
nificant contribution. The world’s population continues to increase, management of severe malnutrition.
1882 SECTION 11 Nutrition

if function is to be restored. Silent infections are common. There marked for subcutaneous fat and muscle. The result is a thin ap-
have been unusual losses of nutrients from the body, which cannot pearance, with pinched features, thin arms and legs, and a scaphoid
be corrected adequately on a standard diet. The damaged systems abdomen. Qualitative changes are usually associated with unusual
of the body are not able to cope with excess energy or further stress. losses of nutrients from the body, for example, through diarrhoea
Effective treatment requires the ordered correction of the underlying or infection, reordered metabolism to deal with metabolic stress, or
problems before any attempts are made to correct the tissue deficits. the toxic effects of a range of noxious exposures. The end result of
this process is likely to be the loss of cellular integrity and control,
leading to oedema.
Clinical syndromes

Severe malnutrition can present with an array of clinical symptoms Classification

and signs, which depend upon the duration of the illness, the extent
of coinfection, the particular pattern of nutrient deficiencies and An effective classification differentiates those at greatest risk, guides
metabolic disturbances, and other associated complications such suitable interventions, and helps determine the extent to which
as diarrhoea and vomiting with attendant disturbances in fluid and interventions have successfully corrected the problem. The more
electrolytes (Table 11.4.2). All descriptions of the condition empha- severely malnourished an individual, the greater the risk of com-
size one or other feature of the presentation. The archetypal descrip- plications, and the risk of an adverse outcome is related to the se-
tive terms for childhood malnutrition—​kwashiorkor, marasmus, or verity of the weight deficit or the extent to which normal function
marasmic kwashiorkor—​were originally used to characterize clin- is deranged. The term ‘severe acute malnutrition’ (SAM) has been
ical syndromes. introduced to differentiate those who are in need of immediate clin-
The first description of the kwashiorkor syndrome emphasized ical care associated with wasting, from the more chronic problems
the development, location, and timing of the skin lesion, with pro- associated with stunting. These changes can all be marked either
gression from friable hyperpigmented skin, which stripped to re- quantitatively or qualitatively. SAM is defined as severe wasting (a
veal hypopigmented skin, which ulcerated easily to provide a ready score of less than –​3 standard deviations weight for height, or on
portal for infection—​lesions distinct from pellagra. Other features screening a mid upper-​arm circumference of less than 115 mm),
such as abnormal affect and hepatomegaly were noted, but were less or the presence of oedema of both feet, or clinical signs of severe
remarkable. Placing emphasis upon variability in clinical presenta- malnutrition (Table 11.4.3). Recently, WHO/​UNICEF introduced
tion has made comparison difficult and encouraged the idea that guidance on the identification of severe malnutrition and the use in
the underlying pathophysiology, and hence its treatment, differs in practice of the new WHO growth standards for infants and children
important ways between locations. This has diverted attention from from 6 months to 5 years of age.
similarities in the fundamental changes that take place across the Quantitative measures indicate the extent to which the expected
range of clinical presentations. pattern of growth in height and weight has not been achieved: low
The function of the body is controlled through the integration of height for age, low weight for height, and low weight for age. Low
many systems. A fault in any one has implications for the function height for age (shortness or stunting) is indicative of longer-​term
of all the others. Thus, there is the need for adequate amounts of malnutrition or poor health. Low weight for height (thinness or
energy, energy-​generating nutrients (carbohydrate, lipid, and pro- wasting) implies recent or continuing current severe weight loss.
tein), minerals, and a range of micronutrients for the body to func- Low weight for age (insufficient weight relative to age) implies
tion effectively in a harmonized way. Lack of any one component, or stunting and/​or wasting. Weight is more easily measured than
an imbalance, leads to deranged handling of other components. By height, and assessing weight for age is the simplest way of excluding
adopting an agreed classification, relevant comparisons have been severe malnutrition in the absence of oedema. Weight for age is in-
drawn, and it is clear that the range of clinical features represent fluenced by both height for age and weight for height. Where de-
varying manifestations of a clinical disorder with the interaction of privation is common, there is a high prevalence of low height for
qualitative and quantitative factors. The quantitative change results age. Weight for age is more strongly influenced by stunting than by
from an inadequate intake of food and leads to a wasting syndrome, wasting, and requires broader public health approaches for its al-
classically marasmus, with the progressive loss of tissue, especially leviation, being unlikely to respond in the short term to aggressive

Table 11.4.2 Important clinical features to enable immediate clinical decisions for emergency management of severe malnutrition

Feature Details/​relevance
Anthropometry Stunting, wasting, presence of pitting oedema
Gastrointestinal History of anorexia, poor appetite, vomiting, diarrhoea. Appearance of mouth. Distended or scaphoid abdomen, with succussion splash
Liver Degree of enlargement, jaundice, petechiae
Cardiovascular Circulatory collapse, anaemia, shock (depleted intravascular volume, cold hands and feet, weak radial pulse, diminished consciousness)
± signs of ‘dehydration’ (sunken eyes, sunken fontanelle, decreased skin turgor)
Infection Hypothermia, fever, localizing signs (respiratory distress, broken skin, mouth, ears)
Specific deficiencies Eye signs of xerophthalmia, vitamin A
 11.4 Severe malnutrition 1883

Table 11.4.3 Classification of malnutrition. The diagnoses are not Multiple infection is common and often silent, so that specific
mutually exclusive sites of infection may be difficult to identify or localize. A high index
of suspicion is required for the presence of silent infections, which
Moderate malnutrition Severe malnutrition
should be presumed to be present. Infection is not part of the diag-
Symmetrical oedema
nostic criteria.
No Yes (oedematous malnutrition)a
Weight for height
SD score between –​3 and –​2b (70–​79%)c SD score below –​3 (<70%) Natural history and clinical presentation
(severe wasting)d
Height for age Inadequate nutrition slows the pace of growth and development
SD score between –​3 and –​2 (85–​89%) SD score below –​3 (<85%) and the greater the severity of the limitation or insult, or the longer
(severe stunting) its duration, the greater the difference between the achieved de-
Mid upper-​arm circumference velopment and that expected. The stress of an insult of greater se-
Below 125 mm Below 115 mm verity evokes a metabolic response that is associated with a loss of
body weight and a reordering of function, so that resources and
effort devoted to growth and development are diverted to maintain
a
This includes kwashiorkor and marasmic kwashiorkor in older classifications. To avoid
confusion with the clinical syndrome of kwashiorkor, which includes other features, the
term ‘oedematous malnutrition’ is preferred. the integrity of the individual. The nutritional health of the infant
b
Below the WHO growth standard; the SD score is defined as the deviation of the value is critically determined by how well prepared the mother was to
for the individual from the median value for the reference population, divided by the
standard deviation of the reference population.
carry the pregnancy, and the effectiveness with which breastfeeding
c
Percentage of the median WHO growth standard. is established and maintained. During pregnancy and for the first
d
This corresponds to marasmus (without oedema) in the Wellcome clinical classification, months of life, the infant is totally dependent upon the mother for
and to grade III malnutrition in the Gomez system. To avoid confusion the term severe its nutrient supply. During early pregnancy, there is the elaboration
wasting is preferred.
of structure in the embryo and maturation of function in the fetus.
The last trimester is of critical importance as it is when the fetus
clinical intervention. Around one-​third of stunting is present at accumulates effective reserves of nutrients, helping survival and
birth, but the prevalence starts to increase at around 3 months of facilitating development during the first year of life. The fetus ac-
age, and the progression of stunting slows down at around 3 years cumulates reserves of energy, as subcutaneous lipid, and of min-
of age, after which mean heights run below but parallel to the refer- erals and vitamins, such as iron, zinc, copper, vitamin A, riboflavin,
ence. Weight for height has the advantage that it can be used when and pyridoxine, in liver and muscle. At birth, the relative protection
age is not known reliably and suggests recent severe weight loss, of the intrauterine environment is replaced by the many hazards
indicating those children who are most likely to benefit from im- of the external world. Gastrointestinal and respiratory infections
mediate aggressive nutritional intervention and support. The rate at are among the serious dangers to survival, and breastfeeding pro-
which weight improves is used to assess progress during recovery, vides effective protection from both. Even in affluent societies,
and success of care is indicated by the achievement of a weight breastfeeding provides the infant with a level of protection against
that is appropriate for the individual’s height. The measurement of ill health that identifies effective breastfeeding as a singularly im-
mid upper-​arm circumference provides simple, robust indication portant feature in any rational policy in public health nutrition.
of the degree of wasting in this age group and is recommended in There is a massive increase in the risk of ill health for infants who
screening for SAM. are not breastfed during the early months of life. This risk is mag-
In places where SAM is common there is the need to differen- nified enormously for infants exposed to unsanitary environments
tiate those who can be effectively and reliably managed by super- with limited access to healthcare. Anything that limits the growth
vised care in the community, and those who require the level of care of the fetus, impairs its development, or causes it to be delivered
that can only be provided in a facility. This differentiation is made early will limit its ability to cope with extrauterine life, and increase
using qualitative criteria on the basis of appetite, the presence of oe- the risk of problems, infections, and malnutrition. There is en-
dema, or other identifiable serious comorbidity. Qualitative criteria hanced mother–​infant bonding and emotional development with
are more difficult, because of their variability and uncertainty about breastfeeding, and other special benefits include the remarkable bio-
whether they mark any particular pathophysiological process. It has availability of energy and nutrients, the presence of non​nutritional
been agreed that the presence of pitting oedema is the archetype of factors, protective factors, and growth factors.
qualitative change, identified as kwashiorkor in the Wellcome classi-
fication and now called oedematous malnutrition. In milder forms,
oedema might be restricted to the limbs, but in more severe forms Screening: Identification and prevention
it embraces the entire body. Obtaining a reliable measure of body
weight is difficult in the presence of oedema, because of the uncer- Malnutrition is a preventable condition, and the early identification
tain contribution of oedematous fluid. The overall appearance might of those at risk and the implementation of interventions that correct
be of a child who superficially appears full, but has evident wasting underlying problems and prevent further deterioration are central
below the oedema when examined carefully with the clothes re- to strategies for effective care. Early growth failure can be detected
moved. The extent of poor appetite or anorexia may be elicited by by regular weighing, as an integral part of immunization and other
history, but a formal appetite test should be carried out if there is health programmes. A series of plotted weights is most valuable,
any uncertainty. and intervention is required for those whose weight crosses two
1884 SECTION 11 Nutrition

growth centiles on successive measurements. If measurements are related directly to the food consumed, but none of which can be
only available for a single time point, then height for age, weight easily understood simply by a consideration of food:
for height, or mid upper-​arm circumference provides an indication
• reductive adaptation
of any past or ongoing growth failure. Advice and demonstration
• inflammatory and immune responses
of best practice in child care and feeding may be sufficient to cor-
rect a mild degree of growth failure, but persistent or more severe • specific nutrient deficiencies
growth failure requires closer investigation to exclude underlying Food helps meet the many needs for normal function, growth, and
problems. Poor anthropometry, with a history of poor appetite and development in childhood, but also the ability to cope with environ-
weight loss, should always be taken very seriously and pursued until mental challenge. A diet that is adequate, but marginal under normal
a cause has been identified and corrected. Severe malnutrition is a circumstances, is inadequate for the increased demands during re-
medical emergency. covery from frequent intercurrent illness with the double burden of
Childhood malnutrition is a clinical problem for the individual, the need to catch-​up growth and to make good the unusual losses
but is also a symptom of ineffective public health policy. Targeted of nutrients during the infective episode itself. The time available
interventions should address the immediate needs of the child, but for successful convalescence before the next bout of infection is too
should also embrace broader considerations. For the child, there is short to adequately make up the deficit.
the need to effectively immunize against infection, recognize and
treat infection in a timely way, and ensure an effective period of nu- Reductive adaptation: Failure to meet
tritional support following infection. For the family, there is the need the body’s usual demands for macronutrients
to enhance the child-​rearing skills of the parents, create a stimu- Reductive adaptation takes place when the demands of the body for
lating environment, acquire and practice simple skills in hygiene energy and nutrients are not adequately met by the dietary intake. The
and food preparation, and strengthen family dynamics and coping general features are similar, regardless of the basis for the inadequate
strategies. For the community, there is the need to improve the eco- intake. It is a general response to preserve essential function, but car-
nomic base of households, increase food purchasing power, increase ries a cost. Normal metabolism takes place within a highly regulated
food security or household food availability, and treat specific nu- environment, through the control and integration of exchange and
trient deficiencies. Sound hygienic practices have to be strengthened turnover among cells and tissues. For the cellular machinery of the
at the group or household level, and where necessary, the amount body to remain functionally intact and operationally effective, it re-
and quality of water and the safe and effective removal of solid waste quires a constant supply of energy and other nutrients. An estimated
improved. Each activity can exert a beneficial effect on growth and one-​third of resting energy expenditure may be consumed through
development. Any one might be relatively easy to introduce, but the the synthesis and degradation of macromolecules such as protein,
real difficulty is to ensure that all are sustained. The need is for a fun- and a further one-​third is associated with the movement of material
damental change in the health culture and the creation of a frame- across membranes (e.g. through the pumping activity of the sodium/​
work of behaviour in which development activities become rooted potassium pump, Na+,K+-​ATPase). These processes represent the in-
and take place as a matter of course. A failure to establish and main- ternal work of the body at cellular level and underlie the functioning
tain an effective system of healthcare leads to a progressive deteri- of all the organs and tissues. They take place continuously, and the
oration in the clinical state of the most vulnerable infants, leading total activity can be measured as energy expenditure. As food con-
eventually to severe malnutrition. The World Bank has identified the sumption is intermittent, the processes are independent of the im-
severe limitation this places on national development, and the need mediate food intake. However, a sustained lack of food leads to
to have effective interventions before 2 years of age if this critical po- progressive impairment of the cellular machinery as damage due to
tential is not to be lost. the wear and tear of normal use can no longer be replaced effectively.

Structure
Aetiology and pathophysiology When food consumption is significantly reduced, metabolic pro-
cesses continue to enable the body to function, and the energy to
Children may become malnourished simply because there is not support these processes is derived from reserves within the body.
enough food available. Community-​based interventions place em- The body is in negative energy balance, and tissue mass cannot be
phasis on providing adequate amounts of food of high nutritional maintained, leading to loss in weight. The losses are uneven between
value, if necessary as ready-​to-​use therapeutic-​foods, but sick mal- tissues, with major losses in subcutaneous fat and muscle, and rela-
nourished individuals have no appetite for food. It seems paradox- tive preservation of the metabolically more active visceral tissues.
ical that a child who has obviously lost weight and needs to eat may One important consequence is that heat generated by muscle is
refuse food even when it is readily available. If food is forced, there reduced, and at the same time, insulation in the skin is impaired
is the possibility that the child will become worse, or even die. In leading to greater heat loss. The altered body composition under-
managing severe malnutrition, appetite is one of the most important lies all anthropometric methods that are used to assess nutritional
symptoms. A loss of appetite is an important protective mechanism status. In addition to the changes in mass, efficiencies in the utiliza-
against consuming food, which is likely to stress the systems of the tion of energy have to be found.
body. In experimental studies, there are two major biological reasons
why appetite is lost: a deficiency of a specific nutrient and infection. Function
Severe malnutrition is a disorder that results from the interaction Efficiencies are achieved by reducing the amount of work carried
of three distinct but related processes, each of which appears to be out by the body. External work is reduced by decreasing physical
 11.4 Severe malnutrition 1885

activity. Internal work is reduced by decreasing cellular metabolic Skin

activity, with subsequent effects upon tissue function. Significant The skin wastes, loses its ability to retain heat, and readily becomes
efficiencies might be achieved for the major energy-​consuming breached and infected.
processes such as membrane pumping, protein turnover, and cel-
lular replication. The relative distribution of potassium in the intra- Immune system
cellular space and sodium in the extracellular space is fundamental There is increased exposure to pathogens and a decreased capacity
to maintaining the chemical environment of cells. As potassium to respond (inflammation and immune response—​see following
tends to leak out of the cell and sodium tends to leak into the cell, paragraphs).
for the cell membrane to maintain the effective partitioning of elec-
trolytes requires that sodium is pumped out of the cell in exchange Liver
for potassium, consuming ATP. The cell membrane tends to be- There is downregulation of synthetic and excretory processes. The
come more ‘leaky’ in malnutrition as its lipid composition changes, reduced functional reserve makes it more difficult to maintain
and the Na+,K+-​ATPase is down-​regulated as one way in which to glucose homeostasis in the face of increased bacterial exposure.
reduce energy expenditure. Therefore, compared with normal, all Intermediary metabolism is impaired, and transport proteins for the
people with malnutrition have reduced intracellular potassium and delivery of lipid, vitamins, and minerals to other parts of the body
increased intracellular sodium, hence decreased total body potas- are reduced. The formation of clotting factors is impaired. Reduced
sium and increased total body sodium, which is not necessarily bile and bile salt formation affect digestion. Metabolism and clear-
identified on standard biochemical tests. The ability to maintain ance of drugs, toxins, and xenobiotics is also reduced.
protein synthesis is fundamental but energetically expensive; en-
ergetic efficiency requires a reduction in protein synthesis, which Cardiovascular system
is not divided equally among tissues. Liver normally accounts for A reduction in the functional reserve of the heart, slower pulse, and
about 25% of protein synthesis, with the synthesis of nutrient trans- increased circulation time make heart failure more likely if excess
port proteins playing a critical role in the delivery of lipid, minerals, fluid is given intravenously. There is poor circulatory control, with a
and vitamins to the other tissues. Reduced synthesis of nutrient tendency to reduced intravascular volume with an expanded inter-
transport proteins may save energy, but at the cost of reduced de- stitial fluid space.
livery to peripheral tissues (e.g. limited synthesis of apolipoproteins Iron is an integral part of haemoglobin in red blood cells, involved
limits the delivery of lipid to peripheral tissues and enhances the in the transport of oxygen from the lungs to the tissues. The mass
accumulation of lipid in liver). Cellular replication is energetic- of red cells is related to the amount of oxygen that has to be trans-
ally demanding, requiring the ready availability of all nutrients. ported, which, in turn, relates to the mass of active lean tissue. As
A reduction in cellular replication provides efficiencies in energy part of reductive adaptation, there is a decrease in the lean tissue
and nutrient use but impairs the function of systems critically de- of the body with an associated decrease in the red cell mass. The
pendent upon cellular replication: the skin, gastrointestinal tract, iron that is released from haemoglobin is not required immediately
respiratory tract, and immune system. for the formation of more red cells. The level of iron in the body is
controlled by the rate at which it is absorbed from the gastrointes-
Functional and metabolic cost of reductive adaptation
tinal tract, as, once in the body, there are no recognized mechan-
The function of the cells in all tissues is affected by reductive adap- isms through which iron can be lost. The iron released from red cells
tation. With relative protection of more vital functions, the cost is therefore cannot be excreted and is placed into storage. Free iron is
a reduction in those functions that are not immediately vital, but highly reactive and acts as a focus for uncontrolled excess generation
which provide the functional reserve capability that enables the of free radicals, thereby damaging other cellular components. Excess
metabolic flexibility to respond to a changed internal environment iron is stored in the liver, bound to ferritin. A demand for ferritin
or a challenge from the external environment. As a consequence, synthesis is energetically expensive and diverts amino acids from
changes that would be readily managed in the normal state present the formation of other proteins. As part of reductive adaptation, the
a metabolic stress in the reductively adapted state. What would nor- ability to effectively sequester iron in a chemically quiescent state is
mally be a modest challenge can induce a major metabolic perturb- impaired.
ation. Reductive adaptation represents the loss of reserve capacity,
which leads to increased metabolic brittleness and vulnerability. Renal
The cellular machinery is no longer capable of responding effect- There is decreased functional capacity of the kidney, with an im-
ively to the usual challenges. There is a change in the function of paired ability to concentrate, dilute, or acidify urine.
all systems.
Muscle
Gastrointestinal tract Muscle mass is reduced, and muscle function impaired by reduced
There is loss of mucosa and submucosal tissues, loss of gastric potassium, which together lead to reduced generation of heat.
acidity, and a reduced capacity for digestion and absorption. This
leads to impaired bioavailability of nutrients from food, decreased Brain
transit time, and predisposition to small bowel bacterial overgrowth. Brain function is relatively well preserved. Nevertheless, there is
An impaired ability to repair and maintain the integrity of the endo- blunting of higher functions with decreased mentation, apathy, and
thelium predisposes to bacterial translocation and overexposure to depression, and impaired control of hormonal and integrative re-
endotoxins. sponses. There is a decrease in activity, poor work performance, and
1886 SECTION 11 Nutrition

a decrease in discretionary activities, which together contribute to a • Bone acts as a very effective buffer for many nutrients and there-
slowing of learning. fore severe total body depletion can develop without obvious bio-
chemical change or loss of function (e.g. magnesium).
Infection: The inflammatory and
• During an inflammatory response, redistribution of nutrients
immune responses
within the body makes standard tests for nutrient deficiency very
Survival in a potentially hostile world requires effective non​specific difficult to interpret (e.g. vitamin A, zinc, or iron).
and specific defence mechanisms. Non​specific physical barriers
Infection causes an unbalanced loss of nutrients, which may be ob-
(skin and mucous membranes) and chemical protection (gastric
vious in association with diarrhoea and vomiting, or may be more
acidity, secretions such as tears and mucins) depend upon cellular
subtle as in the increased urinary losses of vitamin A and zinc which
replication, which is less well maintained during reductive adapta-
are an integral feature of the acute-​phase response. For an individual
tion, and even minor damage leads to a breach that is not repaired.
consuming a diet that is marginal in one or other nutrient, increased
Local damage with bacterial invasion usually elicits local inflamma-
losses may make the critical difference to achieving balance, which
tion, a systemic or acute-​phase response, and a specific immune re-
cannot be restored unless additional nutrients are provided during
sponse. The mounting, coordination, and regulation of an effective
the convalescent period. All cellular functions are likely to be af-
response require energy, increased cellular replication, and pro-
fected to a greater or lesser degree by specific deficiencies, but one
tein synthesis. The changes in hormones and cytokines associated
process that is of special importance is the ability to cope with free
with reductive adaptation impair the establishment and control of
radicals or oxidation-​induced cell damage.
normal inflammatory and immune responses. The localized signs
of tissue damage or infection—​enlarged lymph nodes, enlargement Antioxidant protection
of the spleen or liver, and the normal features of the acute-​phase re-
In severe malnutrition, there is a major imbalance between the po-
sponse (fever, rapid pulse, and respiration)—​are blunted or lost in
tential for damage induced by free radicals and protective antioxi-
malnutrition, making diagnosis more difficult.
dant systems. Infection, oxidative burst, and free iron all contribute
Loss of appetite is a central feature of a more severe acute-​phase
to an increased potential for damage. Mortality is greatest in those
response, as the body raids its own tissues for the nutrients it re-
with an obvious impairment of the antioxidant defences. Children
quires to satisfy this unusual demand. There is a shift from the
with oedematous malnutrition have severely reduced concentra-
usual pattern of protein synthesis, with less emphasis on growth.
tions of glutathione in blood, and mortality is highest in those with
As muscle wastes, the amino acids are made available for the syn-
impaired activity of glutathione peroxidase. Although the pattern
thesis of proteins for the immune system, and the liver shifts from
varies with location, deficiencies of micronutrients are common and
synthesizing large amounts of nutrient transport proteins to the for-
result in impaired cell function and membrane damage. The many
mation of acute-​phase response proteins, which limit cell damage
layers of antioxidant protection, which are specific for each compart-
and help repair. Intravascular albumin is redistributed to the third
ment of the cell, provide a measure of safety. However, the system
space, leading to a reduced plasma albumin concentration. A low
is potentially vulnerable to deficiencies or limitations in multiple
plasma albumin is frequently seen in malnourished people and is
micronutrients (e.g. niacin, folate, thiamine, riboflavin, cobalamin,
indicative of ongoing infection rather a dietary deficiency of protein.
ascorbic acid, carotenoids, tocopherol, selenium, zinc, copper, mag-
Correcting the problem requires that the underlying infection be ef-
nesium). A deficiency might not be readily identifiable, either clin-
fectively treated, not that dietary protein be increased. The cells of
ically or biochemically, and a high index of suspicion is required.
the inflammatory and immune systems increase their utilization of
glucose, with increased gluconeogenesis from amino acids. A feature Oedema
of the acute-​phase response is a profound change in the handling of
Oedema reflects an inability to maintain the correct distribution
micronutrients. There is a block in the absorption of iron. Net tissue
of fluid in the intracellular space, the vascular space, and the inter-
breakdown releases components for which there is no immediate
stitial space, and is a final common pathway representing a loss
use. The circulating concentrations may be reduced (iron and zinc,
of metabolic control. Incorrect approaches to the management of
which are sequestered in the liver), or increased (copper), and there
oedema—​the use of diuretics or of high-​protein diets—​are among
may be increased losses from the body in urine or stools (zinc and
the commonest reasons for increased mortality. The rationale be-
vitamin A). In childhood, diarrhoea is a frequent accompaniment of
hind the incorrect approach to management presumes that oedema
infection, which adds an excessive loss of nutrients from the body,
is simply the consequence of hypoalbuminaemia, itself the result
especially potassium, magnesium, zinc, and vitamin A.
of inadequate dietary protein. There are profound perturbations of
Specific nutrient deficiencies protein metabolism in kwashiorkor, but these are due to concurrent
infection, loss of appetite, and increased losses of nitrogen in stools
Deficiency of specific nutrients is the most difficult aspect of severe
rather than a diet deficient in protein. A low plasma albumin usu-
malnutrition to manage effectively. Whereas in classical deficiency
ally indicates an acute-​phase response to an unrecognized infection.
states, inadequate dietary intake is usually the major underlying cause,
Treatment with a high-​protein diet or infusions of albumin does not
in severe malnutrition, it is the failure to correct excessive losses of nu-
correct the oedema, but does increase mortality. A low plasma con-
trients, which leads to major imbalances. Major losses of intracellular
centration of albumin might contribute to formation of oedema, but
nutrients can be difficult to identify reliably, for three reasons:
is seldom the sole or primary cause. Although diuretics exert a direct
• Losses of intracellular content may not be readily identified using effect on cell membranes, giving a diuretic is less likely to be effective
standard biochemical tests on blood (e.g. potassium). if the intravascular space is reduced. Diuretics that lead to increased
 11.4 Severe malnutrition 1887

Table 11.4.4 Major factors that contribute to the development of pitting oedema in severe malnutrition

Hypoalbuminaemia Associated with impaired protein metabolism, infection or stress, impaired hepatic function, toxic damage
Salt and water retention Potassium deficiency, phosphate deficiency, acid–​base imbalance, impaired renal function
Impaired membrane function Altered composition (phospholipid composition and fatty acid profile). Impaired or downregulation of Na+K+-​
ATPase. Free-​radical-​induced damage

urinary losses of potassium make the underlying problem of a defi- deficiency in the face of a potassium deficiency. They have to be cor-
ciency of body potassium even worse. rected together.
The normal distribution of water between the different body com-
partments is tightly controlled through several interlinked factors.
Disruption of one or more of these factors may lead to the develop- Principles of facility-​based care
ment of oedema, and will need to be corrected for the oedema to be
effectively cleared (Table 11.4.4). Phases of treatment: The 10 steps
Potassium deficiency leads to retention of sodium. Altered mem- (See Fig. 11.4.1 and Table 11.4.5.)
brane structure and reduced activity of Na+,/​K+-​ATPase allows One of the important reasons why mortality from malnutrition
intracellular potassium to fall and intracellular sodium to rise. has not been reduced in many centres is because the primary ob-
All malnourished individuals should be presumed to be deficient jective of treatment has been to try to correct the obvious weight
in potassium and to have excess intracellular sodium, regardless deficit. In attempting to replace the lost tissue as soon as possible,
of the composition of the plasma measured on routine biochem- generous intakes of food have been provided, encouraged, and even
istry. Indeed, plasma sodium concentrations might be low and forced. If appetite is poor, or anorexia is a feature, then generous
it is tempting to give extra sodium, which is absolutely the wrong force-​feeding by nasogastric tube has been used. This can be very
thing to do. There is more than enough sodium in the body, but it dangerous. The 10-​step approach to treating malnutrition clearly
is in the wrong place. A direct approach that seeks to correct the identifies that treatment must be divided into different phases: the
disordered biochemistry is less likely to succeed than an approach cellular machinery has to be repaired before it can be used to enable
which recognizes that the fundamental problem is disordered cel- tissue growth.
lular function. Similar factors lead to cellular damage in any severely Two clinical features that are directly related to specific nutrient
undernourished person, and by treating the malnutrition and re- deficiencies and are particularly difficult to manage are oedema and
pairing the metabolic machinery of the cells of the body, oedema will persistent diarrhoea. Any specific nutrient deficiency impairs cel-
be effectively treated. What is required are generous supplements of lular function and increases the risk of infection. Infection increases
potassium and correction of the underlying membrane dysfunction, nutrient losses through tissue wasting as an intrinsic feature of the
which enables fluid and electrolyte balance to be restored. There is acute-​phase reaction and as vomitus or diarrhoea. Increased gen-
a close metabolic interdependence of potassium and magnesium, eration of free radicals is part of the body’s attempts to deal with
both of which are readily lost from the body in diarrhoea. It is ex- infecting organisms, and deficiencies of specific micronutrients dir-
tremely difficult to correct potassium deficiency in the presence of ectly impair the ability to cope with free-​radical generation. Even if
an associated magnesium deficiency, or to correct a magnesium an individual recovers from an infection, nutrients which have been

Table 11.4.5 Outline clinical management of severe malnutrition

1. Resuscitate
Manage infection, fluid and electrolyte imbalance and shock: oxygen, glucose, reduce heat loss, give antibiotics, maintain circulation, treat vitamin A deficiency
2. Stabilize
Control energy and protein intake at maintenance: 400 kJ/​kg/​day (100 kcal/​kg/​day), 1–​1.5 g protein/​kg/​day
Small frequent meals: eight meals every 3 h, or six meals every 4 h, throughout 24 h
Correct deficiencies of specific nutrients by addition to food: potassium (4 mmol/​kg/​day), magnesium (0.4 mmol/​kg/​day), folic acid (1 mg/​day), zinc (2 mg/​kg/​day),
copper (0.3 mg/​kg/​day), multivitamin supplement
Treat bacterial infection: broad spectrum antibiotics, cotrimoxazole or ampicillin with gentamycin
Treat small bowel overgrowth with metronidazole
Treat helminth infections with mebendazole
Transfuse for severe anaemia
Topical treatment and care for skin lesions
Exclude tuberculosis and HIV
Give sensory stimulation and emotional support
3. Weight gain (rapid catch-​up growth)
Ad libitum intake to achieve at least 600 kJ/​kg/​day (150 kcal/​kg/​day), 4 g protein/​kg/​day
Continue with micronutrient supplements
Add supplemental iron
Give sensory stimulation and emotional support
1888 SECTION 11 Nutrition

depleted from the body are not easily replaced. This has two im- there is competition from other tissues or functions (e.g. in order to
portant effects. First, the individual is deficient in a specific nutrient maintain body temperature or to deal with infection). Malnourished
and carries the specific and general features of the deficiency, im- individuals generate less heat and have reduced thermal insulation
portantly loss of appetite. Secondly, if the deficiency is severe it may and therefore cool rapidly when exposed. Any attempt to generate
be very difficult for it to be corrected by consuming a normal diet more heat consumes glucose and other energy-​providing fuels.
without the addition of specific nutrient supplements. Under this A normal effective response to infection is a burst of activity in white
circumstance, poor appetite, persistent reductive adaptation, and blood cells, which places heavy demands on available glucose, com-
continued risk of further infection are maintained. peting with the brain and leading to hypoglycaemia, and increasing
If energy is provided in excess of the requirements for mainten- the rate of heat loss leading to hypothermia. Therefore, the triad of
ance, there are few ways in which it can be excreted or handled meta- hypoglycaemia, hypothermia, and infection indicates a very serious
bolically. Any significant excess is deposited as new tissue, either as situation in which the body is no longer able to adequately main-
cells or as cells filled with fat. There is a considerable underlying tain the supply of glucose to support essential functions. The treat-
drive to form new cells, but in addition to energy this requires the ment is to increase the supply by giving oral or intravenous glucose,
availability of all the nutrients contained within the cell structure. reducing competing demands through decreasing the amount of
When specific deficiencies have not been corrected individual nu- heat lost, and by effectively treating infections. To deliver glucose
trients are limiting for cell formation and it is not possible to handle and oxygen to the brain effectively requires an adequate circulation,
the excess energy through the formation of new tissue. The excess which is compromised by intravascular dehydration. The correction
energy creates a very serious metabolic upset (see ‘Recovery syn- of dehydration is closely associated with the correction of electro-
drome’, later). Therefore, during the period when nutrient deficien- lyte imbalances, with energy homeostasis, and with normal cellular
cies are being corrected and infections treated, it is important to give function. Care has to be taken to ensure that each is corrected in
sufficient energy to cover the needs of the body, but not so much that concert with the other to ensure that imbalances do not arise. All
the body is forced to make new tissue. This is the basis for identifying malnourished individuals are deficient in potassium and carry ex-
the different phases of treatment: first to repair the machinery and cess sodium.
gain control of metabolism by providing only enough energy to
satisfy the needs for maintenance, but not enough to drive growth. Specific micronutrients: Vitamin A, zinc, and iron
Managing reductive adaptation, specific nutrient deficiencies, infec- Iron is highly reactive chemically, and fulfils many important func-
tion, and free-​radical-​induced membrane and cellular damage lie at tions related to the generation of energy for normal cellular function.
the heart of the problems associated with immediate care during the High reactivity, if not adequately controlled, carries the potential for
resuscitation period. cell damage. Red cell mass reduces in malnutrition as the lean body
A loss of appetite is an important protective mechanism limiting mass decreases. The iron is not used for further haemoglobin forma-
food consumption, which is likely to stress the systems of the body. tion and cannot be excreted, so has to be stored innocuously, as any
Hence the loss of appetite is a cardinal sign of an underlying meta- unbound iron is liable to increase oxidative cell damage. In severe
bolic problem that is ongoing. If the problem is identified and cor- malnutrition, there is increased stored iron and free iron. The avail-
rected, then appetite is restored very quickly. Severely malnourished able iron is not used for haemoglobin formation, and giving iron
children may have a profound loss of appetite due to a combination supplements to treat anaemia simply adds to the load, stresses the
of infection and deficiencies of specific nutrients, which interact to system further, and increases mortality, especially in the presence of
make the problem worse. Correcting the loss of appetite is central infection such as malaria. Initially, it is more important to repair and
to effective care. The restoration of appetite marks the restoration of restore the capacity to cope with free radicals by improving vitamin
metabolic control and is a key component of therapy and a marker and trace element status. Later, when the acute problems have been
of progress. Once the emergency treatment required to resuscitate resolved, the iron will be removed from storage and used to form
the child has been completed, the emphasis of care is to treat the new tissue. As stored iron is used up, supplemental iron will have to
underlying problems that are associated with a loss of appetite. be provided to keep pace with the rate of tissue demand.
Blindness and other eye signs of overt vitamin A deficiency are
Resuscitation common in many parts of the world. Less obvious changes lead to
Severely malnourished children present a medical emergency be- impaired integrity of mucosal surfaces in the gastrointestinal and
cause of two sets of problems: the deadly triad of infection, hypo- respiratory tracts, lowering resistance to gastroenteritis and respira-
thermia, and hypoglycaemia, and marked fluid and electrolyte tory infections. During infection, vitamin A is lost from the body,
disturbances (Table 11.4.5). severe deficiency may develop rapidly, and the eye signs often deteri-
orate during early treatment. In areas where vitamin A deficiency is
The deadly triad: Hypoglycaemia, hypothermia, and infection common, a large dose of vitamin A given very early in the treatment
Brain cells are absolutely dependent upon a regular supply of glucose is an urgent necessity.
and oxygen to maintain the availability of ATP. Death occurs within Zinc is required for the function of a wide range of enzymes, and a
5 min if the supply of either is impaired, through poor circulation, deficiency has widespread effects. A shortage of zinc impairs the rep-
reduced respiration, or low blood glucose. The glucose required is lication of cells such as the gut mucosa, leading to further mucosal
either made in the liver or taken in the diet. Reductive adaptation damage and increased diarrhoea. Zinc deficiency leads to diarrhoea,
limits the capacity for glucose formation and delivery, and a regular and diarrhoea leads to zinc deficiency. Similar changes take place in
dietary supply is required if blood concentrations are to be main- damaged skin leading to ulcerated skin which is readily damaged
tained. The availability of glucose for the brain can be impaired if with mild trauma.
 11.4 Severe malnutrition 1889

Persistent diarrhoea associated with an overloaded circulation. This may progress to vas-
Many malnourished children have diarrhoea, which can take time cular collapse with abdominal distension as the circulating vascular
to settle. The diarrhoea may be infective in origin or have an in- volume is poured into the bowel as profound secretory diarrhoea.
fective component, due to viruses, bacteria, fungi, or helminths. The first sign of the onset of the recovery syndrome is an increase in
However, diarrhoea that has persisted for any time will also have an pulse and respiratory rate. If food continues to be consumed at the
element due to specific nutrient deficiencies (zinc and vitamin A) same rate, the load on the heart will progress to heart failure. This is
or chemical injury (bile salt deconjugation). With continued diar- a medical emergency, and it is vitally important that the food intake
rhoea, there are ongoing losses of nutrients. Few bacteria exist in the is reduced or stopped. If the changes are identified early and are rela-
healthy small intestine, but small bowel overgrowth develops readily tively mild, then food intake should be reduced. If the condition has
in malnutrition, due to a combination of gastric achlorhydria, re- advanced and is severe, then it may be necessary to stop all food for
duced motility (potassium and magnesium deficiency), leading to 12 to 24 h. The problem will then resolve.
bile salt deconjugation, damaged mucosa, and bacterial transloca- Replacing lost weight
tion. For the bowel to repair and re-​establish its resistance requires
adequate nutrients, especially zinc, vitamin A, and folates. Thus, the The ultimate objective of treatment is to replace the lost tissue.
effective treatment of chronic diarrhoea requires a three-​pronged Cellular hypertrophy and hyperplasia are critically dependent
approach: correction of potassium deficiency, treatment of bacterial upon and limited by the available energy and nutrients. For tissue
overgrowth (with metronidazole), and effective repletion of specific of average composition, the formation of 1 g tissue requires 20 kJ of
nutrient deficiencies (such as zinc, vitamin A, and folate). energy. A normal 1-​year-​old infant gains 1 g/​kg body weight per day,
but for catch-​up weight gain during recovery from malnutrition, it is
Management possible to form tissue at up to 20 g/​kg per day, by consuming an add-
The objectives of the resuscitation phase are to stabilize vital func- itional 400 kJ/​kg per day. Achieving this requires an energy-​dense
tions, by giving oxygen, supporting respiratory and cardiac func- diet, which is consumed throughout the 24 h of the day. Energy is
tions, and correcting fluid imbalance, to ensure that adequate necessary but not sufficient for new tissue formation. The nutrients
amounts of glucose are delivered to the brain. Body temperature needed for the formation of cell membranes and protoplasm are re-
must be maintained by maintaining glucose supply to the system, quired in adequate amounts and suitable proportions. As the lean
limiting heat loss through the skin, and starting to control infection. body mass grows it has an increased need for oxygen, and the red
As the capacity for the body to carry out metabolic functions is im- blood cell mass increases. Iron is taken out of storage to form new
paired, external support has to be supplied regularly on a 24-​h cycle. red cells, and eventually these stores are depleted with the need to
The regular intake of small amounts over 24 h (especially at night) add supplemental iron to the diet. There is an increased demand for
is a very effective way of achieving this (Table 11.4.5). All infections amino acids to meet the needs of new tissue formation. It is safe to
must be treated. Specific nutrient deficiencies must be corrected, but allow quite large intakes of protein. As the amino acids are deposited
no iron or extra sodium should be provided. The metabolic state in tissue and do not accumulate in the free form, there is no risk of
must be controlled by limiting the intake of energy and protein to toxicity. However, meeting the pattern of amino acids required by
that required to maintain body weight, and ensuring that there is the body will require the endogenous biosynthesis of relatively large
no excess (see following paragraphs). These steps will enable the re- amounts of the ‘nonessential’ amino acids in the body, which in itself
pair of the metabolic machinery and allow cellular function to move will require the generous availability of minerals and vitamins.
towards normal. The response to a successful intervention will be a
return of appetite; the patient will feel better, and smile.
Important general aspects of care
Recovery syndrome
Limited availability of one or more nutrients leads to competition The physical care that is provided to correct the biochemical, meta-
between all cells for the little available. Some nutrients become rela- bolic, and infective problems is critical for success. However, there
tively more deficient, upsetting the balanced function between tis- is also a need to address the broader needs of the child for healthy
sues, and the clinical signs of a deficiency become more obvious. development. In part, this is provided by creating a warm, caring
There is a similar explanation for why the clinical signs of a deficiency environment; in part, by suitably structured activities that provide
are not always apparent, even though the body might be particularly an appropriate level of stimulation to encourage brain function to
deficient. During reductive adaptation, the demand for nutrients recover and develop.
is decreased, and the signs of a deficiency are masked. Signs of de- All aspects of care need skill and sympathy. The severely mal-
ficiency become exposed in rapidly dividing tissues, when the de- nourished child is desperately sick and must be nursed as a crit-
mand for nutrients is greatest. Vitamin A and zinc are examples, but ically ill child with minimum physical disturbance. With correct
the same principles apply to many other nutrients, especially the B treatment, progress can be very rapid, and it is desirable to involve
vitamins. The recovery or refeeding syndrome develops when indi- the parents and siblings, to encourage and demonstrate preferred
viduals who have undergone reductive adaptation are suddenly pro- childcare practices. This will facilitate the transfer between hos-
vided with a relative excess of food. Excess energy drives metabolism pital and home, and make it more likely that the practices become
while specific nutrient deficiencies are inadequately corrected, and embedded. Less seriously ill children can be effectively managed
the metabolic machinery is still compromised. The syndrome may as outpatients, using the same principles and approach to the man-
vary in its details, but consists of left-​and right-​sided heart failure agement decisions.
1890 SECTION 11 Nutrition

Valid International (2006). Community-​based Therapeutic Care: A

FURTHER READING
Field Manual. https://​www.fantaproject.org/​sites/​default/​files/​re-
Black RE, et al.; Maternal and Child Undernutrition Study Group sources/​CTC-​Field-​Manual-​Oct2006-​508.pdf
(2008). Maternal and child undernutrition: global and regional ex- Waterlow JC (2006). Protein-​energy malnutrition. Smith-​Gordon,
posures and health consequences. Lancet, 371, 243–​60. London.
Black RE, et al.; Maternal and Child Nutrition Study Group (2013). WHO (1995). Physical status: the use and interpretation of anthropom-
Maternal and child undernutrition and overweight in low-​income etry. Report of a WHO Expert Committee, WHO Technical Report
and middle-​income countries. Lancet, 382, 427–​51. Series 854. World Health Organization, Geneva.
de Onis M, et al. (2007). Comparison of the WHO child growth stand- WHO (1999). Management of severe malnutrition: a manual for physi-
ards and the CDC 2000 growth charts. J Nutr, 137, 144–​8. cians and senior health workers. World Health Organization, Geneva.
Grantham-​McGregor S, et al. (2007). Developmental potential WHO (2013). Guideline. Updates on the management of severe acute
in the first 5 years for children in developing countries. Lancet, malnutrition in infants and children. World Health Organization,
369, 60–​70. Geneva.
Picot J, et al. (2012). The effectiveness of interventions to treat severe WHO/​UNICEF (2000). Management of the child with a serious infec-
acute malnutrition in young children: a systematic review. Health tion or severe malnutrition: guidelines for care at the first-​referral level
Technol Assess, 16, 1–​316. in developing countries. World Health Organization, Geneva.
Ricci C, et al. (2018). Determinants of undernutrition prevalence in WHO/​UNICEF (2009). WHO child growth standards and the identi-
children aged 0-59 months in sub-Saharan Africa between 2000 fication of severe acute malnutrition in infants and children. A joint
and 2015: a report from the world bank database. Public Health Nutr, statement by WHO and UNICEF, 2009. World Health Organization,
11, 1–​9. doi: 10.1017/S1368980018003415 Geneva.
UNICEF/​WHO/​WBG (2015). Levels and trends in child malnutrition. World Bank (2006). Repositioning Nutrition as Central to
Joint child malnutrition estimates. Key findings of the 2016 edition. Development: A Strategy for Large Scale Action. Directions in
UNICEF, WHO, WBG; New York. Development. World Bank, Washington, DC. https://​www.intf.org
11.5
Diseases of affluent societies and
the need for dietary change
J.I. Mann and A.S. Truswell

ESSENTIALS • Vegetables, fruit, and pulses (which are also sources of protein)
and whole-​grain cereals should provide most of the carbohydrate
Nutritional problems of many countries depend increasingly upon • Intake of salt and foods rich in salt should be reduced so that so-
the stage of technical and economic development rather than geo- dium intake is below 100 mmol/​d (6 g NaCl)
graphical location. People in affluent societies have ready access to • Alcohol should be consumed in moderation (1 to 2 drinks/​day) by
food all year round. Traditional dietary patterns are being eroded and those who choose to drink
in many affluent societies replaced by diets which are higher in fats
and/or free sugars and consequently more energy dense. Obesity is All dietary patterns should include a wide variety of foods to en-
the most obvious and important nutritional disease in affluent soci- sure a nutritionally adequate diet
eties, with comorbidities including type 2 diabetes, coronary heart
disease, hypertension, some cancers, gallstones, osteoarthritis, and
obstructive sleep apnoea. Obese people may also be disadvantaged Introduction
by social, economic, and psychological effects. Particular dietary
constituents promote or protect against coronary heart disease by The current nutritional problems of many countries depends more
their effect on cardiovascular risk factors, and some promote or pro- upon the stage of technical and economic development than geo-
tect against various cancers. graphical location (Table 11.5.1). Until about 10 000 years ago our
While those at the highest personal risk are likely to show the ancestors were hunter-​gatherers, most of whom collected a variety
greatest individual benefit from dietary and lifestyle changes, national of plant foods, but also ate meat and fish. They ate little or no salt,
rates of nutrition-​related diseases will best be reduced if changes are alcohol, milk (other than breast milk), cereal, and no free sugar apart
made by the population at large. The main purpose of such recom- from honey. Studies of contemporary hunter-​gatherers suggest that
mendations is to reduce the risk of morbidity and mortality in those malnutrition was uncommon unless illness or injury supervened,
who are in the prime of life. Even greater reduction in morbidity and and that the noncommunicable diseases (NCDs) of affluent societies
mortality and an improvement in life expectancy may occur in suc- were rare. However, the facts that life expectancy was short and that
ceeding generations if they have reduced lifetime exposure to risk today’s food supply bears little resemblance to the food consumed by
factors related to lifestyle. our ancestors suggest that the diet of hunter-​gatherers does not ne-
Many different dietary patterns are compatible with widely ac- cessarily provide indicators as to appropriate dietary practices in the
cepted nutritional recommendations for overnourished societies. 21st century. Furthermore, a hunter-​gatherer type diet would not be
More recent recommendations include a wider acceptable range sustainable today.
of macronutrient intakes than had previously been suggested. There In most parts of the world hunter gatherers acquired a more set-
are multiple sources of nutritional advice, not all based on sound tled existence and became predominantly agriculturists and pastor-
science. The following statements are representative of universally alists. Where traditional dietary patterns based on a variety of food
accepted advice: sources were retained, diet-related NCDs and premature mortality
• Energy balance is essential for body weight control, hence energy-​ from them remained relatively uncommon. However where there
dense foods high in fat and sugars should be restricted to avoid has been reliance on a single staple food which may lack essential
excess weight gain nutrients or fail, malnutrition may result. A similar situation may
• Wide ranges of fat (25–​40% total calories) and carbohydrate (45–​ occur, in developing countries where many people live in urban
60% total calories) intakes are acceptable provided appropriate slums or periurban shanties, often in overcrowded insanitary ac-
food sources predominate commodation, or in relatively affluent societies where poverty and
• Saturated fat and trans-​unsaturated fat intake should together affluence may co-exist. People have lost contact with the land and
provide less than 10% total energy, the remainder being from cis their food traditions. Food is expensive. Mothers of young chil-
mono-​and polyunsaturated fat dren are required to go out to work and often cannot breastfeed.
Undernourished young children are susceptible to infectious diseases
1892 SECTION 11 Nutrition

Table 11.5.1 Nutrition issues at different stages of technical and pharmaceutical (e.g. antioxidant nutrients given as a tablet), and some
economic development trials have been undertaken to study the effects of dietary manipulations
on relatively common nutrition-​related diseases (e.g. diabetes, hyper-
Hunter-​gatherers Occasional seasonal hunger
tension). Clinical trials to demonstrate the effect of various dietary
Malnutrition uncommon
measures on the risk of coronary heart disease have been undertaken
General nutritional health good and have generated meaningful results when considered in aggregate,
No obesity but the magnitude and duration of trials required to demonstrate the ef-
No hypertension fect of dietary change on cancer are such that few have been attempted.
Low serum cholesterol Much research involving the role of diet in chronic degenerative
disease has centred around the effects of diet on modifying risk fac-
Peasant agriculturists Single crop staple
tors rather than the disease itself. For many chronic diseases there are
Clinical disorders may result from single or
biochemical or clinical markers of risk. High plasma cholesterol is
multiple nutrient deficiencies
an important risk factor for coronary heart disease, for example, and
Hypertension may occur
high blood pressure is a major risk factor for strokes. Innumerable
Obesity rare studies have examined the role of different nutrients and foods
Urban slum and periurban Inadequate breastfeeding on plasma cholesterol, blood pressure, or other risk factors. Such
shanty town dwellers studies are easier to undertake and cheaper than population-​based
Inadequate food security
Diarrhoea and other infective disorders, studies because far fewer people are studied over a relatively short
especially in young children period of time. They have shown which foods lower cholesterol and
Marasmus so should help protect against coronary heart disease.
Obesity and alcoholism may occur
Epidemiological studies have also played a pivotal role in establishing
the role of nutritional factors as determinants of NCDs and the poten-
Affluent societies Energy-​dense diets, high in fats and sugars
tial of dietary modification in risk reduction. The first clue to the as-
Physical inactivity sociation between a food, or nutrient, and a disease often comes from
Obesity, coronary heart disease, and observing striking differences in disease incidence between countries
hypertension common
(or groups within a country) that correlate with differences in nutri-
Malnutrition may occur in frail elderly and tional intake. Sometimes, dietary changes over time in a single country
sick people
have been found to coincide with changes in disease rates. Such obser-
vations give rise to hypotheses about possible diet–​disease links, ra-
ther than proof of causation, because many potential causative factors
and may develop marasmus. Some adults are excessively lean, others may be confounded by parallel dietary changes. Case–​control studies
become obese, and excessive intake of alcohol is frequent. have sometimes been used as a rapid and inexpensive way of testing
A totally different situation prevails among the prosperous people hypotheses. These have been of value when comparing biochemical
in affluent societies, especially when traditional dietary practices have markers of nutrient intakes in the blood of people with (cases) and
been abandoned or modified and increasingly among the affluent without (controls) various diseases, but they are of limited value when
in developing countries. They have access to a wide variety of safe, nutrient intake has been determined by recall of dietary intake.
relatively cheap foods all year round. The environment is generally Prospective or cohort studies avoid the biases involved in asking
conducive to the consumption of a diet which is typically high in fats people to recall past eating habits as information about food intake
and or free sugars and dense in energy. Among such societies deaths and other characteristics are collected well before onset of the disease.
from infectious diseases are infrequent, life expectancy has increased, These have played a key role in identifying nutritional factors involved
and non​communicable diseases, many linked in some way to in- in coronary heart disease and cancer, but even strong nutrient or food
appropriate nutrition, are the major causes of premature death and ill and disease associations can be explained by confounding (i.e. the as-
health. Malnutrition occurs mainly in frail elderly people and the sick. sociation between the nutritional factor and some other disease deter-
minant). Sometimes the confounding can be quantified, but it is never
possible to be absolutely certain that it has not been explained by some
Approaches to the study other factor which has not been measured, viz residual confounding.
of nutrition-​related diseases Given the difficulty in establishing casual associations between
nutrients or individual foods and disease states, a decision as to
The nutritional component of non​communicable diseases is more whether or not to recommend dietary change needs to be based on
difficult to study than classical nutrition deficiency diseases because a portfolio of evidence when evidence from randomized controlled
non​communicable diseases develop slowly and are multifactorial. The trials is not available. Such evidence might include consistent and
practice of evidence-​based medicine ideally requires that an inter- strong associations in longitudinal studies, biological plausibility,
vention recommended for the treatment or prevention of a disease and corroborative experimental evidence in animals and humans.
should be proved to be of benefit in one or more randomized con-
trolled trials. The evidence for the benefit of an intervention may be
strengthened by the aggregation of the results of like studies in a meta-​ Obesity
analysis. However, trials involving nutritional interventions and clinical
endpoints are much more difficult to undertake than those involving Obesity (see also Chapter 11.6) is the most obvious and important
drugs. It is possible to study the effects of a food component given as a nutrition-​
related disease in affluent societies, its comorbidities
 11.5 Diseases of affluent societies and the need for dietary change 1893

including type 2 diabetes, coronary heart disease, hypertension, factors in the aetiology of coronary heart disease and the potential
some cancers, gallstones, osteoarthritis, and obstructive sleep ap- for dietary modification to reduce cardiovascular morbidity and
noea. Obese people may also be disadvantaged by social, economic, mortality in the population as a whole, in individuals at high risk,
and psychological effects. The psychological well-​being of children and in those who have already experienced a cardiovascular event.
may be particularly affected, and childhood obesity has recently Prospective and experimental studies suggest a variety of foods
been recognized as a risk factor for fractures in children. Most of the and nutrients that may be involved (Table 11.5.2). Foods that in-
adverse consequences of obesity are appreciably reduced by weight crease the risk of coronary heart disease when consumed in large
loss, though gallstone formation may not be reduced. amounts probably do so because they are rich in saturated or trans-​
Although the genetic component of obesity is acknowledged, its unsaturated fatty acids. ‘Protective’ foods contain several different
dramatic increase in virtually all westernized countries and many nutrients that may reduce cardiovascular risk. Vegetable oils and
developing countries in recent years provides ample evidence of nuts contain several potentially ‘protective’ fatty acids (linoleic and
overwhelming environmental factors. Physical inactivity is an im- oleic acids). Oily fish is rich in very long-​chain polyunsaturated
portant cause, but frequent consumption of large portions of readily fatty acids (eicosapentaenoic and docosahexaenoic acids). Fruit and
available energy-​dense foods (high in fats and/​or sugars) which vegetables are good sources of antioxidant nutrients, folate, potas-
contribute to an energy intake in excess of expenditure probably sium, and other biologically active substances. Whole-​grain cereals
accounts for much of the global increase in obesity. Frequent con- are good sources of dietary fibre as well as of some unsaturated oils.
sumption of sugar-​sweetened soft drinks (and fruit juice) appears to Data presented in Table 11.5.3, derived from well-​known pro-
enhance excessive weight gain, especially among children. Whole-​ spective studies of cardiovascular disease, provide an indication
grain cereals and cereal products, non​starchy vegetables, and dietary of the extent of the potential cardioprotection and risk afforded by
fibre help to reduce the energy density of the diet, promote satiety, some foods and nutrients. Each of the foods and nutrients listed in
and thus reduce the risk of inappropriate weight gain. Tables 11.5.2 and 11.5.3 has an appropriately favourable or adverse ef-
Current pharmaceutical measures have little to offer in the man- fect on one or more of the cardiovascular risk factors (Table 11.5.4).
agement of obesity. While bariatric surgery results in weight loss and As the global prevalence of obesity increases, risk factors associated
reduction of comorbidities for some obese people, it seems unlikely with excess adiposity (notably dyslipidaemia, dysglycaemia, inflam-
that the epidemic of obesity will be reversed unless the environ- mation) contribute increasingly as ‘causes’ of coronary heart disease.
ment in which we live is made more conducive to appropriate food Thus, it may be appropriate to also consider nutrition-​related causes
choices and more opportunities for physical activity are provided. of obesity as causes of coronary heart disease.
Such measures will also facilitate attempts by individuals to achieve The strongest evidence for recommending dietary change to re-
weight reduction. Reducing the obesogenic environment requires duce risk of coronary heart disease relates to replacing an appreciable
commitment from national and local governments. proportion of dietary saturated fat with polyunsaturated fatty acids.
Despite all of the aforementioned points, there is some cause for Systematic reviews and meta-​analyses of both prospective cohort
optimism in that obesity rates are relatively low among those of a studies and randomized controlled trials suggest a reduction in car-
higher socioeconomic status, and the increase in rates of childhood diovascular events which, in the case of the randomized controlled
obesity appears to have been halted in countries where preventative trials, is proportional to the reduction in total and low-​density lipo-
measures have been implemented. protein (LDL) cholesterol achieved and comparable with benefit
predicted from epidemiological data. LDL cholesterol appears to be
a key risk factor for coronary heart disease, and a similar ‘dose re-
Coronary heart disease sponse’ benefit in terms of cardiovascular risk reduction is seen when
LDL cholesterol is lowered by means of statin drugs. It is unclear why
The totality of evidence from experimental, epidemiological, and meta-​analyses do not show similar cardioprotection when saturated
clinical trial data provide strong evidence for the role of nutritional fatty acids are replaced by monounsaturated fats or carbohydrate,

Table 11.5.2 Foods and nutrients which may protect against or promote coronary heart disease

Protective Promoting
Foods Nutrients Foods Nutrients
• Fruits • Antioxidant nutrientsa, folatea • High-​fat dairy products Saturated fatty acids (especially
• Vegetables • Dietary fibre (non​starch polysaccharide) • Fatty meats myristic and palmitic acids)
Whole-​grain cereals • Dietary fibre (non​starch polysaccharides) Eggs Dietary cholesterol
• Unsaturated fatty acids
Vegetable oils (e.g. sunflower, Unsaturated fatty acids (linoleic, oleic, α-linolenic) Some margarinesb, cooking • Trans-​unsaturated fatty acids
safflower, olive, and canola) oils, confectionery, and • Saturated fatty acids
manufactured foods
Oily fish Eicosapentaenoic and docosahexaenoic acids
Nuts Unsaturated fatty acids (oleic, linoleic), vitamin Ea
Alcohol (moderate amounts only)
a
When present in foods, not supplements.
b
When containing appreciable quantities of trans-​unsaturated fatty acids.
1894 SECTION 11 Nutrition

Table 11.5.3 Age adjusted relative risk of coronary heart disease according to quintile of intake of certain foods or nutrients

Study population Relative risk according to quintile of intake p for trend

1 2 3 4 5
43 757 male health professionals (40–​75 years) Total dietary fibre
(Rimm et al., 1996) 1.00 0.97 0.91 0.87 0.59 <0.001
75 521 female nurses (38–​63 years) Whole-​grain consumption
(Liu et al., 1999) 1.00 0.87 0.82 0.72 0.67 <0.001
84 136 female nurses (30–​55 years) Nuts <0.001
(Bernstein et al., 2010) 1.00 0.73 0.91 0.76 0.68
43 757 male health professionals (40–​75 years) Trans fatty acids
(Ascherio et al., 1996) 1.00 1.24 1.33 1.40 1.57 <0.001

although it may be relevant that monounsaturated fat replacement fish two or more times per week, or a small amount of fish oil taken
was undertaken in only a small number of trials, and trials involving as a supplement, has been shown to reduce cardiovascular death in
carbohydrate replacement did not emphasize the need to consume those with pre-​existing coronary artery disease. Although increased
minimally processed carbohydrate-​containing foods rich in dietary intakes of vegetables and fruit may confer a cardioprotective effect,
fibre which would be more likely to be cardioprotective than rapidly there is no convincing evidence from clinical trials of benefit asso-
digested carbohydrate. ciated with the use of antioxidant nutrient supplements. The role
It is noteworthy that the reduction in coronary heart disease of margarines rich in plant sterols and stanols, which may further
which has been occurring in most Western countries since the 1970s lower dietary cholesterol by preventing absorption and reabsorption
has paralleled the reduction in saturated and increase in polyunsat- of dietary cholesterol, is yet to be established with certainty.
urated fats, although improved medical management of the disease Community programmes aiming to change diet along the lines
and its risk factors and reduction in smoking in some sections of indicated here have been shown to reduce cardiovascular risk fac-
the populations will also have contributed to the trend. Trials that tors and one, the North Karelia Project in Finland, has shown that
have examined potential benefits of dietary manipulations other cardiovascular disease mortality in the intervention county de-
than those designed to lower plasma cholesterol suggest that fur- creased to a greater extent than might have been expected on the
ther clinical benefit might accrue from favourable changes in other basis of experience in other Finnish counties. The availability of
risk factors, but the evidence is less conclusive. Consumption of oily appropriate food choices at reasonable cost is an essential compo-
nent of any programme aimed at reducing cardiovascular risk, since
rates are highest in people of the lowest socioeconomic status. While
those at the highest personal risk are likely to show the greatest indi-
Table 11.5.4 Some effects of nutrients which promote or protect
against coronary heart disease on cardiovascular risk factors vidual benefit from dietary and lifestyle changes, national coronary
heart disease rates will best be reduced if changes are made by the
Nutrient Effect population at large. The main purpose of such recommendations is
Promoting to reduce the risk of morbidity and mortality from coronary heart
Saturated fatty acids ↑ total and LDL cholesterol disease in those who are in the prime of life. Even greater reduction
↑ thrombogenesis
in morbidity and mortality and an improvement in life expectancy
may occur in succeeding generations if they have reduced lifetime
↓ insulin sensitivity
exposure to risk factors related to lifestyle.
Trans-​unsaturated fatty acids ↑ total and LDL cholesterol and Lp(a)
Dietary cholesterol (when taken in ↑ total and LDL cholesterol
large amounts) Hypertension and stroke
Protective
Dietary fibre ↓ total and LDL cholesterol Salt (sodium chloride)
↑ insulin sensitivity Three dietary factors are well established as raising blood pressure.
Antioxidant nutrientsa ↓ oxidation of LDL The longest known is salt, sodium chloride. In a few isolated com-
Unsaturated fatty acidsb ↓ total and LDL cholesterol munities salt was not available until recently, and there high blood
↓ arrhythmias, thrombogenesis pressures were rare or absent. Usual sodium intakes of around
↑ increase; ↓ decrease 150 mmol/​(8.8 g NaCI) or more per day are about six times more
than the physiological requirement (human milk contains only
a
When consumed in fruits and vegetables, rather than supplements
b
C18:1, n-​9: oleic acid
C18:2, n-​6; linoleic acid
7 mmol sodium/​litre).
C18:3, n-​3; α-linolenic acid Salt used to be important for preserving food before canning, re-
C20:5, n-​3: eicosapentaenoic acid frigeration and rapid transport, and people are now habituated to its
C22:6, n-​3; docosahexaenoic acid flavour in foods like bread. The relationship between sodium intake
 11.5 Diseases of affluent societies and the need for dietary change 1895

and blood pressure cannot be studied by asking people to recall vegetables. In these trials the addition of low-​fat dairy foods pro-
dietary intake of salt. Most of the salt consumed (c.85%) is added at duced additional blood pressure lowering, but the effects of calcium
the time of manufacture, rather than during food preparation or at have been less marked in controlled trials.
the table, hence 24-​h urinary sodium excretion rather than dietary Blood pressure is an important determinant of ischaemic stroke
intake measurements are needed to accurately assess salt intake, al- and cerebral haemorrhage, so that all the nutritional determinants
though sodium measurements in spot urine samples are considered of hypertension may be regarded as relevant to their cause. In add-
to be adequate for assessing intakes of populations. ition, prospective studies have consistently demonstrated that fruit
Sodium excretion (reflecting intake) and blood pressures fluc- and vegetables protect against ischaemic stroke. Although it appears
tuate markedly, and some individuals are more salt-​ sensitive that most categories of fruit and vegetables are protective, the effect
than others. Nevertheless, surveys within one country (e.g. the is particularly striking for cruciferous vegetables, green leafy veget-
1986–​1987 British National Dietary and Nutrition Survey) and ables, and citrus fruits.
internationally (the Intersalt Study involving 10 000 people in 32
countries) have shown a clear relationship between urinary so-
dium and blood pressure, and a Finnish cohort study found an Diabetes mellitus and the metabolic syndrome
increased risk of cardiovascular disease in those who had high
24-​h urinary sodium. There is strong confirmation from carefully Rates of type 2 diabetes have escalated in most affluent societies to
controlled primate research that salt is causally related to essential the extent that the condition is considered to have reached epidemic
hypertension. Blood pressure rose significantly over an 18-​month proportions in many countries. The precise nature of the metabolic
period when salt was added to the diet of chimpanzees that nor- syndrome is not clearly understood, and some have questioned
mally eat a vegetarian and fruit diet, and fell again when the salt whether it should be regarded as a clinical entity. Nevertheless, the
was stopped. Several controlled clinical trials in humans have constellation of abnormalities (including abdominal obesity, hyper-
shown that when salt intakes are reduced to around 70 mmol/​litre, glycaemia, raised blood pressure, dyslipidaemia, and increased in-
blood pressure falls more in people with mild to moderate hyper- sulin levels, which constitute the ‘syndrome’), does identify people
tension. Salt restriction can contribute to the treatment of hyper- likely to develop type 2 diabetes and who are at appreciably increased
tension, but major dietary change is needed because so much is risk of cardiovascular disease. Where information is available, it ap-
derived from manufactured food, emphasizing unprocessed foods pears that the frequency of the ‘syndrome’ has also increased and
and low-​salt bread (ordinary bread contains over 100 times more that risk factors are the same as for type 2 diabetes.
salt than wheat flour). Epidemiological evidence suggests that type 2 diabetes is un-
common in people eating a range of ‘traditional diets’ high in fresh
Weight reduction fruit, vegetables and minimally processed cereals, and relatively
Overweight and obese people have higher blood pressures than low in fat, especially saturated fat. Diabetes prevalence seems to
those who are lean and, if they lose weight, blood pressure falls even increase rapidly when traditional lifestyles are exchanged for the
if the usual salt intake is maintained. An Australian clinical trial Western way of life, particularly when such transitions occur over
showed that weight reduction (maximum loss 7.4 kg) compared a short time span. Such changes are occurring in China and India,
favourably with metoprolol in the treatment of mild hypertension, where type 2 diabetes has already created an enormous public health
and diet was associated with an improved plasma lipid profile not problem. Similar findings had been noted earlier in Micronesians,
seen on the drug. Polynesians, American Indians, and Aboriginal Australians, as
well as in Asian Indian immigrants to Fiji, South Africa, the United
Alcohol Kingdom, and Mauritius and among Chinese in Singapore, Taiwan,
Alcohol intake is emerging as the third of the important envir- Hong Kong, and Mauritius.
onmental factors associated with raised blood pressure. In epi- The change from traditional to a Western way of life is gener-
demiological studies, blood pressure, especially systolic, increases ally associated with a reduction in physical activity and an increase
progressively when reported alcohol intake increases above three in the energy density of the diet, resulting from increased intakes
drinks per day. Several intervention studies have shown that reduc- of fats and sugars, with the resultant energy imbalance leading to
tion of alcohol intake can produce an appreciable reduction in blood increasing rates of overweight and obesity. Lack of physical ac-
pressure among hypertensive heavy drinkers. For example, one trial tivity and increasing degrees of obesity (especially abdominal adi-
showed that replacing standard beer (5% alcohol) with a reduced-​ posity) have consistently been shown in longitudinal studies to be
alcohol beer (0.9% alcohol) produced a reduction in alcohol intake associated with the risk of developing type 2 diabetes. Globally and
from 450 to 64 ml/​week and a significant fall in blood pressure. nationally, rates of type 2 diabetes have increased in parallel with
increasing obesity. Genetic determinants of diabetes should not be
Other factors underestimated, but they clearly cannot explain the exponential in-
Other components that may lower blood pressure are not as clearly crease in so many countries.
established. Potassium, probably acting as an antagonist to sodium, While any cause of energy imbalance leading to excessive weight
has been shown in controlled trials to lower blood pressure modestly, gain will increase the risk of type 2 diabetes, there is less certainty re-
but this was when given in pharmacological doses. Potassium may garding the role of individual macronutrients in the aetiology. Excess
have been one of the operative factors in the Dietary Approaches to sucrose has not been clearly established as an important dietary
Stop Hypertension (DASH) trials that have shown an appreciable factor, except when high intakes contribute to an increase in energy
blood pressure lowering effect of substantial quantities of fruits and density. However excessive energy intakes though sugar-​sweetened
1896 SECTION 11 Nutrition

beverages have been implicated as a cause of type 2 diabetes inde- Although diet is important in the management of type 1 diabetes,
pendent of an effect on body fatness. nutritional factors do not appear to have contributed to the aeti-
A high intake of saturated fatty acids increases insulin resistance, ology of the disease to the same extent as for type 2 diabetes. Genetic
an underlying abnormality in type 2 diabetes and the metabolic and other environmental factors are believed to be more important.
syndrome, independently of an effect of excess adiposity, hence sat- Some studies have suggested, however, that infants who have been
urated fats are regarded as a probable contributor. One large pro- breastfed may have a reduced risk of type 1 diabetes in later life, and
spective study of health professionals in the United States of America this observation could be linked with immune mechanisms known
has found that a high intake of low glycaemic index foods tends to to be associated with this condition.
protect against type 2 diabetes and that this effect is independent of
other individual dietary attributes. A high intake of dietary fibre has
been shown to enhance insulin sensitivity in insulin-​resistant indi- Cancers
viduals, so that foods rich in dietary fibre and with a low glycaemic
index are probably protective. Thus, it seems most likely that a com- The development of cancer involves several stages and occurs over a
bination of factors is responsible. long period of time. Nutritional factors may operate at one or more
Although we do not fully understand the complex mechanisms by of these stages, but given the time scale of cancer development it is
which genes and environment interact to result in type 2 diabetes, hardly surprising that few data from intervention trials are available,
randomized controlled trials among individuals with impaired glu- and data relating dietary factors to various cancers are principally
cose tolerance carried out in Finland, the United States, China, and derived from epidemiological associations and animal experiments.
India provide strong support for the suggestion that lifestyle modi-
fication can help to prevent or at least appreciably delay the onset Causal factors
of type 2 diabetes. Interventions in the Finnish Diabetes Prevention Despite the difficulty in assessing dietary intake over the prolonged
Study (Box 11.5.1) resulted in an approximately 60% reduction in period during which cancer develops, it has been estimated that
rate of progression from impaired glucose tolerance to type 2 dia- about one-​third of all cancers in Western countries may be asso-
betes, a benefit which has persisted for well beyond the six-​year dur- ciated with diet. The dietary and nutritional factors that may play
ation of the Study. Of particular interest is the fact that remarkably a role in human cancer are listed in Table 11.5.5. Restriction of
few of those individuals who complied with at least four of the five total energy intake, provided that nutrient requirements are met,
target interventions progressed from impaired glucose tolerance to has been clearly shown to reduce the risk of cancer in experimental
type 2 diabetes. The benefits appear to accrue principally from re- animals, and obesity in humans is one of the most powerful and
duction in excess body fat rather than a change in any of the indi- consistent epidemiological associations with cancers. Obesity is as-
vidual nutrients. The United States, Chinese, and Indian studies have sociated with insulin resistance and increased levels of inflamma-
reported comparable results. Similar lifestyle interventions have been tory markers and insulin-​like growth factors, which may increase
shown to increase insulin sensitivity in insulin-​resistant individuals cancer risk. These effects are reversed by weight loss.
prior to the development of impaired glucose tolerance or diabetes. High intakes of total fat are strongly correlated with colorectal,
Convincing randomised controlled trial evidence has shown breast, prostatic, and pancreatic cancer in ecological (between coun-
that appreciable weight reduction (around 15kg), especially when tries) studies.
achieved relatively soon after diagnosis can result in remission of The effects of alcohol as a risk factor for breast cancer as well as
established type 2 diabetes even in those already on drug treatment. cancer of the mouth, larynx, and pharynx are consistent and strong.
It is yet to be established for how long remission can be sustained. Alcohol probably increases the risk of liver cancer because large
Less marked weight loss and appreciable dietary change (high in- intakes lead to cirrhosis of the liver, which is associated with liver
takes of dietary fibre, especially soluble forms, low glycaemic index, cancer, regardless of cause.
minimally processed wholegrain foods and reduced saturated fats) High intakes of red meat have been associated with an increased
even in the absence of appreciable weight loss, can improve gly- risk of colon cancer. Processed meats (the definition of which differs
caemic control (often with reduced requirements for hypoglycaemic in different countries) have also been linked with colorectal cancer.
drug treatment) and cardiovascular risk factors in those with type 2 Haem rather than iron per se is one possible explanation since it is
diabetes regardless of the duration of the disease. susceptible to endogenous nitrosation by bacterial flora in the colon,
and nitroso compounds can increase the likelihood of neoplastic
change. Such effects are not seen with fish or poultry, which appear
Box 11.5.1 Lifestyle modifications, targets for the intervention to be protective against colorectal cancer.
group in the Finnish Diabetes Prevention Study Other clearly established nutrition-​related promoters of cancers
• Weight loss of 5–​7% initial body weight or a weight loss of 5–​10 kg tend to operate regionally: salt and salted fish increase the risk of
depending upon degree of obesity. stomach and nasopharyngeal cancer in Japan and China, and maté,
• Reduce total and saturated fat by encouraging low-​fat dairy and meat consumed at high temperatures in Brazil, is an important cause of
products. oesophageal cancer.
• Prefer unsaturated soft margarines and vegetables oils rich in mono-
unsaturated fatty acids. Protective factors
• Increase whole grains, vegetables, and fruit. Vegetables and fruit are generally accepted as important protective
• Physical activity, at least moderate intensity for a minimum of 30
factors, particularly against lung, stomach, and colorectal cancers.
minutes daily.
Antioxidants (especially vitamin C, vitamin E, carotenoids, and
 11.5 Diseases of affluent societies and the need for dietary change 1897

Table 11.5.5 Nutritional associations of various cancers

Factor Causal (↑) Cancers

Protective (↓)
Obesity ↑ Postmenopausal breast, colorectum, endometrium,
gallbladder, kidney, oesophagus, pancreas, prostate
Processed and red meat ↑ Colorectum
Alcohol ↑ Liver, breast, mouth, larynx, pharynx, oesophageal
Salt ↑ Stomach
Salted fish (Cantonese style) ↑ Nasopharynx
Hot drinks (maté) ↑ Oesophagus
Vegetables ↓ Colorectum, oesophagus, stomach
Fruits ↓ Lung, stomach, oesophagus
Non​starch polysaccharide/​dietary fibre ↓ Colorectum
Selenium ↓ Prostate

flavonoids), glucosinolates (found in brassica vegetables), sulphur populations of many countries where unrefined foods form the
components (in Allium species—​onions and garlic) and folates have bulk of the diet (e.g. China, Uganda), and this increased rapidly
all been shown to have anticancer properties, which may explain within a few years of the addition of sugar and other refined foods.
the protective effects that have been demonstrated mainly in case–​ A similar change has been shown experimentally in monkeys. In a
control studies. classical experiment carried out in a Swedish mental hospital, vo-
Possibly of even greater importance is the protection (particu- lunteers given toffee apples, chocolate, and caramel in addition to
larly against colorectal cancer) conferred by dietary fibre (non​starch their controlled diet had a 13-​fold greater number of tooth surfaces
polysaccharide) present in many minimally processed cereal foods, becoming carious each year, compared with those eating the con-
as well as fruits and vegetables. Dietary fibre and resistant starches trolled diet alone. A 2013 meta-​analysis of cohort, population and
escape digestion in the small intestine and are fermented in the large cross-​sectional studies, and a small number of intervention trials
bowel by the colonic microbial flora. Short-​chain fatty acids are pro- conducted on behalf of the World Health Organization (WHO),
duced, one of which, butyric, is an antiproliferative agent. Dietary found evidence of moderate quality that caries is lower when free
fibre may further reduce the risk of large-​bowel cancer by increasing sugars intake is less than 10% total energy and some evidence of a
stool bulk and decreasing transit time, which in turn reduces the op- further reduction when intakes are below 5%. Although fluoride in
portunity for colonocytes to be in contact with carcinogens. the water at one part per million or in toothpaste can appreciably
While there is renewed interest in the potential protective ef- reduce the risk of dental caries, the association between free sugars
fects of selenium, tomatoes, and lycopene against prostate cancer, and dental caries remains even in areas where fluoridated water is
and possible protection of folate and calcium against cervical and consumed.
colorectal cancers, respectively, it seems likely that reducing rates of
obesity may have a more marked effect on reducing nutrition-​related
cancers than modifying intakes of individual nutrients or foods. Diverticular disease of the colon

The first suggestion that deficiency of dietary fibre may be impli-

Dental caries cated in the aetiology of diverticular disease of the colon came from
geographical variations and trends over time in several countries
Archaeological evidence shows that in ancient times dental caries which were compatible with a causative link with low-​fibre diets,
was exceptionally rare in young people. In a recent survey of but such associations could also be explained by several alternative
children’s dental health in the United Kingdom the overall preva- dietary and other environmental influences. The best-​documented
lence of dental caries was 43% and the average number of decayed evidence comes from comparisons of asymptomatic groups of vege-
missing and filled teeth among 12-​year-​olds (permanent teeth) was tarians and meat eaters who volunteered to undergo radiological
0.8. Among adults in the United Kingdom there appears to be an imaging. Radiological diverticular disease was found more fre-
improvement. The Adult Dental Health Survey 2009 reported that quently among omnivores than vegetarians, who had appreciably
in the 85 plus age group, 30% were edentulous (compared with al- higher intakes of dietary fibre. Furthermore, when comparing in-
most 80% in 1988). In the 75–​84-​year-​old group 15% are edentu- dividuals with and without diverticular disease, in both the vege-
lous and only 5% of those aged 65–​74 years. The extent to which tarian and non​vegetarian groups those with diverticular disease
dental caries contributes to ill health throughout the life course has had appreciably lower intakes of dietary fibre than those with no
resulted in the condition being considered as a major chronic non-​ evidence of diverticula. An increase in dietary fibre intake is widely
communicable disease. recommended to patients with symptomatic diverticular disease, a
Several strands of evidence suggest a nutritional cause. Dental treatment justified by the findings of some (but not all) controlled
caries once had a very low prevalence among the indigenous clinical trials.
1898 SECTION 11 Nutrition

Plausible theories concerning pathogenesis have been suggested; periods of growth, pregnancy, lactation, and in the postmenopausal
small, hard faeces associated with a fibre-​deficient diet lead to nar- years. Fruit, vegetables, and adequate physical activity have also
rowing of the colon and the formation of closed segments in which been identified as protective factors.
pressure increases. Additional work is needed by colonic muscles
to provide the pressure to move the more solid faeces, producing
muscular hypertrophy in addition to diverticula at sites of weakness Other diseases
where blood vessels penetrate the muscular coat.
Gallstones, appendicitis, haemorrhoids, varicose veins, and hiatus
hernia all occur frequently in developed countries and rarely in
Constipation and the irritable bowel syndrome developing countries, but the evidence linking these diseases to a
nutritional cause is tenuous.
Ninety-​nine per cent (99%) of a large population sample studied Gallstones are undoubtedly associated with obesity. Both gall-
in the United Kingdom reported that they defecated at least three stones and appendicitis are more common in omnivores than
times per week but perceived constipation as a frequent com- vegetarians, and there are some rather indirect data suggesting an
plaint. Approximately 3% of all prescriptions written in the United association with diets high in sugars and deficient in dietary fibre.
Kingdom’s National Health Survey were for purgatives and laxatives, The addition of bran to the diet can make bile less saturated, and
at a cost of around £4 000 000, and many times this amount must experimentally induced gallstones in animals tend to be reduced if
have been spent in over-​the-​counter purchases. In another survey, fibre-​rich foods rich are given. Historical studies provide interesting
6% of people aged 18 to 80 years described straining when passing information; appendicitis rates were compared in two matched
stools. By contrast, constipation is uncommon in populations with a groups of South African whites, the privileged group living in uni-
high intake of dietary fibre. versity halls of residence and the other living in establishments for
In Britain, stool weights in omnivores are usually around 100 g the indigent, where the diets contained more fibre. Annual rates
(with a very wide range), whereas in vegetarians with a high fibre in- were 7.8/​1000 and 1.8/​1000, respectively. Of course, factors other
take, the average stool weight is over 200 g. Furthermore, vegetarians than diets might explain this, but the rates were similar to those
and omnivores with high average daily fibre intakes have transit times found in an almost identical study in Bristol (7.6/​1000 in a fee-​
of less than 75 h and rarely report constipation, whereas those with paying boarding school and 0.8/​1000 in an orphanage).
lower fibre intakes have transit times ranging from 20 to 124 h and
frequently complain of constipation. Controlled clinical trials con-
firm that increasing dietary fibre (especially that derived from cereals) The case for dietary change
relieves the symptoms of constipation. Diets rich in dietary fibre are
widely recommended in the treatment of irritable bowel syndrome, Nutrition research often generates results that may be translated
despite the absence of good evidence from formal clinical trials. by researchers, self-​styled ‘experts’, or the media into potentially
confusing and conflicting messages. It is therefore important for
governments who develop food and nutrition policies, for doctors
Osteoporosis and others involved in health and nutrition education, and for con-
sumers to have authoritative recommendations that represent con-
Osteoporosis is an important cause of morbidity among elderly sensus opinions of nutrition scientists. Dietary or nutrient reference
people, especially women, and the incidence of osteoporotic frac- values define intakes of nutrients which are required for growth and
tures is increasing steadily as people are living longer. The aetiology maintenance of health and considered to reduce the risk of chronic
of osteoporosis is complex; women have a lower peak bone mass diseases. These recommendations are intended for policy makers
in their twenties than men and lose bone rapidly after the meno- and health professionals who recommend diets for populations,
pause in association with a decline in oestrogens. Women lose ap- special groups of people within populations, and individuals. Such
proximately one-​half their trabecular bone and one-​third of their reference values are unhelpful to the population at large. For the
cortical bone, while men lose one-​third of their trabecular bone and general public, dietary guidelines have been developed to translate
one-​fifth of their cortical bone. Genetic factors influence peak bone reference values into practical advice.
mass and bone loss. These may operate by some established risk
factors: family history of osteoporosis, short stature, early meno- Dietary fat
pause, white or Asian race, and leanness. However, there are also Reference values for macronutrients were initially centred around the
environmental factors, including cigarette smoking, excessive salt evidence showing that alteration of dietary fat intake from that typical
and alcohol intakes, and lack of vitamin D, especially in housebound of most Western countries would be expected to reduce population
people with little sun exposure. The role of dietary calcium has been and individual risk of coronary heart disease. Restriction of saturated
uncertain but there is now convincing evidence that the best way fatty acids and trans-​unsaturated fatty acids to no more than 10% total
of avoiding osteoporotic fractures in later life is to achieve optimal energy has been a consistent feature of all sets of national and inter-
skeletal mass for one’s genetic potential and to retain this as long as national reference values. Some have suggested an even lower propor-
possible. The best means of doing so is by ensuring lifelong adequate tion of total energy from these fatty acids for populations, groups, or
consumption and maximum absorption and retention of calcium. individuals considered to be at increased risk of coronary heart dis-
The need for substantial amounts of dietary calcium, in conjunc- ease. Until relatively recently recommendations regarding dietary fat
tion with adequate vitamin D, is particularly important during the included a restriction on total fat intake, typically to less than 30%
 11.5 Diseases of affluent societies and the need for dietary change 1899

Table 11.5.6 Nutrient intake goals as recommended by WHO and societies are unaccustomed to a high carbohydrate intake and are
FAO and in the United Kingdom (unless otherwise stated, the goals reluctant to accept substantial increases. WHO and most countries
are expressed as percentage total energy) recommend a relatively wide range of acceptable intakes, recog-
WHO/​FAOa (2003) Nordicb (2012) nizing that source of carbohydrate is likely to be more important
than the proportion of total energy provided by carbohydrate
Total fat 15–​30% 25–​40%
(Table 11.5.6). A high intake of free sugars (principally sucrose and,
Saturated fatty acids (SFA) <10% <10%
in the United States, high-​fructose corn syrup) increases the risk
Cis polyunsaturated fatty 6–​10% 5–​10% of obesity by increasing the energy density of the diet, or simply
acids
by increasing total energy intake (and energy imbalance) when
c
n-​6 PUFA 5–​8% sugary drinks are consumed in excess. Sugars are also associated
n-​3 PUFA 1–​2% >1%d with dental caries and in large amounts may enhance the metabolic
Cis monounsaturated fatty By differencee 10–​20% derangements in people with insulin resistance. Foods with a high
acids
<1% As low as possible intake of free sugars are frequently nutrient poor (i.e. contain rela-
c tively few essential nutrients), so limiting such foods has no adverse
Dietary cholesterol (mg/​day) <300 mg/​day
nutritional consequences. Limiting free sugar intake of individuals
Total carbohydrate 50–​75%g 45–​60%
to below 10% total energy is widely recommended and WHO has
Free sugarsf <10% <10% suggested that further reductions may be associated with additional
Dietary fibre (NSP) >25 g/​dayg 25–​35 g/​day benefits. On the other hand, intrinsic sugars (i.e. those incorpor-
Protein 10–​15% 10–​20% ated into the natural structure of foods, like fruits), milk sugars,
Sodium chloride <5 g/​day c and starches are not restricted and generally provide the balance of
c dietary energy not provided by protein, fat, and free sugars. Similar
Potassium
advice has been offered by the Specialist Advisory Committee on
Fruit and vegetables >400 g/​day >400 g (5 portions)
Nutrition (SACN) in the United Kingdom in their 2015 report
a
Source: WHO (2003). Diet, Nutrition and the Prevention of Chronic Diseases. Report (Carbohydrates and Health). They suggest that population average
of a joint WHO/​FAO Expert Consultation, Technical Series Report 916, World Health intakes of total carbohydrate should be around 50% total energy
Organization, Geneva.
b
Nordic Council of Ministers. Nordic Nutrition Recommendations 2012. Main and free sugars around 5% total energy.
conclusions of the NNR. Online . Copenhagen: 2013. There has been much discussion regarding the most appropriate
carbohydrate-​ containing foods. Intact fruit and vegetables and
c
No specific recommendation.
d
Mainly from oily fish.
e
minimally processed cereals and grains tend to be rich sources of
Total fat (SFA & PFA & TFA).
f
All monosaccharides and disaccharides added to foods by manufacturer, cook, or
dietary fibre, essential micronutrients, and some essential fatty acids.
consumer, plus sugars naturally present in honey, syrups, and fruit juice. The SACN Report suggests that population average intake of fibre
g
WHO/​FAO Scientific Update on CHO (Nishida et al., 2007). should be about 30 g/​day, an appreciable increase from current levels.
Cooked dried beans, chickpeas, and some whole-​grain products are
total energy. However, increasing evidence relating to the benefits rich sources of dietary fibre and resistant starch, which having largely
of replacing saturated with unsaturated fatty acids has (other than avoided digestion in the small intestine enter the colon in a largely
trans-unsaturated fatty acids) resulted some countries including the undigested state. Resistant starch, oligosaccharides, and some com-
Nordic group of countries suggesting an appreciably higher accept- ponents of dietary fibre (e.g. gum, pectins, mucilages) undergo fer-
able upper limit, around 40% total energy (Table 11.5.6). mentation that leads to the production of fatty acids, which provide
While an increase in unsaturated fatty acids (with a cis-​ a fuel source (via conversion to glucose in the liver) and may also re-
configuration) is associated with a reduced risk of coronary heart duce the risk of colon cancer because of their antiproliferative effects.
disease, the potential contribution of total fat to the energy density Other components of dietary fibre remain largely intact and act as
of the diet appears to be the continuing justification for the World stool-​bulkers (e.g. cellulose and hemicellulose). Thus, a wide variety
Health Organisation’s recommendation for continuing the recom- of fruits and vegetables, whole grains, and minimally processed cer-
mendation to restrict total fat. There is evidence that high fat diets eals are particularly appropriate sources of carbohydrate.
may promote and perpetuate excessive weight gain and obesity in Some fruits, white rice and hot cooked potato are largely digested
individuals and populations but the extent to which this should be in the small intestine and provide an immediate or fairly rapid source
reflected in a restriction of total fat intake especially as it relates to of energy, depending upon the speed of digestion. Free or added
populations rather than individuals remains a matter of opinion. sugars in jams and manufactured foods (e.g. confectionery prod-
The lower limit of fat intake in some recommendations is based on ucts) or added by the consumer to food and beverages are also rapid
the minimum requirement considered to ensure an adequate in- sources of energy, but increase energy density and promote obesity,
take of fat-​soluble vitamins, and the fact that there is no evidence so that foods rich in them should be restricted by most people. The
of untoward effects in some Asian and African populations who glycaemic response following the ingestion of a specified amount of
traditionally consume low-​fat diets. carbohydrate in a food, expressed as a percentage of the glycaemic
response following a similar amount of glucose (glycaemic index),
Dietary carbohydrate has been suggested as a useful approach to identifying the most ap-
About 50 g of carbohydrate daily is required to avoid ketosis, but propriate carbohydrate-​containing food choices (i.e. those with a low
many populations maintain an adequate nutritional status when glycaemic index are particularly appropriate). While this is of some
carbohydrate provides up to 80% total energy. Most Western value in comparing different varieties of similar foods (e.g. different
1900 SECTION 11 Nutrition

types of bread) there are several limitations, including that some low intakes. Such untoward effects do not occur when diets are rich in
glycaemic index foods, especially those containing fat and sugars, vegetables, fruit, and minimally processed cereals.
may be very energy dense despite having a low glycaemic index (e.g. It has also been claimed that low carbohydrate diets, which tend
ice cream) and that there is considerable inter-​and intraindividual to be relatively high in fat and protein, are associated with greater
variation in glycaemic response to foods. Synthetic forms of dietary weight loss than Mediterranean-​type diets or diets with a higher pro-
fibre or fibre extracted from plant material favourably influence portion of calories from carbohydrate. This is only true in short term
cardiometabolic risk factors but there is as yet no corroborative epi- studies. Macronutrient distribution is not an important determinant
demiological evidence that they have an effect on clinical outcomes of long-​term weight loss and diets with a higher carbohydrate con-
comparable with those convincingly demonstrated for dietary fibre tent may be more likely to facilitate weight maintenance. Not only
naturally found in foods. is there no information about long-term clinical benefit of very low
carbohydrate diets which are typically high in fat often saturated
Dietary protein fat, there are also no data regarding their safety. Low carbohydrate
Dietary protein, the most fundamental macronutrient, has been diets have not been endorsed by expert committees or appropriately
largely taken for granted in affluent societies. The mixture of foods qualified government and non​government bodies.
in the diets of Britain and similar countries provide dietary protein While appropriate distribution of macronutrients and good food
that contributes around 15% dietary energy across genders, occupa- choices might be expected to reduce cardiovascular risk, improve
tions, and socioeconomic levels, against nutrient reference amounts bowel function, and reduce the risk of certain cancers and other dis-
of 10% of energy. Protein-​containing foods are also good sources eases of the large bowel, the importance of ensuring energy balance
of critical nutrients iron, calcium, and zinc. There is only one main cannot be overstated. Obesity and its comorbidities, especially type
subdivision of dietary proteins: animal source and plant source pro- 2 diabetes, account for a public health problem of enormous mag-
teins. The constituent amino acid patterns are somewhat nearer to nitude throughout the world. Increasing carbohydrate-​containing
human requirements in meats and dairy products. Vegetarians (who bulking foods rich in dietary fibre at the expense of saturated fat
consume dairy products) should have no difficulty to achieving ad- is likely to enhance satiety. Such positive advice, along with the re-
equate intakes. The diet of vegans whose protein intake is derived commendations to reduce frequent consumption of large portions
solely from plant sources requires more careful planning, but they of all energy-​dense foods and sugary drinks, is likely to help reduce
have compensatory health advantages of less obesity and eating less excessive energy intake. Increasing energy output by increasing
saturated fat. physical activity may contribute to public health measures de-
Protein intake can be critical in old people. In Australia and New signed to stem the tide of the global obesity epidemic, but to a lesser
Zealand, the 2005 recommended dietary intake moves up at age 70 extent than dietary measures. There is increasing recognition of
plus from 46 to 57 g per day in women and from 64 to 81 g/​d in men. the need to consider sustainability issues when making nutrition
In old people dietary protein appears to be used less efficiently. There recommendations.
is increased splanchnic extraction and declining anabolic response
to ingested protein. To help prevent sarcopenia, loss of muscle with Reference intakes for vitamins and minerals
ageing, the PROT-​AGE international committee of geriatricians rec- Reference nutrient intakes (adequate for most individuals) are pro-
ommend protein intake should be 1.0–​1.2 g/​kg (i.e. 65–​78 g/​d for a vided for vitamins and minerals by official bodies, such as the Institute
65 kg woman or man). The usual daily pattern of our protein intake of Medicine (IOM). They are set at a level of two standard deviations
is to eat the bulk of it at one meal (dinner) of the day (with meat, fish, above the average of all individual requirements, so that requirements
or beans). Most modern breakfasts provide some cereal, coffee, and for the vast majority in the population are assured. Clinical vitamin
a little milk, so much less than a third of the daily protein intake. It deficiencies, discussed in detail in Chapter 11.2, are uncommon in
may be better for muscle maintenance to add a protein source at affluent societies except in at-​risk subgroups within populations. For
breakfast. example, immigrants who have migrated from sunny tropical regions
to cloudy high-​latitude countries may be at risk of vitamin D defi-
Overall diet ciency; strict vegetarians (who consume no animal or dairy prod-
The appreciation that a wider range of macronutrients than was pre- ucts) may become deficient in vitamin B12, and disadvantaged groups
viously recommended is appropriate for reducing the risk of many (especially the very young, pregnant, and lactating women, and older
chronic diseases enables the translation of nutrition recommenda- people) may have generally inadequate intakes.
tions into many acceptable dietary patterns which are diverse as those By contrast, inappropriate intakes of certain minerals and other
traditional to Mediterranean countries, where intake of unsaturated nutrients are fairly common. Many groups are particularly vul-
vegetable oils is relatively high, and to some Asian countries where nerable to iron deficiency due to high physiological requirements
diets relatively high in carbohydrate are consumed. Although a var- (infants and toddlers, adolescents, pregnant women), high losses
iety of carbohydrate intakes is acceptable, a very low carbohydrate (menstruating women), or poor absorption (older people and those
high-​fat diet is not included among the acceptable dietary patterns. consuming foods high in inhibitors of absorption, such as fibre and
The suggestion by some nutritionists and other health profes- tannin in tea). Vegetarians are also at increased risk of iron defi-
sionals that populations and individuals at high risk of obesity and ciency, even when total intake of iron appears to be adequate, since
type 2 diabetes (or those who have already the disease) should be non​haem iron from plant foods is less bioavailable than haem iron
on very low carbohydrate diets (less than 20% total energy) is based from animal sources. Bioavailability is enhanced by the consump-
principally on deleterious effects on lipids and measure of carbo- tion, at the same time, of foods rich in vitamin C.
hydrate metabolism observed when diets high in rapidly digested Iodine and selenium are deficient in soils in various parts of the
and absorbed carbohydrates are compared with lower carbohydrate world. Clinical selenium deficiency has only been reported from
 11.5 Diseases of affluent societies and the need for dietary change 1901

China, although the consequences of lesser degrees of selenium defi- Box 11.5.2 Dietary guidelines for which there is almost
ciency have yet to be established with certainty, especially in regions complete agreement
where soils are known to be deficient. Endemic iodine deficiency is
1 Eat a nutritionally adequate diet composed of a variety of foods.
widespread, especially in the Himalayas and the Andes, and clin-
2 Eat less of foods rich in saturated fat and use mono-​and polyunsatur-
ical deficiency states are largely avoided by the use of iodized salt ated fats instead.
and sanitizers containing iodine used by the dairy industry. In New 3 Adjust energy balance for body weight control: energy-​dense foods
Zealand, where goitre due to iodine deficiency had virtually been high in fat and sugars should be restricted and exercise increased to
eliminated, mild iodine deficiency appears to be reoccurring pos- avoid excess weight gain.
sibly as a result of reduced use of iodized salt and the introduction 4 Eat more of a variety of vegetables, fruits, and whole grains.
by the dairy industry of alternative sanitizers. Young women often 5 Reduce intake of salt and foods rich in salt.
have insufficient calcium to help achieve peak bone mass, and older 6 Drink alcohol in moderation, if you do drink.
women may have an inadequate intake to help reduce an age-​related
bone loss.
Excessive intakes of salt (sodium chloride), to such an extent that to achieve in many Western countries, where farmers may have con-
it probably contributes to hypertension and its consequences, are siderable political influence, and subsidies may be available for some
common throughout the world. Targets for reduction may be more high-​fat dairy products such as butter and cheese.
important than reference nutrient intakes for sodium. An intake of Governments and intergovernmental agencies also have the re-
100 mmol/​day (2.3 g sodium/​day, roughly equal to 6 g NaCl), a level sponsibility for ensuring that food labels and health claims are ac-
currently exceeded in most countries, are considered to be an appro- curate, interpretable, and likely to facilitate health-​promoting food
priate maximum. choices, a particularly important issue given the increased con-
Reference nutrient intakes need to be reviewed when new research sumption of packaged food. In countries in transition where poverty
becomes available. In the 1990s, a value of 200 μg/​day for folate was (undernutrition) and affluence (overnutrition) coexist, achieving
widely recommended. It is now acknowledged that intakes of 400 appropriate food choices for the population as a whole presents an
μg/​day can appreciably reduce the risk of neural tube defects. Most even greater challenge.
countries have altered their recommended intake to 400 μg/​day. The Dietary guidelines are necessary to provide clear directions to
case for increasing the recommended intakes of other nutrients be- individuals and families who wish to aim for a healthy diet pat-
yond established requirements in order to reduce the risk of chronic tern. These guidelines vary slightly from country to country,
diseases is less clear-​cut. Prospective cohort studies suggested that but some are almost universal (see Box 11.5.2). Others are less
high intakes of several antioxidant nutrients can reduce cardiovas- consistent (see Box 11.5.3). The public also need education re-
cular disease, but these findings have not been replicated in large garding food groups and the nutrients they contain, the inter-
randomized controlled trials in which these nutrients were given pretation of food labels, the meaning of health claims, and the
as supplements. It is conceivable that these micronutrients are only methods of food preparation. The increased use of convenience
protective when consumed as food constituents rather than as sup- and packaged food has meant that many people no longer possess
plements such that it is not possible to specify optimal intakes in basic cooking skills. They also need (and usually want) to know
terms of reducing the risk of chronic disease. Much current interest the merits and demerits of obtaining certain essential micronu-
centres around optimum dietary intakes of vitamin D, long known trients by taking supplements or fortified food products rather
to be critically important in prevention and treatment of rickets and than conventional foods.
osteomalacia. Many non​bone actions of vitamin D have now been Doctors are frequently asked to give nutritional advice but
recognized and there is experimental and epidemiological evidence may lack the necessary expertise. Dietitians, nutritionists, and
that vitamin D might protect against osteoporosis, some cancers, appropriately trained practice nurses play an invaluable role in
hypertension, type 1 diabetes, multiple sclerosis, and tuberculosis. providing the public with practical advice to facilitate changes
Further research including clinical trials are needed before firmly from the typical Western diet, as well as providing instruction re-
establishing the most appropriate intakes and form in which this garding therapeutic diets for those with diseases requiring spe-
vitamin is most appropriately consumed. cific diet therapy. The enormous potential for dietary change to
reduce the effects of a wide range of diseases should encourage
Implementing nutrition recommendations physicians to approach the nutritional management of their pa-
Substantial changes in what have become traditional eating habits tients with enthusiasm.
of many affluent societies are required in order to achieve the ad-
vised changes in distribution of macronutrients and recommended
intake of all essential micronutrients. A multipronged approach is
Box 11.5.3 Additional dietary guidelines in some countries
necessary if there is to be a real chance of achieving dietary change.
At the policymaking and government level there needs to be a ser- 1 Recommendation regarding sugar and sugary foods may vary from ‘no
ious commitment to enabling the population as a whole to make increase’ to ‘decrease’.
2 Drink plenty of fluids each day.
appropriate food choices. Fatty cuts of meat, high-​fat products (e.g.
3 Make sure you get enough calcium or milk.
meat pies), and convenience foods (e.g. fish and chips, burgers) are
4 Eat foods containing iron.
relatively inexpensive and therefore frequently eaten by those of
5 Drink fluoridated water.
lower socioeconomic status who have the highest rates of coronary 6 Preserve the nutritive value of food (by good food preparation).
heart disease. Policies are required which ensure that more appro- 7 Eat three good meals a day.
priate food choices are available at reasonable cost. This is not easy
1902 SECTION 11 Nutrition

Moynihan PJ, Kelly SA (2014). Effect on caries of restricting sugars

FURTHER READING
intake: systematic review to inform WHO guidelines. J Dent Res,
Ascherio A, et al. (1996). Dietary fat and risk of coronary heart dis- 93, 8–​18.
ease in men: cohort follow up study in the United States. BMJ, Nordic Council of Ministers (2012). Nordic Nutrition Recommendations
313, 84–​90. 2012. Main conclusions of the NNR, Copenhagen. https://​norden.
Bauer J, et al. (2013). Evidence-​based recommendations for optimal diva-​portal.org/​smash/​get/​diva2:704251/​FULLTEXT01.pdf
dietary protein intake in older people: a position paper from the Reynolds, A, Mann, J, Cummings, J, Winter, N, Mete, E, Te Morenga, L
PROT-​AGE Study Group. J Am Med Dir Assoc, 14, 542–​59. (2019). Carbohydrate quality and human health: A series of system-
Bernstein AM, et al. (2010). Major dietary protein sources and risk of atic reviews and meta-analyses. Lancet. Advance online publication.
coronary heart disease in women. Circulation, 122, 876–​83. doi: 10.1016/S0140-6736(18)31809-9.
FAO/WHO Scientific Update on Carbohydrates in Human Nutrition Rimm EB, et al. (1996). Vegetable, fruit, and cereal fiber intake and risk
(2007). Eur J Clin Nutr, 61(Suppl 1), S132–S137. of coronary heart disease among men. JAMA, 275, 447–​51.
Food and Nutrition Board, Institute of Medicine (1998/​2011). Dietary Schwab U, et al. (2014). Effect of the amount and type of dietary fat on
Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, cardiometabolic risk factors and risk of developing type 2 diabetes,
Vitamin B12, (1998); and Dietary Reference Intakes for Calcium and cardiovascular diseases, and cancer: a systematic review. Food Nutr
Vitamin D (2011). National Academies Press, Washington DC. Res, 58. doi: 10.3402/​fnr.v58.25145. eCollection 2014.
https://​www.nap.edu. Scientific Advisory Committee on Nutrition (SACN) (2015).
Lean M, et al. (2018). Primary care-led weight management for remis- Carbohydrates and health. The Stationery Office Limited, London.
sion of type 2 diabetes (DiRECT): an open-label, cluster-randomised Te Morenga L, Mallard S, Mann J (2013). Dietary sugars and body
trial. Lancet, 391, 541–51. weight: systematic review and meta-​analyses of randomised con-
Liu S, et al. (1999). Whole-​grain consumption and risk of coronary trolled trials and cohort studies. BMJ, 346, e7492.
heart disease: results from the Nurses’ Health Study. Am J Clin Nutr, Truswell AS (2010). Cholesterol and beyond: the research on diet and
70, 412–​19. coronary heart disease 1900–​2000. Springer, Dordrecht, Heidelberg,
Mann J, Truswell AS (eds) (2017). Essentials of human nutrition, 5th London.
edition. Oxford University Press, Oxford. U.S Department of Agriculture (2015). Scientific Report of the 2015
Mann J, et al. (2014). Low carbohydrate diets: going against the grain. Dietary Guidelines Advisory Committee. United States Department of
Lancet, 384, 1479–​80. Agriculture, Washington, DC. https://​health.gov/​dietaryguidelines/​
Mann J, et al. (2015). Diverging global trends in heart disease and 2015-​scientific-​report/​
diabetes: implications for dietary guidelines. Lancet Diabetes WHO (2003). Diet, nutrition and the prevention of chronic diseases. WHO
Endocrinol, 3, 584–​5. Technical Report Series 916. World Health Organization, Geneva.
11.6
Obesity
I. Sadaf Farooqi

naturally fat than in the lean’. Galen elaborated upon earlier descrip-
ESSENTIALS tions of the obese state, distinguishing between different degrees of
Obesity is defined as an excess of body fat that is sufficient to affect obesity; ‘moderate’ or common obesity and ‘immoderate’ or morbid
health adversely. While the quantification of fat mass is usually only obesity. Many Greek and Roman physicians documented some of
performed in the research setting, body mass index (weight in kg/​ the clinical complications associated with obesity, including reduced
height in metres2) is a useful surrogate marker for fat mass. Using the frequency of menses and infertility. The first known description of
World Health Organization definition of a body mass index more obesity and sleep apnoea dates from Roman times; Dionysius, the
than 30 kg/​m2 to define obesity, 30% of Americans, and 10 to 20% of tyrant of Heraclea of Pontius who reigned from about 360 bc, was
Europeans are classified as obese, with the prevalence rising in many described as ‘an enormously fat man who frequently fell asleep’.
developing countries. The obesity-​ related changes in respiratory function, which are
As body mass index increases, so does the relative risk of type 2 most prominent during sleep, are now recognized as the obesity–​
diabetes, hypertension, and cardiovascular disease. As such, obesity hypoventilation or Pickwickian syndrome.
is associated with disability, mortality, and substantial health costs.
At an individual level, severe obesity can be associated with sleep
disturbance and respiratory difficulties, joint and mobility disorders, Definition of obesity as a medical disorder
as well as considerable social stigma which can affect quality of life,
educational attainment, and employment opportunities. The recognition that obesity represents a serious medical disorder
Management of patients with severe obesity is a challenge, but at a population level came with pooled life insurance data from
success is enhanced by a sympathetic approach from the physician, the United States of America, showing that increasing degrees of
with realistic weight loss goals and monitoring of the effects of treat- overweight and obesity were important predictors of decreased
ment. Interventions include (1) low-​calorie diets which often aim longevity, much of which was attributed to cardiovascular dis-
to provide a 600 kcal/​day (2.5 MJ/​day) energy deficit, based on es- ease. Subsequently, several epidemiological studies, including the
timated energy requirements; (2) motivational and behavioural ap- Framingham Study and the Build and Blood Pressure Study, have
proaches to implement and sustain changes in eating and activity shown that the adverse effects of excess weight tend to be delayed,
behaviour; (3) drug treatment—​which should be regarded as a thera- sometimes for 10 years or longer. These observations led to the rec-
peutic trial and stopped if weight loss is not apparent after one to ognition that obesity should be defined as a disorder in which excess
two months; (4) surgery—​an option for people with morbid obesity/​ body fat has accumulated such that health may be adversely affected.
obesity with associated complications. We now recognize that obesity is associated with substantially in-
creased mortality from cardiovascular and cerebrovascular disease,
type 2 diabetes, and certain cancers. Obesity is also associated with
increased morbidity from musculoskeletal, gastrointestinal, psychi-
Introduction atric, and reproductive diseases (Table 11.6.1) and is associated with
lowered quality of life, self-​esteem, and socioeconomic performance.
Obesity is frequently considered to be a ‘modern’ disease—​a re- The precise measurement of body fat is challenging and accurate
flection of the excesses of urbanized society. However, descriptions methods are not applicable to large populations, hence surrogate
of obese individuals in medical texts from many of the ancient markers such as the body mass index (BMI—​weight in kilograms
civilizations, suggest that, throughout history, certain individ- divided by the square of the height in metres) are most often used to
uals have harboured the tendency to store excess energy as fat. define obesity in population studies and in the clinic. The underlying
Hippocrates recognized that obesity posed a threat to health when assumption is that most variation in weight for persons of the same
he wrote that, ‘sudden death is more common in those who are height is due to fat mass. A World Health Organization Expert
1904 SECTION 11 Nutrition

Table 11.6.1 Medical complications associated with obesity prevalence of overweight preschool children is greatest in lower-​
middle-​ and upper-​middle-​income countries.
Type 2 diabetes 90% of type 2 diabetics have a BMI of >23 kg/​m2
Although there is no accepted definition for severe or morbid
Hypertension 60–​80% of hypertension is linked to excess weight obesity in childhood, a BMI of more than 2.5 standard deviations
Coronary artery 3.6-​fold risk of CAD for each unit change in BMI from the mean (weight off the chart) is often used in specialist
disease (CAD) centres, and the crossing of major weight percentile lines upwards is
and stroke
an early indication of risk of severe obesity.
Respiratory Neck circumference of >43 cm in men and >40.5 cm in
effects women is associated with obstructive sleep apnoea, daytime
somnolence, and development of pulmonary hypertension
Cancers 10% of all cancer deaths among non​smokers are related Aetiology of obesity
to obesity (30% of endometrial cancers)
Reproductive 6% of primary infertility in women is attributable to obesity Humans, like other mammals, are able to regulate their body weight
function over long periods of time despite day-​to-​day variation in the amount
Impotency and infertility are frequently associated with
obesity in men of calories consumed and in levels of energy expenditure. However,
Osteoarthritis Frequent association in older people with increasing
this homeostatic regulation of energy balance is easily overwhelmed
(OA) body weight by external stimuli.
Liver disease Non​alcoholic fatty liver disease and non​alcoholic Body weight is determined by an interaction between genetic, en-
steatohepatitis (NASH); 40% of NASH patients are obese vironmental, and psychosocial factors acting through the physio-
Gallbladder Threefold risk of gallbladder disease in women logical mediators of energy intake and expenditure. By definition,
disease obesity results from an imbalance between energy intake and en-
ergy expenditure and, in any individual, excessive caloric intake or
low energy expenditure, or both, may explain the development of
Committee has proposed a classification of overweight and obesity obesity. A third factor, nutrient partitioning, a term reflecting the
(Table 11.6.2) using BMI. propensity to store excess energy as fat rather than lean tissue, may
contribute.

Worldwide prevalence of obesity Environmental factors

The increasing prevalence of obesity worldwide (an approximate
Obesity, defined as a BMI of more than 30 kg/​m2, is a common condi- doubling in the last 30 years), the inverse relationship between
tion in Europe and the United States of America—​20% of American obesity and socioeconomic class, and the secular trend towards
men and about 25% of American women are obese. In Southeast increasing obesity in developing countries associated with urban-
Asia and the Middle East a dramatic rise is being seen in all popu- ization, provide clear evidence of the environmental influences on
lations. Figure 11.6.1 shows the prevalence of obesity in high, low, weight gain. The adoption of relatively sedentary lifestyles due to
lower-​middle, and upper-​middle income countries. reduced physical activity at work and in leisure time coupled with
In children the relationship between BMI and body fat varies an abundance of easily available, energy-​rich, highly palatable foods
markedly with age and with pubertal maturation. BMI percentile represents a nutrition transition (see http://​www.hsph.harvard.edu).
charts using national BMI reference data facilitate the graphical Interestingly, some recent analyses of trends in obesity preva-
plotting of serial BMI measurements in individual patients. The lence have suggested a decline or stabilization of obesity preva-
International Obesity Task Force (IOTF) has recommended the use lence. However, many countries have either increasing (China) or
of BMI data derived from six countries, which extrapolate risk from decreasing (European countries) birth rates, so the potential global
the adult experience to children. These age-​and gender-​specific BMI impact of these estimations is not readily predictable. Recent studies
cut-​offs (overweight as approximately 91st percentile or greater and show that second generation migrants to the United States from all
obesity as approximately 99th percentile or greater) allow the com- ethnic groups are heavier than their parents who migrated, but that
parison of obesity prevalence in different populations. Using these people from some ethnic groups are more likely to gain weight than
criteria, it is clear that the prevalence of overweight and obesity in others on transitioning to a more obesogenic environment, sug-
childhood is a global concern, and—​as shown in Fig. 11.6.2—​the gesting that in addition to strong environmental drivers, genetic fac-
tors play a role in influencing obesity susceptibility.
The two priority areas for public health strategies aimed at
Table 11.6.2 Cut-​off points proposed by a World Health
Organization Expert Committee for the classification of preventing obesity are increasing physical activity and improving
overweight and obesity the quality of the available diet within a community. However, such
strategies must address the need to improve the population’s under-
BMI WHO classification standing of the nature of obesity and its management and reduce
<18.5 Underweight exposure to an environment that promotes obesity.
18.5–​24.9 Normal weight
Genetic factors
25–​29.9 Overweight
In any environment, whether energy rich or energy lacking, there
30.0–​39.9 Obesity
is considerable individual variation in body weight and fat mass.
40.0 or greater Morbid obesity There is considerable evidence from family, twin, and adoption
 11.6 Obesity 1905

50%

(a)

Andorra 29.5
Urug

Barbuda 30.9

28.6
Uni

8.4

6.2
Un

ria 1
uay 2
te d

lia
40%

ited

as 3
Austra

.1
Un

Stat

Aust

35
6.7
it

am
Kin

.3
ed

in
Tr

es o

31
hra
High-income

Bah
in

gdo

Antigua and
Ar
Sw .2

id

os
20

f Am
ab

Ba
ad
itz

ad
m2
er 30%

Em
um

an

rb
Sw lan i .1

8.1

eric

Ba
d
lg 18

ira
ed d
Be

To
en 19
lam

tes 1.1

a 33
b
20 .4 .0
ssa

ag
Spa .5 28

37
ru

o
in 2 da

.7
Da na

.2
3
3.7
Slov
20%
ne
i Ca 7.8
Br
u le 2
enia
25.1 Chi
3.3
Slova tia 2
kia 2
5.7 Croa
10%
23.8
Singapo
re 6.2 Cyprus
8
Saudi Arabia 34.7 Czech Republic 26.
0% Denmark 19.3
vis 28.3
Saint Kitts and Ne Equatori
n 24.1 al Guinea
ti o 17.5
Federa
Russian
a 5.8 Eston
Kore ia 22
u b li c of .6
Rep Finl
and
2.3 20.6
ar 4 Fra
Qat 20
.1 Ge
nce
gal rm 23
.9
rtu an
P o 5.2 Gr y2
d2 ee 0.1
o lan .9 ce
P 30

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22

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29
.9

lan
23

8
m

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nd

19.
O

d
ay

23.1

lan
ala

22
rw

ds

Isra

.8
d2
Ze
No

rlan

.9
bourg
.6

5.6
w

el 2
Italy
Kuwait 39
Lithuania 25
a 26

Japan
Ne

the

Latvia23.7

5.3
Ne

21.0
Luxem
Malt

3.3
.7
50%
Afghanistan 2.9

.6
Zim

desh 3

.3
in 9
bab
Un

40%
ite

Ben

6.3
Low-income
we 1

Bangla
dR
Ug

so
Fa
0.5
ep
an

.6
da

ub

i2
To na

nd
4.9

rki
go
lic

30%

ru
7.5
Bu
of

Bu 3.2
dia
Tan

Taj bo
zan

ikis
tan C am
ia 7

13 20% .1
.6 ic 5
ubl
.1

Som ep
alia nR
4.6 rica
l Af 8.1
tra Chad
10% Cen
Sierra Le
one 7.6
Comoros 6.6

Rwanda 4.0 0% Democratic Peo

ple’s Republic of
Dem Korea 2.4
ocrati
c Rep
.3 ublic
Niger 4 of the
Cong
o 4.4

.3
al 3
Nep Erit
rea
.9 4.1
r2
ma Eth
M yan 5.3 iop
ia
e
qu 4.0
bi
Ga

am
m

oz
bi
Gui

M
a1
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0.
nea
6.8

9
ar 5.4

ine
5.3
ali

-Bis

a6
M

i
law

sau

.8
Haiti
agas

Liberia 6.6

Kenya 7.0
Ma

7.2
Mad

11.9

Fig. 11.6.1 Age-​standardized prevalence of obesity (percentage with BMI >30 kg/​m2) in adults aged 18 years
and over, by individual country and World Bank Income group, 2014.
Reprinted from Global status report on noncommunicable diseases 2014, Copyright © World Health Organization 2014.
1906 SECTION 11 Nutrition

50%
(b)

Armenia 19.5

Bhutan 6.7
Zamb

7.1
Yem

13.0
of ) 1
Vie

ia

1.4
40%

en 1

rde
8.9
tN

n1
Va

1. 0
State
7.2

o Ve
am
nu

roo

o1
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atu
Uz

3.6

me

2
Cab

ng
onal

9.
be

35

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Ca
Uk

k
30%

.4
.6

ist
ra

vo
ti 9

rinati
an
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d’I
ou

15
20

te
Tim ib
.1 Dj

.5

Cô
8.9

ia (Plu
or-
Le t2
ste yp
Syr 2.2 20% Eg
.8

Boliv
ian
Ara r 21
bR
alv ado
epu
Swaz blic El S 0 .8
iland 23. gia 2
17.7 5
10% Geor
Sudan 7. .2
5 Ghana 12

Sri Lanka 6.5 Guatemala 18.6

0%
7.5 Guyana 22.9
South Sudan
land s 27.7 Hond
uras 1
Solomon Is 8.2
2.3

La
9 .8 e1 Indi
cip

o
egal rin a 4

Pe
Sen

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.9
dP Ind

o
n on

pl
ea .9

rone
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am of

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tic
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ic n
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2
14

ra
pu
s5

pu
ea
.4

ted S
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ne

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bl
uin

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ic
pi

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so
y1
lip

wG

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tates

tho
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ua

Mongo
Ph

Nicaragua 17.1
Ne

Morocco 22.3
.4
rag

14
a
a 11.0

o
an 5

nia

.2
Pa

f ) 37
ua
Pap

9.7
lia 16.7
t
Pakis

Nig eri

.2
50%
Albania 17.6
Algeria 24.8

0.2
Vene

26.3
Tuv

2.5
Tur

Angola
zuela
a

4
ntina

2
lu 4

40%
23.
Tu

km

ijan

Upper-middle-income
.5
rk

0.3

us
eni

22
(Boliv
ey
Tu

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r ba

lar
sta

ze
n

To
29

7.9
isi

Be
Aze

eli
n
n2
.5
a2

ga a1 2.4
arian

th 43
7.1

30% a2
in
0.1

ef
ov

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or an 0.0
eg
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m il 2
Th er tsw
rz

a Bo az
He

ila Yu Br .2
nd g 23
blic o

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d

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an

lav
ina Re
20% lga
ia

me Bu 6.9
sn

pu na
f ) 24.8

26.
Chi
Bo

Sou 1 bli
th A co
frica fM 21.0
26.8 ac mbia
Seych
elles 2 ed 10% Colo
on 0.8
6.3 ia lands 5
Serbia 19.5 19 Cook Is
.6 .3
Costa Rica 24
Saint Vincent and the Grenadines 24.3
0% Cuba 25.2%
.9
Saint Lucia 26 Dominica
Domin 25.8
ican R
ia 21.7 epubli
Roman c 23.9
1.1 Ecua
2 dor
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Fig. 11.6.1 Continued

 11.6 Obesity 1907

Prevalence of overweight in children aged under 5 years, by WHO region and World Bank income group,
comparable estimates, 2013

14%

12%

10%

8%

6%

4%

2%

0%
AFR AMR SEAR EUR EMR WPR Low- Low- Upper- High-
income middle- middle- income
income income

Fig. 11.6.2 Prevalence of overweight in children under 5 years by World Health Organization (WHO) region
and World Bank income group (estimates in 2013). AFR, African region; AMR, region of the Americas; SEAR,
Southeast Asia region; EUR, European region; EMR, Eastern Mediterranean region; WPR, Western Pacific region.
Reprinted from Global status report on noncommunicable diseases 2014, Copyright © World Health Organization 2014.

studies that genetic factors contribute to this variability. Heritability the gut (peptide-​YY, glucagon like peptide-​1 (GLP-​1), cholecysto-
estimates can change over time and can differ between populations. kinin, and ghrelin; see Fig. 11.6.3). The hypothalamus integrates
Recent studies in a UK sample of 5092 twin pairs aged 8–​11 years these sensory inputs, compares those inputs to ‘set-​points’ for en-
growing up during a time of dramatic rises in obesity, confirmed ergy homeostasis, and then initiates a set of responses by activating
substantial heritability for BMI and waist circumference (77% for autonomic, endocrine, and behavioural outputs that aim to maintain
both), while there was a very modest shared-​environment effect, and these set-​points (homeostasis). Leptin stimulates the expression of
the remaining environmental variance was unshared. Interestingly, pro-​opiomelanocortin (POMC), which is cleaved by prohormone
similar heritability estimates have been found when studying mono- convertases to yield the melanocortin peptides, which act as
zygotic and dizygotic twins who were reared together and apart and
in adoption studies, where adopted children were discovered to have
body sizes that were more similar to those of their biological parents
than their adopted parents.
Recently, genome-​wide association have led to the identification
of multiple genomic regions/​loci that are strongly associated with
increased BMI and/​or obesity. However, to date, the common vari-
ants that have been identified explain less than 5% of the heritability
of increased BMI. It is likely that rare variants that are more highly Hypothalamus
penetrant will explain more of the missing heritability of obesity.

Programming and epigenetics

Recent evidence suggests that undernutrition of the fetus during
intrauterine development can influence the later onset of obesity,
hypertension, and type 2 diabetes, independent of genetic factors.
Such a phenomenon suggests the possibility of long-​term program- Ghrelin
CCK
PYY
ming of genetic expression as a consequence of altered intrauterine Nutrients GLP-1
growth. The influence of maternal diet and other factors on the regu- (glucose, fatty acids, etc.)
lation of genes in their offspring, referred to as epigenetics, is the Leptin
Vagus nerve
focus of much current research. Insulin

Hypothalamic circuits regulating

energy homeostasis Pancreas Adipose tissue GI tract
Energy homeostasis is tightly regulated, with the hypothalamus Fig. 11.6.3 Interactions between the hypothalamus, adipose tissue, and
playing a pivotal role in integrating signals from adipose tissue gastrointestinal tract. CCK, cholecystokinin; GI, gastrointestinal; GLP-​1,
stores, such as leptin, and short-​term meal-​related signals from glucagon like peptide-​1; PYY, peptide-​YY.
1908 SECTION 11 Nutrition

Fig. 11.6.4 Several single-​gene defects that disrupt the molecules in the leptin–​melanocortin
pathway cause severe obesity (indicated by *). Leptin is released from adipose tissue to act on
receptors expressed on the surface of distinct populations of neurones in the arcuate nucleus
of the hypothalamus. Leptin stimulates a neuropeptide called pro-​opiomelanocortin (POMC),
which is then cleaved by the enzyme prohormone convertase 1 (PC1) to yield the melanocortin
peptides. Leptin inhibits the expression of neuropeptide Y (NPY) and agouti-​related peptide
(AgRP). Both sets of neurons project to synapse, with second-​order neurons expressing the
melanocortin 4 receptor (MC4R), ultimately leading to an inhibition of food intake.

suppressors of feeding through the melanocortin 4 receptor (MC4R). by a careful clinical history (Box 11.6.1), examination, and inves-
This is a key circuit in the regulation of body weight, but numerous tigations (Table 11.6.3), which should also address the potential
other pathways involving the mesolimbic system, the hindbrain, and hidden complications of severe obesity such as sleep apnoea, cor-
orbitofrontal cortex influence eating behaviour (Fig 11.6.4). onary heart disease, type 2 diabetes, gynaecological abnormalities,
osteoarthritis, gallstones, and stress incontinence.
Height should be measured accurately using a stadiometer and
Clinical history, examination, and investigation weight measured by accurate scales in light clothing. BMI does not
distinguish between excess fat and lean body mass, hence waist cir-
For the assessment of severely obese patients, the consultation room cumference (or waist-​to-​hip ratio), which is a predictor of metabolic
should be properly equipped with larger than average chairs, access complications, should be measured. Ethnicity should be taken into
for wheelchairs for patients with mobility problems, and medical consideration as individuals from some groups (e.g. South Asians)
equipment of appropriate size (examination couch, blood pressure have a greater metabolic risk than would be expected for their BMI
cuff, weighing scales, stadiometer (for measurement of height), and and waist circumference. Waist circumference is taken as the mid-​
tape measure). point between the lower rib margin and the iliac crest.
In addition to a general medical history, a specific weight his- An examination of the skin is important: thin, atrophic skin is
tory should be taken, carefully establishing the age of onset (clinical a feature of excess corticosteroids; acanthosis nigricans (pigmented
photographs are helpful here), as it is useful to distinguish obesity ‘velvety’ skin creases, especially in the axillae) suggests insulin re-
that began in childhood (stronger genetic component) from that sistance; severe hirsutism in women may indicate polycystic ovary
occurring later in life either in relation to specific physiological ‘crit- syndrome. A neck circumference of more than 43 cm indicates a
ical periods’ such as pregnancy, illness, or concomitant medications. likelihood of obstructive sleep apnoea.
A history of previous treatment for obesity, diet, and levels of phys- Clinicians should use laboratory testing to evaluate overweight
ical activity should be noted. and obese patients who may be at high risk for cardiovascular dis-
The assessment of severely obese children and adults should ease and type 2 diabetes. Some useful tests to consider are fasting
include screening for potentially treatable endocrine and neuro- plasma glucose or 2-​h postprandial glucose levels and serum lipid
logical conditions and identifying genetic conditions so that ap- levels. Thyroid-​stimulating hormone (TSH) may be helpful in
propriate genetic counselling and, in some cases, treatment can be excluding hypothyroidism. Urinary free cortisol can be obtained if
instituted. In most patients, these specific causes can be excluded hypercortisolism is suspected clinically.
 11.6 Obesity 1909

Box 11.6.1 History Table 11.6.4 Obesity syndromes in the absence

of developmental delay
• Age of onset—​use of growth charts and family photographs. Early
onset (<5 years of age) suggests a genetic cause. Name of syndrome Clinical characteristics
• Duration of obesity—​short history suggests endocrine or central cause. Alstrom Progressive nephropathy, photophobia, retinitis
• A history of damage to the CNS (e.g. infection, trauma, haemor- pigmentosa, deafness, diabetes mellitus due to
rhage, radiation therapy, seizures) suggests hypothalamic obesity marked insulin resistance
with or without pituitary growth hormone deficiency or pituitary Leptin Severe hyperphagia, frequent infections,
hypothyroidism. A history of morning headaches, vomiting, visual hypogonadism
disturbances, and excessive urination or drinking also suggests that
Prohormone Neonatal diarrhoea, postprandial hypoglycaemia,
the obesity may be caused by a tumour or mass in the hypothalamus.
convertase 1 multiple endocrine abnormalities
• A history of dry skin, constipation, intolerance to cold, or fatigue sug-
gests hypothyroidism. Mood disturbance and central obesity suggests Leptin receptor Severe hyperphagia, frequent infections,
Cushing’s syndrome. Frequent infections and fatigue may suggest hypogonadism
ACTH deficiency due to POMC mutations. POMC Isolated ACTH deficiency, hypopigmentation
• Hyperphagia—​often denied, but a sympathetic approach is needed MC4R Increased linear growth, severe hyperinsulinaemia,
and responses to specific questions, such as waking at night to eat or ‘big-​boned’ appearance
demanding food very soon after a meal, suggest hyperphagia. If se-
vere, especially in children, suggests a genetic cause for obesity. ACTH, adrenocorticotropic hormone; MC4R, melanocortin 4 receptor; POMC,
• Developmental delay—​milestones, educational history, behavioural pro-​opiomelanocortin.
disorders. Consider craniopharyngioma or structural causes (often
relatively short history) and genetic causes.
• Visual impairment and deafness can suggest genetic causes. sleep apnoea; and head CT or MRI when pituitary or hypothalamic
• Onset and tempo of pubertal development—​onset can be early or disorders are suspected. Genetic testing is needed to confirm the
delayed in children and adolescents. Primary hypogonadotropic diagnosis in patients with rare genetic disorders. The measurement
hypogonadism or hypogenitalism associated with some genetic of serum leptin is not recommended as a routine examination, but
disorders. should be undertaken in cases of severe early onset obesity, since,
• Family history—​consanguineous relationships, other children affected, although it is rare, congenital leptin deficiency is a potentially treat-
family photographs useful. Severity may differ due to environmental
able disorder.
effects.
• Treatment with certain drugs or medications. Glucocorticoids, Genetic obesity syndromes
sulphonylureas, oral contraceptives, antidepressants, and
antipsychotics. Classically, patients affected by genetic obesity syndromes have been
identified as a result of their association with developmental delay,
dysmorphic features, or other developmental abnormalities. More
Other tests to consider depend on clinical assessment and include recently, several single-​gene disorders resulting from disruption
ultrasonography for hepatic steatosis, gallstones, and the polycystic of the hypothalamic leptin–​melanocortin signalling pathway have
ovary syndrome; electrocardiography in patients at high risk for car- been identified. In these disorders, obesity itself is the predominant
diovascular disease; polysomnography for patients with possible presenting feature, although frequently accompanied by character-
istic patterns of neuroendocrine dysfunction that will only become
apparent on investigation. Mutations in several of these molecules
Table 11.6.3 Key points in the examination and investigation of an cause severe obesity associated with specific neuroendocrine abnor-
obese patient malities (Table 11.6.4). One rare genetic disorder, leptin deficiency,
is entirely treatable with daily subcutaneous injections of recom-
Examination Height, weight—​calculate BMI
binant human leptin, and another, MC4R deficiency, is relatively
Blood pressure common, with a population prevalence of 1 in 1000 unselected indi-
Waist circumference viduals and 1 in 100 obese people.
Neck circumference For the purposes of clinical assessment, it remains useful to cat-
Acanthosis nigricans egorize the genetic obesity syndromes as those with dysmorphism
and/​or developmental delay, and those without these features. There
Body fat distribution
are about 30 Mendelian disorders with obesity as a clinical feature
Secondary sexual characteristics
but often associated with mental retardation, dysmorphic features,
Any evidence of cardiac disease and organ-​specific developmental abnormalities: the commonest of
Signs of hyperlipidaemia these are listed in Table 11.6.5.
Signs of thyroid disease
Ophthalmic evidence of diabetes or sustained
hypertension Approach to the treatment of obesity
Investigations Fasting and postprandial blood glucose
Fasting lipid profile
The recommendation to treat obesity is based on evidence that re-
lates obesity to increased mortality and the results from randomized
Strip test for urine glucose and protein
controlled trials, which demonstrate that weight loss reduces the
Free thyroxine and thyroid-​stimulating hormone risk of many metabolic complications. Professional, governmental,
1910 SECTION 11 Nutrition

Table 11.6.5 Obesity syndromes with developmental delay

Name of syndrome Gene/​genetic region involved Clinical characteristics

Prader–​Willi Deletion or uniparental maternal disomy Hypotonia, short stature, hypogonadotropic hypogonadism, feeding difficulties
of chromosome 15q11.2–​-​q12 <2 years of age, then hyperphagia with pica behaviour
Bardet–​Biedl Mutations in multiple genes affect the Polydactyly, retinitis pigmentosa, and hypogonadism are consistent features
function of cilia
Fragile X Unstable expansion of trinucleotide Moderate to severe developmental delay, macro-​orchidism, prominent jaw, and
repeats in the FMR1 gene high-​pitched jocular speech
Cohen COH1 mutations Microcephaly, characteristic facial features, progressive retinochoroidal dystrophy,
myopia, and a cheerful disposition
Albright hereditary GNAS1 mutations Short stature, round facies, brachydactyly, and ectopic soft tissue ossification (osteoma
osteodystrophy cutis), variable hormone (TSH, PTH) resistance, short fourth metacarpal
BDNF/​TrkB deficiency Mutations/​deletions in BDNF or its Delayed speech and language development, impaired short-​term memory, and loss of
receptor TrKB nociception

BDNF, brain-​derived neurotrophic factor; PTH, parathyroid hormone; TrkB, neurotrophic tyrosine kinase, receptor, type 2; TSH, thyroid-​stimulating hormone.

and other bodies have drawn up guidelines for obesity management Dietary management
and it is advisable to seek out the latest national and international Many dietary approaches have been advocated for the treatment
guidelines as newer evidence is incorporated. These strategies pro- of obesity. Recent evidence-​based reviews support the use of low-​
vide useful evidence-​based guidance for clinical management, but calorie diets as being most likely to be effective for modest weight
it is important to remember that an individually tailored approach loss. A review of 48 randomized control trials shows that an average
is often required and that any treatment programme for obese pa- weight loss of 8% of the initial body weight can be obtained over 3
tients should address weight reduction and the maintenance of the to 12 months with a low-​calorie diet. Such a treatment may require a
lowered weight and take account of individual circumstances. period of supervision for at least 6 months.
Goals of weight loss The weight-​reducing dietary regimen should initially provide a
600 kcal/​day (2.5 MJ/​day) energy deficit, based on estimated en-
Achievement of normal or ideal body weight is not a necessary goal ergy requirements. After 6 months, the rate of weight loss usually
in the management of obesity and is rarely reached in practice. There declines and a further adjustment of calorie intake may be indi-
is evidence from epidemiological studies of intentional weight loss cated at this stage. The use of very low-​calorie diets can be con-
that modest weight loss, of the order of 5 to 10% from presenta- sidered, ideally under close supervision as preparations must
tion weight, is associated with clinically worthwhile reductions in provide a minimum of 400 kcal (1.7 MJ) per day for women and
comorbidities, such as hypertension, dyslipidaemia, and diabetes 500 kcal (2.1 MJ) per day for men. Evidence from randomized trials
risk (Table 11.6.6). In some patients, particularly in those with se- confirms that over the longer term (more than a year), weight loss
vere comorbidity, prevention of weight gain may be a reasonable aim following very low-​calorie diets is no different from that obtained
of treatment. Weight loss should be approached incrementally, with with low-​calorie diets.
new goals for weight loss negotiated with the patient once the ori-
ginal target has been achieved. Behavioural therapy and exercise
Behavioural approaches aim to help people to implement and sus-
Table 11.6.6 Potential health benefits that may accrue from the tain changes to their eating and activity behaviour. There is evi-
loss of 10 kg from the initial body weight dence that combining a behavioural approach with more traditional
dietary and activity advice leads to improved short-​term weight loss.
Mortality 20–​25% fall in total mortality In general, weight loss with these approaches is modest (about 4 kg
30–​40% fall in diabetes-​related deaths or 4% of body weight on average).
40–​50% fall in obesity-​related cancer deaths Although modest physical activity has undoubted health bene-
Blood pressure c.10 mm Hg fall in both systolic and diastolic values fits and can contribute to weight loss, it is not usually advocated as
a sole treatment option. Many studies, however, do suggest that it
Diabetes >50% reduction in risk of developing diabetes
can be helpful to improve weight loss maintenance once weight loss
30–​50% fall in fasting glucose
has been achieved. The results from randomized controlled trials
15% fall in haemoglobin A1c suggest that a combination of diet and exercise generally produces
Lipids 10% fall in total cholesterol more weight loss than diet alone. The optimal approach should be a
15% fall in LDL cholesterol high-​quality diet to which patients will adhere, accompanied by an
30% fall in triglycerides exercise prescription describing frequency and intensity of exercise
with a minimum of 150 min moderate weekly activity. The type of
8% increase in HDL cholesterol
physical activity (e.g. aerobic versus resistance) does not seem to af-
HDL, high-​density lipoprotein; LDL, low-​density lipoprotein. fect overall weight loss.
 11.6 Obesity 1911

Two large randomized clinical trials—​the Look AHEAD and Adverse effects of orlistat are predominantly related to
the Diabetes Prevention Programme—​support the use of intensive malabsorption of fat. These include loose or liquid stools, faecal ur-
weight loss programmes with face-​to-​face (group or individual) gency, and oily discharge; they can be associated with malabsorption
sessions. The delivery of such programmes is often expensive and of fat-​soluble vitamins. As the consumption of a high-​fat meal will
a useful alternative is the use of commercial programmes to deliver inevitably lead to severe gastrointestinal symptoms, it is possible
advice within communities. A meta-​analysis comparing named that some of the weight loss with orlistat treatment results from an
diets and several comparisons of diets with different amounts of ‘Antabuse effect’, leading to behavioural change.
fat/​carbohydrate/​protein have found that there was no significant
difference between diets in terms of weight loss achieved. A key Sibutramine
goal is identifying a diet that a particular patient finds that they can Sibutramine inhibits the reuptake of noradrenaline and serotonin,
adhere to. promoting, and prolonging satiety. It may also have an enhancing
effect on thermogenesis through the stimulation of peripheral
Drug therapy noradrenergic receptors. Adverse effects include nausea, dry mouth,
General principles rhinitis, and constipation. It produces 5 to 10% weight loss in 60 to
70% of patients, which in clinical trials is well maintained for at least
While intervention programmes that focus on supporting people to
2 years. The noradrenergic action increases heart rate by 1 to 2 beats/​
change their diet and/​or levels of physical activity can be effective in
min and attenuates the fall in blood pressure expected with weight
inducing weight loss in the short to medium term in some people,
loss. Some patients, especially if they fail to lose weight, may record a
they lose efficacy in the long term. In addition to the focus on pre-
rise in their blood pressure; it is therefore essential to monitor blood
vention of obesity, treatment of obese patients, preferably at a stage
pressure during treatment.
before complications has emerged, is therefore an important priority.
Recent concerns about increased cardiovascular morbidity as-
Previous antiobesity drugs targeted cannabinoid signalling
sociated with Sibutramine have led to prescribing restrictions, par-
(rimonabant), noradrenergic (phentermine), serotoninergic signalling
ticularly relevant to those patients with established cardiovascular
(fenfluramine, dexfenfluramine), and reuptake (sibutramine). These
disease. Current guidelines in Europe and the United States vary and
compounds were moderately effective but, as with many centrally
physicians should consult local guidelines where available.
acting agents, at the expense of many off-​target effects, reflecting lack
of specificity of the neural targets. Newer centrally acting antiobesity drugs
The use of obesity drugs should follow the same principles as for
Over the last few years, certain weight loss drugs have been ap-
any condition and be prescribed after assessment of the potential
proved by the US Food and Drug Administration (FDA) and other
benefits and risks with appropriately informed patients, and with
regulators, expanding the number of options available to physicians
medical monitoring of the results of treatment. Some healthcare
seeking to treat patients with severe obesity and/​or obesity with
providers still believe that a short course of drug treatment might
complications.
‘cure’ obesity or that efficacy is measured only by ever-​continuing
Lorcaserin, a selective 5HT2cR agonist with limited activity at the
weight loss. These ideas are inconsistent with the known biology as
other serotonin receptors, leads to weight loss, lowers blood pres-
people who become obese have a persistent tendency both to defend
sure, total cholesterol, low-​density lipoprotein cholesterol, and tri-
their excess weight and to continue to gain extra body fat. Effective
glycerides, although concerns about potential cardiac valvulopathy
management must be lifelong and focused on weight loss mainten-
and cancer risk remain. Adverse effects include headache, nausea,
ance in a similar fashion to the effective treatment for hypertension
fatigue, and dizziness.
or diabetes. Starting drug treatment should always be regarded as a
An extended release combination of the anticonvulsant topiramate
therapeutic trial and stopped if weight loss is not apparent after 1 or
(which modulates GABA-​ergic transmission and inhibits carbonic
2 months.
anhydrase) and phentermine, which increases central noradren-
The initiation of drug treatment will depend on the physician’s
aline levels, is also approved in some countries. Topiramate is asso-
judgement about the risks to an individual from continuing obesity.
ciated with fetal toxic effects and a pregnancy test before and during
A drug should not be considered ineffective because weight loss has
therapy is recommended.
stopped, provided that the lowered weight is maintained. However,
Bupropion, a dopamine and noradrenaline reuptake in-
continuation of the drug should depend on the balance between the
hibitor, has anorexigenic properties resulting in modest weight
health benefits of maintained weight and the potential adverse ef-
loss. The effectiveness of bupropion is increased (and thus the
fects of the drug.
dose can be reduced) when combined with the opioid receptor
Particular drugs antagonist naltrexone, resulting in the combination product,
naltrexone-​bupropion.
Orlistat The synthetic GLP-​I receptor agonist liraglutide, effective in the
Orlistat inhibits pancreatic and gastric lipases, thereby decreasing treatment of type 2 diabetes, has been approved for the treatment
the hydrolysis of ingested triglycerides. It produces a dose-​dependent of obesity alone by the FDA. Nausea remains a significant problem
reduction in absorption of dietary fat that is near maximum at a dose in many, but those who can tolerate the dug do well. Several other
of 120 mg, three times daily. It leads to 5 to 10% weight loss in 50 to gut peptide analogues, gut hormone receptor agonists, and cen-
60% of patients, and in clinical trials the loss (and related clinical trally active compounds are currently being studied in clinical
benefit) is largely maintained up to at least 4 years. trials.
1912 SECTION 11 Nutrition

More recently a potent melanocortin receptor agonist, RM-​493,

Concluding remarks
has been administered as part of a phase 1b proof-​of-​concept clinical
trial in obese patients, including one cohort with heterozygous loss
As the prevalence of obesity is rising, we are seeing more and more
of function mutations in MC4R where there was promising weight
patients with severe obesity. It is important to have a practical ap-
loss after four-​weeks. If this compound moves forward, this may be
proach to the investigation and management of these patients who
one of the first examples of a personalized medicine approach for
have considerably increased morbidity and mortality. The clinical
treating obesity in people with a genetically characterized subtype
evaluation of severely obese patients will become increasingly so-
of obesity.
phisticated, and novel biochemical and molecular genetic diagnos-
Surgical treatment of obesity tics will need to be combined with the more traditional nutritional
and behavioural approaches to optimize treatment for individual
Randomized controlled trials confirm that surgery for obesity is an
patients.
effective option for carefully selected patients with severe obesity
(BMI >40 kg/​m2 or BMI >35 kg/​m2 with comorbid conditions). The
nature of the surgical procedures necessitates long-​term hospital
follow-​up for such patients. The initial findings from the Swedish FURTHER READING
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its own risks and benefits which need to be considered carefully on
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Tan T, Bloom S (2013). Gut hormones as therapeutic agents in ment. Am J Clin Nutr, 87, 398–​404.
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996–​1001. obesity: a systematic and clinical review. JAMA, 311, 74–​86.
11.7
Artificial nutrition support
Jeremy Woodward

ESSENTIALS supplementation in selected patient groups is associated with signifi-

cant reduction in both morbidity and mortality.
The prevalence and relevance of undernutrition in affluent societies A multiprofessional team is required to coordinate and monitor
is often unrecognized, but nutritional status significantly impacts out- the necessary support for patients fed artificially in hospital and the
comes in all disease states. community. Patients can receive artificial nutrition support indefin-
Nutrition screening identifies patients at risk of undernutrition and itely in the community. Outcomes of intestinal transplantation have
should be carried out in hospitals and community: its components improved significantly over recent years, but due to excellent long-​
comprise past weight loss, current body mass index, and likely fore- term outcomes on home parenteral nutrition, this is usually con-
seeable nutritional challenges. A body mass index less than 18.5 kg/​m2; sidered only where there are life-​threatening complications of such
weight loss of more than 10% over 6 months; or BMI of less than treatment.
20 kg/​m2 with weight loss of more than 5% over 6 months, are all
indicative of undernutrition.
Nutrition support is indicated for malnourished patients or
those at risk of undernutrition in view of inadequate oral intake or Introduction
malabsorption. Timing of the intervention depends on the pre-​
existing nutritional status and the likelihood of restoring adequate In affluent societies where food is plentiful the extent of under­
intake. Nutrient requirements are calculated using weight-​based nutrition is poorly recognized, affecting more than 10% of all adults
formulae for basal energy and protein requirements, with additional over the age of 65 years in the community, and around 40% of all
factors for physical activity, severity of illness, or desired weight gain. hospital inpatients or elderly care home residents. Undernutrition
Increased requirements due to disease are often counterbalanced by usually arises from social or disease-​related factors, and in turn has
reduced activity. profound implications for the progression of illness and outcome of
Institutional provision of food (in a conducive environment) treatment by altering physiological responses and having effects on
of appropriate quantity, texture, temperature, and variety, with immunity and healing as well as psychology, motivation, and social
encouragement and assistance to eat, may obviate the requirement interaction. Chronic illness often increases nutritional require-
for artificial nutrition support. ments, but this is often balanced by a reduction in physical activity.
Artificial nutrition support can be provided in the form of oral nu- The associated anorexia or inability to feed orally usually contrib-
tritional supplements, or enteral or parenteral tube feeding. Enteral utes more significantly to undernutrition and is directly amenable to
feeding is physiologically preferable to parenteral nutrition as it intervention by nutrition support.
maintains gut integrity, stimulates hormonal regulation of metab-
olism and gastrointestinal functions, and delivers nutrients to the liver
via the portal circulation. Nutritional screening and assessment
Tube feeding can be associated with significant complications re- of nutritional status
lating to the means of access or delivery of nutrients. It is easy to
overfeed with parenteral nutrition, especially in catabolic patients Weight is easier to lose than regain, and although weight may be ul-
who are unable to utilize excess protein or energy. The potential timately restored, the body composition takes longer to normalize
risks of the route of feeding need to be balanced against the benefits as initial weight gain comprises significant fluid and fat components
for any individual, which influences the timing of the intervention. rather than lean mass. The risk of undernutrition related complica-
Tube feeding is only instituted where oral feeding is impossible or tions therefore relates to the disease trajectory as well as the current
inadequate and hence benefits are unclear due to the ethical im- nutritional status. These components—​prior weight loss, current
possibility of randomized trials in this setting. However, oral nutrition nutritional status, and pending threats to nutritional intake—​are
combined into a nutrition ‘risk score’, and such scores are routinely
 11.7 Artificial nutrition support 1915

Fig. 11.7.1 The ‘Malnutrition Universal Screening Tool’ (MUST)—​an example of an algorithm
for screening and identification of malnutrition and the appropriate actions to be taken based
on risk score.
This tool is reproduced with kind permission of BAPEN—​British Association for Parenteral and Enteral Nutrition.

used in clinical practice to identify patients requiring nutritional op- alcohol intake can be associated with thiamine and folic acid
timization (Fig. 11.7.1). deficiency.
Oral conditions may make ingestion painful; abdominal symp-
History toms such as nausea, bloating or pain can reduce intake and patients
A nutrition history will include the nature of the baseline diet—​not may not admit to (or even be aware) of significant changes in appe-
only for vegans and vegetarians who may be lacking in haem iron tite. Medication side effects may alter dietary intake and a variety of
and vitamin B12, but also for poor fresh fruit and vegetable intake conditions can lead to taste disturbances. Psychosocial circumstances
(vitamin C and folic acid) and dairy avoidance (calcium), or other can have a profound impact on oral intake—​for instance, in depres-
dietary restrictions due to intolerances, dislikes, or fads. Excessive sion, bereavement, social isolation, impaired mobility, or poverty.
1916 SECTION 11 Nutrition

Examination Table 11.7.1 Common indications for enteral nutrition support

Patients may not have weighed themselves or be aware of weight Impaired conscious level Head injury
loss, but clinical features may be present such as prominent cheek- Ventilated patients in critical care setting
bones, muscle wasting, redundant skin folds, and concave abdomen. Cerebrovascular disease
Ill-​fitting clothing, belt notches, and loose rings on fingers provide Neurological dysphagia Motor neuron disease
additional clues. Many of these signs are apparent even in obese in- Cerebrovascular disease
Multiple sclerosis
dividuals who remain overweight despite recent weight loss. Signs Bulbar palsy
of specific nutritional deficiencies (see Chapters 11.2 and 11.3) may Cerebral palsy
be identified, particularly in hair, eyes, skin, nails, teeth, and tongue. Upper gastrointestinal Head and neck cancer
obstruction Oesophageal cancer
Body mass index, and its limitations Gastric cancer
Gastric outlet obstruction—​benign or malignant
The ratio of weight (in kg) to the square of the height (in m2) is known
Dysmotility Severe oesophageal dysmotility
as the body mass index (BMI) and provides a useful indication of Gastroparesis
nutritional status. It may, however, be misleading, for instance in
Related to treatment Prior to chemoradiation therapy for head and
younger patients, those with skeletal deformity due to cerebral palsy, modalities neck cancer
or elderly patient with osteoporosis. A BMI of less than 18.5 kg/​m2 Post complex upper gastrointestinal surgery
is considered indicative of undernutrition, as is weight loss of more (i.e. Whipple’s procedure, oesophagectomy)
than 10% over 6 months or a BMI of less than 20 kg/​m2 in associ- Inability to meet nutritional Malabsorption
ation with weight loss of more than 5% over 6 months. In children requirements orally Borderline short gut
Anorexia secondary to chronic illness
the use of centile charts is valuable as sustained undernutrition leads Respiratory disease (i.e. cystic fibrosis)
to reduced height velocity and failure to meet predicted height.
The major drawback of using BMI for nutritional assessment is
that it is affected by changes in body composition, with clinically gastroparesis, whereas thickening fluids with starch reduces the risk
important changes in lean body mass being masked by shifts in fluid of pulmonary aspiration in neurological causes of dysphagia.
distribution and adipose tissue. The entity of sarcopenic obesity—​ Artificial nutrition support is required if such measures are in-
overweight individuals with reduced muscle mass or function—​has effective in maintaining sufficient oral intake. If swallowing is in-
recently been described associated with ageing or inflammatory tact and palatability is acceptable then oral nutrition supplements
pathology and highlights the weakness of using body mass alone can be provided. Unconscious patients, those unable to swallow or
without considering its components. with upper gastrointestinal obstruction can receive enteral nutrition
Bio-​impedance measurement can provide measurements of extra- support if intestinal function is preserved. Access can be achieved
cellular water and estimates of fat-​free mass from which lean body by pernasal or transabdominal feeding tubes to the stomach or in-
mass can be calculated, but validation in disease settings is still re- testine. Patients without adequate intestinal function require total
quired. Sequential measurements of mid-​upper arm circumference or partial parenteral nutrition support via an intravenous catheter.
and triceps skin fold thickness using a tape measure and callipers Common indications for enteral and parenteral artificial support are
can provide estimates of changes in lean body mass, and hand-​grip given in Tables 11.7.1 and 11.7.2.
dynamometry measurements are a useful surrogate of changes in The timing of nutritional support interventions depends on the
functional muscle mass. Used at a single point in time, however, pre-​existing nutritional status of the patient and likely subsequent
wide reference ranges make these tools unreliable for nutritional events. It has proven difficult to demonstrate any benefit for short
assessment. Dual energy X-​ray absorptiometry (DEXA) and volu- term artificial nutrition support, but it is equally challenging to
metric analysis of CT scans are becoming more widely available as predict when a patient will become nutritionally independent.
tools for measuring body composition.

Table 11.7.2 Common indications for parenteral nutrition support

Indications for artificial nutrition support
Enteric dysmotility Hirschsprung’s disease
Undernutrition can be prevented in patients at risk by simple meas- Visceral neuropathy
Visceral myopathy
ures to optimize appetite such as reducing symptoms such as pain Systemic sclerosis
or nausea that lead to anorexia. The range of menus and the presen- Radiation enteritis
tation and temperature of meals in hospital affect the amount con- Postoperative ileus
sumed, as well as limiting interruptions at mealtimes or ‘nil by mouth’ Intestinal obstruction Malignancy
orders. Institutional catering needs to accommodate the require- –​ Gastrointestinal
–​Metastatic ovarian or peritoneal
ments of patients with altered feeding patterns, such as after upper –​Metastatic breast
gastrointestinal surgery or with dysmotility, and older people often Sclerosing peritonitis
prefer to snack rather than take large meals. Patients with disabil- Postsurgical adhesions
ities may require assistance with eating and sufficient staff and time Mucosal disease Microvillous inclusion disease
are required to provide this. Food texture may need to be altered—​ Autoimmune enteropathy
Refractory coeliac disease
pureed or liquid diets benefit patients with oesophageal strictures or
 11.7 Artificial nutrition support 1917

However, the benefits of early nutrition support have been clearly Phosphate requirements increase greatly during refeeding from a
demonstrated in a variety of settings and the timing of intervention baseline of approximately 0.3 mmol/​kg per day.
therefore requires an individual assessment balancing the benefits of Feeds with minimal electrolyte content are required in oliguric
early intervention against its cost and risks. renal impairment where solute clearance is reduced, but the com-
monest cause of excessive electrolyte administration in hospitals
is the inappropriate use of normal (0.9%) saline, which contains
Estimating nutrition requirements 154 mmol/​litre of sodium, and salt-​rich colloid solutions for main-
tenance fluid requirements.
Energy
Macronutrients
Energy expenditure under basal conditions reflects physiological
cellular metabolism and therefore correlates with body mass. Protein
Derivative equations based on weight and corrected for age and Protein is required to meet obligatory catabolic losses (minimal
gender provide estimates of energy consumption that adequately requirement) and to stimulate protein synthesis (optimal require-
match measurements based on oxygen uptake and CO2 production ment). The World Health Organization (WHO) recommendation
(indirect calorimetry) for most clinical purposes. Additions are re- of minimal requirement is 0.75 g protein/​kg per day (0.12 g N/​kg
quired for activity and the thermal effect of food. Disease states such per day) based on nitrogen balance studies on a protein-​free diet
as burns, sepsis, or trauma increase energy expenditure, but this is (Fig. 11.7.2). Increasing the dietary protein intake will increase pro-
usually compensated for by reduced physical activity and overall tein synthesis in depleted patients as long as sufficient calories are
may equate to an increase of only 10–​20% over resting energy ex- taken, and the optimal calorie:nitrogen ratio may vary depending
penditure. Corrections also need to be made for patients with oe- on the disease state. Although net protein synthesis can be achieved
dema or obesity and energy requirements in these circumstances by increasing dietary protein in undernourished patients, the same
may be based on a proportion of body mass or ideal body weight. is not true in the catabolic state induced by sepsis, burns, or trauma,
Most hospital patients’ requirements lie within the range of 25–​40 where excess amino acids can exert detrimental effects. Intakes of
kcal/​kg per day (105–​168 kJ/​kg per day). above 1.5 g protein/​kg per day (>0.24 g N/​kg per day) are not gener-
ally recommended.
Fluid Amino acids have physiological roles beyond protein synthesis
Fluid balance must be considered a part of the nutritional require- and individual amino acid levels vary significantly between dif-
ments, and nutrition and hydration should be considered together. ferent disease states. Most artificial feeds provide standard amino
Most hospitalized patients require 30–​35 ml/​kg per day, with add- acid solutions that do not cater for such differences and may result
itions to replace losses. Fluid losses from the kidneys—​with diabetes in relative imbalances of amino acid that could compromise amino
insipidus or when recovering from acute tubular necrosis—​can be acid utilization. Histidine levels are low in renal impairment, and
excessive and obligatory, while volumes of 10 litres a day can be branched chain amino acids (valine, leucine, isoleucine) are reduced
lost from the gastrointestinal tract via a proximal jejunostomy or in chronic liver disease. Glutamine is significantly depleted in crit-
enterocutaneous fistula. Fluid restriction is indicated in overloaded ical illness and improvement in nitrogen balance has been demon-
states or in renal or cardiac failure and diluents for intravenous drugs strated with supplementation.
and line flushes can reduce the fluid allowance available for the feed An important demonstration of amino acid imbalance affecting
in ill patients. Most enteral feeds provide 1 kcal/​ml but specialized protein synthesis is the (diagnostic) rise in blood urea associated
feeds with up to 2 kcal/​ml are available for such circumstances. with an upper gastrointestinal haemorrhage. While previously
thought to be associated with an excess nitrogen load absorbed
Electrolytes from the protein in the ingested blood, it appears that the cause
Average requirements for sodium and potassium are of the order of is the lack of isoleucine residues in haemoglobin that leads to a
1 mmol/​kg per day for most adults. However, significant losses of relative deficiency of isoleucine in the circulation which thereby
sodium and other electrolytes can occur through the gastrointes- inhibits protein synthesis. The rise in urea is endogenous, due to
tinal tract (Table 11.7.3), and potassium deficits may also be large in the ongoing breakdown of protein without utilization of resultant
patients receiving thiazide diuretics, during recovery of metabolic amino acids in protein synthesis, and can be abrogated by simultan-
acidosis, and during refeeding of severely underweight individuals. eous isoleucine infusion.

Table 11.7.3 Electrolyte composition of gastrointestinal fluids (in order to calculate replacement of losses)

Fluid Na+ K+ (mmol/​litre) HCO3–​ Cl–​ Volume (/​24 h)

(mmol/​litre) (mmol/​litre) (mmol/​litre)
Gastric juice 60 15 –​ 90 2500
Pancreatic juice 140 5 90 75 1500
Bile 140 5 35 100 500
Small intestinal contents 100 10 25 100 1000 (Succus entericus)
Diarrhoea 60 30 45 45
1918 SECTION 11 Nutrition

Severe are prone to deficiency. Vitamin deficiencies can have profound ef-
nutritional fects on cellular metabolism and few vitamins are toxic in excess,
200 depletion
hence vitamin levels in commercial feed preparations generally ex-
160 ceed estimated requirements. This excess helps to compensate for
the degradation of some vitamins that occurs in solution—​vitamin
120
Nitrogen balance (mg/kg/day)

Moderate A and riboflavin are photosensitive (hence the need to protect

80 nutritional depletion hanging parenteral nutrition solutions from the light), thiamine
+ reacts with preservatives required to maintain shelf life in paren-
40
No nutritional teral nutrition, and vitamins C and E are ineffective when oxidized.
depletion The latter is used in excess in parenteral nutrition to prevent lipid
peroxidation.
40 Vitamin K is normally not required in artificial nutrition, due to
− No nutritional enteric bacterial synthesis, and its addition could affect therapeutic
80 depletion: anticoagulation. Biotin (vitamin B7) and pyridoxine (vitamin B6) are
Severe injury
120
also made by enteric bacteria. The latter has been associated with a
reversible toxic neuropathy if taken in excess. Fat soluble vitamins—​
160 A, D, and E—​can be provided in a water-​miscible solution in paren-
teral nutrition.
200
0.1 0.2 0.3 0.4 0.5 Minerals and trace elements
Nitrogen intake (g/kg/day) In contrast to vitamins, toxicity is associated with excess delivery of
Fig. 11.7.2 Relationship of nitrogen intake and nitrogen balance in some trace elements. The enterocyte regulates iron uptake and rela-
patients receiving sufficient energy. Normal subjects reach nitrogen tively small amounts of trace elements are absorbed from the intestine,
balance at approximately 0.1 g/​kg/​day nitrogen intake; positive nitrogen hence overadministration is more likely to occur with parenteral than
balance can be achieved in malnourished patients. Severe illness (trauma, with enteral nutrition. Manganese and copper undergo biliary ex-
sepsis, burns) results in net catabolism. Patients with a combination of cretion and accumulation can occur in parenterally fed patients with
depletion and severe illness react in an intermediate fashion.
cholestasis: basal ganglia deposition can be detected on brain MRI
Reprinted from Clinical Nutrition, Vol. 1. Elia M, ‘The effects of nitrogen and energy
intake on the metabolism of normal, depleted and injured man: Considerations for scanning, but neurological effects are rarely reported. Chromium is
practical nutritional support’, pp. 173–​92, Copyright © 1982, with permission from excreted through the kidneys and can accumulate in renal failure, but
Elsevier.
toxic effects have not been reported. Zinc is lost through the intestine
in high output states and in wound exudates leading to requirement
Carbohydrate for supplementation. Selenium plays a key role in cellular redox main-
tenance as a cofactor in glutathione peroxidase and some authorities
Carbohydrates should make up 50–​65% of calories in a healthy diet.
recommend supplementation in critical illness.
In excess of 5 g/​kg per day, glucose is stored as glycogen up to a max-
Analysis of trace element levels in the blood can be inaccurate
imum storage capacity of 15 g/​kg. Continued administration of glu-
and affected by the acute-​phase response and serum albumin con-
cose results in lipid synthesis and hepatic steatosis. Maximal glucose
centration, and interpretation of low levels is always complicated by
oxidation rates are frequently lower in disease states due to insulin
the possibility that it reflects a physiological response to acute illness
resistance and excessive glucose administration can therefore result
such as in the case of iron sequestration in infection.
in hyperglycaemia.

Lipid
Complications of artificial nutrition support
The lower limit constraint on lipid provision is the need for essential
fatty acids (linoleic and α-​linolenic acids), which can be provided The ease with which full nutrition requirements can be delivered by
in 3–​4.5% of the total energy requirements as fat. Lipid is used in artificial means results in a risk of ‘refeeding syndrome’ on initiating
artificial nutrition to provide the energy that cannot be supplied as feeding in chronically undernourished patients. Features include elec-
carbohydrate due to the limit of glucose oxidation. The amount of trolyte imbalance (hypokalaemia, hypophosphataemia, hypomagnes-
CO2 produced by oxidation of lipid is 30% less than that of glucose, aemia) and an associated risk of cardiac arrhythmia and sudden death,
which could theoretically help patients with respiratory failure or hyperglycaemia, and fluid shifts that can precipitate heart failure.
weaning from a ventilator, but clinical benefits are small in practice. The rapid depletion of thiamine—​an essential cofactor of pyruvate
Micronutrients decarboxylase—​results in inhibition of glycolysis on refeeding and
damage to glucose dependent cells such as neurons, the clinical pres-
Vitamins entation of Wernicke–​Korsakoff syndrome. This is preventable by the
A balanced diet provides sufficient vitamins in most cases. There administration of high-​dose intravenous thiamine prior to refeeding
are no body stores of the water-​soluble B vitamins, which can be de- (or glucose administration) in patients considered at risk.
ficient in a variety of different disease states including alcoholism, Other complications of artificial nutrition support are specific to
recurrent vomiting, and diabetes. Vitamin B12 is only present in the route of delivery. Access devices in common use, with their ad-
animal dietary sources and therefore those following a vegan diet vantages and disadvantages are listed in Table 11.7.4.
Table 11.7.4 Types of enteral and parenteral access devices in common use

Type of tube Description Use Advantages Disadvantages

Enteral (EN)
Nasogastric Fine-​bore (6–​8 F) polyurethane tube; can be Short-​to-​medium term intragastric Bedside placement without sedation; Risk of malposition; difficult to manage in confused
secured with a nasal bridle—​a loop of tape feeding due to inability to swallow, well tolerated patients
around the nasal septum nutritional supplementation; bolus or
infusion feed
Nasojejunal Fine-​bore polyurethane tube with tip passed Inability to swallow complicated Can be placed non​invasively at May require endoscopy or fluoroscopy for
into distal duodenum/​proximal jejunum by gastro-​oesophageal reflux bedside; accurate delivery into placement; easily displaced
or gastroparesis; gastric outlet proximal intestine. Infusion feed only
obstruction; acute severe pancreatitis
PEG (percutaneous Tube passed through abdominal wall into Long-​term intragastric feeding; Difficult to displace; reliable in Requires endoscopic placement and endoscopy to
endoscopically placed stomach using an endoscopic technique mucositis due to head and neck cancer long-​term use; can be exchange for change tube. Early complications include peritonitis,
gastrostomy) (‘push’ or ‘pull’). Retained internally by therapy; palliative venting use in skin level (‘button’) device, ideal for bleeding, PEG site infection. Late complications
balloon or internal bumper/​disc. Available terminal intestinal obstruction ambulant or younger patients include overgranulation of the PEG site and ‘buried’
in sizes up to 24 F bumper (see Fig. 11.7.3)
RIG (radiologically Radiologically placed transabdominal Intragastric feeding where endoscopic Can be a safer option than standard Requires gastric insufflation through a nasogastric
placed gastrostomy) gastrostomy tube placement is not possible due to PEG in some patients tube which may not always be possible to place.
risks of endoscopy or anatomical Some centres report higher numbers of significant
considerations complications with RIGs than PEGs
PEG-​J (PEG with jejunal Transgastric tube with tip positioned in Long-​term intestinal feeding where Minimally invasive route for long-​ Jejunal tube can reflux back into the stomach
extension) distal duodenum/​proximal jejunum through gastric feeding is not available due to term postpyloric feeding
existing PEG tube gastric dysfunction o outlet obstruction
DPEJ (direct PEG tube placed endoscopically into the Long-​term intestinal feeding Reliable for long-​term feeding Endoscopic placement not always possible. High
percutaneous jejunum risk of complications including pain and volvulus
enteroscopic (given single point of contact of intestine and
jejunostomy tube) abdominal wall)
Surgical jejunostomy Feeding tube placed surgically into the Postoperative feeding in upper Permits early enteral feeding in Not ideal for long-​term use due to risk of
jejunum gastrointestinal surgery and liver postoperative setting displacement and adhesional obstruction
transplantation
Parenteral (PN)
Midline catheter Short peripheral (22 G) cannula inserted into Short term parenteral nutrition support May allow effective peripheral Limited range of available feeds due to the osmolality
antecubital vein nutrition support or and pH considerations which usually limits use of this
supplementation without risks or route to 2–​3 days
delays of central venous access
PICC (peripherally ‘Long-​line’—​tube placed via the cephalic Short-​to-​medium term parenteral Reduced risk of infection and Thrombophlebitis and thrombosis. Not practical for
inserted central venous vein into large central veins nutrition support (suitable for majority generally preserves central access use at home or by patients
catheter) of inpatient PN episodes) points
Triple lumen venous Multiple lumen direct puncture central Fluid and drug delivery—​central Ease of access in critically ill patients High risk of local complications and infection. Should
catheter venous catheter venous pressure monitoring be discouraged for parenteral feeding except in time
limited circumstances with a dedicated lumen to PN
Tunnelled Hickman Single or double lumen line tunnelled Medium-​long-​term parenteral Low risk of infection if properly Care needed with the external portion to avoid
catheter subcutaneously to the skin surface with a nutrition support maintained; low risk of displacement accidental displacement. Risk of exit site infection or
Dacron cuff for retention once cuff is grown in mechanical dysfunction
Implantable Line accessed via a hub placed in a Long-​term parenteral nutrition support Ideal for patients with active Skin puncture required for every access; consequences
subcutaneous port subcutaneous pocket—​no part of the device lifestyle—​evidence of different of infection more significant than with tunnelled
device visible above skin level rates of line infection compared to line—​more difficult to replace. Limited lifetime of
tunnelled lines is controversial membrane depending on the frequency of puncture
11.7 Artificial nutrition support
1919
1920 SECTION 11 Nutrition

Enteral tubes can be placed endoscopically, radiologically, or surgically into

Complications of access the stomach or proximal intestine (Fig. 11.7.3). There is a high risk
of death following placement due to cardiorespiratory complications
Incorrectly placed nasogastric tube can kill. Inadvertent intra­ in patients who are at high risk due to dysphagia and pre-​existing
pulmonary placement is the most frequent, but insertion into cra- pneumonia. Asymptomatic pneumoperitoneum is common after
nial, pleural, and peritoneal cavities has occurred. Feeding should PEG insertion, but chemical peritonitis can result from feed leakage
only be initiated after confirmation of gastric placement by pH meas- into the peritoneal cavity. Superficial infections at the PEG site
urement of aspirated stomach contents (<5.5) or by radiography. should occur in less than 5% of cases: these are usually easily treated
Interruptions due to frequent tube displacement causes a signifi- but should not be confused with chemical burns due to leakage of
cant reduction in feed delivery—​as little as 55% of prescribed feed enteric contents. Skin swabs are rarely useful in suspected PEG site
in one study. This can be prevented by the use of a loop of tape that infection. Too much tension on the device can lead to erosion of
can be safely and simply passed around the nasal septum to secure the internal retaining bolster into the gastric mucosa and through
the tube (‘nasal bridle’). Modern tube material does not cause sig- the abdominal wall (‘buried bumper’), leading to blockage, external
nificant erosion or irritation of the face, nares, or mucosal surfaces, feed leakage and infection, and may only be apparent on attempted
even with long-​term use, but difficulties in managing such tubes in PEG removal.
the community make them undesirable for long-​term use.
Transabdominal feeding tubes are therefore used in preference Complications of enteral feeding
in the community for enteral feeding. Percutaneous endoscopically The role of the intestine in regulating nutrient uptake is demon-
guided (PEG) tubes are most frequently employed, but a variety of strated by the reduced metabolic complications of enteral compared

(a)

(b) (c)

Fig. 11.7.3 (a) A range of endoscopically placed gastrostomy tubes—​from left to right—​bumper-​retained
gastrostomy; traction-​removable bumper-​retained gastrostomy; balloon retained gastrostomy; skin level
‘PEG-​button’ device (balloon retained). (b) Endoscopic photograph of PEG tube with bumper in place in
the stomach. (c) ‘Buried bumper’—​the bumper of the gastrostomy has eroded into the gastric mucosa as
a result of pressure necrosis and the mucosa has overgrown the bumper. A wire has been passed through
the lumen of the tube to demonstrate its position.
 11.7 Artificial nutrition support 1921

to parenteral feeding: nutritional deficiencies in patients fed appro- and disposal of nutrients from the circulation are controlled by
priately with commercial preparations are highly unusual. the presence or absence of nutrients in the gut.
Patients who require enteral feeding often have impaired con- • Parenteral feeds cannot replicate the complexity of circulating nu-
scious level or swallowing and are therefore at risk of pulmonary trient molecules, being constrained by requirements of chemical
aspiration. Delayed gastric emptying—​as frequently occurs in crit- stability within the solution.
ical illness—​increases the likelihood of aspiration of stomach con-
The metabolic risks of parenteral nutrition have previously been
tents. Gastro-​oesophageal reflux may be exacerbated rather than
overestimated due to the ease of overnutrition via this route and de-
reduced by PEG feeding. Patients at risk should be fed by infusion
liberate ‘hyperalimentation’. Hyperglycaemia is especially common
pump rather than intermittent bolus and at a 30-​degree tilt. Passage
due to insulin resistance associated with critical illness and re-
of a feeding tube beyond the pylorus is beneficial in cases of delayed
sults in increased infection and adverse outcomes. Imbalances of
gastric emptying or gastric outlet obstruction.
other nutrients may occur as a result of variable losses associated
Diarrhoea is common in enterally fed hospital patients and is
with the underlying condition and require regular monitoring and
often due to the concomitant use of antibiotics. Liquid feed emp-
replacement.
ties rapidly from the stomach compared to solids and can result in
The gut derives a proportion of its nutrient requirements from the
an osmolar load that precipitates fluid influx and intestinal hurry,
lumen rather than the bloodstream, hence parenteral nutrition may
and neuroendocrine mechanisms have been described that result in
result in mucosal atrophy and impaired barrier function. Although
right colonic fluid secretion with nasogastric feeding. Constipation
physiological and anatomical changes have been described, adverse
may be encountered more frequently in enterally fed patients in
consequences due to bacterial translocation appear to be rare from
the community: fibre-​supplemented feeds are available for such
this cause in clinical practice.
instances.
Intestinal-​failure-​associated liver disease
Parenteral
Hepatic complications are commonly described in patients receiving
Complications of access
parenteral nutrition. Asymptomatic elevation of liver enzymes indi-
Intravenous feed should not be delivered via peripheral cannulae cative of cholestasis occurs after about 4 weeks of feeding via this
due to the risk of thrombosis and thrombophlebitis, and available route, but can progress to profound jaundice and cirrhosis, espe-
preparations are constrained by pH and osmolality requirements. cially in children. Intestinal-​failure-​associated liver disease tends to
Central venous access is required for longer-​term parenteral nutri- progress more insidiously through hepatic steatosis to cirrhosis in
tion but carries attendant risks of pneumothorax and haemothorax adults. Causes are likely multifactorial, including a reduced portal
on placement. Peripherally inserted central lines can be used suc- inflow due to short bowel syndrome and lack of enteric stimula-
cessfully for feed delivery, and arteriovenous fistulae for renal dia- tion of cholecystokinin release. Several factors associated with par-
lysis have also been used successfully in this setting. enteral feed have been implicated in both excess and deficiency
Infection is the major hazard of intravenous feeding catheters and (Table 11.7.5). Maintaining oral intake, even if contributing only
is reduced by dedicating a single lumen to the feed and employing minimally to nutrient requirements, using cyclical rather than con-
strict aseptic precautions. Use of opiates, presence of a stoma, and tinuous feed, and keeping exogenous lipid delivery under 1 g/​kg per
frequent line access are risk factors for infection. Tunnelled or day appears to reduce the risk of developing liver disease. The use of
peripherally inserted lines should be used in preference to non-​ new lipid substrates containing fish oil and rich in omega-3 lipids
tunnelled central lines. appears to be preferable to the use of older soy-oil based preparation.
Staphylococci, Gram-​negative bacilli, and candida are common
infecting organisms. Infection can present insidiously with low grade Intestinal-​failure-​associated bone disease
fever and result in complications by dissemination such as bacterial Metabolic osteopenia is common in intestinal failure requiring
endocarditis, discitis, osteomyelitis, or fungal endophthalmitis. long-​term parenteral nutrition. Prolonged bed rest, immobiliza-
Catheter-​related infections are infrequent in longer-​term commu- tion, and vitamin D malabsorption contribute prior to the initiation
nity parenteral nutrition, with infections occurring on average every
2 to 5 years.
Venous thrombosis associated with frequent line replacement
Table 11.7.5 Aetiological factors implicated in intestinal-​failure-​
may limit options for access and require creative solutions such as associated liver disease (IFALD)
direct translumbar or transhepatic caval access, intra-​atrial access,
or surgical reconstruction of venous anatomy. Cholestasis Steatosis
Reduced enteral stimulation Excess provision of calories as
Complications of parenteral feeding carbohydrate or lipid
Metabolic complications are more likely to arise as a result of paren- Phytosterols present in soy-​based Choline deficiency
teral than enteral feeding for the following reasons: formulae
Infection Carnitine deficiency
• Parenteral feeding bypasses the enterocyte which actively regu-
Bacterial translocation Reduced very low-​density lipoprotein
lates uptake, metabolizes nutrients, and re-​exports them via the synthesis
portal circulation.
Taurine deficiency Inadequate Glucagon secretion
• Insulin, glucagon, and incretin secretion (as well as that of other
Methionine deficiency
entero-​endocrine hormones) that regulate metabolic processes
1922 SECTION 11 Nutrition

of parenteral nutrition. A low bone turnover state has been rarely Intestinal transplantation
described. Careful monitoring of bone density and treatment with Patients with irreversible intestinal failure who experience life-​
intravenous bisphosphonates is often required. threatening complications of parenteral nutrition can be con-
sidered for intestinal transplantation, which can be combined
with other abdominal organs where required for reasons of asso-
Long-​term artificial nutrition support and ciated organ failure or anatomical considerations. Multivisceral
intestinal transplantation transplantation including liver, stomach, intestine, pancreas, and
colon may be required for patients with complications of exten-
Long-​term artificial nutrition support sive portomesenteric thrombosis, or urgently in acute abdominal
Patients can receive oral, enteral, or parenteral nutrition support ischaemia. Transplantation of the ileocecal valve and a segment of
in the community. In the United Kingdom, the British Artificial colon along with intestine is now routine to improve fluid absorp-
Nutrition Survey (BANS) carries out an annual survey of the number tion postoperatively.
of tube-​fed patients. Approximately 350 per million British adults Most patients undergoing intestinal transplant can become in-
receive enteral tube feed in the community, compared to about dependent of artificial nutrition support, and survival rates are
40 per million receiving parenteral nutrition at home. The latter has now equivalent to—​or better than—​those of other solid organ
increased significantly over recent years due to improvements in transplant operations (Fig. 11.7.4). However, the operation is
homecare provision and a recognition of previous underutilization currently not considered as a routine alternative to home paren-
leading to patchy uptake across the United Kingdom. teral nutrition, which is associated with excellent long-​term out-
Quality of life is often adversely affected by the underlying dis- comes, although it may offer benefits in some cases. There is a
ease process more than the route of artificial nutrition support, but realistic prospect that further improvements in the field will re-
infusing feed overnight can minimize lifestyle disruption. Life ex- sult in better identification of cases that would benefit from earlier
pectancy is also mostly dictated by the underlying disease process, transplantation.
with relatively few deaths attributed to failure of feeding or compli-
cations of delivery. Ten-​year survival on long-​term home parenteral
nutrition is approximately 59–71% in adults and 81% in children. Ethics of artificial nutrition support
The patients receiving enteral nutrition at home tend to be more eld-
erly and infirm than those receiving parenteral nutrition and have a Nutrition and starvation evoke emotive responses, but although it is
survival of around 25% at five years. a basic human right not to be deprived of fluid or food, the same is

Patient three-year survival, including super urgent patients, following first intestinal transplant, by
ITR group, for patients transplanted between 1 February 2006 and 31 December 2015 at
Cambridge transplant unit
Transplanted and follow-up data were extracted from the UK Transplant Registry on 14 April 2016

100

90 MMV

80 SB

70
% patient survival

60

50
MVT

Transplant No No % Patients survival (95%

40 type patients deaths confidence interval)

30 MMV 12 1 89 (43–98)
MVT 34 14 62 (32–69)
SB 12 2 81 (42–95)
20
Total 58 17 65 (60–77)
10

0
0 1 2 3
Years post-transplant

Fig. 11.7.4 Survival post intestinal transplant. SB, small bowel transplant; MVT, multivisceral
transplant (stomach, pancreas, liver, intestine, colon); MMV, modified multivisceral transplant
(stomach, pancreas, intestine, colon).
Source: NHSBT, courtesy Cambridge University Hospitals NHS Foundation Trust, 2016 data.
 11.7 Artificial nutrition support 1923

not true of artificial nutrition support which requires invasive tube inflammatory responses, such as the use of lipid substrates enriched
placement that may be associated with risks of morbidity or mor- with omega-​3 fatty acids, and encouraging results have been demon-
tality. Ethically, withdrawing or withholding artificial nutrition are strated in sepsis and postsurgery.
considered equivalent, but in practice it is often difficult to cease
feeding when established through a tube, and the progress of an Renal disease
underlying condition can be affected by the continued delivery or Renal failure results in wasting, electrolyte and fluid imbalances, and
withdrawal of feed. Institution of artificial nutrition support there- anorexia with attendant malnutrition. Patients undergoing dialysis
fore requires careful multidisciplinary discussion and appropriate lose protein into the dialysate—​up to 10 g/​day on haemodialysis
patient and carer information in order to identify appropriate goals and up to 15 g/​day on peritoneal dialysis. Water-​soluble vitamins
and expectations of feeding. are also lost in the dialysate and require replacement. Adequate pro-
tein intake is essential to minimize catabolism of endogenous pro-
tein. Specialized feeds with minimal electrolytes and reduced fluid
Special situations in nutrition support volume are available for renal patients (Table 11.7.6). Parenteral nu-
trients may be infused to replace losses at the time of dialysis. The
Critical illness—​burns, trauma, and sepsis use of reduced (but high-​quality) protein feeds may delay the re-
The metabolic response to stress is characterized by hypermetabolism quirement for dialysis in renal failure but this should not be at the
and rapid tissue catabolism with resulting insulin resistance and expense of inadequate nutrition support.
hyperglycaemia. Direct effects of inflammatory mediators and cyto-
kines such as tumour necrosis factor–​α and interleukins 1 and 6 Liver disease
are responsible. Protein loss can be rapid, particularly in the case of Malnutrition is common in patients with established liver dis-
burns where exudates add to catabolic loss. ease as a result of reduced appetite, altered carbohydrate and lipid
Feeding during acute metabolic decompensation can be detri- metabolism, and (in severe cases) impaired urea synthesis from
mental and should be withheld during such time. Otherwise, early ammonia leading to increased muscle catabolism. Cholestasis
institution of feeding has been shown to be beneficial in most set- also results in fat malabsorption. Glucose intolerance limits glu-
tings, with a graded increment to meet requirements and avoid cose intake and complex polysaccharides are required to provide
overfeeding. Gastric stasis is common after severe burns and head a slow release of carbohydrates in view of diminished glycogen
injury and intestinal ileus may occur in circulatory failure requiring stores. The lack of carbohydrate stores in the liver makes patients
inotropic support. Prokinetic use may assist gastric emptying of en- prone to significant protein catabolism during fasting and there-
terally delivered feed, but where gastric aspirate volumes remain fore periods without nutrient intake—​even overnight—​should be
high or increase during intragastric feeding, postpyloric or paren- avoided.
teral feeding may avoid the risk of pulmonary aspiration and ensure High protein feeds may precipitate encephalopathy in cirrhosis,
adequate nutrient delivery. but restricting protein is nutritionally undesirable and an intake of
Avoidance of underfeeding is also important in critical illness and 1.2–​1.5 g protein/​kg per day is recommended. Optimization of the
relies on appropriate recognition of the transition from a catabolic amino acid composition—​by enriching with branched chain amino
to anabolic phase. Attempts to reverse catabolism using inhibitors acids which are deficient in liver disease—​can improve protein syn-
of inflammatory cytokines or anabolic agents have unfortunately thesis and result in improved survival for patients with end stage
been unsuccessful. Nutrients themselves may be used to modulate liver disease awaiting transplant.

Table 11.7.6 Examples of disease-​specific and therapeutic feeds designed to have disease modifying activity (‘nutraceuticals’)

Composition Intended use Rationale

Low protein, high essential amino acids, and Renal impairment Appropriate matching of amino acid composition to requirements may
histidine, low electrolytes, high calorie density improve protein metabolism; low protein reduces urea synthesis; high calorie
density allows fluid restriction
Low protein, reduced aromatic and increased Hepatic impairment Reduced risk of encephalopathy with low protein; appropriate amino acid mix
branched chain amino acids, low sodium to allow optimal protein metabolism
High lipid, low carbohydrate Pulmonary disease; weaning Reduced CO2 production
from artificial nutrition
High lipid (especially monounsaturated fatty Diabetes Reduced glycaemia, improved diabetic control
acids); low carbohydrate, high fructose
Oligopeptides, medium chain triglycerides Severe pancreatic exocrine Reduced dependence on luminal digestion for absorption
deficiency
Arginine, n-​3 fatty acids, nucleotides ‘Immune enhancing’—​critical Substrates for rapidly dividing cells such as lymphocytes and competitive
illness/​perioperative nutrition inhibition of proinflammatory eicosanoid production may enhance immune
response and reduce inflammatory response
Glutamine Critical illness Glutamine levels severely depleted in critical illness; supplementation may improve
nitrogen balance and act as fuel for rapidly dividing cells such as lymphocytes and
enterocytes; maintaining immune responses and gut mucosal integrity
1924 SECTION 11 Nutrition

Gastrointestinal disease the full range of nutrition support services. By appropriate use of nu-
Nutrition support is required in gastrointestinal conditions that re- trition support, reducing catheter-​related complications, and moni-
sult in impaired access to the gut, for instance as a result of proximal toring patients receiving parenteral nutrition, such teams have been
obstruction or dysmotility, or intestinal failure due to short bowel or shown to provide significant cost savings as well as providing high-​
mucosal disease. Liquid, oral, or enteral feeds may be used to induce quality clinical care.
remission in Crohn’s disease with equivalent efficacy to steroids. Cost-​effectiveness of nutrition support
Patients with proximal enterocutaneous fistulae may have high
fluid and nutrient losses from the fistula. Parenteral nutrition may be Public health and social care expenditure relating to malnutrition
essential to provide nutritional and fluid intake and reduce effluent in 2011–​2012 in the United Kingdom was estimated at £19.6 billion,
that may compromise wound healing. However, in patients with low equivalent to 15% of the healthcare budget. Oral nutrition support
output fistulae who are able to manage their fluid and nutrient re- has been demonstrated to reduce mortality by up to 24% in some
quirements orally or enterally, there is no evidence to suggest that hospital and community settings, and to reduce complications (odds
‘gut rest’ and parenteral nutrition increase rates of fistula closure. ratio 0.29—​confidence intervals 0.18–​0.47) and lengths of hospital
In severe acute pancreatitis, nutrition requirements are increased inpatients’ stay. Modelling suggests that appropriate nutrition sup-
by the systemic inflammatory response and there are theoretical port is highly cost-​effective despite high initial outlays in nutrition
concerns of stimulation of pancreatic secretion by enteral feeding. screening and costs of supplements.
Enteral feeding is often limited by gastric stasis in severe cases and
intrajejunal feeding is associated with lower complications than par- Future developments
enteral nutrition in this setting.

Perioperative nutrition An increased awareness of the critical importance of nutrition in

clinical care is likely to improve the recognition of malnutrition and
Malnourished patients undergoing surgery experience up to three lead to the institution of appropriate preventive measures with sig-
times as many complications and a fourfold increase in mortality nificant benefits in all areas of clinical medicine.
compared to well-​nourished individuals. Patients may be starved An unfortunate lack of adequately powered trials has limited the
for prolonged periods prior to surgery due to obstruction or after application of innovative nutritional interventions, including novel
surgery as a result of ileus. Surgery should be delayed where feasible nutrient substrates, to modulate inflammatory responses or explore
in severely malnourished patients to provide a minimum of 10 to disease-​specific feeds (Table 11.7.6), hence there is much potential
14 days of adequate perioperative nutrition. still to be unlocked in the field of therapeutic nutrition.
Starvation immediately prior to surgery results in increased in-
sulin resistance and complications postoperatively, and the simple
expedient of providing a 50 g carbohydrate load orally two hours FURTHER READING
prior to surgery can speed postoperative recovery. Early reintroduc-
Andrews PJ, et al. (2011). Randomised trial of glutamine, selenium
tion of oral feeding after routine abdominal surgery is feasible and
or both to supplement parenteral nutrition for critically ill patients.
results in more rapid rehabilitation than waiting for unreliable clin-
BMJ, 342, d1542.
ical signs of gastrointestinal function to return prior to feeding. Bozzetti F, et al. (2002). Central venous catheter related complications
Palliative care in 447 patients on home parenteral nutrition; an analysis of over
100,000 catheter days. Clin Nutr, 21, 475–​85.
Terminal illness—​whether due to benign or malignant disease—​is Briet F, et al. (2004). Effect of feeding malnourished patients for 1 mo
frequently associated with poor nutritional status resulting from on mitochondrial complex 1 activity and nutritional assessment
catabolic effects of the underlying disease and associated anor- measurements. Am J Clin Nutr, 79, 787–​94.
exia. Limited observational evidence suggests that both length and Campbell SE, et al. (2002). Assessment of nutritional status in hospital
quality of life can be maintained for a period of time in some such in-​patients. QJ Med, 95, 83–​7.
patients with good initial performance status by the appropriate Cano NJM, et al. (2009). ESPEN guidelines for adult parenteral nutri-
use of nutrition support. Patients with intestinal obstruction due to tion. Clin Nutr, 28, 359–​479.
slow growing malignancy may derive benefit from parenteral nutri- Dibb M, Soop M, Teubner A, et al. (2017). Home parenteral nutrition:
tion, particularly if associated with a venting gastrostomy to prevent Three decades of experience from a single referral centre. Clin Nutr.,
36(2), 570–76.
vomiting. However, the use of artificial nutrition support in all such
Druml C, et al. (2016). ESPEN guideline on ethical aspects of artificial
cases needs to be carefully considered to ensure that the benefits out-
nutrition and hydration. Clin Nutr, 35, 545–​56.
weigh the additional burdens of feeding and that valuable time is not Elia M (1982). The effects of nitrogen and energy intake on the me-
wasted setting up artificial nutrition in hospital for minimal gain. tabolism of normal, depleted and injured man. Considerations for
practical nutrition support. Clin Nutr, 1, 173–​92.
Elia M (2003). The MUST Report: Nutritional Screening of Adults: A
Delivering a nutrition service Multidisciplinary Responsibility. Development and Use of the
Malnutrition Universal Screening Tool (MUST) for Adults. A report
The hospital nutrition support team by the malnutrition advisory group of the British Association for
Parenteral and Enteral Nutrition. BAPEN, Redditch. https://​www.
A multiprofessional team comprising clinician, specialist nurse, bapen.org.uk/​pdfs/​must/​must-​report.pdf
dietitian, and pharmacist as its core members is required to provide
 11.7 Artificial nutrition support 1925

Elia M, et al. (2015). The Cost of Malnutrition in England and Potential Ljungqvist O, et al. (2002). Modulation of post-​operative insulin re-
Cost Savings from Nutritional Interventions. https://​www.bapen.org. sistance by pre-​operative carbohydrate loading. Proc Nutr Soc, 61,
uk/​pdfs/​economic-​report-​full.pdf 329–​36.
Gauderer MW, Ponsky JL (1981). A simplified technique for con- Maple JT, et al. (2005). Direct percutaneous endoscopic jejunostomy:
structing a tube feeding gastrostomy. Surg Gynecol Obstet, 152, 83–​5. outcomes in 307 consecutive attempts. Am J Gastroenterol, 100,
Harvey SE, et al. (2014). Trial of the route of early nutritional support 2681–​8.
in critically ill adults. N Engl J Med, 371, 1673–​84. Matsumoto CS, Subramanian S, Fishbein TM (2018). Adult Intestinal
Hashimoto K, et al. (2015). Recent advances in intestinal and Transplantation. Gastroenterol Clin North Am, 47(2), 341–54.
multivisceral transplantation. Adv Surg, 49, 31–​63. Mayer K, et al. (2003). Parenteral nutrition with fish oil modulates
Heyland DK (2000). Parenteral nutrition in the critically ill pa- cytokine response in patients with sepsis. Am J Respir Crit Care
tient: more harm than good? Proc Nutr Soc, 59, 457–​66. Med, 167, 1321–​8.
Jeejeebhoy KN (2012). Malnutrition, fatigue, frailty, vulnerability, McWhirter JP, Pennington CR (1994). Incidence and recognition of
sarcopenia and cachexia: overlap of clinical features. Curr Opin Clin malnutrition in hospital. BMJ, 308, 945–​8.
Nutr Metab, 15, 213–​19. Planck L, et al. (2008). Nocturnal nutrition supplementation im-
Kalm LM, Semba RD (2005). They starved so that others could be proves total body protein status of patients with liver cirrhosis: a
better fed: remembering Ancel Keys and the Minnesota experiment. randomised 12 month trial. Hepatol, 48, 557–​66.
J Nutr, 135, 1347–​52. Shaw JF, et al. (1987). Whole body protein kinetics in severely septic
Keys A (1946). Human starvation and its consequences. J Am Diet patients. Ann Surg, 205, 288–​94.
Assoc, 22, 582–​7. Stratton R, Smith T, Gabe S (2018). Managing malnutrition to im-
Lewis SJ, et al. (2001). Early enteral feeding versus ‘nil by mouth’ after prove lives and save money. BAPEN October 2018. www.bapen.
gastrointestinal surgery: systematic review and meta-​analysis of org.uk/pdfs/reports/mag/managing-malnutrition.pdfUm adist, ut
controlled trials. BMJ, 323, 773–​6. idunt vit eaquas peruptate labore pa volorum im qui underfe
SECTION 12
Metabolic disorders
Section editor: Timothy M. Cox

12.1 The inborn errors of metabolism: 12.8 Lysosomal disease 2121

General aspects 1929 Patrick B. Deegan and Timothy M. Cox
Timothy M. Cox and Richard W.E. Watts
12.9 Disorders of peroxisomal metabolism
12.2 Protein-​dependent inborn errors of in adults 2157
metabolism 1942 Anthony S. Wierzbicki
Georg F. Hoffmann and Stefan Kölker
12.10 Hereditary disorders of oxalate metabolism:
12.3 Disorders of carbohydrate metabolism 1985 The primary hyperoxalurias 2174
12.3.1 Glycogen storage diseases 1985 Sonia Fargue, Dawn S. Milliner, and
Robin H. Lachmann and Timothy M. Cox Christopher J. Danpure
12.3.2 Inborn errors of fructose metabolism 1993 12.11 A physiological approach to acid–​base
Timothy M. Cox disorders: The roles of ion transport and
12.3.3 Disorders of galactose, pentose, and body fluid compartments 2182
pyruvate metabolism 2003 Julian Seifter
Timothy M. Cox
12.12 The acute phase response, hereditary periodic
12.4 Disorders of purine and pyrimidine
fever syndromes, and amyloidosis 2199
metabolism 2015
12.12.1 The acute phase response and C-​reactive
Anthony M. Marinaki, Lynette D. Fairbanks,
protein 2199
and Richard W.E. Watts
Mark B. Pepys
12.5 The porphyrias 2032 12.12.2 Hereditary periodic fever syndromes 2207
Timothy M. Cox Helen J. Lachmann, Stefan Berg,
and Philip N. Hawkins
12.6 Lipid disorders 2055
12.12.3 Amyloidosis 2218
Jaimini Cegla and James Scott Mark B. Pepys and Philip N. Hawkins
12.7 Trace metal disorders 2098 12.13 α1-​Antitrypsin deficiency and the
12.7.1 Hereditary haemochromatosis 2098 serpinopathies 2235
William J.H. Griffiths and Timothy M. Cox David A. Lomas
12.7.2 Inherited diseases of copper metabolism:
Wilson’s disease and Menkes’ disease 2115
Michael L. Schilsky and Pramod K. Mistry
12.1
The inborn errors of metabolism:
General aspects
Timothy M. Cox and Richard W.E. Watts†

ESSENTIALS or pharmacological chaperones, to prevent premature aggregation

and denaturation; (6) repression of an overproduced protein or me-
The inborn errors of metabolism are those inherited diseases in tabolite by stable RNA inhibition (e.g. in transthyretin-​induced amyl-
which the phenotype includes a characteristic constellation of bio- oidosis or by supressing 5-​aminolaevulinic acid synthase in acute
chemical abnormalities related to an alteration in the catalytic ac- porphyria syndromes); (7) transplantation of cells (e.g. haematopoi-
tivity of a single specific enzyme, activator, or transport protein. etic stem cells) or organs (e.g. liver) as a ‘gene replacement therapy’;
Mechanism of diseases—​mutations in the proteins giving rise to and (8) activation of a poorly functioning protein (e.g. the successful
the inborn errors of metabolism affect primary, secondary, tertiary, use of an oral activator of a relatively uncommon mutant cystic fi-
or quaternary structure. This can lead to an enormous variety of con- brosis transmembrane regulator protein such as the G551D missense
sequences, including (1) abolishing, decreasing, or (occasionally) variant in patients with the cognate disease).
increasing protein activity; (2) affecting activator proteins, or binding
of hormones and other ligands to cell surfaces or other structures;
(3) impeding intracellular trafficking and folding of proteins, as
well as their post-​translational modification through, for example, Introduction
glycosylation, phosphorylation, or prenylation; (4) affecting the
transport of metabolites across cellular membranes; and (5) affecting Definition and prevalence
the formation, activation, or transport of key cofactors for enzymes
The inborn errors of metabolism are those inherited diseases in which
and other proteins (e.g. vitamins or metal ions).
the phenotype includes a characteristic constellation of biochemical
Clinical presentation—​the manifestations of metabolic disease are
abnormalities related to an alteration in the catalytic activity of a
protean and may seem nondescript, especially in adults, hence a
single specific enzyme, activator, or transport protein. About 1500
high level of suspicion may be required to make a correct diagnosis.
such disorders have been characterized with an estimated overall
Inborn errors of metabolism usually come to light in the neonatal
birth frequency of 1 in 1500 live births in nonconsanguineous popu-
period or infancy, but they may arise even in mature adults for the
lations. While these are now recognized as belonging individually
first time, when their rate of progression may be indolent.
to the category of ‘rare diseases’, they can also be viewed as para-
Prevention and screening—​there is a strong case for mass popu-
digmatic examples of the interplay between the constitutional and
lation screening for some inborn errors of metabolism at the
environmental aspects of disease as well as selective factors acting
presymptomatic stage to allow early detection and introduction of
over the long course of human evolution.
proven treatment before irreversible damage occurs.
Management—​ definitive cure of the underlying abnormality Historical perspective
is available for a few disorders, but precise characterization of the
biochemical disturbance often permits rational treatment to be or- Inborn errors of metabolism were the brainchild of the physician
ganized and provides the basis for further therapeutic endeavours. Archibald Garrod in the early 20th century. In the century since
General approaches include (1) restriction of a substrate that cannot their discovery, this brilliant concept has proved to have far-​reaching
be metabolized including molecules derived from the diet; (2) re- implications in biochemistry, genetics, evolutionary biology, and
placement of a missing metabolic product; (3) removal of poisonous medical practice. William Bateson, a biologist and early champion
metabolites or rebalancing overproduction of toxic intermediates; of Mendel, showed Garrod that central to his idea of the ‘inborn’
(4) administering pharmacological doses of a cofactor, sometimes a was the concept of the gene. Garrod proposed that genetic deter-
vitamin, that may also stabilize a mutant enzyme; (5) replacement of minants specify the activity of enzymes which catalyse particular
a missing gene product, usually by enzymatic augmentation therapy metabolic reactions. Thus Garrod was the first physician and clin-
ical biochemist who, with Bateson, applied Mendelian genetics to

†
It is with great regret that we report that Richard W.E. Watts died on 11 February, 2018.
1930 SECTION 12 Metabolic disorders

humans: they came to understand the segregation of recessive traits selection in human evolution is also played out within the micro-
in pedigrees affected by hereditary metabolic diseases and the fre- cosm of disease.
quent role of consanguinity in very rare disorders. Since Garrod’s While it has been pointed out that Garrod did not use the terms
original description, the term ‘inborn error’ has broadened to in- ‘multifactorial’ or ‘susceptibility’ and had a rudimentary under-
clude mutations affecting the function of other proteins, such as the standing of genetics, his ideas foresaw the concept of ‘complex’ dis-
structural proteins fibrillin and collagen as well as transport proteins eases with their dynamic gene–​environment interactions. After the
in which mutations also cause disease. more accessible monogenic disorders, the immense technological
Garrod considered that some ‘simple’ biochemical traits inherited power available for molecular analysis of the human genome is
as Mendelian recessive characters, such as alkaptonuria, appeared to yielding extraordinary information of both therapeutic and diag-
have little, if any, apparent effect on health (in fact, in this emblem- nostic significance. As to the complex diseases, it now seems that
atic disorder, the focus of much of his early experimentation, the the discovery, characterization, and quantification of environmental
great man was mistaken: alkaptonuric subjects develop severe arth- factors and their interactions with human genetic variants is perhaps
ritis, renal and prostatic calculi, and often die prematurely from the the greatest impediment to the mechanistic understanding of these
consequences of cardiovascular disease (see Chapter 12.2)). In other disorders.
conditions, such as albinism or porphyria, environmental factors To summarize: like many others before and after him, the inten-
(e.g. sunlight, barbiturates) cooperate with host determinants in the sive study of rare human phenotypes led Archibald Garrod to make
development of clinical manifestations. Thus Garrod promulgated observations of astonishing relevance to large fields of medicine.
the notion of ‘chemical individuality’ and genetic predisposition Perhaps the greatest, most penetrating—​and lasting—​insight to
to disease; in so doing, he adduced a strong theoretical underpin- emerge from the concept of the ‘inborn’ has been the realization that
ning to the concept of ‘diathesis’—​a hitherto pervasive term of the disease can no longer be viewed solely in the context of the ‘broken
19th century, largely concealing prejudice and ignorance but long machine’ metaphor, but rather is the consequence of interactions
persistent in clinical thinking. Indeed, years after the publication of between individual uniqueness and an environment for which that
Garrod’s work, the great American geneticist Thomas Hunt Morgan individual is, at a given time, maladapted or ‘unfit’. Although the
stated in his Nobel lecture of 1934: constraint of space prevents full consideration of this theme, the
Darwinian perspective clearly has far-​reaching consequences for
I am aware, of course, of the ancient attempts to identify certain
gross physical human types—​the bilious, the lymphatic, the ner-
the teaching and practice of medicine, indeed a new field of evolu-
vous, and the sanguine dispositions, and of more modern attempts tionary medicine emerges directly (see Chapter 2.2).
to classify human beings into the cerebral, respiratory, digestive
and muscular, or, more briefly into asthenics and pycnics. Some
of these are proposed to be more susceptible to certain ailments or Classifications of inherited diseases
diseases than are other types, which in turn have their own consti- of metabolism
tutional characteristics. These well-​intended efforts are, however,
so far in advance of our genetic information that the geneticist may Almost all the inborn errors of metabolism arise from mutations in
be excused if he refuses to discuss them seriously. the nuclear genome and have Mendelian patterns of inheritance, but
13 genes are encoded by the mitochondrial genome, and when these
In fact, by 1931 Garrod had developed his ideas in a prescient
are mutated the cognate diseases are maternally transmitted.
essay, Inborn Factors in Disease, which has prodigious implications
Mutations in the proteins giving rise to the inborn errors of me-
for a modern synthesis of the concept of disease; he had advanced his
tabolism affect primary, secondary, tertiary, or quaternary structure.
logic from the inborn error to chemical individuality—​a universal
These can lead to an enormous variety of consequences, including
quality of the whole species, as opposed to the single individual. It
(1) abolishing, decreasing, or (occasionally) increasing protein ac-
is clear that Garrod had in mind the operation of Darwinian prin-
tivity; (2) affecting activator proteins, or binding of hormones and
ciples: in the example of infectious disease, he refers to the individu-
other ligands to cell surfaces or other structures; (3) impeding intra-
ality of the human individual and the microbe:
cellular trafficking and folding of proteins, as well as their post-​
In our fight against infective diseases we are not confronted with translational modification through, for example, glycosylation,
blind forces, acting at random, but with the disciplined offensive phosphorylation, or prenylation (a post-​translational modification
of highly trained foes. Whilst on the one hand the weapons of in which a isoprenyl group is added to a cysteine residue—​a process
attack have been improved by evolution, there has been a corres-
which mediates protein interactions, especially protein–​membrane
ponding evolution of protective mechanisms of great ingenuity,
interactions); (4) affecting the transport of metabolites across cel-
and of no small efficiency, for the defence of the individual
lular membranes; and (5) affecting the formation, activation, or
attacked.
transport of key cofactors for enzymes and other proteins (e.g. vita-
To understand the diverse manifestations of disease, including mins or metal ions).
those clearly due to infectious agents such as Mycobacterium tu-
berculosis, and variable responses to drugs (many of which were The complex genome
metabolized by enzymes in the liver), Garrod further considered The complexity of the human genome is becoming ever more ap-
the idea of individual uniqueness and interactions with the envir- parent, with recent findings from a project called the Encyclopedia
onment: he realized that an infinite multitude of responses to en- of DNA Elements (ENCODE) confirming that, contrary to previous
vironmental factors were determined by constitutional (genetic) supposition, most of the 3 billion base pairs that it contains have a
variation in the individual and, in effect, that the operation of function. Regulation of gene function is proving to be much more
 12.1 The inborn errors of metabolism: General aspects 1931

intricate that at first thought. There are nearly 20 000 genes that en- in the enzyme protein may affect the primary, secondary, tertiary,
code proteins, and DNA sequences also encode thousands of add- or quaternary structure, decreasing, increasing, or abolishing its
itional RNA molecules. Of the greater than 11 000 DNA sequences catalytic activity. Some mutations affect the function of an acti-
classified as pseudogenes, several are now known to be active in vator protein, others reduce the binding of hormones and para-
some cell types or individuals. We now know that genes can overlap crine factors to cell surfaces and/​or subcellular structures, and
and may have multiple start and termination points. ENCODE has some derange the migration of proteins within cells; another group
uncovered 4 million short stretches of DNA that control gene ac- impairs the transport of metabolites across cellular and subcellular
tivity, which can act combinatorially and in different cell types to membranes (Table 12.1.1). Most intracellular enzymes are lo-
give each a unique identity. Some of the RNA strands (transcribed as cated in the cytosol where they are correctly orientated in relation
microRNAs) also influence gene expression. to one another, sometimes as macromolecular complexes, and to
In a reference to the lexicon of human genetics (Mendelian their substrates. Some are linked to cellular membranes and sev-
Inheritance in Man), there are estimated to be 24 600 potential eral are located in anatomically defined subcellular structures or
human phenotypes and 8670 known or suspected Mendelian dis- organelles: the Golgi apparatus, mitochondria, lysosomes, and
eases, the inheritance of which can be described as being auto- peroxisomes.
somal recessive, autosomal dominant, sex-​linked, or transmitted
maternally through the mitochondrial genome (Online Mendelian Mitochondrial diseases
Inheritance in Man, http://​www.ncbi.nlm.nih.gov/​Omim/​, http://​ The mitochondrial genome is a circular double strand containing
www.omim.org/​statistics/​entry as of 27 June 2018). 16.5 kb of DNA. It encodes 13 of the polypeptide subunits of re-
The inborn errors of metabolism are those inherited diseases spiratory chain enzymes, the remainder of which (c.60) are encoded
in which the phenotype includes a characteristic constellation in the nuclear DNA. Hitherto, mutations in 26 genes in the mito-
of chemical abnormalities related to an alteration in the catalytic chondrial genome are associated with defined human phenotypes
activity of a single specific enzyme, activator, or transport pro- (see Chapter 24.19.5). Abnormal mitochondrial function impairs
tein. There are unifactorially inherited diseases in which the cur- the supply of energy for biochemical work in all tissues and there-
rent techniques are too insensitive for a chemical abnormality to fore has wide-​ranging effects. Each mitochondrion also contains 24
be identified, so that the syndrome has to be defined in clinical, RNA genes that participate in intramitochondrial protein synthesis.
gross structural, and/​or pathological terms; further study is likely Transcription and translation of mtDNA are regulated by the nu-
to demonstrate that many of these fall into the category of inborn cleus through interactions with the noncoding D-​loop region of the
errors of metabolism. mitochondrial genome. Human cells contain about 1000 copies of
Almost all the so-​called single-​gene diseases arise from muta- mtDNA, but the individual mitochondria in a cell may not all carry
tions in the nuclear genome. A few mitochondrial proteins have a given specific mutation and different cells carry different propor-
their structures encoded in the mitochondrial DNA (mtDNA). tions of mutated mitochondria (heteroplasmy). The proportion of
This genetic information is transmitted only through the female mutant mtDNA must exceed a critical level before the mitochon-
line and maternal inheritance inborn errors of metabolism in- drial respiratory chain disease declares itself. This variability, as well
clude mitochondrial diseases. The nuclear and the maternally in- as tissue-​specific differences in dependence on oxidative metab-
herited diseases stem from mutations of DNA which directs the olism, explains, at least partially, why some tissues are preferentially
synthesis of a specific polypeptide chain. The molecular changes affected in patients with mtDNA diseases.

Table 12.1.1 Examples of diseases in which there is defective transport of an enzyme or metabolite within cells or across cell membranes

Disease Metabolic abnormality

Cystinuria Failure to transport cystine, lysine, ornithine, arginine, and homoarginine across the plasma membrane of the proximal renal
tubular epithelium and the small intestinal mucosa
I (inclusion body)-​cell disease Failure to generate the key molecular recognition signal, mannose 6-​phosphate, on nascent lysosomal glycoproteins that
(mucolipidosis II/​III) allows them to bind and enter the organelle via mannose 6-​phosphate receptors. Multiple acid hydrolases are mistargeted and
deficient in lysosomes, leading to build up of undegraded macromolecules (as inclusions). The disease is due to defective action
of N-​acetylglucosamine-​1-​phosphotransferase—​a heteromeric complex of polypeptides that are the products of two genes
Cystinosis (cystine storage Failure to transport cystine produced by intralysosomal proteolysis across the lysosomal membrane and into the cytosol
disease, Lignac’s disease)
Salla disease Failure to transport N-​acetylneuraminic acid (sialic acid) across the lysosomal membrane and into the cytosol
Mucopolysaccharidoses Failure to degrade glycosaminoglycans (mucopolysaccharides), the undegraded mucopolysaccharides are neither transportable
across lysosomal membranes nor capable of being removed from the lysosomes by exocytosis
Tay–​Sachs disease Defective post-​translational processing of the α chain of β-​N-​acetylhexosaminidase (hexosaminidase A) in some mutants.
This prevents the enzyme from migrating from the endoplasmic reticulum, where it is glycosylated, to the Golgi apparatus for
phosphorylation of its mannosyl residues and hence to lysosomes and the exterior of the cell
Primary hyperoxaluria type 1 Mislocation of alanine: glyoxylate aminotransferase in mitochondria as opposed to its normal location in peroxisomes. This
(some cases) arises because a rare mutation (Gly 170 → Arg) is present simultaneously with the common polymorphism (Pro 11 → Leu).
The mutation (Gly 170 → Arg) prevents dimerization of the molecule which, in turn, allows the weak mitochondrial targeting
sequence generated by the polymorphism (Pro 11 → Leu) to direct the molecule to mitochondria instead of peroxisomes
1932 SECTION 12 Metabolic disorders

Table 12.1.2 The main clinical manifestations of diseases due

Box 12.1.1 Some mitochondrial diseases
to mitochondrial dysfunction
Mitochondrial DNA defects
Disease group Clinical manifestations
Rearrangements (deletions and duplications)
Defects of fatty acid oxidation Hypoglycaemia • Chronic progressive external ophthalmoplegia
Hepatic dysfunction • Kearns–​Sayre syndrome (hypoparathyroidism with deafness)
Cardiac failure • Diabetes and deafness
Myopathy Point mutations in protein encoding genes
Sudden infant death • Leber’s hereditary optic neuropathy
• Leber’s hereditary optic neuropathy/​dystonia
Respiratory chain disorders Lactic acidosis
• Neurogenic weakness, ataxia, and retinitis pigmentosa
Encephalopathy • Leigh’s syndromea
Hypotonia
Point mutations in tRNA genes
Poor feeding • Mitochondrial encephalopathy with lactic acidosis and stroke-​like
Failure to thrive episodes
Convulsions • Myoclonic epilepsy with ragged-​red fibres
• Myopathy
• Cardiomyopathy
• Diabetes and deafness
Postmitotic tissues (e.g. neurons, muscle, and endocrine tis-
• Encephalomyopathy
sues) have high levels of mutated mtDNA and are often clinically
• Leigh’s syndromea
affected, whereas rapidly dividing tissues (e.g. bone marrow) tend
to be less often clinically affected. Differences in the proportions of Point mutations in rRNA genes
mutated and nonmutated mtDNA between and within family mem- • Nonsyndromic sensorineural deafness
bers also contribute to the wide phenotypic range encountered in • Aminoglycoside-​induced nonsyndromic deafness
the mitochondrial diseases. The spermatozoal cytoplasm, including Nuclear DNA defects
its mitochondria, is entirely lost at fertilization and for this reason Nuclear genetic disorders with a mitochondrial basis
mitochondrial diseases are only transmitted through the female line. • Friedreich’s ataxia (frataxin)
Clinically affected women rarely transmit a mtDNA deletion to their • Autosomal recessive hereditary spastic paraplegia
children. However, a woman with a heteroplasmic mtDNA point Nuclear genetic disorders of the mitochondrial respiratory chain
mutation or duplication may transmit a variable amount of mutated • Leigh’s syndrome (complex I deficiency)a
mtDNA to her progeny. The number of mtDNA molecules in each • Optic atrophy and ataxia
oocyte is reduced and then amplified to a total of about 105 during • Leigh’s syndrome (complex IV deficiency)a
early development of the oocyte; this presumably random process
Nuclear genetic disorders associated with multiple mtDNA deletions
contributes to the different amounts of mutated mtDNA in different
• Autosomal dominant external ophthalmoplegia
children in the same family. Women whose gametes contain high
• Mitochondrial neurogastrointestinal encephalomyopathy (thymidine
concentrations of mtDNA are more likely to have clinically affected phosphorylase deficiency)
children than mothers with lower concentrations of mtDNA. The
a
general clinical manifestations of the mitochondrial diseases are An example of different mutations providing the same clinical syndrome
(phenocopies). mtDNA, mitochondrial DNA; rRNA, ribosomal RNA; tRNA,
shown in Table 12.1.2 and specific examples of mitochondrial dis-
transfer RNA.
eases are given in Box 12.1.1.
Data from Chinnery PF and Turnbull DM (1999) The Lancet 354 (supplement 1),
Peroxisomal diseases S17–​S21.

Some enzymes and other proteins that are encoded in the nuclear
DNA are specifically expressed in peroxisomes, to which they are
imported soon after translation. Mutations in these genes result in
the peroxisomal diseases listed in Box 12.1.2. Diseases due to de- Box 12.1.2 Peroxisomal diseases
fects in peroxisomal proteins are discussed in Chapters 12.9, 12.10, • Zellweger’s syndrome (absent peroxisomal membranes)
and 24.17. • Pseudo-​Zellweger’s syndrome
• Adrenoleukodystrophy
Lysosomal diseases • Pseudo-​neonatal adrenoleukodystrophy
Lysosomes are subcellular organelles containing hydrolases with low • Acatalasia
optimum pH values (‘acid hydrolases’) which catalyse the degrad- • Infantile Refsum’s disease
ation of cellular macromolecules. The macromolecules are either • Refsum’s disease (classical form)
• Hyperpipecolic acidaemia
derived from the metabolic turnover of structural cellular compo-
• X-​linked adrenoleukodystrophy
nents or have entered the cell by endocytosis. The products of this
• Chondrodysplasia punctatum rhizomelia
macromolecular degradation process leave the lysosomes by specific • Primary hyperoxaluria type 1
efflux processes.
 12.1 The inborn errors of metabolism: General aspects 1933

In most of the lysosomal storage diseases, an inborn error of diseases and the nature of their metabolic defects together with
metabolism affects a specific lysosomal enzyme so that either examples of each group are presented in Table 12.1.3.
undegraded or partially degraded macromolecules accumulate in
the lysosomes (see Chapter 12.8). The engorged lysosomes distort Heterogeneity in the inborn errors of metabolism
the internal architecture of the cell, disturb its function, and in- The individual inborn errors of metabolism are defined on the
hibit the activities of other lysosomal enzymes so that macromol- basis of the phenotype, including the specific enzyme lesion, and
ecules other than those related to the primary enzyme deficiency by their pattern of inheritance. Close study of any particular in-
also accumulate. born error of metabolism reveals unexpected heterogeneity and
Cystinosis (cystine storage disease) and Salla disease (N-​ we are increasingly recognizing diverse patterns of inheritance
ace­tylneuraminic (sialic) acid storage disease) are due to metabolic due to a variety of mechanisms, including somatic mosaicism,
lesions involving the specific efflux processes by which these small dominant negative effects in complex multimeric pathways, as
molecules generated by the intralysosomal hydrolysis of complex well as transcriptional silencing of imprinted genes. This may be
substrates cystine and sialic acid, respectively, leave the lysosome due to:
(Table 12.1.1).
Lysosomal enzymes are glycoproteins which are subject to exo- • multiple allelism
cytosis and reuptake by endocytosis. Their protein moieties are • mutations at different gene loci affecting the structure of different
synthesized on the rough endoplasmic reticulum and the oligosac- polypeptide chains in a single enzyme protein
charide side chains are added in the Golgi apparatus. The addition • mutations at different gene loci affecting different proteins with
of a terminal mannose 6-​phosphate residue recognition marker similar catalytic functions
is necessary if the enzyme molecule is to be correctly routed into • differences in the overall genetic background against which the
the lysosomes, and if it is to be available for receptor-​mediated re- single mutation acts
uptake from the interstitial fluids. The types of lysosomal storage • environmental factors.

Table 12.1.3 Lysosomal storage diseases other than cystinosis and Salla disease; a more complete listing is given in Chapter 12.8
(Table 12.8.1)

Name Defect Example

Sphingolipidoses Failure to degrade compounds containing a sphingoid (sphingolipids, ceramides, Tay–​Sachs disease
sphingomyelins, and glycosphingolipids including the gangliosides (sialoglycosphingolipids)) (GM2-​gangliosidosis)
Gaucher disease
(glucocerebrosidosis)
Mucopolysaccharidoses Failure to degrade the glycosaminoglycans: dermatan, heparan, and keratan sulphates. Hurler’s disease
Incompletely degraded glycosaminoglycan fragments accumulate in the lysosomes as well Hunter’s disease
as extracellularly. This causes secondary deficiencies of other lysosomal enzymes and other Morquio disease
undegraded macromolecules, particularly sphingolipids, accumulate (MPS 1, 2, 4)
Glycoproteinoses A group of enzyme defects in the catabolism of glycoproteins in which characteristic abnormal Fucisidosis
macromolecules accumulate Mannosidosis
Acid lipase deficiency Two clinically distinct variants. Cholesteryl esters and triglycerides accumulate in most tissues Wohlman’s disease
due to deficiency of lysosomal acid lipase Cholesteryl ester storage disease
Glycogenosis II Lack of intralysosomal hydrolysis of glycogen Glycogenosis type II (only
member of this group)
Mucolipidoses Originally defined as being clinically intermediate between the sphingolipidoses and See text
mucopolysaccharidoses but without mucopolysacchariduria (abnormal glycosaminoglycan
excretion). Subsequently shown to include patients with (1) deficient neuraminidase
activities with respect to either glycoprotein substrates (mucolipidosis I, also classified as a
glycoproteinosis and termed sialidosis) or ganglioside substrates (mucolipidosis IV); (2) clinically
mild and severe variants of uridine-​diphosphate-​N-​acetylglucosamine: lysosomal enzyme
precursor N-​acetylglucosamine phosphate transferase (mucolipidoses II (I-​cell disease) and III
(pseudo-​Hurler polydystrophy) respectively—​see Table 12.1.1)
Miscellaneous Numerous defects affect the action or activation of lysosomal enzymes—​sulphatase-​modifying Multiple sulphatase deficiency
factor, which is critical for a post-​translational modification of a common cysteine residue in GM2 gangliosidosis (AB variant)
eight of 18 putative human sulphatases; the four sphingolipid activator proteins, A–​D, and GM2 Action myoclonus–​renal failure
activator protein, which act as enzymatic activators in multiple stages of lysosomal sphingolipid Danon’s disease
degradation, as well as lysosomal membrane digestion
Deficiency of the lysosomal integral membrane protein, LIMP-​2, associated with selective
deficiency of glucocerebrosidase in nonmacrophage lineage cells and action myoclonus–​renal
failure syndrome.
Mutations in the X-​chromosome-​linked LAMP-​2 lysosomal membrane protein cause Danon’s
disease with defective clearance of autophagic debris, including glycogen, principally affecting
heart, skeletal muscle, and the brain
1934 SECTION 12 Metabolic disorders

the ethnic and geographical origins of the parents. Impaired func-

General approaches to the management
tion of proteins that are localized to the mitochondria, lysosomes,
of inborn errors of metabolism
and peroxisomes are associated with particular clinical and bio-
chemical characteristics that reflect the compartmentalized func-
Clinical indicators of an inborn error of metabolism
tions of these organelles.
The manifestations of metabolic disease are protean and may seem
nondescript, especially in adults. Some clinical settings suggest A broad perspective of the physician’s role
the presence of an inborn error of metabolism (Box 12.1.3), but Inborn errors of metabolism encompass diseases that are disabling,
in other circumstances a high level of suspicion may be required disfiguring, and painfully life-​shortening, hence—​as in many areas
to make a correct diagnosis. Inborn errors of metabolism usually of medicine—​the role of the physician is much broader than dis-
come to light in the neonatal period or infancy, but can occur at any pensing the perceived and much-​awaited ‘magic’ of a cure. From the
time—​even in mature adults for the first time and in whom the rate clinical aspect, often the best achievable goals are preventing rapid
of progression may be indolent. In an appropriate clinical context—​ deterioration and ensuring that emergency measures are in place
for example, unexplained acute neonatal illness and/​or failure to so that acute metabolic decompensation can be quickly contained,
thrive in early infancy, developmental slowing and arrest followed with preservation of tissue integrity and organ function, especially
by retrogression, or unusual physiognomy—​the critical clue often of the brain. The time-​honoured adage: ‘to cure sometimes, to re-
comes from taking an appropriate family history, with specific in- lieve often—​but comfort always’ is particularly telling in this field of
quiries about affected siblings, possible parental consanguinity, pa- practice. It is also important to emphasize the critical importance
ternity, miscarriages, perinatal deaths, abortions, about the sexes of of prompt diagnosis—​even of what might prove to be an incurable
possibly affected relatives and their placement on the maternal or disease—​together with the mandatory requirement for providing
paternal side of the family, the ages at death of relatives, as well as genetic advice.

Principles of treatment
Box 12.1.3 Clinical presentations which, in the absence While many inborn errors of metabolism have severe and poten-
of acquired or other congenital causes, suggest an inborn error tially lethal effects, as a group, effective treatments are continually
of metabolism being introduced. Therapeutic advances are increasingly based on a
• Unexplained acute neonatal illness and/​or failure to thrive in early in- scientific understanding of the inherited defect, to which bio­
fancy. (Marked muscle hypotonia, recurrent fits, comas, acidosis, and chemical knowledge can be rationally applied. The treatments
vomiting, especially if withholding milk feeds causes temporary im- available for the individual disorders are diverse and often must
provement, are especially suggestive)
be specially developed for individual patients. General approaches
• Developmental slowing and arrest followed by retrogression
include (1) restriction of a substrate that cannot be metabolized
• Developmental slowing and arrest leading to unexplained intellectual
disability including molecules derived from the diet; (2) replacement of a
• Unusual physiognomy, multiple skeletal deformities with develop- missing metabolic product; (3) removal of poisonous metabol-
mental delay and retrogression ites or rebalancing overproduction of toxic intermediates; (4) ad-
• Multiple skeletal deformities alone (dysostosis multiplex especially ministering pharmacological doses of a cofactor, sometimes a
suggests a lysosomal storage disease) vitamin, that may also stabilize a mutant enzyme; (5) replacement
• Gross visceromegaly of a missing gene product, usually by enzymatic augmentation
• Specific dietary intolerances therapy or pharmacological chaperones, to prevent premature
• Haemolytic anaemia ­aggregation and denaturation; (6) repression of an overproduced
• Unusual body odoura
protein or metabolite by stable RNA inhibition; (7) transplant-
• Urolithiasis
ation of cells (e.g. haematopoietic stem cells) or organs (e.g. liver)
• Cataracts in early lifeb
• Dislocation of the optic lensc
as a ‘gene replacement therapy’; and (8) activation of a poorly
• Persistent jaundice and hepatic cirrhosis in infancy. ­functioning protein. The principles involved are summarized in
• Abnormal cutaneous photosensitivity Table 12.1.4.
• Hypopigmentation While dealing with the complexities of each individual disorder,
• Abnormal drug sensitivity the essence of clinical care for these chronic disorders requires
• A history of recurrent perinatal deaths and/​or stillbirths maturity, vigilance, and the perspective of the generalist in paedi-
• Hydrops fetalis in the absence of blood group incompatibility between atric or adult medicine to ensure provision of what is now termed
mother and fetus (red cell enzyme defects) holistic medicine. Palliative surgical and other measures may be
a
Examples are phenylketonuria (mousy, musty), branched chain ketoacidosis needed to deal with specific complications (e.g. corneal grafting to
(maple syrup), methionine malabsorption (oast house, dry celery), isovaleric restore vision in patients with corneal clouding due to one of the
acidaemia (sweaty feet), trimethylaminuria (stale fish), multiple carboxylase mucopolysaccharidoses). Consideration should also be given to
deficiency (tom cat’s urine), and hawkinsinuria (swimming pool). meeting the educational and social needs of these patients as well as
b
Examples are Fabry’s disease, galactosaemia, galactokinase deficiency, to optimizing their overall clinical state and correcting the biochem-
Lowe’s syndrome, mannosidosis, osteogenesis imperfecta, Refsum’s disease,
ical parameters.
and Wilson’s disease.
c
Beyond the skills of other physicians, surgeons, biochemists, and
Examples are Ehlers–​Danlos syndrome, homocystinuria, hyperlysinuria,
geneticists, successful management of patients with inborn errors
Marfan’s syndrome, and sulphite oxidase deficiency.
of metabolism requires multidisciplinary engagement by colleagues
 12.1 The inborn errors of metabolism: General aspects 1935

Table 12.1.4 General approaches to the treatment of inborn errors of metabolism

Method Examples
General measures (directed to mitigate) Ultraviolet radiation (congenital erythropoietic and variegate porphyrias, and in albinism)
Ionizing radiation in the DNA repair enzyme defects (xeroderma pigmentosum, ataxia
telangiectasia)
Infections (agammaglobinaemia).
Restriction of a dietary substrate which cannot be metabolized Phenylalanine restriction in phenylketonuria
Partial inhibition of formation of toxic metabolites (inhibitors of
Protein restriction in the hyperammonaemias
biosynthesis)
Elimination of galactose in galactosaemia
Restriction of dietary phytanic acid and congeners (Refsum’s disease)
Medications (oestrogens, barbiturates, etc. in acute intermittent porphyria)
statins (hypercholesterolaemia); haem arginate (acute porphyrias); nitisinone (hereditary
tyrosinaemia type I); allopurinol (gout); eliglustat (type I Gaucher disease)
Supplying a missing metabolic product Orotic aciduria: treatment with uridine triacetate which is metabolized to uridylic acid
Hartnup disease: nicotinic acid to control pellagra
Removal of toxic metabolite Haemodialysis and peritoneal dialysis as temporary treatment of an acute metabolic crisis due to
a diffusible toxic metabolite, and to correct certain secondary biochemical abnormalities quickly
Either specific chemical detoxication (e.g. penicillamine in Wilson’s disease) or solubilization
(e.g. penicillamine in cystinuria); accelerated metabolic disposal (phenylbutyrate and sodium
benzoate in hyperammonaemia due to urea cycle defects)
Pharmacological doses of a cofactor (only some cases of Propionic acidaemia: biotin
each disease respond). Note: this stratagem has features of Ubidecarenone (respiratory chain disorders due to coenzyme Q10 deficiency)
pharmacological chaperone therapy since natural cofactors such Homocystinuria: pyridoxine
as vitamins also stabilize mutant enzymes Primary hyperoxaluria (type I): pyridoxine
Methylmalonic acidaemia: vitamin B12 and other cobalamins
Replacement of a missing gene product Adenosine deaminase deficiency
Gaucher disease: β-​glucosylceramidase (mannose-​terminated to confer selective uptake by
tissue macrophages)
Haemophilia: clotting factor VIII
Activating a membrane transporter Cystic fibrosis (due to G551D mutation—​a relatively uncommon variant of the cystic fibrosis
transmembrane regulator protein, CFTR, a chloride channel)
Bone marrow transplantation Adenosine deaminase deficiency; infantile Krabbe’s disease; α-​mannosidosis
Haematopoietic stem cell transplantation Adenosine deaminase deficiency
Liver transplantation Hereditary tyrosinaemia (type I)
Antitrypsin deficiency
Primary hyperoxaluria (type I)
Urea cycle disorders
Crigler–​Najjar syndrome (type I)
Gene replacement Adrenoleukodystrophy adenosine deaminase deficiency
RNA interference therapy (siRNA) Patisiran for transthyretin-​related polyneuropathy (systemic amyloidosis)

Note: the examples chosen are situations in which either the proposed treatment is established or in which it can be recommended as elective therapy even though the results of
prolonged evaluation are still awaited.

with special skills related to metabolic medicine—​including diet- Particular treatments

itians, social workers, educationalists, and occupational therapists. Protein replacement therapies
It is particularly important to plan for the handover of specialist
care from the paediatrician to the most appropriate adult physician The ability to clone human genes into bacteria and eukaryotic cells
when follow-​up in a paediatric department becomes inappropriate. for ectopic expression which can then produce large amounts of
The perfect outcome is to achieve a physically and mentally healthy the human gene product is opening the horizons for treatment by
and fulfilled adult who is capable of begetting healthy children. protein replacement or more accurately, augmentation. The devel-
Unfortunately, the nature of many of the inborn errors militates opment of macrophage-​targeted β-​glucosylceramidase enzyme re-
against this ideal so treatment has to aim at optimizing the child’s placement therapy for Gaucher’s disease is a notable development
potential in all its physical, mental, and social aspects. Treatment in this field and is now regarded as the definitive treatment for the
and support also have to be extended to the parents and siblings non-neuronopathic manifestations.
who, if not overtly affected themselves, may be carriers of the ab- Attempts to utilize transplanted fibroblasts and amniotic cells as
normal gene concerned and require appropriate advice about the a source for enzyme replacement therapy have not been successful.
transmission of the disease to other offspring and other aspects of Bone marrow transplantation (‘haematopoietic stem cell transplant-
the condition. ation’) has been used for the treatment of two groups of inherited
1936 SECTION 12 Metabolic disorders

metabolic disorders: those in which it is desired to replace a par- neurological complications of the sphingolipidoses, who would
ticular type of nonfunctioning bone marrow cell by its normally otherwise be without hope. Currently two such agents are in active
functioning counterpart, and those in which an attempt has been clinical development.
made to utilize the fact that the bone marrow produces leucocytes In alkaptonuria, a disease in which Garrod maintained a lifelong
and that these cells exocytose (release) their lysosomal enzymes interest, the use of substrate-​reduction therapy is also far advanced.
for endocytic uptake by enzyme-​deficient cells in the body tissues Nitisinone, a triketone inhibitor of the precursor to homogentisic
generally. acid at the level of hydroxyphenylpyruvate dioxygenase in the tyro-
Bone marrow transplantation has been more successful with the sine degradation pathway, is a licensed agent for tyrosinaemia type
first group of diseases, which includes disorders of neutrophil func- 1. In very small doses, this agent has a striking effect on the forma-
tion (e.g. cyclic neutropenia), functional abnormalities of lympho- tion of toxic oxidative metabolites of homogentisic acid which lead
cytes, and osteopetrosis; the beneficial effect on the latter being due to the life-​shortening manifestations of alkaptonuria, and it appears
to the introduction of normal osteoclast precursors derived from likely that at last a well-​tolerated and definitive treatment for this
granulocyte–​macrophage progenitors in the marrow. landmark disorder is within sight.
The results of bone marrow transplantation in the second group
of diseases, namely those in which the white cell lineage derived Pharmacological chaperones
from the transplanted bone marrow is used to supply normal en- The concept of pharmacological chaperones, based on the ability of
zyme to enzyme-​deficient tissues, for example, Hurler’s disease small molecules to bind to mutant proteins to prevent their inactiva-
(mucopolysaccharidosis type 1) and Krabbe’s disease, has been less tion by abnormal folding, intracellular aggregation, and mistargeting,
effective. In the latter case, recent courageous studies have shown is receiving much attention. It has yet to be adopted extensively in
that transplantation of HLA-​matched umbilical cord blood in the practice, although the chaperone approach is in late-​phase clinical de-
first 10 days of life has been moderately successful in promoting velopment in Fabry’s disease and is being explored in Pompe disease.
neurological development in infants born to couples with previously
affected offspring and detected by screening early for this otherwise Organ transplantation
rapidly progressive neurodegenerative disorder. Haematopoietic Liver transplantation is used as a form of functional complementa-
stem cells have been implanted into the fetus in utero to correct se- tion in some inborn errors of metabolism such as glycogen storage
vere congenital immunodeficiency, but this has not, so far, been ap- disease type I and severe recurrent acute porphyria where this organ
plied to diseases without immunodeficiency. This procedure takes is the specific site of the metabolic lesion. Liver transplantation has
advantage of the immunological tolerance of the fetus. the advantage that the enzyme is introduced in the correct organ, in
The possibility of using liposomes and resealed erythrocyte en- the correct cell with its correct subcellular location, and correctly
velopes as carriers of therapeutic enzymes is also being explored; orientated with respect to its substrate and other enzymes with
linking purified or recombinant therapeutic enzymes such as adeno- which it must act in concert, for example, in the urea cycle disorders
sine deaminase to polymers such as polyethylene glycol may usefully such as ornithine transcarbamylase deficiency.
prolong their survival in circulating plasma. Liver transplantation can also be regarded as a form of gene re-
placement therapy in that the donor liver contains the normal gene
Receptor-​targeted therapies which will direct the synthesis of a normal enzyme protein. Prenatal
Definitive enzymatic augmentation with receptor-​targeted therapies transplantation of fetal liver stem cells has potential in the treatment
has attracted much attention. In Gaucher’s disease, this strategy has of some inborn errors of metabolism. Successful engraftment at the
proved to be very effective and commercially successful: global sales of 12th to 24th week after fertilization with partial correction of the
the mannose-​terminated glucocerebrosidase for about 6000 patients metabolic defect has been demonstrated in β-​thalassaemia.
worldwide enabled the Genzyme corporation to rise to a leading pos-
ition in the biotechnology industry. Other industrial competitors have Gene replacement and cell-​based therapies
followed suit with targeted enzyme preparations approved for this and Gene therapy and cell-​ based therapies including bone marrow
other lysosomal diseases such as Fabry’s disease, Pompe’s disease, and transplantation are at various stages of clinical evaluation and devel-
mucopolysaccharidosis types I and II (see Chapter 12.8). opment, assisted by the recent capacity to develop credible models of
specific disorders in genetically modified animals.
Substrate-​reduction therapies
Substrate-​reduction therapy with the use of specific inhibitors to Haematopoietic stem cell gene therapy
regulate the flux through impaired degradative pathways, by partial Gene replacement using retroviral vectors and gene constructs can
blockade of the rate-​limiting step is useful in low-​density lipoprotein be used to introduce the desired DNA sequence into the patient’s
receptor deficiency (heterozygous familial hypercholesterolaemia as explanted haematopoietic stem cell genome. These genetically cor-
well as the very rare homozygous variant), and thus was born the rected cells are cultured and then returned to the patient’s circula-
pharmaceutical star of the statin drugs, which are in wide general use. tion, where they may have therapeutic potential in diseases where
An analogous approach involving inhibition of the first committed expression of the metabolic lesion in the haematopoietic system
step in the biosynthesis of glycosphingolipids is already showing determines the phenotype or in those situations where genetic-
promise in the glycosphingolipid diseases such as Gaucher’s dis- ally corrected migratory cells of haematopoietic origin can deliver
ease. Small-​molecule inhibitors of this pathway that are safe, well normal enzyme to the enzyme-​deficient tissues. This approach
tolerated, and that penetrate the blood–​brain barrier have the po- has recently been reported in young patients with metachromatic
tential to improve the outcome for many patients with progressive leukodystrophy, with the phase I/​II clinical trial results indicating
 12.1 The inborn errors of metabolism: General aspects 1937

convincing evidence of some neurological benefit or ‘rescue’ com- The unique capacity for complementation of soluble lysosomal
pared with historical and family control patients not so treated, and proteins to be secreted by cells and taken up at a distance by others
retrospectively with patients treated by transplantation of haem- (‘secretion–​recapture’) renders those lysosomal diseases in which
atopoietic stem cells from healthy donors. Despite the difficulty in neurological manifestations are prominent as excellent targets for
determining efficacy directly in such studies, the disease did not clinical exploration of gene therapy (see Chapter 12.8). Here, the
manifest or progress in the three patients 7 to 21 months beyond the principle of allowing a proportion of neural cells to be stably trans-
age at which this would have been predicted. duced by vector, thus to serve as a source of a given corrective pro-
tein that can be taken up into the lysosomes that lack the enzyme in
Somatic cell gene therapy nearby neurons, is an attractive strategy for therapeutic exploration.
Although somatic cell gene therapy using viral vectors and/​or gene Although there are some prospects of correcting some enzyme
constructs to introduce the desired DNA sequences into other cell defects in the somatic cell genome, the correction of defects in the
types is currently being investigated extensively in in vitro model germline seems remote, although the development of advanced in
systems and in animal models of some human inborn errors of me- vitro fertilization techniques, preimplantation DNA analysis, gene
tabolism (e.g. using hepatocytes), few of these have reached appli- transfer, insertion or conversion, and embryo implantation pro-
cation in clinical practice. However, this approach, using lentiviral cedures may render this possible. However, the prospect of human
vectors which have the advantage that they can be used to transduce germline modification will arouse many complex ethical issues, and
by nuclear integration of viral sequences in mitotic cells, has had these may hold up research and clinical application.
qualified therapeutic success in trials in children with combined
immunodeficiency. Several patients in this Anglo-​French trial un-
fortunately developed a late-​onset T-​cell lymphocytosis leading to Screening for inborn errors of metabolism
leukaemia, later shown to be related to the integration of vector
sequences at a genomic ‘hot spot’ leading to activation of a neigh- The realization that very early diagnosis is essential in order to achieve
bouring endogenous proto-​oncogene. These patients responded good results in the treatment of many inborn errors of metabolism,
to antileukaemic chemotherapy with satisfactory control of the such as phenylketonuria and galactosaemia, has stimulated interest
complication—​with continued amelioration of their disabling im- in the possibility of examining either whole populations or selected
munodeficiency disease—​but safety considerations have retarded groups of predisposed individuals for the biochemical differences
clinical development until improved vector systems can be utilized. which characterize particular inherited metabolic diseases. Diagnosis
Promising results of a gene therapy trial using a lentiviral vector is needed at a stage which is not only presymptomatic but which pre-
to correct the enzymatic abnormality in leucocytes derived from cedes the onset of self-​perpetuating secondary pathological changes.
haematopoietic precursors in a very rare immunodeficiency disease, Screening for inborn errors of metabolism may be either non-
adenosine deaminase deficiency, have also been reported—​so far selective (whole population) or selective. The latter, which includes
with no mutagenic effects. Eight years after the procedure, eight of carrier detection studies, aims to cover a part of the population. This
ten patients with severe combined immunodeficiency no longer re- may be defined on clinical, genetic, ethnic, or geographical grounds.
quired enzyme-​replacement therapy and lived normally. Phenylketonuria and congenital hypothyroidism are the only
Gene therapy with autologous CD34+ haematopoietic stem cells metabolic disorders for which neonatal whole-​population screening
transduced with a third generation lentiviral vector reduced or elimin- is generally practised, although medium chain fatty acid dehydro-
ated the need for long-term red-cell transfusions in 22 patients with se- genase deficiency has been included recently in the United Kingdom
vere β-thalassemia without serious adverse events related to this vector. and many other countries. There is wide international variation
Given the challenges of donor availability and the added risks of allo- and galactosaemia, cystic fibrosis, and congenital adrenal hyper-
geneic haematopoietic stem-cell transplantation in this disease and the plasia (21-​hydroxylase deficiency) have been proposed. Until recently
prior occurrence of neoplastic change or of preferential integration of it has been held that whole-​ population screening should only
vector at specific sites in the host genome, early regulatory approval of be established for treatable or preventable diseases, and the con-
this stratagem, is encouraging for numerous inborn metabolic diseases. sistency of the association of the proposed biochemical or other
The possibility of using adeno-​associated viral vectors as a means of marker and the serious clinical phenotype must have been proved
introducing corrected genes for into nonmitotic cells of the nervous beyond any doubt. There must be a reliable and robust analytical
system is being explored in human patients; these vectors are main- method suitable for use with a sample of blood or urine which can
tained as episomal elements which do not integrate readily into the be obtained without distressing either the parents or the baby. The
host genome (with the attendant risk of mutagenesis) but persistently possibility that metabolic screening will bring to light previously
express the corrective protein. Adeno-​associated vectors have been unrecognized variants, which are either mild and do not require
successfully used in early gene therapy trials of the retinal disease, treatment, or which by virtue of a fundamentally different bio-
Leber’s congenital amaurosis, with direct intraorbital gene delivery. chemical lesion will resist the currently established therapies, has
Recombinant adeno-associated viral vector serotype 9, which supplies to be borne in mind. Phenylketonuria illustrates these difficulties.
the deficient Smn1 protein, was approved by the FDA as Zolgensma Here, beside classical phenylketonuria, whole-​population screening
after a phase 3 clinical trial in infants less than 2 years of age with spinal has identified both the clinically unimportant essential (mild)
muscular atrophy—including the pre-symptomatic phase. The agent hyperphenylalaninaemia, and the devastatingly serious, but treat-
prolongs event-free survival and increases motor function. Salutary able, inborn errors of tetrahydrobiopterin synthesis which produce
outcomes in rapidly progressive genetic diseases open up the field for the ‘malignant’ hyperphenylalaninaemia syndrome. In a subset of
further exploration of gene therapy in the human brain. patients with classical phenylketonuria, tetrahydrobiopterin also
1938 SECTION 12 Metabolic disorders

improves blood phenylalanine control, and may, in the long term, • demonstration of intermediate levels of a characteristic metabolite
allow the burden of stringent dietary treatment to be relaxed. It is in an accessible body fluid
also possible that in some cases immediate postnatal screening and • demonstration of mosaicism with respect to the product of the
treatment may be too late to prevent minor manifestations of the mutant gene on the X chromosome in the case of sex-​linked reces-
disease (e.g. in congenital hypothyroidism). sive disorders
The incidence of disease which merits whole-​ population • direct gene analysis using either a specific gene probe or a linked
screening should be at least similar to that of phenylketonuria in restriction fragment length polymorphism.
white Europeans (between 1 in 6000 and 1 in 14 000). Cystic fibrosis
has a birth frequency of approximately 1 in 2500 (heterozygous car- The ability to recognize asymptomatic carriers of serious recessive
rier frequency l in 25) in white persons of European ancestry and diseases and presymptomatic individuals in the case of dominant
would merit neonatal whole-​population screening on this basis. disorders raises major ethical and social issues with respect to the
Molecular genetic approaches are potentially useful. If the dis- psychological impact that this information will have on the affected
ease is not too genetically heterogeneous, and when the full range of individuals and their families. This is especially so with the clinically
possible causative mutations is known, the specific mutation could normal carriers of a crippling, lethal, and untreatable disease such as
be sought directly. Some individuals classified as being homozy- Huntington’s disease.
gotes on the basis of classical genetic analysis prove to be compound
(‘double’) heterozygotes, that is, they carry two different mutations, Applications of genome sequencing
each affecting either the maternal or paternal allele of the same gene. Recent years have seen astonishing improvements in the accuracy,
The number of inborn metabolic errors in which the affected indi- extent, and rate at which genetic information can be accessed
viduals and the heterozygous carriers can be identified by molecular by sequencing of human DNA. In the four decades since robust
analysis of genomic DNA is increasing rapidly. The conditions methods for determining the nucleotide base order in natural DNA
which are identified by the application of DNA analytical methods molecules were first reported, the growth of sequence information
include such numerically important diseases as sickle cell anaemia, has been astronomical as a result of ‘next-generation sequencing’
β-​thalassaemia, haemophilia, Duchenne muscular dystrophy, cystic methods. Meanwhile, the desire to generate and store these data has
fibrosis, medium-​chain acyl-​CoA dehydrogenase deficiency, and also burgeoned. The simultaneous explosion in bioinformatics and
phenylketonuria, as well as rarer but devastating conditions such as statistical genetics combined with the need for clinical prognostica-
the Lesch–​Nyhan syndrome. tion is driving a revolution. Analysis dependent on massive parallel
sequencing has intensified knowledge of the pathological anatomy of
Prenatal diagnosis the human genome; research is ongoing to conduct simulations and
The procedures used in prenatal diagnosis are: molecular modelling and incorporate empirical structural biology
to realize a key scientific ambition with the aim of improving the
• direct examination of the fetus by ultrasonography and fetoscopy
capacity to predict the clinical consequences of genomic variants.
• chemical analysis of amniotic fluid
DNA sequencing now extends far beyond the domain of laboratory
• biochemical and cytological analysis of cultured amniotic cells science and evolutionary studies: in biology it has proliferated cat-
(amniocytes) obtained by amniocentesis at weeks 15 to 16 of egorically and dominantly for clinical use. Rapid, cheap, and increas-
pregnancy ingly reliable, DNA sequencing applications in medicine are enabling
• DNA analysis on uncultured amniocytes predictive testing in certain circumstances, for example, highly pene-
• karyotypic enzymological and DNA analysis of chorionic villi trant Mendelian disorders caused by recurrent variants, but this is the
obtained by biopsy at weeks 10 to 12 of pregnancy exception rather than the rule for most genetic disorders. Now DNA
• biochemical studies on tissue obtained by fetal biopsy in utero analysis is beginning to support natural appetites for clinical prognos-
• sequencing of circulating cell-​ free DNA (cfDNA) during tication: for diagnosis, decision-​making, therapeutic discovery, and
pregnancy. drug targeting, but knowledge of the clinical implications of genomic
variation is currently very incomplete, as emphasized by the fact that,
Carrier state diagnosis of approximately 20 000 genes in the human genome, only about 30%
Carriers are either individuals carrying the gene for a recessive dis- have a known role in human disease. Each human genome contains
order, which does not express itself in the heterozygous state (e.g. 4 to 5 million variants (positions where the genetic code in the indi-
phenylketonuria), or those who carry the gene for a dominant dis- vidual differs from the human reference sequence), and distinguishing
order, that is, one which does express itself in the heterozygous state, disease-​causing variants from rare background variants can be very
but in which symptoms occur in later life (e.g. Huntington’s disease). challenging. We are only beginning to learn how to integrate DNA
The general approaches to carrier state diagnosis are: sequencing information into clinical practice, and there can be con-
siderable dangers in assuming that a particular DNA sequence has (or
• detection of minor clinical, radiological, and clinicopathological
will have) a particular clinical impact in a particular patient.
abnormalities
In clinical contexts where there is limited experience of sequencing
• demonstration of levels of enzyme activity in tissue (e.g. leuco- methodology, there needs to be caution in the diagnostic field and
cytes or cultured fibroblasts) which are intermediate between it has been suggested that the following stratagems be adopted: (1)
those observed in individuals homozygous for the abnormal and obtain detailed clinical phenotyping to create a carefully thought out
the normal forms of the enzyme respectively (the observed level of and justifiable differential diagnosis—​if it seems biologically unlikely
activity may not be exactly 50% of the normal value) that a particular gene is involved in the generation of a particular
 12.1 The inborn errors of metabolism: General aspects 1939

phenotype, then it is likely to be wrong to assume that a mutation In vitro fertilization and the inborn errors of metabolism
in that gene is causal; (2) scrutinize the family history and mode The human embryo produced by in vitro fertilization can be biopsied
of inheritance, and compare (when possible) gene sequence in the at a very early stage of development (i.e. at the eight-​cell stage). A single
proband with that in other family members; and (3) confirm DNA cell is removed and examined for the DNA mutation responsible for
sequence data by manual inspection of the sequencing reads for the disease which the parents are known to be carrying or for parental
genes that are of interest, and check these by independent methods haplotypes tightly linked to the parental mutations). This technique,
approved for clinical use. It is also appropriate to point out that mas- known as preimplantation genetic diagnosis, enables only embryos
sive parallel sequencing does not detect all genetic abnormalities: it which do not carry the disease-​causing genotype to be implanted.
may be necessary to deploy alternative sequencing such as Sanger
sequencing and deletion/​duplication testing to detect single nucleo-
tide and copy number deletion and in-​frame deletions/​duplications Animal genetic models of inborn errors
that can readily be missed. of metabolism in humans
In the field of rare diseases, of which the huge catalogue of inborn
errors of metabolism occupies a central place, DNA sequencing is of Animal models of the inborn errors of metabolism occur spontan-
arresting interest for practitioners. The perennial need for prompt eously and have been used in therapeutic research for many years,
diagnosis carries with it the prospect of comfort and utility when but the capacity to generate models of genetic disease by transgenic
faced with diagnostic challenges and countless choice, and also has techniques has greatly advanced this avenue of exploration. Not
potential implications for mass screening as much as for the stricken only do such models offer the hope of shedding important light on
individual. the mechanisms of disease, they have much to offer in the develop-
Sequencing circulating cell-​free DNA in pregnancy ment of innovative treatments before attempting to transfer these
to patients—​now referred to as translational medical research.
The most widespread clinical application of DNA testing is pre- The discovery of embryonic stem cells in the mouse and the ability to
natal testing for fetal chromosomal abnormalities, such as trisomy manipulate the mammalian genome by targeted homologous recom-
21 in Down’s syndrome. As of 2017, up to 6 million women have bination have been instrumental in generating ‘knock-​out’ models of
undergone sequence analysis of cfDNA for fetal aneuploidy (see human genetic diseases. Once the cognate nuclear gene of the mouse
Chapter 3.9). cfDNA is obtained at about 10 weeks of pregnancy from has been disrupted in embryonic stem cells, these cells are injected into
small samples of maternal blood. Described accurately as the ‘fastest the inner cell mass of individual host blastocysts. In some of the resultant
growing genetic test in medical history’, this technology, introduced chimeric embryos, the embryonic stem cells harbouring the mutant
as a plasma analyte after 20 years of research by Dennis Lo and col- locus contribute to the development of the gonads in the adult progeny;
leagues, offers great hope for applications of DNA sequencing in clin- ultimately, when this is the case, offspring can be bred to homozygosity
ical medicine—​for example, in cancer diagnosis and monitoring and for the disrupted locus and studied. Refinements of this technology
for diagnosis and screening in single-​gene disorders. based on the use of regulatory sequences and tissue-​specific promoter
In relation to screening for inborn errors and rare diseases gener- elements permit the target locus to be manipulated at will in the whole
ally, ‘liquid’ biopsy of fetal DNA circulating in maternal blood offers animal at a predefined stage of development by the administration of
potentially easy access to the genomic DNA of the fetus at risk in a small molecules that bind to control elements (inducible ‘knock-​out’
noninvasive manner. However, while testing for fetal aneuploidy and and/​or ‘knock-​in’ models models) or allow the genetic locus of interest
some cancers has little need for nucleotide-​level accuracy (chromo- to be deleted in particular tissues (conditional knock-​out model).
somes can be counted without checking for sequence variation), the Murine and other living experimental models of human diseases
application to noninvasive diagnosis of suspected genetic diseases are valuable in medicinal research but limitations to the method-
as well as de novo screening for single-​gene disorders has more fas- ology remain when cognitive and behavioural abnormalities are
tidious requirements. Given the potential value and need for such critical features of the clinical phenotype in patients; even with the
testing, however, rapid progress has been made: there are reliable constraints of recruitment in individually rare diseases, the experi-
means to detect fetal rhesus D genotypes in rhesus D-​negative mental system by which innovative treatments are best tested for use
women, and some skeletal dysplasias can be identified when the in human patients remains the clinical trial.
ultrasonographic findings prompt suspicion.
Most inborn errors of metabolism are autosomal recessive dis-
orders and here it is first necessary to quantify the abundance of The future
maternal alleles or haplotypes in the fetus relative to the wild-​type
counterpart in the maternal DNA component. Relative dosages Astonishing progress has been made in the understanding, diag-
of maternal DNA and fetal in plasma have been used successfully nosis, and treatment of inborn errors of metabolism and it is clear
to predict transmission of sickle cell anaemia, ß-​thalassaemia and that the future holds immense promise for continued advancement
haemophilia-​care being taken to obtain sequence from fetal cfDNA and introduction of credible therapies for conditions that until re-
components to assemble the structure of the haplotype flanking cently were beyond hope—​either for clinical control, rescue, or
the putative mutant locus. At the time of writing, inborn errors even reversal. Prodigious research efforts to accelerate and perfect
such as congenital adrenal hyperplasia due to 21-​hydroxlase de- understanding of many rare inborn disorders are now bearing fruit.
ficiency and the X-​linked lysosomal disease, Hunter syndrome Molecular genetics, cell biology, and biochemistry have been pro-
(mucopolysaccharidosis type II), have been successfully diagnosed ductively collated into clinical practice as a result of a contemporary
by analysis of cfDNA in maternal plasma. explosion of knowledge about the genome, the associated lexicon of
1940 SECTION 12 Metabolic disorders

inherited disease, and the derived information about protein struc- also recently been approved for clinical use (transthyretin-​related
ture and function. amyloidosis and polyneuropathy).
For these reasons, it seems that the future highlights of this rare Other molecular therapies offering generalizable principles for
and formerly neglected clinical field will be dominated by spin-​out expanded application include the protein channel potentiator drugs
discoveries that ultimately relate to the study of DNA. for class III mutations of the cystic fibrosis transmembrane regulator
protein, CFTR. Mutation-​specific stratification of CFTR therapy
Genetic sequence data with the singe agent, ivacaftor, facilitates increased chloride trans-
Incremental improvements in the application of genomic sequen- port by potentiating the channel-​open probability (or gating) of the
cing will be used routinely to investigate infants and children with G551D-​CFTR variant protein.
undiagnosed conditions, especially those in whom a strong gen-
etic basis is suspected. Increasingly in private health facilities and Progress in access to orphan therapies
services available in resource-​rich societies, this technology will With a burgeoning interest in so-​called personalized medicine, in
be extended to older patients. Depending on the analytical strata- part driven by the pharmaceutical industry, beyond distinct cancer
gems chosen and whether whole-​exome or genomic sequencing is variants, inborn errors of metabolism are increasingly seen as the
adopted, even now some providers claim that disease-​causing muta- exemplary case for therapeutic exploration. The advantages of the
tions are identified in up to one-​third of patients. orphan drug legislation (including 7–​10 years of marketing exclu-
It is almost inevitable that economies of scale resulting from cen- sivity in the United States of America and Europe, respectively) pro-
tralized national provision, and refinements in the bioinformatic vide strong incentives for the development of innovative agents for
interrogation and hierarchical stratagems used to analyse the data, such rare diseases with identified genetic targets. On an individual
will enhance its value for earlier diagnosis, and (one hopes) better basis, many orphan agents are exceptionally costly for each patient
coordinated access to counselling and specialized care. With ex- and thus have attracted considerable political attention for reim-
perience and improved information about human genetic variation bursement. More challenging will be the commercial development
in different populations, greater clarity will emerge on the clinical of treatments involving one-​off interventions such as gene therapy,
value of this approach. because here the ‘cost models’ allowing credible investment by bio-
With introduction of large population-​scale studies such as the pharmaceutical organizations and shareholders have yet to be put
Biobank resource in the United Kingdom and the All of Us research in place. While there is not space here to discuss these matters (see
programme in the United States of America, data interpretation and ‘Further reading’), they will undoubtedly come to increasing polit-
family studies will become better aligned to the experience and prac- ical importance as new and effective medicines are introduced for
tices of local diagnostic teams. In many cases, the validated diag- inborn errors of metabolism and cognate rare disorders.
noses obtained by next-generation sequencing lift the health of the
patient and ultimately enhance clinical care with appropriate service
provision. Greater experience with these methods will overcome the FURTHER READING
numerous pitfalls of whole-​exome and whole genome sequencing, Accurso FJ, et al. (2010). Effect of VX-​770 in persons with cystic fibrosis
where overzealous betrayal of time-​honoured clinical principles can and the G551D-​CFTR mutation. N Engl J Med, 363, 1991–​2003.
lead to diagnostic errors and chaotic management. Careful clinical Alison MR, Islam S, Lim SM (2009). Cell therapy for liver disease. Curr
testing and the importance of phenotype-​guided molecular testing Opin Mol Ther, 11, 364–​74.
to drive diagnosis, together with confirmation of diagnosis by in- Altshuler D, Daly MJ, Lander ES (2008). Genetic mapping in human
dependent methods (e.g. biochemical analysis), should, with time, disease. Science, 322, 881–​8.
minimize these disturbing errors due to lack of experience and Auricchio A, Smith AJ, Ali RR (2017). The future looks brighter after
expertise. 25 years of retinal gene therapy. Hum Gene Ther, 28, 982–​7.
Bainbridge JWB, et al. (2008). Effect of gene therapy on visual function
Liquid biopsy and maternal plasma cfDNA sequencing will in-
in Leber’s congenital amaurosis. N Engl J Med, 358, 2231–​9.
creasingly translate to clinical care of genetic diseases. As the discov-
Barry PJ, Donaldson AL, Jones AM (2018). Ivacaftor for cystic fibrosis.
erers of this technology are aware, the application of more precise
BMJ, 361, 287–​9.
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need for invasive procedures will attract significant policy debate as Oxford University Press, Oxford.
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Specific therapies Biffi A (2017). Hematopoietic gene therapies for metabolic and neuro-
The benefit of specific therapies that target specific molecular defects logic diseases. Hematol Oncol Clin North Am, 31, 869–​81.
in which cause-​and-​effect pathogenesis has been established is an Buckley B (2008). Clinical trials of orphan medicines. Lancet, 371,
area of intense aspiration and, now, productive endeavour for fu- 2051–​5.
ture application. The interventions already include augmenting gene Cartier N, et al. (2009). Haemopoietic stem cell therapy with a lentiviral
therapies (e.g. recombinant adeno-​associated viral vectors systems vector in X-​linked leukodystrophy. Science, 326, 818–​23.
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12.2
Protein-​dependent inborn errors
of metabolism
Georg F. Hoffmann and Stefan Kölker

ESSENTIALS are initially asymptomatic. The onset of the first symptoms is varied,
ranging from neonatal metabolic decompensation to onset of symp-
Protein-​dependent inborn errors of metabolism are caused by in- toms during adulthood. Irreversible organ damage and/​or early
herited enzyme defects of catabolic pathways or intracellular trans- death often follow if the diagnosis is delayed or missed. Metabolic
port of amino acids. Most result in an accumulation of metabolites decompensations in childhood are triggered by excess intake of pro-
upstream of the defective enzyme (amino acids and/​or ammonia), tein and—​most importantly—​secondary to breakdown of body pro-
causing intoxication. tein during episodes that induce catabolism.
Protein-​dependent metabolic diseases usually have a low preva- Family history—​if carefully taken, this may reveal important clues to
lence except for some high-​risk communities with high consan- the diagnosis of protein-​dependent inborn metabolic errors. Most
guinity rates. However, the cumulative prevalence of these disorders disorders are inherited as autosomal recessive traits, which may
is considerable (i.e. at least >1:2000 newborns) and represents an be suspected if the parents are consanguineous or the family has
important challenge for all public health systems. a confined ethnic or geographic background. Carriers for particular
Types of protein-​dependent inborn errors of metabolism disorders and affected children may be more frequent in certain
Amino acid disorders—​enzyme deficiencies in the proximal part of communities (e.g. Amish), ethnic groups (e.g. Ashkenazi Jews, Arabic
amino acid catabolism result in accumulation of precursor amino tribes), or countries that have seen little immigration over many cen-
acids which are detectable by ninhydrin (a chemical used to detect turies (e.g. Finland). Specialist investigations are often started only
ammonia or primary and secondary amines) and thus are called after a second affected child is born into a family: older siblings may
amino acid disorders. Phenylketonuria (PKU) is the most frequent be found to suffer from a similar disorder as the index patient or have
such condition in white people. died from an acute unexplained disease.
Organic acid disorders—​distal enzyme defects of amino acid deg- Disease spectrum—​this is broad, but follows a distinct pattern in
radation result in pathological accumulation of organic acids but not specific disorders, for instance: (1) untreated patients with classical
the precursor amino acid. These disorders became detectable after PKU and cerebral organic acid disorders characteristically present
the introduction of gas chromatography–​mass spectrometry and are with neurological symptoms. (2) Acute life-​threatening decompen-
called organic acid disorders. sation is common in classical organic acid, urea cycle defects, and
Urea cycle defects—​breakdown of amino acids results in the re- maple syrup urine disorder; the young infant vomits or refuses to feed
lease of ammonia that is detoxified by the urea cycle, which is com- and then deteriorates rapidly. (3) Asymptomatic protein-​dependent
posed of five catalytic enzymes, a cofactor producer, and at least two inborn metabolic errors are rare, but there are a few known enzyme
transport proteins. The biochemical hallmark of urea cycle defects is defects, such as histidinaemia, which do not produce disease.
hyperammonaemia. Investigation and management
Understanding of the protein-​dependent inborn errors is based
Every infant presenting with symptoms of unexplained metabolic
on the observation that some pathological metabolites impair key
crisis, intoxication, or encephalopathy requires urgent evaluation
intracellular functions, such as energy metabolism, and thus when
of metabolic parameters, including analyses of arterial blood gases,
elevated may become toxic. These metabolites are excreted by urine
serum glucose and lactate, plasma ammonia and amino acids,
or following conjugation to L-​carnitine or L-​glycine. However, in
acylcarnitine profiling in dried blood spots, and organic acid analysis
some diseases, such as disorders of tetrahydrobiopterin metabolism,
in urine.
clinical symptoms result from inadequate production of essential
Acute emergency therapy—​basic principles are to (1) suppress
metabolites, such as the monoaminergic neurotransmitters.
muscle and liver protein catabolism and ensure a glucose supply
Clinical presentation above the basal metabolic demand; (2) treat any precipitating illness;
Children with inherited disorders of amino acid, organic acid, or the (3) reduce increased production of toxic metabolites by reduction
urea cycle are usually born at term after an uneventful pregnancy and or omission of natural protein; (4) enhance detoxifying mechanisms
 12.2 Protein-dependent inborn errors of metabolism 1943

of the latter phases of amino acid degradation induce accumulation

and urinary excretion of pathological metabolites; (5) aggressively
of organic acids but not amino acid precursors, these disorders be-
treat dehydration and acidosis; (6) prevent secondary carnitine de-
came detectable after the introduction of gas chromatography, es-
pletion; and (7) provide alternative routes of ammonia disposal in
pecially gas chromatography–​mass spectrometry (GC/​MS) in the
hyperammonaemia.
1960s and 1970s and have been termed organic acid disorders. Thus
Long-​term treatment—​this aims principally to mitigate the meta-
the terminology amino acid and organic acid disorders is not based
bolic consequences of enzyme deficiencies by compensating for
on pathophysiological differences but simply on the different analyt-
them, including: (1) reduction of toxic metabolites by dietary restric-
ical approaches.
tion of precursor amino acids, prevention of catabolism, stimulation
In this chapter, amino acid disorders, urea cycle defects, and or-
of residual enzyme activity (e.g. with cofactors), and detoxification
ganic acid disorders are described; defects in mitochondrial me-
strategies; and (2) substitution with depleted substrates, such as
tabolism and amino acid transport in the kidney tubule and small
biotin, cobalamin, or L-​dopa. However, efficacy is often low in pa-
intestine are not considered.
tients in whom diagnosis is made after the onset of symptoms, hence
newborn screening programmes have been introduced in many
countries, the criteria for implementation of which include: (1) reli-
Historical perspective
able presymptomatic disease detection, (2) treatability of the disease,
and (3) starting of treatment in presymptomatic children.
In 1902, Archibald Garrod introduced the term ‘inborn errors of
Successful treatment of affected individuals is often difficult to
metabolism’. An extraordinary scientist and paediatrician, he used
achieve. Careful supervision in metabolic centres involving an ex-
consanguinity and distribution of cases in families to introduce
perienced multidisciplinary team is invaluable for the best outcome.
the hypothesis that autosomal recessive inheritance according to
Treatment is time-​and cost-​intensive, often lifelong, and mostly per-
Mendel’s rediscovered laws would explain the occurrence of the
formed at home, hence regular training and support of patients and
alkaptonuria phenotype, a defect in tyrosine degradation. Soon
their families is essential to prevent irreversible complications. All
afterwards he also recognized albinism, cystinuria, and pentosuria
patients should carry an emergency card that gives details of their
as inborn errors.
condition and relevant contact numbers. Parent and patient organ-
Metabolic medicine is closely linked with advances in laboratory
izations can offer useful support.
techniques. The use of paper chromatography by Bickel and Dent
Detailed description of individual disorders is to be found in the
and of automated column chromatography by Moore and Stein
text of this chapter, and further information on diagnosis, genetic
opened the field of amino acid disorders. In the late 1960s, Tanaka
testing, treatment and follow-​up is available from several online
discovered isovaleric aciduria by GC/​MS, and this was followed
databases (see ‘Further reading’).
by the identification of numerous organic acid disorders. More re-
cently, the rise of molecular biology has revolutionized the field, and
now tandem mass spectroscopy and next-​generation sequencing
Introduction are proving powerful tools in screening and diagnosis. Monogenic
defects have been identified for almost every known enzymatic
Humans depend on dietary protein as a source of amino acids; they step of protein metabolism. Often it was the discovery of patients
are the metabolic basis of all functional and structural proteins in the with enzyme defects which unravelled individual steps in human
body. Some amino acids—​termed essential—​cannot be synthesized metabolism.
by the human body, such l-​isoleucine and l-​phenylalanine. Renal Until the early 1950s, no treatment of any genetic disorder ex-
conservation of amino acids is extremely effective, with clearance isted; destiny would take its course, and genetic counselling about
values mostly less than 1%. Stool nitrogen losses are about 1 g/​day recurrence risks was all that could be offered. That changed when,
and are mostly of bacterial origin. in 1953, Bickel showed that PKU can be successfully treated and
In contrast to glucose and fatty acids, amino acids taken in excess that early diagnosis and dietary treatment change the outcome
of requirement cannot be stored but are used for energy. The initial from severe learning difficulties to normal psychosocial develop-
step of degradation is the removal of the amino group. Ammonia ment. Subsequently, many other metabolic diseases became man-
enters the urea cycle for conversion to urea. The remaining carbon ageable in a similar way using the substrate deprivation strategy.
skeletons are degraded via multistep individual pathways to central Pharmacological doses of vitamins proved useful in defects of
metabolic intermediates such as acetyl coenzyme A (CoA) or tricarb- cobalamin and biotin metabolism, homocystinuria, and others.
oxylic acid cycle intermediates. Some enzymes require coenzymes, Simultaneously with the perception that identification of chil-
and inherited disease may be due to defects of the apoenzymes or dren before the onset of clinical symptoms is indispensable to im-
their vitamin coenzymes, for example, biotin, pyridoxine (vitamin prove the outcome, reliable and cheap screening methods have
B6), or cobalamin (vitamin B12). been developed. In the United States of America, Guthrie set the
Amino acids can be specifically detected by the ninhydrin re- cornerstone for newborn screening by developing a bacterial in-
action, which became available in the late 1940s, resulting in the hibition assay to detect PKU. Despite early disagreement and re-
identification of disorders such as phenylketonuria (PKU) or maple sistance by the medical profession, newborn screening has proven
syrup urine disease. Breakdown of many amino acids occurs mostly its worth over the years and the test is still called the ‘Guthrie test’
intramitochondrially through degradation of CoA-​activated car- worldwide.
bonic acids, the so-​called acyl-​CoA compounds. These nonamino In 1999, the World Health Organization announced orphan dis-
organic acids are not detectable by amino acid analysis. Since defects eases as a major future health challenge. Among these diseases,
1944 SECTION 12 Metabolic disorders

disorders of amino acid and organic acid metabolism are especially

Prevention
important because of their cumulative prevalence (>1:2000 new-
borns) and because successful therapy is available for most of them.
With the first successful treatment of a young girl with PKU, the
Inborn metabolic diseases have become a significant challenge for
need for timely diagnosis and implementation of treatment became
healthcare systems, particularly in countries where infectious dis-
imperative. In most inborn errors, affected neonates are completely
eases and other perinatal problems are receding in importance.
asymptomatic and onset of irreversible symptoms during infancy
and childhood can often be prevented if treatment is started while
the child is asymptomatic. Since inborn errors of metabolism are
Aetiology, genetics, pathogenesis, and pathology rare, only neonatal mass screening can guarantee timely detection.
However, which diseases are the most appropriate for screening re-
The clinical manifestations of most protein-​ dependent inborn
mains debatable. The criteria of Wilson and Jungner (1968) for an
errors are thought to result from toxicity of the accumulating key
implementation to newborn screening include: (1) reliable disease
metabolites to specific organs inducing selective or multiple organ
detection in a presymptomatic state of the disease, (2) treatability of
failure. This ‘toxic metabolite hypothesis’ has influenced research
the disease, and (3) the start of treatment in the presymptomatic chil-
and allowed the development of effective treatment.
dren. In the 1960s, these criteria were achieved for PKU screening,
Despite increasing knowledge of pathophysiology, the most rele-
which developed into one of the most important programmes of
vant concepts are derived from clinical research. For example, de-
preventive medicine. Additional inborn errors such as maple syrup
fects of all six enzymes in the degradation pathway of phenylalanine
urine disease, galactosaemia, congenital hypothyroidism, and
and tyrosine are known by now (see also ‘Defects of phenylalanine
biotinidase deficiency were incorporated into newborn screening
and tyrosine metabolism’). Defects in the first enzyme, phenyl-
programmes of some countries.
alanine hydroxylase, cause PKU (learning difficulties, seizures,
In the 1990s, a revolutionary technology, tandem mass spectros-
ataxia, paresis, behavioural problems) and deficiency of tyrosine
copy (MS/​MS), was adopted for newborn screening. The possi-
aminotransferase, the next enzyme, induces tyrosinaemia type II
bilities of multianalyte detection by MS/​MS led to a change in the
(corneal erosions, painful hyperkeratotic lesions, behavioural prob-
screening paradigm, that is, one test for many diseases (instead of
lems). A defect of 4-​hydroxyphenylpyruvate dioxygenase is the
one test for one disease). MS/​MS improved screening for diseases
cause of tyrosinaemia type III which is possibly a nondisease, only
from the conventional screening panels and opened the chance for
a few patients develop neurological manifestations. A block in the
inclusion of many other inborn errors of metabolism. However,
next step of the pathway, 4-​hydroxyphenylpyruvate dioxygenase,
each novel candidate disease has to be evaluated with respect to
results in alkaptonuria (ochronosis, arthritis, heart disease),
whether this disease fulfils the criteria for a disease to be screened
whereas deficiency of the last enzyme, fumarylacetoacetase, pro-
(see Chapters 2.12 and 12.1), taking into consideration differences
duces a disease deadly in early childhood, tyrosinaemia type I,
in national healthcare systems. As a consequence, the number of
presenting with failure to thrive, liver failure, hepatosplenomegaly,
screened inborn errors of metabolism varies considerably ranging
hepatocarcinoma, and porphyria-​like crises. The distinct syndromes
from two disorders (United Kingdom, Switzerland) up to more than
resulting from defective breakdown of aromatic amino acids could
50 disorders (some parts of the United States of America). Notably,
never have been inferred simply by biochemical exploration of the
the United States screening panel also includes conditions that can
metabolic pathway.
be regarded as nondiseases or have at least a doubtful pathological
meaning, such as the 3-​methylcrotonyl CoA carboxylase deficiency.
It should be appreciated that a liberal expansion of the screening
Epidemiology panel burdens the healthcare system, the affected individuals, and
the increasing number of false-​positive individuals and their fam-
As a group, protein-​ dependent disorders are by far the most ilies. Given these difficulties, it is to be hoped that screening politics
common, acutely life-​threatening inborn errors of metabolism (esti- will become harmonized in a joint international effort.
mated prevalence >1:2000 newborns). However, reliable epidemio-
logical data are scarce as all reports suggest a significant portion of
patients who evade diagnosis and are considered to have neonatal
sepsis or sudden infant death syndrome. All disorders cannot be re- Clinical considerations and diagnostic work-​up
liably ascertained clinically, and until recently population neonatal
screening has only been implemented for PKU. Most epidemio- History
logical data are available from European countries, Japan, and the A careful family history may reveal important clues to the diagnosis
United States of America, highlighting variations based on ethnic of protein-​dependent inborn metabolic diseases. Most disorders are
background, migrations, and/​or genetic isolation. In a few com- inherited as autosomal recessive traits which may be suspected if
munities, the prevalence of individual disorders may increase up the parents are consanguineous or the family has a confined ethnic
to five times the cumulative prevalence of amino acid and organic or geographic background. Carriers for particular disorders and
acid disorders in European countries, Japan, and the United States of affected children may be more frequent in certain communities
America. For example, glutaric aciduria type I is found in up to 1 in (e.g. Amish), ethnic groups (e.g. Ashkenazi Jews, Arabic tribes),
300 newborns in the Amish Community (United States of America) or countries that have seen little immigration over many centuries
and the Oji-​Cree First Nations (Canada), and in Qatar the preva- (e.g. Finland). Often specialist investigations are started only after
lence of classic homocystinuria is 1 in 600 newborns. a second affected child is born into a family. Older siblings may be
 12.2 Protein-dependent inborn errors of metabolism 1945

found to have a similar disorder to the index patient, or to have died Box 12.2.2 Clinical chemical indices of organic acidurias
from an acute unexplained disease classified as ‘sepsis with uniden-
tified pathogen’, ‘encephalopathy’, or ‘sudden infant death syndrome’. • Metabolic acidosis
• Increased anion gap
Notably, the disease course of the same disorder may vary consid-
• Hyperglycaemia
erably even within families depending on genotype–​phenotype
• Ketosis and ketonuria (especially suggestive in newborns)
correlation (if any), varying X-​inactivation in female carriers (e.g.
• Lactic acidosis
ornithine transcarbamylase deficiency), and dominant disorders • Hyperammonaemia
with variable penetration (e.g. Segawa’s disease). • Hyperuricaemia
As a result of the successful treatment of inborn errors of metab- • Hypertriglyceridaemia
olism, an increasing number of affected women are reaching repro- • Increase of transaminases
ductive age. If they become pregnant, there may be a risk for their • Granulocytopenia, thrombocytopenia, and anaemia
fetuses to be harmed by toxic metabolites from the mother. Especially • Hypoketotic hypoglycaemia (fatty acid oxidation defects)
important is maternal PKU, which is likely to become a major health • Increased creatine kinase (fatty acid oxidation defects)
problem. Other maternal conditions may cause ‘metabolic’ disease • Myoglobinuria (fatty acid oxidation defects)
in the neonate or infant postnatally, for example, methylmalonic
aciduria and hyperhomocystinaemia, in fully breastfed children of
mothers who have pernicious anaemia or who are on a vegan diet, number of therapeutic measures. Timely and correct intervention
which fosters nutritional vitamin B12 deficiency. during the initial episode is a critical prognostic factor.
Many protein-​dependent metabolic errors already manifest in
Clinical spectrum the first days of life with progressive irritability or drowsiness. Most
The range of clinical and biochemical manifestations of the protein-​ typically, a young infant may vomit or refuse to feed and then rap-
dependent metabolic errors is wide. Here we focus on the clinical idly deteriorates. The initial erroneous diagnoses are usually neo-
manifestation and differential diagnosis of disorders presenting natal sepsis or intracranial haemorrhage: a presumptive diagnosis of
with acute metabolic decompensations (Boxes 12.2.1 and 12.2.2). a protein-​dependent inborn error should be considered with equal
There is only a limited repertoire of pathophysiological sequences in priority. Children with milder forms may be repeatedly admitted,
the response to metabolic intoxication and, consequently, a limited for example, with unusual metabolic acidosis, hypoglycaemia, or
neutropenia in the course of common infections especially gastro-
enteritis, before an inborn disorder of metabolism is considered, and
Box 12.2.1 Presentation of organic acidurias routine clinical chemistry may be normal in between crises.
Intoxication A substantial number of patients with protein-​dependent inborn
• Kussmaul tachypnoea/​acidotic breathing errors of metabolism may present differently with acute encephalop-
• Peculiar smell athy or chronic and fluctuating progressive neurological disease. The
• Refusal of/​adverse reaction to feeding so-​called cerebral organic acidaemias (e.g. glutaric aciduria type I)
• Protracted episodic vomiting characteristically present with (progressive) neurological symptoms
• Erroneous diagnosis of pyloric stenosis (with acidosis) such as ataxia, myoclonus, extrapyramidal symptoms, and metabolic
• Reye’s syndrome presentation stroke. Routine clinical chemistry is often unrevealing. Important diag-
• Hepatomegaly/​liver failure nostic clues such as progressive disturbances of myelination, cere-
• Rhabdomyolysis bellar atrophy, frontotemporal atrophy, signal abnormalities, and/​or
• Sudden infant death syndrome (SIDS) or ‘near miss’ SIDS infarcts of the basal ganglia can be derived from MRI of the brain.
Acute encephalopathy Chronic subdural effusions, haematomas, and retinal haemorrhages
• Coma in infants and toddlers are characteristic findings in glutaric aciduria
• Seizures (myoclonic, intractable) type I, although they are more commonly due to child abuse.
• Acute profound dyskinesia
• Pseudotumour cerebri Laboratory investigations
• Cerebral/​intraventricular haemorrhage in full-​term babies The early consideration of metabolic diseases is of the utmost im-
• Stroke-​like episodes portance. Basic evaluation of metabolic parameters including ana-
Chronic encephalo(myelo)pathy lyses of blood gases, serum glucose and lactate, plasma ammonia and
• Progressive psychomotor deterioration amino acids, acylcarnitine profiling in dried blood spots (MS/​MS),
• Macrocephaly and organic acid analysis in urine (GC/​MS) should be performed on
• Ataxia (progressive) an emergency basis in every patient presenting with symptoms of
• Hypotonia unexplained metabolic crisis, intoxication, or encephalopathy.
• Dystonia, athetosis
• Myoclonus Routine laboratory parameters
• Seizures (myoclonic, intractable) Diagnostic clues can be obtained from routine laboratory inves-
• Peripheral neuropathy
tigations such as electrolytes (also required for the calculation of
• Pyramidal signs—​‘cerebral palsy’
the anion gap), urinary ketones, serum transaminases, and cre-
• Pronounced deficiency of speech
• Congenital cerebral malformations
atine kinase. Any child admitted to an intensive care unit with life-​
threatening nonsurgical illness should be tested for these parameters.
1946 SECTION 12 Metabolic disorders

Box 12.2.3 Some pitfalls of amino acid analysis Principles of treatment

• Shipping/​storage without adequate cooling: ↓ glutamine, asparagine,
cysteine, homocysteine; ↑ glutamate, aspartate General aspects
• Haemolysis: ↓ arginine, glutamine; ↑ aspartate, glutamate, glycine, Protein-​dependent metabolic disorders are chronic conditions that
ornithine
involve various organ systems and thus require a multidisciplinary
• Postprandial changes: all amino acids
approach to care and treatment. Patients with genetic diseases that
are prone to acute decompensations should carry an emergency card.
Amino acid analysis Vaccinations should be carried out as recommended and should also
include vaccinations against varicella, hepatitis A, pneumococcus,
Many metabolic parameters show considerable diurnal fluctu-
and influenza. Special precautions must be taken before, during, and
ations. For example, plasma amino acid concentrations are highly
after surgery/​anaesthesia.
dependent on the metabolic status, and standard samples should
be obtained at least 4 h postprandially. Many amino acids can be Dietary treatment
reliably quantified in dried blood spots by MS/​MS (e.g. for PKU).
In many protein-​dependent errors of metabolism, therapy is based
Homocysteine and tryptophan require specific methods (usu-
on reduced intake of precursors in deficient pathways, prevention
ally high-​performance liquid chromatography (HPLC)) for exact
of catabolism, and an intensification of therapy during intercurrent
quantification. Regular amino acid analyses are required in pa-
illnesses. This aims to diminish the supply of toxic metabolites and
tients on specific dietary treatments to adjust intake of amino
restore energy supply. Dietary treatment must meet the general, age-​
acids and to recognize a deficiency of essential amino acids and
dependent, and individual requirements for energy and essential
micronutrients. For optimal results, it is important to separate
nutrients to ensure normal growth and development (Table 12.2.1).
plasma as soon as possible and to ship samples frozen on dry ice.
Protein deficiency induces catabolism, failure to thrive, and growth
Haemolysis or shipment of whole blood results in useless values
retardation, and secondary depletion of essential amino acids and
for some amino acids. Some potential problems are summarized
micronutrients may induce life-​threatening complications such as
in Box 12.2.3.
lactic acidosis (thiamine or biotin depletion) or pellagra (niacin
Quantitative urinary amino acid analysis is indicated only
depletion). Supplementation of precursor-​free mixtures of amino
if a renal tubular reabsorption defect such as cystinuria is sus-
acids and semisynthetic supplements of minerals and trace elements
pected, and (in addition to plasma analysis) in hyperammonaemia
minimizes the risk for malnutrition.
when increased urinary excretion of specific metabolites (e.g.
argininosuccinate) may be diagnostic. Pharmacotherapy
Organic acid analysis Carnitine at daily doses of 50–​200 mg/​kg body weight is essential for
the elimination of accumulating toxic acyl-​CoA compounds and for
Organic acid analysis is best performed on early morning urine
the restoration of intramitochondrial free CoA-​SH in most organic
specimens. Complete information of the clinical status and recent
acid disorders. In cofactor-​responsive disorders, enzyme activity
management of the patient is indispensable for correct interpret-
may be restored by specific vitamins, for example, in biotinidase
ation, which is based on key diagnostic metabolites or character-
deficiency, cobalamin-​ responsive methylmalonic acidurias, and
istic biochemical patterns. Repeated analyses may be necessary,
riboflavin-​responsive multiple acyl-​CoA dehydrogenase deficiency.
preferably during exacerbation of metabolic decompensation,
since analyses may be intermittently normal. Characteristic me-
tabolites may, however, also become masked in severe metabolic Table 12.2.1 Protein requirements
decompensation and ketosis. Some patients with organic acid dis-
orders may exhibit only slight elevations of diagnostic metabol- Age Revised safe values (g/​kg per day)
ites that may be underestimated by conventional analysis, such 0–​1 months 2.69
as in 4-​hydroxybutyric aciduria, glutaric aciduria type I, and 1–​2 months 2.04
N-​acetylaspartic aciduria. In these disorders, quantification by
2–​3 months 1.53
stable isotope dilution assays is preferred. This is also the method
of choice for biochemical prenatal diagnosis of organic acid dis- 3–​4 months 1.37
orders in amniotic fluid, if the causative mutations are not avail- 4–​5 months 1.25
able, providing more rapid diagnosis than enzyme analysis of 5–​6 months 1.19
cultured amniocytes. 6–​9 months 1.09

Acylcarnitine analysis 9–​12 months 1.02

1–​3 years 1.0–​0.92
A complementary and rapid diagnostic technique for some or-
ganic acid disorders is the analysis of acylcarnitine by MS/​ 4–​10 years 0.88–​0.86
MS—​by analogy to newborn mass screening—​since accumu- 11–​18 years 0.86–​0.77
lating acyl-​C oA esters are in equilibrium with corresponding Source data from Dewey KG, et al. (1996). Protein requirements of infants and children.
acylcarnitines. Eur J Clin Nutr, 50 Suppl 1, S119–​47.
 12.2 Protein-dependent inborn errors of metabolism 1947

The accumulation of toxic metabolites derived from gut bacteria, Box 12.2.4 Basic principles for acute emergency therapy
such as propionic acid, can be reduced by intestinal antibiotics
(e.g. metronidazole). 1 Suppress muscle and liver protein catabolism and ensure a glucose
supply above the basal metabolic demand
2 Treat the precipitating illness
3 Reduce increased production of toxic metabolites by reduction or
Emergency treatment omission of natural protein
4 Enhance detoxifying mechanisms and urinary excretion of patho-
Treatment of intercurrent illness at home logical metabolites
5 Aggressively treat dehydration and acidosis
Protein-​dependent inborn errors of metabolism often present with
6 Prevent secondary carnitine depletion
acute life-​threatening decompensation requiring prompt decisions
7 Provide alternative routes of ammonia disposal in hyperammonaemia
and measures. A limited number of therapeutic measures have to be
taken immediately (Box 12.2.4, Table 12.2.2).
It is imperative to decrease catabolism at an early stage of de-
adequate energy supply. For example, in neonates glucose infusion
compensation. As this usually happens at home, it is essential
is usually started at 10 mg/​kg per min (i.e. 14.4 g glucose/​kg body
to educate the family adequately. Home treatment should in-
weight per day). An insulin drip may be necessary to prevent hyper-
clude adequate control of fever and vomiting, moderate protein
glycaemia and to induce an anabolic state. Overhydration is rarely
restriction, and ample calories, glucose, and fluid (Box 12.2.4).
a problem in metabolic crises as they are mostly accompanied by
Intake of natural protein can be completely eliminated for the
dehydration. Electrolytes, glucose, lactate, and acid–​base balance
first 24 h of illness, especially if the patient receives precursor-​
should be checked at least every 6 h and serum sodium should be
free supplements of amino acids. After 24 h, stepwise reintroduc-
maintained at no less than 138 mmol/​litre. If lactate is constantly
tion of natural protein is necessary to prevent protein catabolism.
increasing while the glucose supply is increasing, one should con-
Immediate hospital admission and intravenous treatment is in-
sider a primary defect or secondary inhibition or energy metab-
dicated when vomiting persists, fluid and dextrose intake remain
olism, such as in classic organic acid disorders. Antibiotics should
poor, the clinical condition deteriorates, or the disease course is
be started if there is evidence for an infectious cause. Antipyretics
prolonged. On admission to hospital, these patients must be as-
should be administered liberally since they help to reduce the add-
sessed and treated without delay. If emergency management is
itional bioenergetic costs of fever.
carried out in peripheral hospitals, this should ideally be super-
Carnitine is essential for the elimination of toxic acyl-​CoA es-
vised in consultation with a knowledgeable and experienced
ters in organic acidaemias, to prevent secondary carnitine deple-
physician or paediatrician.
tion, and to replenish the intracellular CoA pool. Carnitine should
Emergency treatment in hospital be administered intravenously at 100 to 200 mg/​kg per day. In
hyperammonaemia, nitrogen-​disposing drugs are used:
Provision of ample quantities and control of fluid and electrolytes is
indispensable and must be continued before any laboratory results • Sodium benzoate, 250 mg/​kg as bolus initially over 1 to 2 h, then
are available. Glucose infusions must be adapted to age to provide an 250 (to 500) mg/​kg per 24 h.

Table 12.2.2 Home and outpatient emergency treatment

Age (years) % kcal/​100 ml Daily amount

A. Glucose polymer/​maltodextrin solutiona
0–​1 10 40 150–​200 ml/​kg
1–​2 15 60 95 ml/​kg
2–​10 20 80 1200–​2000 ml/​day
>10 25 100 2000 ml/​day
B. Protein intake
Natural protein Stop (if amino acid supplements are administered) or reduce to 50% of maintenance therapy (if no amino acid supplements are
administered). Reintroduce and increase within 1–​2 days
Amino acid mixtures If tolerated, amino acid supplements should be administered according to maintenance therapy, e.g. 0.8–​1.0 g/​kg body weight/​dayb
C. Pharmacotherapy
l-​Carnitine Double carnitine intake: 200 mg/​kg body weight/​day orally (if tolerated)
Antipyreticsc If temperature >38.5°C, e.g. ibuprofen (10–​15 mg/​kg body weight per dose, 3–​4 doses daily)
a
Maltodextran/​dextrose solutions should be administered every 2 h day and night. If neonates and infants already receive a specific dietary treatment, protein-​free food can be
continued but should be fortified by maltodextran. Patients should be reassessed every 2 h.
b
All calculations should be based on the expected weight, not the actual weight.
c
Paracetamol administration may be dangerous in acute metabolic decompensation (risk for glutathione depletion).
1948 SECTION 12 Metabolic disorders

• Sodium phenylacetate, 250 mg/​kg as bolus initially over 1 to Box 12.2.5 New treatment strategies in inborn errors
2 h, then 250 (to 600) mg/​ kg per 24 h; alternatively, sodium of metabolism
phenylbutyrate is administered at the same concentration orally.
• Supplementation with end products
• Arginine hydrochloride, 420 mg/​kg (i.e. 2 mmol/​kg) as bolus ini- • Anaplerotic therapy
tially over 1 to 2 h, then 420 mg/​kg per 24 h. • Enzyme replacement
If the response to emergency treatment is poor, the patient de- • Chemical chaperones
teriorates, or the ammonia concentration exceeds 400 to 500 µmol/​ • Specific blockade of biosynthetic pathways
• Specific blockade of degradation pathways
litre (neonate, infant), haemofiltration or haemodialysis should be
• Specific blockade of pathophysiological signalling
urgently considered. Since intracranial pressure due to cerebral oe-
• (Stem) cell therapy
dema appears earlier in older children, adolescents, and adults than
• Gene therapy
in newborns, infants, and younger children, extracorporeal detoxi-
fication should be considered if ammonia concentration exceeds
200 µmol/​litre or even as first-​line treatment. If persisting lactic acid-
osis is present, thiamine (100–​500 mg/​day) and biotin (10–​20 mg) variation in outcome. Even for PKU, the disease with the greatest
should be given empirically. and longest experience in successful therapy, current guidelines
recommend different cut-​offs for the indication of treatment ran-
ging from 400 µmol/​litre in the United Kingdom to 360 µmol/​litre
Monitoring of treatment in the United States of America and 600 µmol/​litre in France and
Germany. The knowledge of the academic community must be
Dietary treatment without adequate monitoring is dangerous since combined and structured, transferred to the physicians and other
disease-​specific complications, therapy-​specific adverse events (e.g. medical staff, and implemented in healthcare systems. Nowadays,
malnutrition), and developmental delay might be overlooked. this process has become much easier by means of numerous re-
Anthropometric parameters such as weight, height, and head cir- commendations, information, and even projects available on the
cumference should be recorded at each visit. Psychomotor devel- Internet, permanent professional email round tables, Internet
opment must be regularly assessed with appropriate tests. Weight editions of book and journals, and open-​access databases. In the
loss or insufficient weight gain in affected children is often caused by necessary implementation process, regional differences such as
inadequate dietary treatment and may herald impending metabolic availability of funds, local pathology, and religious and geographic
decompensation. factors must be taken into account. Accordingly, specialized na-
The major aim of biochemical monitoring is to ensure that nu- tional metabolic centres and appropriate metabolic networks
trition is not compromised. Biochemical evaluation includes blood should be established and properly maintained. Unfortunately,
count, serum electrolytes, calcium, phosphate, magnesium, ferritin novel diagnostic and therapeutic possibilities (Box 12.2.5), such as
level, liver and kidney function tests, alkaline phosphatase, total newborn screening or enzyme replacement therapy, are relatively
protein, albumin, prealbumin, transferrin, cholesterol, triglycer- expensive and are still unrealistic for many countries where there
ides, zinc, copper, retinol (plasma), carnitine, ammonia, lactate, are no screening programmes and perhaps no well-​organized
and plasma amino acids. Although analyses of specific metabolic healthcare system.
parameters are required to confirm the diagnosis of an inborn error
of metabolism, these parameters are often not informative for bio-
chemical follow-​up monitoring since the relationship between the Individual disorders
metabolic parameters and outcome is unclear for most disorders.
However, regular monitoring of some metabolic parameters is ne- A summary of protein-​dependent inborn errors of metabolism
cessary since they are directly related to the outcome. For example, including the enzyme defect, incidence, gene locus, and
plasma phenylalanine is monitored in PKU, plasma leucine in Online Mendelian Inheritance in Man (OMIM) number is given
maple sugar urine disease, plasma glutamine and arginine in urea in Table 12.2.3.
cycle defects, and plasma homocysteine in trans-​sulphuration and Urea cycle defects
remethylation defects.
Aetiology/​pathophysiology
The major source of ammonia is catabolism of protein, which is
Likely future developments detoxified to urea in the liver (Fig. 12.2.1). The efficiency of hep-
atic ammonia detoxification is enhanced through the action of glu-
The scientific and technological advances described in the previous tamine synthase. Hyperammonaemia (plasma ammonia >80 µmol/​
sections have offered much benefit to patients with inborn errors litre in newborns; >50 µmol/​litre after the newborn period) is caused
of metabolism. To implement and utilize them properly, much by increased production (e.g. by intestinal urease-​producing bac-
remains to be done. Initially, metabolic physicians and scientists teria) or decreased detoxification of ammonia. Decreased detoxifi-
need to combine their efforts and concentrate on well-​conducted cation results from inherited or acquired deficiency of key enzymes
international studies and development of evidence-​based guide- and transporters of the urea cycle, or bypassing of the liver (e.g. open
lines. Significant differences still exist in the diagnostic procedures, hepatic duct). Secondary impairment of ammonia detoxification re-
treatment, and monitoring of many diseases, resulting in a wide sults from conditions where glutamate or acetyl-​CoA are decreased,
Table 12.2.3 Summary of protein-​dependent inborn errors of metabolism

Disease Enzyme defect Incidencea Gene map locus Gene name OMIM (phenotype
number)
Defects of the urea cycle
Argininaemia Arginase 1 1:100 000 6q23 ARG1 207800
Argininosuccinic aciduria Argininosuccinate lyase 1:50 000 7cen–​q11.2 ASS1 207900
Citrullinaemia type I Argininosuccinate synthetase 1 1:50 000 9q34 ASL 215700
Deficiency of Citrin <1:200 000 7q21.3 SLC25A13 605814 (neonatal onset)
603471 (adult onset)
Deficiency of N-​Acetylglutamate synthase <1:200 000 17q21.3 NAGS 237310
Deficiency of Carbamoylphosphate synthetase 1 1:50 000 2q35 CPS1 237300
Deficiency of Ornithine carbamoyltransferase 1:30 000 Xp21.1 OTC 311250
Dibasic amino aciduria II, lysinuric protein <1:200 000 14q11.2 SLC7A7 222700
intolerance
Hyperornithinaemia–​hyperammonaemia–​ Ornithine transporter <1:200 000 13q14 SLC25A15 238970
homocitrullinuria syndrome
Carbonic anhydrase VA deficiency Mitochondrial carbonic anhydrase VA Unknown 16q24.2 CA5A 114761
Defects of branched-​chain amino acid metabolism
Isovaleric aciduria Isovaleryl-​CoA dehydrogenase 1:80 000 15q14–​q15 IVD 243500
Maple syrup urine disease Branched-​chain keto acid dehydrogenase 1:200 000 248600
(lipoamide)
Type Ia E1 component α-​chain 19q13.1–​q13.2 BCKDHA
Type Ib component β-​chain 6p21–​p22 BCKDHB
Type II dihydrolipoamide branched-​chain 1p31 DBT
transacylase (E2 component)
3-​Methylcrotonylglycinuria 3-​Methylcrotonyl-​CoA carboxylase 1:60 000 210200
α-​subunit 3q25–​q27 MCCC1
β-​subunit 5q12–​q13 MCCC2
3-​Methylglutaconyl-​CoA hydratase deficiency 3-​Methylglutaconyl-​CoA hydratase <1:200 000 9q22.31 AUH 250950
(3-​methylcrotonyl aciduria type I)
TAZ defect or Barth syndrome (3-​methylglutaconic Tafazzin <1:200 000 Xq28 TAZ 302060
aciduria type II)
OPA3 defect or Costeff’s syndrome OPA3A and OPAB protein <1:200 000 19q13.2–​q13.3 OPA3 258501
(3-​methylglutaconic aciduria type III)
3-​Methylglutaconic aciduria type IV (i.e. MEGDEL E.g. polymerase-​γ, transmembrane protein <1:200 000 e.g. 15q26.1, 8q21.11, e.g. POLG1, TMEM70, 250951 (if not otherwise
syndrome, TMEM70 defect, or not otherwise 70, succinate-​CoA ligase, serine active site-​ 13q14.2, 6q25.3, or ? SUCLA2, SERAC1, or? specified)
specified) containing protein 1 or not yet classified
DNAJ19 defect or DCMA syndrome Translocase of the inner mitochondrial Unknown 3q26.33 DNAJC19 610198
(3-​methylglutaconic aciduria type V) membrane 14

(continued)
12.2 Protein-dependent inborn errors of metabolism
1949
 1950

Table 12.2.3 Continued

Disease Enzyme defect Incidencea Gene map locus Gene name OMIM (phenotype
number)
2-​Methyl-​3-​hydroxybutyryl-​CoA deficiency 2-​Methyl-​3-​hydroxybutyryl-​CoA dehydrogenase <1:200 000 Xp11.2 HSD17B10 300438
Methylmalonic aciduria (mut0/​mut− defects) Methylmalonyl-​CoA mutase 1:100 000 6p12.3 MUT 251000
Propionic aciduria Propionyl-​CoA carboxylase 1:200 000
α-​chain 13q32 PCCA 232000
β-​chain 3q21–​q22 PCCB 232050
SECTION 12 Metabolic disorders

3-​Hydroxyisobutyryl-​CoA hydrolase deficiency 3-​Hydroxyisobutyryl-​CoA hydrolase Unknown 2q32.2 HIBCH 250620

Short-​chain enoyl-​CoA hydratase deficiency Mitochondrial short-​chain enoyl-​CoA hydratase 1 Unknown 10q26.3 ECHS1 616277
Defects of lysine, hydroxylysine, and tryptophan metabolism
2-​Aminoadipic and oxoadipic aciduria Dehydrogenase E1 and transketolase domains-​ <1:200 000 10p14 DHTKD1 204750
containing protein 1
2-​Oxoadipic aciduria Dehydrogenase E1 and transketolase domains-​ <1:200 000 10p14 DHTKD1 245130
containing protein 1
Glutaric aciduria type I Glutaryl-​CoA dehydrogenase 1:100 000 19p13.2 GCDH 231670
Gyrate atrophy of choroid and retina Ornithine-​oxoacid/​ ornithine aminotransferase <1:200 000 10q26 OAT 258870
Hyperlysinaemia Saccharopine dehydrogenase/​lysine:α-​ <1:200 000 7q31.32 AASS 238700
ketoglutarate reductase
Saccharopinuria Saccharopine dehydrogenase/​lysine:α-​ <1:200 000 7q31.32 AASS 268700
ketoglutarate reductase
Multiple carboxylase deficiency
Biotinidase deficiency Biotinidase 1:80 000 3p25 BTD 253260
Holocarboxylase synthetase deficiency Holocarboxylase synthetase <1:200 000 21q22.1 HLCS 253270
Other organic acidurias
N-​Acetylaspartic aciduria (Canavan’s disease) Aspartoacylase; aminoacylase 2 <1:200 000 17pter–​p13 ASPA 271900
Ethylmalonic encephalopathy Mitochondrial matrix protein <1:200 000 19q13.2 ETHE1 602473
D-​2-​Hydroxyglutaric aciduria Type I: D-​2-​hydroxyglutaric acid dehydrogenase <1:200 000 2p25.3 D2HGDH 600721
Type II: isocitrate dehydrogenase 2 <1:200 000 15q26.1 IDH2 613657
(mitochondrial)
L-​2-​Hydroxyglutaric aciduria FAD-​dependent L-​2-​hydroxyglutarate <1:200 000 14q22.1 L2HGDH 236792
dehydrogenase
Combined D-​2-​ and L-​2-​hydroxyglutaric aciduria Mitochondrial citrate transporter <1:200 000 22q11.21 SLC25A1 615182
Defects of phenylalanine and tyrosine metabolism
Alkaptonuria Homogentisate 1,2-​dioxygenase <1:200 000 3q21–​q23 HGD 203500
BH4 deficiency, dopa-​responsive dystonia Guanosine-​5-​triphosphate cyclohydrolase 1:100 000 14q22.1–​q22.2 GCH1 128230
(dominant)
BH4 deficiency
Deficiency of Dihydropteridine reductase <1:200 000 4p15.32 QHPR 261630
Deficiency of Guanosine-​5-​triphosphate cyclohydrolase <1:200 000 14q22.1–​q22.2 GCH 233910
Deficiency of 6-​Pyruvoyltetrahydropterin synthase <1:200 000 11q22.3–​q23.3 PTS 261640
Deficiency of Sepiapterin reductase <1:200 000 2p13.2 SPR 612716
Deficiency of Pterin-​4α-​carbaminoline dehydratase Unknown 10q22.1 PCBD1 264070
Phenylketonuria (PKU) Phenylalanine hydroxylase 1:10 000 12q24.1 PAH 261600
Type I (Classical PKU = Phe >1200 µmol/​litre) c.50%
Type II (Mild PKU = 360–​600 µmol/​litre ≤ Phe ≤
1200 µmol/​litre) c.30%
Type III (Non-​PKU HPA/​MHP = Phe <360–​600 µmol/​
litre) c.20%
Types II+III (BH4-​PAH = Phe <1200 µmol/​litre + BH4-​
responsive) c.35%
Hyperphenylalaninaemia with primapterinuria Pterin-​4α-​carbinolamine <1:200 000 10q22.1 PCBD 264070
Tyrosinaemia type I Fumarylacetoacetase 1:100 000 15q23.1 FAH 276700
Tyrosinaemia type II Tyrosine aminotransferase <1:200 000 16q22.2 TAT 276600
Tyrosinaemia type III 4-​Hydroxyphenylpyruvate dioxygenase <1:200 000 12q24.31 HPD 276710
Neurotransmitter diseases and related disorders
Deficiency of Aromatic L-​amino acid decarboxylase <1:200 000 7p12.1 DDC 608643
Deficiency of Dopamine β-​hydroxylase <1:200 000 9q34.2 DBH 223360
Deficiency of GABA transaminase <1:200 000 16p13.2 ABAT 613163
Deficiency of 3-​Phosphoglycerate dehydrogenase <1:200 000 1p12 PHGDH 601815
Deficiency of Tyrosine hydroxylase <1:200 000 11p15.5 TH 605407
Folinic acid-​responsive epilepsy (see ‘Pyridoxine-​ α-​Aminoadipic semialdehyde dehydrogenase <1:200 000 5q23.2 ALDH7A1 266100
dependent epilepsy’) (antiquitin)
4-​Hydroxybutyric aciduria Succinic semialdehyde dehydrogenase <1:200 000 6p22.3 ALDH5A1 271980
Hyperprolinaemia type II L-​Δ1-​pyrroline-​5-​carboxylate dehydrogenase <1:200 000 1p36 ALDH4A1 239510
Nonketotic hyperglycinaemia (glycine 1:60 000 605899
encephalopathy)
H-​protein deficiency 16q22.24 GCSH
P-​protein deficiency 9p24.1 GLDC
T-​protein deficiency 3p21.31 AMT
Other: transient 605899
Pyridoxal phosphate-​dependent epilepsy Pyridox(am)ine 5′-​phosphate oxidase <1:200 000 17q21.32 PNPO 610090
Pyridoxine-​dependent epilepsy α-​Aminoadipic semialdehyde dehydrogenase <1:200 000 5q23.2 ALDH7A1 266100
(antiquitin)

(continued)
12.2 Protein-dependent inborn errors of metabolism
1951
 1952
SECTION 12 Metabolic disorders

Table 12.2.3 Continued

Disease Enzyme defect Incidencea Gene map locus Gene name OMIM (phenotype
number)
Defects of trans-​sulphuration and remethylation
Deficiency of S-​adenosyl-​homocysteine hydrolase <1:200 000 20q11.22 AHCY 613752
Deficiency of Adenosine kinase <1:200 000 10q22.2 ADK 614300
Deficiency of Cysthationine γ-​lyase < 1:70 000 1p31.1 CTH 219500
Deficiency of Glycine N-​methyltransferase <1:200 000 6p21.1 GNMT 606664
Deficiency of Methionine adenosyltransferase 1 <1:200 000 10q23.1 MAT1A 250850
Deficiency of Methionine synthase reductase (cobalamin E) <1:200 000 5p15.31 MTRR 236270
Deficiency of Methionine synthase (cobalamin G) <1:200 000 1q43 MTR 250940
Deficiency of 5,10-​Methylene-​tetrahydrofolatreductase <1:200 000 1p36.22 MTHFR 236250
Homocystinuria Cystathionine-​β-​synthase 1:100 000 21q22.3 CBS 236200
a
Incidences as estimated in the white population; they vary between populations of different ethnic background. <1:200 000 indicates incidence very low but uncertain because not specifically determined. Of some disorders, only two or
three families are as yet known worldwide.
BH4-​PAH, BH4-​responsive phenylalanine hydroxylase deficiency; Phe, phenylalanine; PKU, phenylketonuria.
 12.2 Protein-dependent inborn errors of metabolism 1953

such as in organic acid defects, mitochondrial β-​oxidation de- Onset of symptoms may occur at any age; however, it is par-
fects, carnitine depletion, or valproate therapy, or where toxic ticularly frequent during the neonatal period, late infancy, and
acyl-​CoAs are increased, such as propionyl-​CoA in propionic and puberty, and is precipitated by excess protein or episodes that in-
methylmalonic aciduria or isovaleryl-​CoA in isovaleric aciduria. duce catabolism such as infectious diseases, trauma, or cortisone
Hyperammonaemia is neurotoxic, resulting in brain oedema, therapy. In general, symptoms are less severe with increasing age
convulsions, and coma. Neuropathological evaluation reveals an at onset. Neonatal presentation starts after a short asymptomatic
alteration of astrocyte morphology including cell swelling (acute interval with poor feeding, vomiting, lethargy, tachypnoea, and/​or
hyperammonaemia) and Alzheimer type II astrocytosis (chronic irritability which cannot be distinguished clinically from neonatal
hyperammonaemia). The brain relies on energy-​dependent glu- sepsis. Untreated, acute encephalopathy rapidly progresses to death.
tamine synthesis by astrocytic glutamine synthetase for the removal In infancy, the symptoms are less acute and more variable than in the
of excess ammonia. As a consequence, increased brain ammonia is neonatal period including anorexia, vomiting, developmental delay,
considered to amplify glutamatergic signalling and cause redistri- and behavioural problems. In X-​linked ornithine transcarbamylase
bution of cerebral blood flow and metabolism, impairment of brain deficiency, female carriers may also be affected due to variable in-
energy metabolism affecting the glutamate/​glutamine cycle, and in- activation of the X chromosome (the Lyon hypothesis). Clinical
creased serotonin secretion. Hyperammonaemia exerts reversible presentation ranges from acute liver failure, cognitive disability,
(mostly serotoninergic) and irreversible effects. Peak plasma am- and behavioural problems to psychiatric disease. In arginase 1 defi-
monia concentrations exceeding 500 µmol/​litre or a coma lasting ciency, patients usually present with progressive spasticity which is
more than 2 to 3 days appears to be associated with irreversible de- often mistaken for cerebral palsy, seizures, and learning difficulties.
fects which worsen with the duration of the coma. All inherited urea Dystonia and ataxia may develop. Acute decompensation occurs
cycle defects follow an autosomal recessive trait except for ornithine rarely. The phenotypic variation of patients with urea cycle disorders
transcarbamylase deficiency which is X-​linked. as well as evidence-​based recommendations for diagnosis, treat-
ment, and follow-​up have recently been reported by an international
Clinical presentation consortium of experts.
Urea cycle defects are among the most common inborn errors of
metabolism (cumulative incidence is approximately 1 in 40 000 Diagnosis
newborns). Six inherited urea cycle defects are well described, Emergency analysis of ammonia must be part of the basic investiga-
that is, deficiencies of N-​acetylglutamate synthetase, carbamoyl-​ tions in all patients at all ages with unclear encephalopathy or acute
phosphate synthase 1, ornithine transcarbamylase, argininosuccinate hepatic failure.
synthetase and lyase, and arginase 1 (Fig. 12.2.1). Deficiency of glu- Among the inherited hyperammonaemias, two-​thirds are due to
tamine synthetase has also been identified but is not described here. urea cycle defects and one-​third to organic acid and other inborn
Five urea cycle defects share a common but variable clinical presen- errors. Blood gas analyses and anion gap determinations may show
tation due to hyperammonaemia. Arginase 1 deficiency and defects alkalosis and normal anion gap in urea cycle defects and acidosis
of cellular transport including transporter proteins for the dibasic and increased anion gap in organic acid disorders. Characteristic
amino acids ornithine (hyperornithinaemia–​hyperammonaemia–​ biochemical changes (glutamine, alanine, citrulline, ornithine, ar-
homocitrullinuria syndrome) and aspartate (citrullinaemia II) ginine, argininosuccinic acid, orotic acid, uracil) can be identified
result in a more subtle disease with predominantly neurological by plasma amino acid analysis, GC/​MS analysis of urinary organic
symptoms. acids, or HPLC analysis of orotic acids and orotidine. The diagnosis
can be confirmed by enzyme analysis in liver tissue (all urea cycle
defects except for N-​acetylglutamate synthase deficiency), fibro-
blasts (argininosuccinate synthase 1 and lyase), or molecular genetic
N-acetylglutamate
NAGS Glutamate studies. Prenatal diagnosis is possible. Autosomal recessive inherited
⊕
urea cycle disorders can be identified by molecular genetic studies
Ammonia CPS1 Carbamyl Orotic acid on chorionic villus biopsy. Enzyme analysis can be performed for
Orotidine
HCO3− phosphate
Uracil deficiencies of argininosuccinate lyase and synthase. Arginase defi-
Citrulline ciency can also be diagnosed biochemically by fetal blood analysis.
OTC Aspartate
Mitochondrion
T Therapy and outcome
Cytosol ASS
Urea The aim of treatment is to correct the biochemical disorder (glutamine
Ornithine Cycle Argininosuccinate in plasma <800–​1000 µmol/​litre, ammonia <80 µmol/​litre, arginine
Urea 80–​150 µmol/​litre) and to ensure that the patient grows normally and
ASL
Arginase 1 thrives. The major metabolic strategies are (1) reduction of natural
Arginine protein to decrease ammonia production, (2) supplementation with
T = Ornithine transporter Fumarate
essential amino acids to prevent malnutrition and to reutilize ni-
Fig. 12.2.1 The urea cycle. ASL, argininosuccinate lyase; ASS, trogen for the synthesis of nonessential amino acids, (3) replacement
argininosuccinate synthase; CPS1, carbamyl phosphate synthase 1; of arginine or citrulline which become essential amino acids in all
NAGS, N-​acetylglutamate synthase; OTC, ornithine transcarbamylase; T,
urea cycle disorders except for arginase 1 deficiency, and (4) utiliza-
ornithine transporter.
Source data from Zschocke J, Hoffmann GF (2011). Vademecum metabolicum.
tion of alternative pathways for nitrogen excretion. This last strategy
Manual of metabolic paediatrics, 3rd edition. Schattauer, Stuttgart. ­includes application of sodium benzoate (250–​500 mg/​kg per day) and
1954 SECTION 12 Metabolic disorders

sodium phenylbutyrate or phenylacetate (250–​600 mg/​kg per day) and organic acids in urine. Notably, newborn screening profiles,
to conjugate glycine or glutamine, resulting in urinary excretion specifically C3 and C5OH levels, were unremarkable in all index pa-
of waste nitrogen in alternative compounds (hippurate, phenyl­ tients. The diagnosis can be confirmed by molecular genetic testing.
acetylglutamine). In N-​acetylglutamate synthase ­deficiency, N-​ Carbamyl phosphate synthase 1 and N-​acetylglutamate synthase de-
carbamylglutamate can be used as an alternative allosteric activator ficiency are the most relevant differential diagnosis. In children with
of carbamoyl ​phosphate synthase. negative molecular genetic test results in CPS1 and NAGS genes, car-
All patients with urea cycle defects are at risk of acute metabolic bonic anhydrase VA deficiency should be considered.
decompensation precipitated by metabolic stress such as protein
load, infection, anaesthesia, or surgery. To prevent or reverse meta- Treatment and outcome
bolic crises, a stepwise implementation of an intensified emergency Treatment with preventive sick-​day management using high-​caloric,
treatment is required (see also ‘Emergency treatment’). If diet and lipid-​rich and low-​protein formula to enhance anabolism and to re-
pharmacotherapy is insufficient to improve hyperammonaemia sig- duce the formation of toxic metabolites as well as carglumic acid to
nificantly and rapidly, haemofiltration or haemodialysis should be enhance the activity of carbamyl phosphate synthase 1 can be ad-
considered. ministered. Although carbonic anhydrase VA deficiency should be
Main factors that determine outcome are duration and severity considered as treatable condition, treatment strategies have not yet
of hyperammonaemia the specific disease, and age at disease onset been studied systematically. The long-​term outcome of this disease
are considered as most important. In general, a beneficial outcome is unknown.
critically relies on rapid diagnosis and immediate start of treatment
after the onset of first symptoms. Defects of branched-​chain amino acid metabolism
Maple syrup urine disease
Carbonic anhydrase VA deficiency
Maple syrup urine disease was first reported in 1954 by Menkes,
Aetiology/​pathophysiology Hurst, and Craig, who noticed an unusual odour reminiscent of
Bicarbonate cannot enter the mitochondria and thus is generated maple syrup in the urines of four infants who died from a rapidly pro-
within the mitochondria by two carbonic anhydrases: VA and gressive neurological disease. In newborn screening programmes, a
VB. Carbonic anhydrase VA provides bicarbonate as a substrate prevalence of approximately 1 in 200 000 newborns is encountered
to carbamyl phosphate synthase 1, the first enzymatic step of the but in the Mennonites in Pennsylvania, the prevalence is as high as 1
urea cycle, as well as to three mitochondrial carboxylases, pyruvate in 200. Maple syrup urine disease is frequent in other ethnic groups
carboxylase, propionyl-​ CoA carboxylase, and 3-​ methylcrotonyl-​ and isolates such as persons of French Canadian origin.
CoA carboxylase which are involved in energy metabolism and the In maple syrup urine disease, the branched-​ chain amino
catabolic pathways of branched-​chain amino acids, respectively. acids leucine, isoleucine, and valine, their corresponding α-​keto
Combined dysfunction of these four mitochondrial enzymes due to acids and hydroxy acid derivatives, as well as l-​alloisoleucine
limited availability of their substrate bicarbonate causes a biochem- are increased in physiological fluids. These amino acids and
ical derangement including hyperammonaemia, impaired energy their metabolites accumulate due to inherited deficiency of the
metabolism (affecting gluconeogenesis and tricarboxylic cycle) with thiamine-​dependent branched-​chain α-​keto acid dehydrogenase
lactic acidosis, as well as organic acidurias resembling propionic complex, consisting of subunits E1α, β, E2, and E3 (Fig. 12.2.2).
aciduria and 3-​ methylcrotonyl-​ CoA carboxylase deficiency (see l-​Alloisoleucine results from racemization of the 3-​carbon of
‘3-​Methylcrotonylglycinuria’). l-​isoleucine during transamination. Its elevation is pathogno-
monic for maple syrup urine disease.
Presentation
Recently, four patients with this disease have been reported. Three Presentation
of them presented with lethargy, tachypnoea, hypoglycaemia, Several clinical presentations have been delineated but there is con-
hyperammonaemia, hyperlactatemia with hyperalaninaemia, and siderable overlap. Most frequently the condition comes to light in
respiratory alkalosis during the first days of life; in one of them, the the first few days of life with lethargy, irritability, poor feeding, and
initial metabolic crisis occurred at age 13 months. During the follow-​ neurological deterioration. Later-​onset forms of maple syrup urine
up, episodes of acute encephalopathy were precipitated by catabolic disease are slower with failure to thrive, developmental delay, and
stress. Motor and mental development was within the normal range sometimes seizures; episodic ataxia and stupor sometimes pro-
in one child, whereas delayed motor development due to ataxia and gressing to coma may be precipitated by high protein intake or
mild axial hypotonia, psychomotor retardation, or learning difficul- intercurrent illness. In patients showing a response to thiamine, the
ties was found in the other children. condition tends to resemble later-​onset maple syrup urine disease.
A very rare related disease results from deficiency of lipoamide de-
Diagnosis hydrogenase presenting after the neonatal period with lactic acid-
Metabolic tests reveal a unique pattern of elevated lactate and osis, hypotonia, developmental delay, abnormal movement, and
hyperammonaemia with elevated glutamine and alanine, but low progressive neurological deterioration.
citrulline and arginine in plasma in combination with increased Most patients with maple syrup urine disease have the classic
urinary excretion of lactate, ketone bodies, propionate metabolites, form. If untreated, these neonates quickly deteriorate, developing
methylcrotonylglycine, and 3-​hydroxyisovaleric acid. The meta- lethargy, hypotonia alternating with muscular rigidity, opisthotonic
bolic pattern can be identified by analysis of plasma amino acids posturing, and seizures (Fig. 12.2.3). Despite giving its name to
 12.2 Protein-dependent inborn errors of metabolism 1955

Valine Isoleucine Leucine

Aminotransferase Aminotransferase Aminotransferase

2-Oxo- 2-OH- 2-Oxo- Alloisoleucine 2-Oxo- 2-Oxoisocaproate

isovalerate isovalerate 3-methylvalerate isocaproate 2-OH-isocaproate
BCKDH BCKDH BCKDH

Isobutyryl-CoA 2-Methylbutyryl-CoA Isovaleryl-CoA 3-OH-isovalerate

Isovalerylglycine
IBD MBD IVD
Tiglyl-
Methylacrylyl-CoA Tiglyl-CoA 3-Methyl- 3-OH-isovalerate
glycine
crotonyl-CoA 3-Methylcrotonyl-
Hydratase Hydratase
MCC glycine
3-OH-isobutyryl-CoA 2-Methyl-
3-OH-butyryl-CoA 3-Methyl- 3-Methylglutarate
Deacylase
glutaconyl-CoA
MHBD
3-OH-isobutyrate Hydratase
2-Methyl-
DH 3-OH-3-methyl-
acetoacetyl-CoA
glutaryl-CoA
Methylmalonate 3-Oxothiolase
HMG-CoA lyase
semialdehyde DH

Propionyl-CoA Acetyl-CoA Acetoacetate

Carboxylase
3-OH-propionate
Methylmalonyl-CoA
Methylcitrate Krebs
Mutase
cycle
Succinyl-CoA

Fig. 12.2.2 Metabolism of branched-​chain amino acids. BCKDH, branched chain α-​keto acid
dehydrogenase (deficient in MSUD); DH, dehydrogenase; hydratase, 3-​methylglutaconyl-​CoA hydratase
(deficient in 3-​methylglutaconic aciduria type I); IVD, isovaleryl-​CoA dehydrogenase (deficient in isovaleric
academia); MCC, 3-​methylcrotonyl-​CoA carboxylase (deficient in methylcrotonylglycinuria); MCM,
methylmalonyl CoA mutase (deficient in methylmalonic aciduria); MHBD, 2-​methyl-​3-​hydroxybutyryl-​CoA
dehydrogenase (deficient in 2-​methyl-​3-​hydroxybutyryl-​CoA dehydrogenase deficiency); PCC, propionyl-​
CoA carboxylase (deficient in propionic aciduria). Accumulating pathologic metabolites are shown in italics.
Source data from Zschocke J, Hoffmann GF (2011). Vademecum metabolicum. Manual of metabolic paediatrics, 3rd
edition. Schattauer, Stuttgart.

the disease, the characteristic odour may be absent. Neuroimaging suppression bursts. Untreated patients succumb within a few days.
shows localized or diffuse generalized cerebral oedema. Convulsions Prominent neuropathological signs of untreated maple syrup urine
appear regularly and electroencephalography reveals abnormalities disease are cerebral atrophy, including neuron loss in pontine nu-
with comb-​like rhythms (5–​9 Hz) of spindle-​like sharp waves over clei and the thalamus and myelin deficiency; spongy degeneration
the central regions and multiple shifting spikes and sharp waves with and astrocytic hyperplasia occur. Hypodensities may be present in
globus pallidus and thalamus. In a few patients, mostly with inter-
mittent or intermediate variants, the metabolic defect can be cor-
rected by thiamine (‘thiamine-​responsive’ variant). Effective doses
vary from 10 mg up to 300 mg per day.

Diagnosis
Maple syrup urine disease is strongly suggested when an odour of
maple syrup is present (most noticeably in the ear wax). Immediate
confirmation by positive 2,4-​dinitrophenylhydrazine testing is suf-
ficient justification to initiate treatment in families at high risk.
Diagnosis is confirmed by detection of increased plasma con-
centrations of leucine, isoleucine, and valine and/​or by increased
urinary excretion of α-​keto and hydroxy acids. The detection of
l-​alloisoleucine is diagnostic. Reduced enzyme activity of the
branched-​chain α-​keto acid dehydrogenase complex in leuco-
Fig. 12.2.3 Opisthotonic hypertonic comatose infant with maple syrup cytes, lymphoblasts, cultured fibroblasts, or amniocytes confirms
urine disease. the diagnosis. Except for the common Mennonite mutation, the
1956 SECTION 12 Metabolic disorders

molecular genetics of maple syrup urine disease are too complex During metabolic crises, patients present with the typical features
for diagnostic use. Prenatal testing is available by enzymatic ana- of classic organic acid disorders, that is, acidosis, ketosis, vomiting,
lysis of amniotic cells. progressive alteration of consciousness, and, finally, overwhelming
illness, deep coma, and death if not given appropriate therapy.
Treatment and outcome Clinical abnormalities often develop within the first days of life.
Emergency treatment aims to reduce branched-​chain amino acids, A pathognomonic foul odour reminiscent of sweaty feet, caused by
particularly leucine. To induce anabolism, high calorie intake is re- isovaleric acid, occurs. Abnormalities of the haematopoietic system
quired. Most importantly, glucose stimulates endogenous insulin such as thrombocytopenia, neutropenia, or pancytopenia develop;
secretion activating protein synthesis. If required, insulin should be hyperammonaemia is usually mild.
started early. In parallel, supplements free of branched-​chain amino In the chronic intermittent form, children slide into recur-
acids should be administered by nasogastric drip feeding. Since low rent metabolic crises because of a high intake of protein or
plasma concentrations of isoleucine and valine limit protein syn- minor infections inducing a catabolic state. Cytopenias develop
thesis, cautious supplementation to decrease leucine concentrations as described earlier, and hyperglycaemia may develop, most
is mostly required. likely due to stress-​induced counter-​regulatory hormonal ef-
Extracorporeal detoxification (haemodialysis, haemofiltration) fects. Pancreatitis may be a complication of isovaleric aciduria.
may be required if leucine exceeds 20 mg/​dl (1500 µmol/​litre). Liver Older patients may have normal psychomotor development or
transplantation may be considered a reasonable treatment option mild to severe learning difficulties, depending on the frequency
for patients with classic maple syrup urine disease. The decision of of decompensation and the age of diagnosis and institution of
medical treatment versus transplantation, however, is very complex treatment.
and must be reached for each patient individually.
Long-​term treatment of maple syrup urine disease is based on Diagnosis
dietary restriction of branched-​chain amino acids and supplemen- The clinical symptoms of isovaleric aciduria resemble other or-
tation of thiamine, if proven beneficial. Management requires close ganic acidaemias; even the suggestive odour may be shared by
and lifelong regulation of diet. similar disorders (Boxes 12.2.1 and 12.2.2). The combination of
Children with the classic form of maple syrup urine disease have a ketoacidosis, dehydration, and hyperglycaemia has led to erro-
satisfactory prognosis only if they are diagnosed and treated before neous diagnosis of diabetic ketoacidosis, and persistent vomiting
symptom onset; for this reason MS/​MS-​based newborn screening in infancy to the wrong suggestion of hypertrophic pyloric sten-
has been introduced in some countries. osis and unnecessary surgery. A reliable way to accomplish the
diagnosis is quantitative analysis of urinary organic acids and
Isovaleric aciduria
acylglycines by GC/​MS or the analysis of acylcarnitine profiles
Aetiology/​pathophysiology by MS/​MS.
Isovaleric aciduria was described by Tanaka in 1966. It is caused by During metabolic decompensation, the urinary organic acid profile
deficiency of isovaleryl-​CoA dehydrogenase, an enzyme located reveals high excretion of isovalerylglycine which remains elevated.
proximally in the catabolic pathway of the essential branched-​chain 3-​Hydroxyisovaleric acid only increases during metabolic decom-
amino acid leucine (Fig. 12.2.2). The encoding IVD gene is local- pensation. Isovalerylcarnitine is the characteristic acylcarnitine of
ized on 15q14–​q15. Due to the metabolic block, isovaleryl-​CoA this disease and its urinary excretion increases following supple-
accumulates, and the pathognomonic metabolite isovalerylglycine mentation with l-​carnitine. The diagnosis of isovaleric aciduria can
is formed by conjugation of isovaleryl-​CoA to the amino group of be confirmed by enzyme analysis in fibroblasts or mutation analysis
glycine through the activity of the mitochondrial enzyme glycine- in specialized laboratories. Several methods have been successfully
​N-​acylase. It is suggested that accumulating acyl-​CoA esters sequester used for prenatal diagnosis including stable isotope dilution ana-
CoA, thereby disturbing energy metabolism. Specifically, isovaleryl-​ lysis of isovalerylglycine, MS/​MS detection of isovalerylcarnitine in
CoA inhibits pyruvate dehydrogenase and N-​acetylglutamate syn- amniotic fluid, or macromolecular labelling from (1-​14C)-​isovaleric
thase causing lactic acidosis and hyperammonaemia. Furthermore, acid in cultured amniocytes. Molecular diagnosis is only available in
isovaleric acid inhibits granulopoiesis and occurs during metabolic a research setting.
decompensations.
Treatment and outcome
Clinical presentation Total natural protein intake is restricted according to the patient’s
Half of the patients with isovaleric aciduria present in the neonatal leucine tolerance and is adjusted to age-​specific requirements. To
period with severe metabolic crises that may lead to coma and death, provide a complementary source of the other amino acids, a leucine-​
whereas the remainder experience chronic intermittent disease with free formula is available. Beyond childhood, a protein-​restricted
episodes of metabolic acidosis and psychomotor retardation. Both diet allowing a moderate restriction of leucine intake is usually suf-
phenotypes can occur within the same family suggesting a modi- ficient. In addition, urinary excretion of isovaleryl-​CoA as nontoxic
fying role of environmental and epigenetic factors. A mild, poten- carnitine conjugates is activated by supplementation with carnitine
tially asymptomatic phenotype exists due to a common mutation (50–​100 mg/​kg per day).
(c.932C>T; p.A282V). This mutation was detected in one-​half of During acute decompensation, isovaleric aciduria is treated fol-
mutant alleles in patients identified by newborn screening and also lowing the general principles for other organic acid disorders (see
in older, healthy siblings. ‘Emergency treatment’).
 12.2 Protein-dependent inborn errors of metabolism 1957

Aspirin is contraindicated in patients with isovaleric aciduria be- tried. 3-​Methylcrotonylglycinuria is usually unresponsive to biotin
cause salicylic acid is a competing substrate for glycine-​N-​acylase, whereas, in those with the p.R385S mutation, biotin responsiveness
interfering with isovalerylglycine synthesis. has been reported. If acute metabolic decompensation occurs, af-
Most children will survive the first life-​threatening episode if fected patients are treated as with other organic acid disorders (see
correct treatment is set in place early. If effective treatment can be ‘Emergency treatment’). Most affected individuals remain asymp-
installed before any severe metabolic decompensation, it will sig- tomatic without specific treatment and thus the benefit of newborn
nificantly improve outcome. Therefore, in some countries isovaleric screening remains to be elucidated.
aciduria is screened for in newborns using MS/​MS.
3-​Methylglutaconic acidurias
3-​Methylcrotonylglycinuria
Increased urinary excretion of 3-​ methylglutaconic acid is the
3-​Methylcrotonylglycinuria is an inborn error of leucine catab- biochemical hallmark of a heterogeneous group of inborn errors
olism due to deficiency of 3-​α-​methylcrotonyl-​CoA carboxylase termed 3-​methylglutaconic acidurias types including a primary
(Fig. 12.2.2). It appears to be the most frequent inborn organic defect in leucine catabolism, primary mitochondrial disorders, for
acid disorder, with a frequency of 1 in 50 000 newborns. The example, Pearson’s syndrome and ATP synthase deficiency, and
3-​methylcrotonylglycinuria enzyme requires biotin as a cofactor, patients with Smith–​Lemli–​Opitz syndrome, a cholesterol biosyn-
and the isolated enzymatic defect must be differentiated from pri- thesis disorder. Whereas in 3-​methylglutaconyl-​CoA hydratase de-
mary deficiencies in the biotin pathway (see ‘Biotinidase deficiency’ ficiency elevated 3-​methylglutaconic is caused by a primary defect
and ‘Holocarboxylase synthetase deficiency’). As a consequence in leucine degradation, in all other diseases with 3-​methylglutaconic
of 3-​methylcrotonylglycinuria deficiency, 3-​hydroxyisovaleric aciduria the increase of this metabolite is thought to be secondary
acid, 3-​hydroxyisovalerylcarnitine, 3-​methylcrotonylcarnitine, and to mitochondrial membrane biosynthesis, maintenance, and
3-​methylcrotonylglycine accumulate. phospholipid remodelling or disturbed cholesterol biosynthesis.
Interestingly, leucine degradation is linked to cholesterol biosyn-
Clinical presentation
thesis via the Popjak shunt and the 3-​hydroxy-​3-​methylglutaryl-​
From the follow-​up of individuals identified by newborn screening CoA salvage pathway. With recognition of an increasing number
it has become evident that deficiency of 3-​methylcrotonylglycinuria of underlying defects in recent years, the initial nomenclature of 3-​
is a genetic condition with low clinical expressivity and penetrance, methylglutaconic acidurias has been revised. In the following, both
representing largely (c.90%) a nondisease. Less than 10% of affected old (type I–​V) and new nomenclature (specifying the syndrome
individuals may develop mostly mild neurological symptoms which and affected gene) are given.
are often not clearly attributed to 3-​methylcrotonylglycinuria de-
ficiency. However, a few patients may develop acute metabolic de- Primary 3-​methylglutaconic aciduria
compensation (ketoacidosis, hypoglycaemia, hyperammonaemia, 3-​Methylglutaconic aciduria type I
Reye-​like syndrome) precipitated by febrile illness during infancy;
Aetiology/​pathophysiology 3-​ Methylglutaconic aciduria type
this may be fatal if untreated.
I is caused by deficiency of 3-​methylglutaconyl-​CoA hydratase
Diagnosis (Fig. 12.2.2) required for the conversion of 3-​methylglutaconyl-​
CoA to 3-​hydroxy-​3-​methylglutaryl-​CoA in leucine catabolism.
The diagnosis is confirmed biochemically by identification of
The hydratase is identical to an RNA-​binding protein (designated
3-​hydroxyisovaleric acid and 3-​ methylcrotonylglycine in urine
AUH) possessing enoyl-​CoA hydratase activity. The defect leads
(GC/​MS) or 3-​hydroxyisovalerylcarnitine in dried blood spots or
to an accumulation of 3-​methylglutaconic, 3-​methylglutaric, and
plasma (MS/​MS whereas in patients with additionally increased
3-​hydroxyisovaleric acids.
3-​hydroxypropionic, methylcitric, or lactic acids multiple carb-
oxylase deficiency or biotinidase deficiency should be considered. Clinical presentation The clinical phenotype of affected individ-
In particular, 3-​hydroxyisovalerylcarnitine concentrations which uals is variable and also includes an asymptomatic disease course.
spontaneously decrease to normal values in follow-​ up inves- Patients present with neurological symptoms including delayed
tigations of any neonate should prompt the investigation of 3-​ speech and motor development. Metabolic decompensation with
methylcrotonylglycinuria deficiency in the mother. hypoglycaemia and metabolic acidosis is rare but can occur fol-
Significantly reduced enzyme activity in fibroblasts or leucocytes lowing a catabolic state. The recent discovery of the disorder in
or mutation analysis confirms the diagnosis. It is important to ex- adult-​onset patients with slowly progressive ataxia, dementia, and
clude multiple carboxylase deficiency by demonstrating normal en- leukoencephalopathy may point to the long-​term nature and mani-
zyme activities of propionyl-​CoA carboxylase, pyruvate carboxylase, festations of this disease.
as well as biotinidase. Prenatal diagnosis is possible by stable isotope
Diagnosis Urinary excretion of large amounts of 3-​methylglutaconic,
dilution analysis of amniotic fluid or by enzymatic and molecular
3-​methylglutaric, and 3-​hydroxyisovaleric acids but normal excretion
analyses in cultivated amniocytes or chorionic villi.
of 3-​hydroxy-​3-​methylglutaric acid points to hydratase deficiency.
Treatment and outcome Increased 3-​hydroxyisovalerylcarnitine is a hint for either type of
3-​methylglutaconic aciduria. The definitive diagnosis is made by en-
Most affected individuals do not require specific treatment, with
zyme analysis in fibroblasts or by mutation analysis.
the exception of carnitine supplementation if secondary carnitine
depletion is found. However, moderate protein restriction and ad- Treatment and outcome The need for treatment has not been es-
ministration of leucine-​free amino acid supplements has been tablished, especially for dietary treatment. The outcome appears
1958 SECTION 12 Metabolic disorders

favourable as a significant number of untreated patients have never levels of 3-​methylglutaconic and 3-​methylglutaric acids is also un-
developed symptoms. known. So far the disorder has only been reported in Iraqi Jews.

Secondary 3-​methylglutaconic acidurias Clinical presentation The determining clinical presentation is

early-​onset optic atrophy, which may be accompanied by nystagmus.
TAZ defect or Barth’s syndrome (formerly,
In later childhood or adolescence, patients may develop extrapyr-
3-​methylglutaconic aciduria type II)
amidal signs and moderate cognitive impairment. In about one-​half
Aetiology/​pathophysiology The molecular basis of Barth’s syn- of the patients, spasticity develops and progresses over years.
drome is deficiency of tafazzin which is localized in the inner
Diagnosis Costeff ’s syndrome should be suspected in patients pre-
mitochondrial membrane affecting phospholipid metabolism,
senting with early-​onset optic atrophy if additional neurological
in particular cardiolipin. The origin of elevated levels of 3-​
symptoms develop. 3-​Methylglutaconic aciduria is a biochemical
methylglutaconic and 3-​methylglutaric acids in Barth’s syndrome is
indicator of Costeff ’s syndrome, which may now be proven by mo-
unknown.
lecular analysis.
The identification of the causative gene allowed the retrospective
classification of different families labelled in the past as X-​linked Treatment and outcome Effective treatment has not been reported.
endocardial fibrosis, severe X-​linked cardiomyopathy, or Barth’s Treatment is symptomatic and focuses on the prevention of disabil-
syndrome. All these entities have been shown to share the same mo- ities due to progressive spasticity. The disease appears stationary but
lecular pathology. the long-​term outcome is unknown.
Clinical presentation In 1983, Barth and colleagues described an Specified and not otherwise specified 3-​methylglutaconic
X-​linked neuromuscular disease characterized by dilated cardio- aciduria type IV
myopathy, skeletal myopathy, retarded growth, and neutropenia.
Patients may present at birth or during the first weeks of life, usually Aetiology/​pathophysiology 3-​Methylglutaconic aciduria type IV
with congestive cardiac failure. With long-​standing cardiac disease, is undoubtedly the most heterogeneous and increasing group of
endocardial fibroelastosis may develop. Delayed gross motor mile- 3-​methylglutaconic acidurias. As unexplained 3-​methylglutaconic
stones, myopathic facies, a waddling gait, and a positive Gower’s aciduria (i.e. type IV) was also found incidentally in asymptomatic
sign are common. Occasionally patients may show moderate lactic adults, it appears doubtful that this biochemical feature by itself is of
acidosis. Postnatal growth retardation may be severe, and beyond pathophysiological relevance.
2 years of age patients are usually very stunted but with normal head Diagnosis Patients are identified by elevated urinary con-
circumferences. centrations of 3-​ methylglutaconic and 3-​ methylglutaric acids.
Diagnosis Barth’s syndrome should be considered in any male Classification of type IV methylglutaconic aciduria is made by ex-
presenting with dilated cardiomyopathy. If neutropenia, idiopathic clusion of known causes of 3-​methylglutaconic aciduria (see other
myopathy, and growth retardation are also present, the diagnosis subsections), primary mitochondrial disorders (e.g. Pearson’s syn-
of Barth’s syndrome is almost certain. Biochemically, increased 3-​ drome), and Smith–​Lemli–​Opitz syndrome. Four clinical pheno-
methylglutaconic acid is usually found in urine but is not a constant typic groups have been delineated including patients with an
feature. 2-​Ethylhydracrylic acid may be also elevated. Muscle dis- encephalopathic, hepatocerebral, cardiomyopathic, and myopathic
ease and lactic acidaemia may initiate a work-​up for mitochondrial disease form. Genetic testing in these patients has elucidated a high
disorders. Muscle biopsy may reveal involvement of deficient re- number of disease-​ causing mutations in the POLG1, SUCLA2,
spiratory chain complexes I and IV. The diagnosis is confirmed by TMEM70, and RYR1 genes which have been associated with known
cardiolipin analysis in thrombocytes or mutation analysis. Mutation diseases. Furthermore, MEGDEL syndrome due to mutations in
analysis makes prenatal diagnosis now available. the SERAC1 gene was recently described. Based on this, the mo-
lecular cause of 3-​methylglutaconic aciduria type IV can be iden-
Treatment and outcome Children affected by Barth’s syndrome tified in many patients. In patients with a known molecular basis
need to be carefully managed mainly by expert cardiologists; im- of 3-​methylglutaconic aciduria, 3-​methylglutaconic aciduria type
munologists and neurologists should also be involved. Cardiac ar- IV shall be replaced by a more specific terminology, for example,
rhythmias carry a poor prognosis and may require implantation of SERAC1 defect or MEGDEL syndrome, or TMEM70 defect.
an internal cardiac defibrillator. Successful heart transplantation has
been carried out. Due to increased susceptibility to severe bacterial Treatment and outcome No effective treatment has been re-
infections, infectious diseases need to be treated promptly and ag- ported. Treatment is symptomatic and focuses on the prevention
gressively. Protein restriction and carnitine supplementation has of neurological deterioration. The identification of type IV 3-​
been employed with unclear benefit. About 25% of patients with methylglutaconic aciduria is not yet of prognostic relevance.
Barth’s syndrome succumb during infancy and early childhood due
DNAJC19 defect or dilated cardiomyopathy with
to cardiac complications or overwhelming bacterial infections.
ataxia (DCMA) syndrome (formerly, 3-​methylglutaconic
OPA3 defect or Costeff’s syndrome (formerly, aciduria type V)
3-​methylglutaconic aciduria type III) Aetiology/​pathophysiology Another type of 3-​methylglutaconic
Aetiology/​pathophysiology Costeff ’s syndrome is caused by mu- aciduria has recently been elucidated in 18 patients of the Canadian
tations in the OPA3 gene resulting in a defect of a putative mito- Dariusleut Hutterite population. It is an autosomal recessive con-
chondrial protein with yet unknown function. The origin of elevated dition caused by a mutated DNAJC19 gene. Proteins of the DNAJ
 12.2 Protein-dependent inborn errors of metabolism 1959

domain are involved in molecular chaperone systems, DNAJ19 cardiac function, (2) neurological examination including elec-
having been localized to the inner mitochondrial membrane. troencephalography and MRI, and (3) assessment of visual and
hearing system. The prognosis is mostly poor, with death in early
Clinical presentation Inherited DNAJ19 deficiency leads to clin-
childhood.
ical presentation which initially resembles Barth’s syndrome (3-​
methylglutaconic aciduria type II) with early-​onset severe dilated Propionic aciduria
(or noncompaction) cardiomyopathy with conduction defects.
However, it also leads to with nonprogressive cerebellar ataxia, tes- Aetiology/​pathophysiology
ticular dysgenesis, and growth failure. In 1961, Childs and coworkers described the index patient with pro-
pionic aciduria. Since ketosis and hyperglycinaemia were the bio-
Diagnosis The diagnosis can be made by genetic testing in patients
chemical hallmarks recognized, the disorder was lumped together
with a suggestive clinical presentation and 3-​methylglutaonic aciduria.
with methylmalonic acidurias as ‘ketotic hyperglycinaemia’ to dis-
Therapy and outcome No effective treatment has been reported. tinguish it from nonketotic hyperglycinaemia. Implementation
Treatment is symptomatic and focuses on the prevention of cardiac of GC/​MS analysis to metabolic diagnostic work-​up allowed the
deterioration. differentiation of these disorders in the 1970s. Propionic aciduria
is caused by an autosomal recessive inherited deficiency of biotin-​
2-​Methyl-​3-​hydroxybutyryl-​CoA dehydrogenase deficiency
dependent duodecameric propionyl-​CoA carboxylase, the first step
Aetiology/​pathophysiology in propionate metabolism, in which propionyl-​CoA is converted to
2-​Methyl-​3-​hydroxybutyryl-​CoA dehydrogenase deficiency is a methylmalonyl-​CoA (Fig. 12.2.2). Over 100 disease-​causing muta-
rare cerebral organic acid disorder. This mitochondrial enzyme is tions have been identified in the PCCA gene (13q32) and the PCCB
involved in the catabolism of isoleucine and branched-​chain fatty gene (3q21–​22).
acids (Fig. 12.2.2). Retrospectively, patients were misdiagnosed Propionyl-​CoA is formed from the catabolism of isoleucine,
as having 3-​oxothiolase deficiency until Zschocke and colleagues threonine, methionine, valine, odd-​ numbered fatty acids, and
(2000) recognized the separate distinct clinical and biochemical the side chain of cholesterol, and from gut bacteria. Deficiency
presentation. Inheritance is X-​ chromosomal semidominant (fe- of propionyl-​ CoA carboxylase gives rise to accumulation of
males may be symptomatic). Disease-​causing mutations were iden- propionyl-​CoA and metabolites of alternative propionate oxidation
tified in the HSD17B10 gene. The pathophysiology of this disease is such as 2-​methylcitric acid, 3-​hydroxypropionic acid, tiglic acid,
unknown. The enzyme is identical to an amyloid β-​peptide-​binding propionylcarnitine, and propionylglycine. All of these can be de-
protein which is implicated in Alzheimer’s disease. tected and quantified by GC/​MS (urine, plasma) or MS/​MS (dried
blood spots, plasma).
Clinical presentation Elevated propionyl-​CoA and its pathological derivatives inter-
2-​Methyl-​3-​hydroxybutyryl-​CoA dehydrogenase deficiency mostly fere with a variety of metabolic pathways including inhibition of
results in a progressive neurodegenerative disease. Regression usu- (1) the glycine cleavage enzyme resulting in hyperglycinaemia,
ally becomes obvious in late infancy or early childhood but is vari- (2) N-​acetylglutamate synthase resulting in hyperammonaemia,
able. Affected boys usually develop truncal hypotonia with spasticity and (3) pyruvate dehydrogenase complex as well as several enzymes
of the limbs, dyskinesia and athetosis, a horizontal nystagmus, and of the tricarboxylic acid cycle resulting in lactic acidaemia and
retinal blindness. Motor and mental skills are completely lost, as are hyperketosis, and severe impairment of energy metabolism.
sensory modalities. Epilepsy is frequently found and is usually dif-
Clinical presentation
ficult to treat. When hypertrophic cardiomyopathy was diagnosed,
deterioration was rapid with death due to progressive heart failure. Propionic aciduria usually presents with severe neonatal meta-
Neuroimaging documents progressive generalized atrophy, basal bolic decompensation characterized clinically by multiorgan
ganglia injury, periventricular white matter abnormalities, and oc- failure and biochemically by hyperammonaemia, metabolic
cipital infarctions in individual cases. Heterozygous female patientsacidosis, hyperketosis, lactic acidaemia, hyperglycinaemia, and
may be asymptomatic or may have variable stationary psychomotor hyperalaninaemia. Propionic aciduria may be misinterpreted as
retardation with impaired hearing. sepsis or ventricular haemorrhage. Acute metabolic decompen-
sation and long-​term complications usually involve organs with a
Diagnosis high energy demand, including the brain, heart and skeletal muscle,
The disease should be considered in children presenting with liver, and bone marrow. Frequent signs and symptoms are failure to
early-​onset progressive encephalopathy, especially if X-​linked in- thrive, microcephaly, mild to severe motor disabilities and learning
heritance is suggested. The biochemical hallmark of this disease difficulties, truncal hypotonia, extrapyramidal symptoms (dystonia,
is increased urinary excretion of 2-​methyl-​3-​hydroxybutyric acid chorea), seizures, cardiomyopathy, myopathy, hepatomegaly, acute
and tiglylglycine. Elevations of 2-​ ethylhydracrylic acid and 3-​ or chronic pancreatitis, leucopenia, thrombocytopenia, anaemia,
hydroxyisobutyric acid in urine may also be found. These abnor- or pancytopenia, whereas renal complications are uncommon.
malities may be subtle. Metabolic decompensations in infancy or childhood are similar to
those in the neonatal period. The first symptom is often vomiting;
Treatment and outcome this has led to erroneous diagnosis of pyloric stenosis or duodenal
No effective rational treatment is known. Care of patients with obstruction, resulting in a number of pyloromyotomies or other
this disease should repeatedly entail (1) assessment of muscle and explorations. Basal ganglia injury, mostly affecting the putamen,
1960 SECTION 12 Metabolic disorders

aciduria is treated like other organic acid disorders (see ‘Emergency

treatment’). Long-​term treatment is based on lifelong dietary restric-
tion of the precursors isoleucine, valine, methionine, and threonine,
as well as by supplementation with l-​carnitine. As significant propi-
onate production occurs in the gut, intermittent decontamination
(10–​14 days/​month) with metronidazole or colistin as well as meas-
ures preventing constipation are often used. Some patients exhibit
recurrent or almost chronic hyperammonaemia, especially during
infancy. This may necessitate additional supplementation with ar-
ginine or citrulline and/​or administration of sodium benzoate or
phenylbutyrate. However, benzoate treatment may aggravate the
depletion of free carnitine and CoA. Biotin responsiveness in propi-
onic aciduria is very rare, if present at all. More than 20 children with
propionic aciduria have undergone orthotopic liver transplantation,
but the outcome is mixed. Auxiliary as well as living-​related liver
transplantations have been successfully performed, but liver trans-
plantation in propionic aciduria seems to be more complicated than
in patients with urea cycle defects.
Patients with neonatal onset of symptoms still have a poor out-
come. Patients with late onset of symptoms reach adulthood but often
have physical and mental disabilities; nonetheless, some patients can
survive to adulthood with normal intellects. The phenotypic vari-
ation of patients with propionic aciduria as well as evidence-​based
Fig. 12.2.4 Transverse MRI image of a 7-​year-​old girl, who had been
diagnosed with propionic aciduria in infancy and had been successfully
recommendations for diagnosis, treatment, and follow-​up have re-
treated since then. While in good metabolic control, she suddenly cently been reported by an international consortium of experts.
became comatose. Massive infarction of the basal ganglia had occurred,
and the child died a few days later. Spin echo technique. Methylmalonic aciduria
Courtesy of Drs R. Haas and W.L. Nyhan, Department of Pediatrics, University of Aetiology/​pathophysiology
California, San Diego, USA.
Methylmalonic aciduria is the biochemical hallmark of a heteroge-
neous group of inborn metabolic errors with a cumulative prevalence
occurs (Fig. 12.2.4); generalized cerebral atrophy and white matter of at least 1 in 100 000 newborns in Europe. Index patients were first
disease is common. described in 1967 by Oberholzer and Stokke. This section focuses on
A small subgroup of patients exhibit almost exclusively encephal- isolated methylmalonic aciduria caused by mutations in the MUT
opathy and progressive neurological disease, resembling a lysosomal gene localized on 6p21 encoding the apoenzyme methylmalonyl-​
storage disorder. A milder form of propionic aciduria reported in CoA mutase. Methylmalonyl-​CoA mutase can alternatively be im-
Japan manifests from childhood with mild learning difficulties or paired by defects in the biosynthesis of 5′-​deoxyadenosylcobalamin,
extrapyramidal symptoms, and only occasionally with metabolic deficient cobalamin transport, or by acquired cobalamin deficiency
acidosis. Finally, some individuals remain asymptomatic until as in pernicious anaemia.
teenage years and are identified during family studies. In infancy, severe progressive disease may develop in breastfed
infants of mothers who have (undiagnosed) pernicious anaemia or
Diagnosis adhere to a strict vegan diet. Methylmalonic acid is a more reliable
The method of diagnosis is GC/​ MS analysis of organic acids index of body stores of cobalamin than cobalamin levels in blood.
(urine) or MS/​MS analysis of acylcarnitines (dried blood spots, d-​Methylmalonyl-​CoA is formed in propionate metabolism by
plasma, urine). Characteristic metabolites are 2-​ methylcitric carboxylation of propionyl-​CoA. l-​Methylmalonyl-​CoA is formed
acid, 3-​hydroxypropionic acid, tiglic acid, propionylglycine, and from d-​methylmalonyl-​CoA by d-​methylmalonyl-​CoA racemase
propionylcarnitine. The absence of methylmalonic acid excludes and, subsequently, is converted to succinyl-​CoA by the dimeric
methylmalonic acidurias, and the absence of β-​hydroxyisovaleric 5′-​deoxyadenosylcobalamin-​dependent mitochondrial enzyme
acid and β-​methylcrotonylglycine rules out multiple carboxylase de- methylmalonyl-​CoA mutase (Fig. 12.2.2).
ficiency. In plasma and urine, increased concentrations of glycine and As with propionic aciduria (see ‘Propionic aciduria’), impairment
ketone bodies may be present. Confirmation of diagnosis is made by of energy metabolism by propionyl-​CoA and 2-​methylcitric acid
enzyme analysis in leucocytes or fibroblasts, or by mutation analysis. plays a key role in the pathophysiology of methylmalonic acidurias,
Prenatal diagnosis can be made by mutation analysis, enzyme ana- resulting in multiorgan failure. In addition, methylmalonic acid may
lysis, or quantitative GC/​MS analysis of 2-​methylcitric acid. exert additional toxic effects.

Treatment and outcome Clinical presentation

Prevention of metabolic decompensation is the most important de- Patients with severe methylmalonyl-​CoA mutase deficiency (mut0)
terminant of outcome. During acute decompensation, propionic usually present with neonatal metabolic crises which are clinically
 12.2 Protein-dependent inborn errors of metabolism 1961

and biochemically (except for methylmalonic acid) indistinguish- of patients with methylmalonic aciduria as well as evidence-​based
able from those of patients with propionic aciduria. In patients with recommendations for diagnosis, treatment, and follow-​up have re-
residual methylmalonyl-​CoA mutase activity (mut−), the onset of cently been reported by an international consortium of experts.
symptoms is more variable. Neonatal onset of symptoms is found
as is a chronic intermittent form, that is, precipitation of recurrent 3-​Hydroxyisobutyryl-​CoA hydrolase deficiency
metabolic crises in infancy and children following a high intake of Aetiology/​pathophysiology
protein or a catabolic state. Long-​term complications are frequent, 3-​Hydroxyisobutyryl-​CoA hydrolase (HIBCH) catalyses the
in particular in mut0 patients. These include failure to thrive, chronic fifth step of valine catabolism converting 3-​hydroxyisobutyryl-​
neurological symptoms such as extrapyramidal movement disorder, CoA to 3-​hydroxyisobutyrate and is due to biallelic mutations
motor disabilities, learning difficulties, and epilepsy, cardiomyop- of the HIBCH gene which is located on 2q32.2. HIBCH de-
athy, myopathy, and pancreatitis. Neuroradiological studies demon- ficiency is biochemically characterized by accumulation of
strate lesions of globus pallidus, generalized cerebral atrophy, and 3-​hydroxyisobutyrylcarnitine deriving from 3-​hydroxyisobutyryl-​
white matter disease. The development of chronic renal failure in a CoA and S-​2-​carboxypropyl-​L-​cysteine and -​cysteamine deriving
large proportion of patients appears inevitable. from methyacrylyl-​CoA. Whereas 3-​hydroxyisobutyrylcarnitine
Diagnosis can be eliminated via urinary excretion, methylacrylyl-​CoA is a
highly reactive compound which readily undergoes addition reac-
A reliable way to make the diagnosis is GC/​MS analysis of urinary tion with sulphhydryl groups. Inactivation of sulhydryl-​containing
organic acids or MS/​MS analysis of acylcarnitines showing ele- enzymes such as respiratory chain complexes and cofactors is con-
vated concentrations of methylmalonic acid as well as of metab- sidered as the major pathomechanism.
olites of alternative propionate oxidation (e.g. propionylglycine,
3-​hydroxypropionic acid, 2-​methylcitric acid, propionylglycine, and Clinical presentation
propionylcarnitine; as in propionic aciduria). These biochemical So far this disease has rarely been described. Patients presented with
abnormalities have a considerable interday and intraday variation a (Leigh-​like) mitochondrial encephalopathy starting in infancy,
and are influenced by responsiveness to cobalamin and metabolic delayed global development, muscular hypotonia, poor feeding,
state. Differential diagnosis of methylmalonic aciduria is acquired and multiple malformations (dysmorphic facial features, vertebral
cobalamin depletion or inherited cobalamin deficiencies, transient anomalies, tetralogy of Fallot, agenesis of cingulate gyrus and corpus
mild methylmalonic acidurias of unknown origin in infants, and callosum) in one patient. Neurological symptoms are progressive.
methylmalonic encephalopathy due to deficiency of succinyl-​CoA
synthase. Concomitant megaloblastic anaemia and an increase of Diagnosis
plasma homocysteine indicates disturbed cobalamin metabolism as The diagnosis is based on metabolic tests demonstrating elevated
the cause of methylmalonic aciduria. 3-​
hydroxyisobutyrylcarnitine by tandem mass spectrometry
Standardized criteria to define responsiveness to hydroxocobalamin and 2-​methyl-​2,3-​dihydroxybutyric acid and 2-​hydroxyisovaleric
are not established. The determination of methylmalonyl-​ CoA acid by organic acid analysis. S-​2-​carboxypropyl-​L-​cysteine and -​
mutase activity in fibroblast extracts, mutation analysis or the in- cysteamine can be determined by specific HPLC analysis. Enzymatic
vestigation of labelled propionate incorporation following transfec- testing of the deficient enzyme in fibroblast and molecular genetic
tion by a vector containing cloned mutase cDNA in intact patients’ testing confirms the diagnosis. Analysis of respiratory chain en-
fibroblasts may be required to differentiate primary defects of zymes in muscle biopsy often show decreased activity of pyruvate
methylmalonyl-​CoA mutase (mut0, mut−) from primary defects of 5′-​ dehydrogenase complex and/​or multiple deficiencies of respiratory
deoxyadenosylcobalamin (cblA and cblB defects). Prenatal diagnosis chain complexes.
is available by enzyme or mutation analyses as well as by quantitative
stable isotope dilution assay of 2-​methylcitric acid. Treatment and outcome
Treatment and outcome Since this disease is thought to be caused by accumulation of toxic
metabolites of the valine catabolic pathway, a low-​valine diet should
Metabolic maintenance and emergency treatment follows the treat-
be considered as a treatment option. Carnitine supplementation
ment principles for organic acid disorders in general and propionic
prevents secondary carnitine depletion. However, the efficacy of this
aciduria in particular (see ‘Propionic aciduria’). In addition, substi-
therapeutic approach has not yet been systematically studied.
tution with cobalamin may be beneficial, since partial or complete
response to cobalamin has been demonstrated (except for mut0 pa- Short-​chain enoyl-​CoA hydratase deficiency
tients). In neonates and infants, intramuscular hydroxocobalamin
is required; children and adults may be treated with oral cyano- Aetiology/​pathophysiology
cobalamin. Chronic renal failure may progress, necessitating Mitochondrial short-​ chain enoyl-​CoA hydratase (ECHS1) is a
haemodialysis or peritoneal dialysis. Kidney transplantation has multispecific enzyme that catalyses the hydration of chain-​shortened
been performed in these patients. Liver transplantation can provide α,β-​unsaturated enoyl-​CoA thioesters in the β-​oxidation spiral of
enzyme activity to ameliorate the metabolic defect and the idea of fatty acids as well as in the catabolic pathways of valine, isoleucine,
combined liver–​kidney or isolated liver transplantation has emerged. tryptophan, and lysine. Deficiency of ECHS1, which is coded by the
The benefit remains doubtful, however, as mortality is significant; in ECHS1 gene located on 10q26.3, induces a very similar biochem-
addition, liver transplantation does not reliably protect against se- ical phenotype as in HIBCH deficiency. In contrast to HIBCH defi-
vere neurological and renal complications. The phenotypic variation ciency, however, tiglylglycine but not 3-​hydroxyisobutyrylcarnitine
1962 SECTION 12 Metabolic disorders

is elevated. Inconsistently, there is evidence of mildly impaired Tryptophan Hydroxylysine Lysine

mitochondrial oxidation of short-​chain fatty acids. The biochemical
Dioxygenase Kinase Reductase
derangement highlights that in analogy to HIBCH deficiency, im-
Saccharopine
pairment of valine catabolism and thus accumulation of the toxic Kynurenine Phospho-
metabolite methacrylyl-​CoA is most important. hydroxylysine Dehydrogenase
3-OH-kynurenine 2-Aminoadipic semialdehyde
Clinical presentation Kynureninase rt
spo
Tran/out ia 2-Aminoadipic acid
Patients present with (Leigh-​like) mitochondrial encephalopathy, in ondr Aminotransferase
och
dystonia, epilepsy, optic nerve atrophy and cardiomyopathy. Onset 2-Oxoadipic acid mti
2-Oxoadipic acid
of symptoms is usually found in the newborn period or during in- 2-Amino-
adipic acid Dehydrogenase
fancy. The disease course is progressive and in its severest form it
might be fatal in infancy or childhood. Glutaryl-CoA
GCDH
Diagnosis Crotonyl-CoA
Diagnosis of this disease should be considered in patients with a Mito-
SCHAD
Cytosol
combination of mitochondrial encephalopathy and cardiomyop- chondrion
athy. Urinary excretion of 2-​methyl-​2,3-​dihydroxybutyric acid is Acetyl-CoA
determined by organic acid analysis, S-​2-​carboxypropyl-​L-​cysteine Fig. 12.2.5 Catabolic pathway of lysine, tryptophan, and hydroxylysine.
and -​cysteamine can be analysed using specific HPLC methods. 2-​Aminoadipic semialdehyde synthase (deficient in hyperlysinaemia/​
Enzymatic testing of the deficient enzyme in fibroblast and mo- saccharopinuria); 2-​aminoadipate aminotransferase (deficiency
lecular genetic testing confirm the diagnosis. Analysis of respira- has not yet been reported), 2-​oxoglutarate dehydrogenase-​like
tory chain enzymes in muscle biopsy often show decreased activity complex (deficient in in 2-​amino-​/​2-​oxoadipic aciduria); glutaryl-​CoA
dehydrogenase (GCDH; deficient in glutaric aciduria type I).
of pyruvate dehydrogenase complex and/​or multiple deficiencies of Source data from Zschocke J, Hoffmann GF (2011). Vademecum metabolicum.
respiratory chain complexes. Manual of metabolic paediatrics, 3rd edition. Schattauer, Stuttgart.

Treatment and outcome

Treatment and outcome
In analogy to HIBCH deficiency, a low-​valine diet should be con-
sidered a treatment option. It remains to be elucidated whether this A clearly effective therapeutic regimen has not been established.
therapeutic intervention is able to improve the disease course. Carnitine supplementation as well as a diet high in carbohydrates
and low in long-​chain triglycerides improved the clinical symp-
Malonic aciduria toms as well as metabolic disturbances in patients. In some patients,
Aetiology/​pathophysiology medium-​chain triglycerides supplements appeared helpful. Little is
known about the long-​term prospects of this disorder. Patients were
First described in 1984, very few patients with malonic aciduria have stable on the different treatment options at least until adolescence.
been delineated until now. Malonic aciduria is caused by malonyl-​
CoA decarboxylase deficiency leading to a disturbed fatty acid me- Defects of lysine, hydroxylysine, and
tabolism. Malonyl-​CoA is the first committed intermediate of fatty tryptophan metabolism
acid synthesis. In addition, it regulates carnitine acyltransferases The common catabolic pathway of lysine, hydroxylysine, and trypto-
among other enzymes steering fatty acid metabolism. The cytocolic phan is summarized in Fig. 12.2.5.
enzyme is found most often in the liver, brain, heart, and skeletal
muscle. Hyperlysinaemia I/​hyperlysinaemia II or saccharopinuria
Clinical presentation Hyperlysinaemia/​saccharopinuria is caused by a recessive deficiency
of the bifunctional protein 2-​aminoadipic semialdehyde synthase.
The clinical presentation is variable but mostly involves acute meta-
As hyperlysinaemia/​saccharopinuria is considered a nondisease, af-
bolic episodes with progressive lethargy, hypotonia, and hepato-
fected individuals do not require specific treatment.
megaly associated with metabolic acidosis. Hypoglycaemia, lactic
acidosis, and/​or mild hyperammonaemia can also develop. Cardiac 2-​Amino-​/​​2-​oxoadipic aciduria
involvement is present in about 40% of patients with cardiomy-
Disease-​causing mutations in the DHTKD1 gene cause autosomal
opathy which can progress to cardiac failure. Other patients were
recessive 2-​amino-​/​2-​oxoadipic aciduria. This gene encodes for the
identified with less specific symptoms such as developmental delay,
E1 subunit of a 2-​oxoglutarate dehydrogenase complex-​like pro-
hypotonia, seizures, and short stature.
tein in the lysine degradative pathway. Most affected individuals re-
Diagnosis main asymptomatic, whereas others may present with variable mild
Urinary organic acids identify increased malonic acid, sometimes in neurological symptoms.
combination with fumaric acid, malic acid, and aethylmalonic acid. Glutaric aciduria type I
During metabolic decompensations ketosis develops with elevated
dicarboxylic acids. Total and free carnitine levels are reduced due Aetiology/​pathophysiology
to the formation of malonylcarnitine, which may allow population Glutaric aciduria type I was described in 1975. It occurs with
newborn screening. an estimated frequency of 1 in 100 000 newborns, but which is
 12.2 Protein-dependent inborn errors of metabolism 1963

considerably higher (up to 1 in 300) in some communities (e.g. the Prenatal diagnosis is possible by determining glutaric acid with
Amish in Pennsylvania, United States of America, and the Oji-​Cree stable isotope dilution techniques and by enzymatic and/​or mo-
First Nations in Canada). Glutaric aciduria type I is caused by de- lecular testing.
ficiency of flavin adenine dinucleotide-​ dependent glutaryl-​ CoA
dehydrogenase, a mitochondrial enzyme in the catabolic pathway Treatment and outcome
common to tryptophan, lysine, and hydroxylysine (Fig. 12.2.5). The principal aim of treatment is the prevention of encephalopathic
Glutaryl-​CoA dehydrogenase is encoded by the GCDH gene lo- crises and neurological deterioration. Strict adherence to the emer-
calized on 19p13.2. More than 200 disease-​causing mutations have gency protocol is especially important (see ‘Emergency treatment’).
been described. There is no genotype–​phenotype correlation. As a During the vulnerable period (i.e. until age 6 years), lysine-​restricted
consequence of glutaryl-​CoA dehydrogenase deficiency, glutaric, dietary treatment (including lysine-​free amino acid supplements)
3-​hydroxyglutaric, and (inconsistently) glutaconic acids as well and carnitine supplementation is recommended. Riboflavin is widely
as glutarylcarnitine accumulate. The limited permeability of the used but is of doubtful benefit. Treatment efficacy of movement dis-
blood–​brain barrier to dicarboxylic acids (such as glutaric acid) orders is still poor. Baclofen, benzodiazepines, and trihexyphenidyl
leads to their accumulation in the brain (trapping hypothesis). Some are widely used to treat dystonia. Botulinum toxin and intrathecal
of these metabolites are neurotoxins. Candidate mechanisms are baclofen are valid additions. If patients are diagnosed while they
stimulation of excitotoxic cell damage via activation of N-​methyl-​d-​ are asymptomatic, treatment prevents brain degeneration in the
aspartate receptors, and inhibition of 2-​oxoglutarate dehydrogenase majority of patients. Notably, best outcome results (≥90% remain
and the dicarboxylate shuttle between astrocytes and neurons. healthy) were achieved for patients following international guide-
line recommendations including a low-​lysine diet and carnitine
Clinical presentation supplementation for maintenance treatment and immediate emer-
Newborns are often asymptomatic but may present with transient gency treatment during any putatively threatening episode such
and subtle neurological symptoms such as truncal hypotonia or as intercurrent infectious diseases. Deviation from this combined
asymmetric posturing. (Progressive) macrocephaly occurs in 75% metabolic treatment increases the risk of motor disability such as in
of patients. Neuroimaging in infancy often reveals hypoplasia of the untreated patients. More than 90% of untreated patients are thought
temporal pole, subependymal pseudocysts, and delayed myelin- to develop neurological disabilities. Life expectancy is markedly re-
ation; subdural fluid collections may be found which may be mis- duced following the manifestation of dystonia.
taken as nonaccidental trauma.
The prognostically relevant event of glutaric aciduria type I is the Hyperornithinaemia
onset of an acute encephalopathic crisis which is usually precipi- (ornithine-​5-​aminotransferase): gyrate atrophy
tated by a catabolic state (e.g. febrile illness) during infancy and early Autosomal recessive hyperornithinaemia associated with gyrate
childhood. Encephalopathic crises characteristically result in acute atrophy of the choroid and retina is caused by deficiency of
striatal injury and, subsequently, dystonia. Approximately 15% of ornithine-​5-​aminotransferase.
patients with glutaric aciduria type I follow a chronic disease course
and develop the same neurological symptoms as the acutely injured Clinical presentation
children over the first 2 years of life without overt crisis (insidious-​ Progressive myopia is the first clinical symptom, followed by pro-
onset variant) or during adolescence/​adulthood presenting with gressive chorioretinal degeneration with night blindness starting
leukoencephalopathy (late-​ onset variant). Asymptomatic indi- late in the first decade. Loss of peripheral vision proceeds to tunnel
viduals occur occasionally. Neuroradiological abnormalities are vision and eventually blindness by the third or fourth decade. The
frequently found, including widening of the sylvian fissure due to re- principal abnormality is an atrophy of choroid and retina. Cataracts
duced opercularization (Fig. 12.2.6a), ventriculomegaly and striatal also develop but optic discs, cornea, and iris remain normal. A few
lesions which develop after the encephalopathic crisis (Fig. 12.2.6b), patients develop mild proximal muscle weakness.
and leukoencephalopathy which is mostly periventricular but may
also affect subcortical U fibres (Fig. 12.2.6c). Diagnosis
Severe isolated hyperornithinaemia is usually discovered by amino
Diagnosis acid analysis with plasma ornithine concentrations ranging from
Glutaric aciduria type I should be suspected in patients with macro- 400 to 1400 µmol/​litre (normal <200 µmol/​litre). The disease can
cephaly and an extrapyramidal movement disorder starting in in- be confirmed enzymatically by decreased activity of ornithine-​
fancy or childhood. The diagnostic process can be guided by further 5-​aminotransferase in fibroblasts as well as by identification of
clinical features. Diagnosis is ascertained by GC/​MS detection of disease-​causing mutations in the OAT gene, but the diagnosis is usu-
glutaric and 3-​hydroxyglutaric acids in organic acid analysis (urine, ally evident.
plasma, or cerebrospinal fluid) or by MS/​MS detection of elevated
glutarylcarnitine (dried blood spots, plasma, urine). Confirmation Treatment and prognosis
by enzymatic analysis in leucocytes or fibroblasts or demonstration Permanent reduction of plasma ornithine into the normal range
of two pathogenic mutations is advisable. A subgroup of patients (<200 µmol/​litre) is required to stop or at least slow chorioretinal
presents with a mild biochemical phenotype (low excretors) and degeneration. Only a small proportion of patients respond to
thus may be missed if diagnostic work-​up does not include quan- pharmacological doses of the ornithine-​ 5-​
aminotransferase co-
titative methods (e.g. stable isotope dilution assay). Examination of factor pyridoxine. Additional therapeutic approaches to reduce or-
the carnitine status usually reveals low total and free carnitine. nithine are the augmentation of renal losses by administration of
1964 SECTION 12 Metabolic disorders

(a) (b)

(c)

Fig. 12.2.6 (a) Axial T2-​weighted MRI spin echo image of a 2½-​year-​old boy with glutaryl-​CoA dehydrogenase deficiency. He was diagnosed
neonatally, never suffered an encephalopathic crisis, and developed no major neurological deficit. Extension of sylvian fissures which was mild during
early infancy had slowly regressed. He did not develop characteristic frontotemporal atrophy and showed a normal myelination. (b) Axial T2-​weighted
spin echo image of a 15-​month-​old boy with glutaryl-​CoA dehydrogenase deficiency 2 weeks after acute encephalopathic crisis. In addition to
extension of sylvian fissures, hyperintensity of putamen, caudate, and pallidum are obvious. (c) T2-​weighted axial and coronal MRIs of a 66-​year-​old
man with glutaryl-​CoA dehydrogenase deficiency demonstrating confluent white matter changes, wide temporopolar and insular cerebrospinal fluid
spaces, and cortical atrophy, but normal signal of basal ganglia. The previously healthy man presented from the age of 50 with slowly progressive
neurological disease, including seizures, dementia, and speech problems. Aggressive behaviour as well as acoustic and visual hallucinations led to the
suggestion of psychiatric disease.
(c) Reproduced with permission from Külkens et al. 2005.

pharmacological doses of l-​lysine or α-​aminoisobutyric acid (which and the catabolism of several amino acids and odd-​chain fatty acids
is not metabolized), or substrate deprivation by dietary arginine re- (Fig. 12.2.7). The covalent binding of biotin with apocarboxylases
striction. Combined treatment appears to be necessary since no forming the active holocarboxylases is catalysed by biotin
single therapy is unequivocally effective. holocarboxylase synthetase. In the biotin cycle, biotin is recycled
after proteolytic degradation of holocarboxylases (Fig. 12.2.8).
Multiple carboxylase deficiency Biotin in small amounts is widely present in natural foods. Within the
The water-​soluble vitamin biotin is a cofactor of four important body, biotin bound to holocarboxylases represents the major source.
carboxylases that take part in gluconeogenesis, fatty acid synthesis, In dietary and in endogenous sources, biotin is protein-​bound as
 12.2 Protein-dependent inborn errors of metabolism 1965

Leucine Glucose Valine abnormalities caused by deficiency of the respective biotin-​dependent

Isoleucine carboxylases are as follows: lactic acidosis due to pyruvate carb-
Threonine
Odd-chain fatty oxylase deficiency; hyperammonaemia and accumulation of me-
acids tabolites of alternative propionate metabolism (see also ‘Propionic
3-Methylcrotonyl-CoA aciduria’) due to propionyl-​CoA carboxylase deficiency; and eleva-
tion of 3-​hydroxyisovaleric acid, 3-​methylcrotonylglycine, and 3-​
1*
hydroxyisovalerylcarnitine (see also ‘3-​Methylcrotonylglycinuria’)
3-Methylglutaconyl-CoA Propionyl-CoA due to methylcrotonyl-​CoA carboxylase deficiency.
2* Clinical presentation
Acetyl-CoA Pyruvate
Methylmalonyl-CoA Onset of first symptoms is variable, ranging from 1 week to 10 years
3* of age. The mean age of presentation is between 3 and 6 months.
Oxaloacetate Provision of biotin by the mother in utero delays symptoms and bio-
4* chemical abnormalities in newborns with biotinidase deficiency.
The most frequent symptoms are lethargy, hypotonia, seizures, and
Citrate Succinate
ataxia often in combination with stridor, episodes of hyperventi-
lation, and apnoea. If undiagnosed and untreated, progression of
Malonyl-CoA the disease can be potentially fatal (Fig. 12.2.9). In older children,
progressive neurological disease is often the leading presentation,
including ataxia, (myoclonic) epileptic encephalopathy, and devel-
Fatty acids
opmental delay. Neurosensory hearing loss and ophthalmic dis-
Fig. 12.2.7 Important carboxylases in amino acid metabolism. orders, such as optic atrophy, develop in most untreated patients.
Asterisked enzymes are 1, 3-​methylcrotonyl coenzyme A carboxylase; 2, Skin rash and/​or alopecia are hallmarks of the disease.
propionyl coenzyme A carboxylase; 3, pyruvate carboxylase; and 4, acetyl
coenzyme A carboxylase. Diagnosis
Urinary organic acid analysis is useful for differentiating isolated
biocytin or short biotinyl peptides. Liberation of biotin from its pro- carboxylase deficiencies from the multiple carboxylase deficien-
tein conjugates is catalysed by biotinidase. cies that occur in biotinidase deficiency and holocarboxylase syn-
thase deficiency. However, metabolic abnormalities are highly
Biotinidase deficiency variable and are absent at birth when the patient is not biotin de-
Aetiology/​pathophysiology pleted. Whereas accumulation of abnormal organic acid metabol-
ites may show characteristic metabolites of propionic aciduria (see
Biotinidase regenerates biotin from endogenous sources and liber-
also ‘Propionic aciduria’), pyruvate carboxylase deficiency, and
ates protein-​bound biotin, which derives from natural foodstuffs
3-​methylcrotonylglycinuria (see also ‘3-​Methylcrotonylglycinuria’)
and the holocarboxylases. Free biotin is recycled and used for the
(Fig. 12.2.2), only 3-​ hydroxyisovaleric acid may be found ele-
reformation of holocarboxylases by the action of holocarboxylase
vated, especially in the early stages of the disease. Notably,
synthetase through the biotin cycle (Fig. 12.2.8). The primary bio-
3-​hydroxyisovaleric acid is also the most commonly elevated
chemical defect in most patients with late-​onset multiple carb-
urinary metabolite in holocarboxylase synthetase deficiency,
oxylase deficiency was shown in 1983 to be a profound deficiency of
3-​methylcrotonyl-​CoA carboxylase deficiency, and acquired biotin
serum biotinidase encoded by the BTD gene (3p25). The metabolic
deficiency. Biotin is decreased in plasma and urine and biocytin is
increased in urine.
Diagnosis is made by analysis of serum biotinidase activity.
Apocarboxylases Enzymatic activity less than 10% is classified as profound biotinidase
(PCC, MCC, PC, ACC)
deficiency and activity between 10 and 30% as partial biotinidase
Protein-bound Biotinidase
Holocarboxylase deficiency. Furthermore, few patients with decreased affinity of
Biotin synthetase
biotin (diet) biotinidase for biocytin (Km variants) exist. They may show erro-
Holocarboxylases neously high residual activity on in vitro testing. Prenatal diagnosis
Lysine Biotinidase
Proteolysis is feasible by measurement of biotinidase activity but may not be
Lysylpeptides necessary because of effective treatment and favourable clinical out-
Biocytin,
short biotinylpeptides come. Newborn screening for biotinidase deficiency is now estab-
Fig. 12.2.8 The biotin cycle. Biotin is cleaved from biocytin (biotinyl-​ lished in many countries.
lysine) or small peptides by biotinidase. Activation of the apoenzymes
resulting in functioning carboxylases (3-​methylcrotonyl-​CoA, Treatment and outcome
propionyl-​CoA, acetyl-​CoA, and pyruvate carboxylases) is carried out Biotinidase deficiency is effectively treated by daily oral adminis-
by holocarboxylase synthetase. ACC, acetyl-​CoA carboxylase; MCC, tration of pharmacological doses of biotin. Restriction of protein is
3-​methylcrotonyl-​CoA carboxylase; PC, pyruvate carboxylase; PCC,
propionyl-​CoA carboxylase.
not necessary. Administration of 5 to 10 mg of oral biotin per day
Source data from Zschocke J, Hoffmann GF (2011). Vademecum metabolicum. promptly reverses or prevents all clinical and biochemical abnor-
Manual of metabolic paediatrics, 3rd edition. Schattauer, Stuttgart. malities. Biotin treatment has to be maintained lifelong and has no
1966 SECTION 12 Metabolic disorders

(a) (b)

Fig. 12.2.9 Two T2-​weighted images of a 7-​month-​old boy with biotinidase deficiency. (a) The image displays absence of
normal myelin signal in the cerebellum as well as hyperintense signal in both pyramidal tracts. (b) The image shows absence
of normal myelin signal, cerebral atrophy, and symmetrical hyperintense lesions of both thalami.
Courtesy of Dr. T. Bast, Department of Pediatric Neurology, University of Heidelberg, Heidelberg, Germany.

side effects. Most patients with biotinidase deficiency known today hypotonia and hypertonia, seizures, and the odour of male cat urine
were detected by newborn screening. Patients with Km variants have are other symptoms. Ataxia, tremor, hyporeflexia, or hyperreflexia
an increased risk of becoming biotin deficient and thus must also be are neurological manifestations of the disease.
treated with biotin. After early detection and consequent treatment,
the outcome of biotinidase deficiency is excellent. Diagnosis

Holocarboxylase synthetase deficiency Biochemical abnormalities of holocarboxylase synthetase deficiency

are analogous to those described for patients with biotinidase de-
Aetiology/​pathophysiology ficiency (see also ‘Biotinidase deficiency’). Importantly, plasma
Holocarboxylase synthetase deficiency is a rare, autosomal reces- biotin is normal in holocarboxylase synthetase deficiency as is
sive disease. Several disease-​causing mutations have been identified serum biotinidase activity. Holocarboxylase synthetase is charac-
in the HLCS gene (21q22.1). Only about 40 patients have been re- terized by deficient activities of carboxylases in peripheral blood
ported. Residual activity has been observed in all affected individuals leucocytes prior to biotin administration; the activities of these
suggesting that complete enzyme deficiency may be lethal in utero. enzymes increase to near-​normal or normal values after biotin
The coenzyme biotin is attached to the various apocarboxylases treatment. Indirect confirmation of holocarboxylase synthetase de-
by the enzyme holocarboxylase synthetase. The carboxyl group of ficiency and differentiation from biotinidase deficiency is feasible
biotin is linked by an amide bond to an ε-​amino group of a specific by measurement of activities of the mitochondrial carboxylases in
lysine residue of the apoenzymes. Deficiency of holocarboxylase skin fibroblasts showing residual activity of 0 to 30% when incu-
synthetase leads to failure of synthesis of all carboxylases, causing bated in low-​biotin (10−10 mol/​litre) medium and an increase, some-
biochemical and clinical abnormalities attributable to the dysfunc- times to normal values in biotin-​supplemented medium (10−6–​10−5
tion of each respective carboxylase. mol/​litre). In biotinidase deficiency, the activity of mitochondrial
carboxylases in fibroblasts is normalized even under low-​biotin
Clinical presentation conditions. Definite diagnosis of holocarboxylase synthetase de-
Although holocarboxylase synthetase deficiency was initially ficiency is not routinely available. Prenatal diagnosis is feasible ei-
termed early-​onset multiple carboxylase deficiency, the age of onset ther by demonstrating decreased carboxylase activities in cultured
of symptoms varies widely, from a few hours after birth to 6 years amniocytes or by demonstration of elevated 3-​hydroxyisovaleric
of age. Nevertheless, about one-​half of patients present acutely in acid and/​or methylcitrate in amniotic fluid. Prenatal molecular
the first days of life with severe metabolic decompensation, leth- diagnosis can be offered in families with previously known disease-​
argy, hypotonia, vomiting, seizures, and hypothermia. Patients causing mutations in the HLCS gene.
with early-​onset presentation exhibit severe metabolic acidosis with
lactic acidaemia, ketosis, and hyperammonaemia in analogy to Treatment and outcome
biotinidase deficiency (see also ‘Biotinidase deficiency’). The meta- Holocarboxylase synthetase deficiency can be treated effectively
bolic derangement may quickly progress from lethargy to coma and with pharmacological doses of biotin. The required dose of biotin
early death. Skin rashes, feeding difficulties, vomiting, muscular is dependent on the severity of the enzyme defect and has to be
 12.2 Protein-dependent inborn errors of metabolism 1967

assessed individually. In most patients, 10 to 20 mg of biotin per

day is sufficient, but some need higher doses, that is, 40 to 100 mg/​
day. In spite of apparently complete recovery, biochemical and clin-
ical abnormalities persist in some patients owing to the high Km for
biotin in the defective holocarboxylase synthetase. In case of acute
decompensation, treatment according to the emergency protocol in
organic acidurias (see ‘Emergency treatment’) has to start without
delay. It is unclear whether prenatal treatment with biotin is bene-
ficial. The prognosis is good if treatment is initiated immediately,
except for affected individuals with Km variants.

Other organic acidurias

d-​2-​Hydroxyglutaric aciduria type I and II

Aetiology/​pathophysiology
d-​2-​Hydroxyglutaric aciduria is an aetiologically heterogeneous
cerebral organic acid disorder first described by Chalmers and col-
leagues in 1980. d-​2-​Hydroxyglutaric aciduria type I is caused by
deficiency of d-​2-​hydroxyglutarate dehydrogenase, a mitochon-
drial enzyme converting d-​2-​hydroxyglutarate to 2-​oxoglutarate.
Pathogenic mutations have been identified in the D2HGDH gene
on 2p25.3. Recently, autosomal dominant germline mutations of Fig. 12.2.10 Axial T1-​weighted spin echo image of a 2-​month-​old girl
the IDH2 gene located on 15q26.1 causing increased conversion of with d-​2-​hydroxyglutaric aciduria type II. The lateral ventricles are highly
2-​oxoglutaric acid to d-​2-​HG using NADPH by isocitrate dehydro- dilated, occipital more than frontal, the cerebral maturation is delayed.
genase 2 were identified as molecular cause for d-​2-​hydroxyglutaric Reproduced with permission from Kölker et al. 2002.
aciduria type II. Neurodegeneration in d-​2-​hydroxyglutaric
aciduria is explained by activation of N-​methyl-​d-​aspartate recep-
tors and inhibition of respiratory chain complexes (cytochrome c acid cycle intermediates are usually also elevated in urine. γ-​
oxidase, ATP synthase) by d-​2-​hydroxyglutaric acid. Aminobutyric acid (GABA) and total protein concentrations may
be elevated in cerebrospinal fluid. d-​2-​Hydroxyglutaric acid can also
Clinical presentation be elevated in multiple acyl-​CoA dehydrogenase deficiency, succinic
Patients with d-​2-​hydroxyglutaric aciduria exhibit variable pheno- semialdehyde dehydrogenase deficiency, and following bacterial
types. They have been divided into two subgroups based on clin- overgrowth of the urine specimen. However, due to characteristic
ical, neuroradiological, and molecular findings. Patients with additional parameters these differential diagnoses are usually easy to
d-​2-​hydroxyglutaric aciduria type I are moderately affected and usu- exclude. Prenatal diagnosis can be performed either through genetic
ally follow a mild clinical course with variable symptoms including testing or by metabolite determination in amniotic fluid by stable
learning difficulties, muscular hypotonia, and macrocephaly. Rarely isotope dilution GC/​MS assay.
individuals remain almost asymptomatic, that is, presenting only Treatment and outcome
with well-​treatable oligoepilepsy or even with no neurological symp-
toms. The clinical presentation of patients with d-​2-​hydroxyglutaric No specific therapy exists to date. Long-​term care of patients should
aciduria type II is usually more severe than in patients with type entail regular evaluation of cardiomyopathy and the progression of
I. Patients present with encephalopathy of early infantile onset, neurological disease. The prognosis of d-​2-​hydroxyglutaric aciduria
demonstrating a combination of catastrophic epilepsy, muscular is extremely variable. Severely affected children may die in infancy,
hypotonia, cerebral visual failure, and severe psychomotor retard- while moderately affected patients have a better prognosis up to an
ation. Facial dysmorphism, macrocephaly, and cardiomyopathy unimpaired life.
may also be present. Neuroimaging findings in these patients show l-​2-​Hydroxyglutaric aciduria
ventriculomegaly, enlarged subarachnoid spaces, subdural effusions,
subependymal cysts, and delayed cerebral maturation (Fig. 12.2.10). Aetiology/​pathophysiology
Recently, agenesis of the corpus callosum, bilateral involvement of the l-​2-​Hydroxyglutaric aciduria is a rare, autosomal recessively in-
striatum, and cerebral artery infarctions were added to the spectrum. herited cerebral disorder. The disease is caused by deficiency of the
flavin adenine dinucleotide-​dependent mitochondrial enzyme l-​2-​
Diagnosis hydroxyglutarate dehydrogenase converting l-​2-​hydroxyglutarate
The biochemical hallmark of this disease is the accumulation of to 2-​oxoglutarate. This enzyme is encoded by the L2HGDH gene on
d-​2-​hydroxyglutaric acid in all body fluids. Type I patients excrete 14q22.1. The pathophysiology of this disease is unknown.
lower concentrations of d-​2-​hydroxyglutarate than type II patients.
Demonstration of elevated levels of 2-​hydroxyglutaric acid must be Clinical presentation
followed up by differential quantitation of the two isomers l-​ and d-​ l-​2-​Hydroxyglutaric aciduria was first described by Duran and
2-​hydroxyglutaric acid. 2-​Oxoglutaric acid and other tricarboxylic coworkers in 1980. It is characterized by progressive loss of
1968 SECTION 12 Metabolic disorders

myelinated arcuate fibres and a spongiform encephalopathy. In the (a)

first 2 years of life, mental and psychomotor development may be
normal or slightly delayed. Febrile seizures, nonspecific develop-
mental delay, and muscular hypotonia are the presenting symptoms.
Progressive ataxia, variable extrapyramidal and pyramidal signs,
epilepsy, and progressive learning difficulties eventually develop. By
adolescence, patients are usually bedridden and severely mentally
disabled (IQ 40–​50). Two patients have developed cerebral tumours.
Two patients presented at birth with depressed vital signs, severe
epileptic encephalopathy, and an abnormal CT scan showing cere-
bellar involvement; however, the disease course is usually slowly
progressive without metabolic decompensation.
The neuroimaging findings in l-​2-​hydroxyglutaric aciduria are
unique and mostly uniform comprising a progressive loss of arcuate
fibres combined with progressive cerebellar atrophy and signal
changes in globus pallidus and the dentate nuclei (Fig. 12.2.11).

Diagnosis
l-​2-​hydroxyglutaric aciduria results in a rather homogeneous clin-
ical picture and characteristic abnormalities on neuroimaging.
Clinical or neuroradiological suspicion should prompt GC/​ MS
analysis of urinary organic acids followed by differentiation of l-​ (b)
2-​ and d-​2-​stereoisomers. Lysine is often increased both in plasma
and cerebrospinal fluid. Prenatal diagnosis is based on the analysis
of l-​2-​hydroxyglutaric acid in amniotic fluid samples or molecular
analysis.

Treatment and outcome

No specific therapy exists to date. Epilepsy can generally be controlled
by antiepileptic medications. Patients with l-​2-​hydroxyglutaric
aciduria can be expected to reach adult life. The oldest known pa-
tients are close to 40 years of age, bedridden, and severely disabled.

Combined d-​2-​ and l-​2-​hydroxyglutaric aciduria

Aetiology/​pathophysiology
The molecular basis of combined d-​2-​ and l-​2-​hydroxyglutaric
aciduria has recently been unravelled. The disease is caused by
homozygous or compound heterozygous mutations in the SLC25A1
gene (gene locus 22q11.21) resulting in a dysfunction of the mito-
chondrial citrate carrier and thus in impaired mitochondrial citrate
Fig. 12.2.11 (a) Axial T2-​weighted spin echo image of an 8½-​year-​
efflux.
old boy with l-​2-​hydroxyglutaric aciduria. Subcortical white matter is
Clinical presentation severely deficient with much less involvement of the internal capsule
and the periventricular white matter. Please note signal changes in the
In a similar manner to patients with d-​2-​hydroxyglutaric aciduria putamen. (b) Axial T2-​weighted spin echo image of an 8½-​year-​old boy
type II, patients with the combined d-​2-​ and l-​2-​hydroxyglutaric with l-​2-​hydroxyglutaric aciduria. Please note hyperintense lesions in
aciduria usually present with a severe clinical manifestation in the both dentate nuclei.
(a) Reproduced with permission from Kölker et al. 2002.
newborn period. This includes epileptic encephalopathy, mus-
cular hypotonia, respiratory insufficiency, extrapyramidal move-
ment disorders, cortical visual failure, microcephaly, and severe Treatment and outcome
developmental delay. Agenesis of corpus callosum and optic nerve
Treatment is symptomatic. Patients with a severe onset and intract-
hypoplasia may be present. Otherwise, brain MRI may be similar to
able epileptic seizures have a poor prognosis: eight of twelve recently
patients with d-​2-​hydroxyglutaric aciduria type II.
reported cases died between 1 month and 5 years of age.
Diagnosis
N-​Acetylaspartic aciduria (Canavan’s disease)
Clinical and neuroradiological suspicion should prompt GC/​MS
Aetiology/​pathophysiology
analysis of urinary organic acids and differentiation of l-​2-​ and d-​2-​
stereoisomers. The diagnosis can be confirmed by molecular genetic N-​
Acetylaspartic aciduria is a devastating infantile neuro­
analysis. degenerative disorder. In 1931, a child with spongy matter
 12.2 Protein-dependent inborn errors of metabolism 1969

degeneration was described by Canavan. In 1986, it was rec-

ognized that N-​acetylaspartic aciduria was caused by deficient
aspartoacylase in a child with a similar clinical presentation.
In 1988, aspartoacylase deficiency was definitely linked to
Canavan’s disease.
Canavan’s disease is found in all ethnic populations but re-
veals a much higher frequency in Ashkenazi Jews (1 in 5000 to 1
in 14 000 newborns). The frequent missense mutation p.E285A in
the aspartoacylase gene, localized on 17p13-​pter, accounts for more
than 80% of alleles in Ashkenazi Jews and for 60% of alleles in pa-
tients of non-​Jewish origin. In healthy individuals, high concen-
trations of N-​acetylaspartic acid (8 mmol/​g tissue) are exclusively
found in brain tissue.
Aspartoacylase is localized in oligodendrocytes catalysing the
deacetylation of N-​acetylaspartic acid to produce acetate, a substrate
for the synthesis of myelin lipids including cholesterol. It has been
proposed that N-​acetyl-​l-​aspartate may function as a molecular
water pump in myelinated neurons, transporting water against its
gradient from neurons to oligodendrocytes. Thus aspartoacylase de-
ficiency may cause both accumulation of metabolic water causing
spongiform white matter changes, and deficiency of acetyl groups
needed for cholesterol biosynthesis, causing demyelination; both are Fig. 12.2.12 Axial fast spin echo image of a 6½-​year-​old girl with
characteristic of Canavan’s disease. aspartoacylase deficiency. Note the marked discrepancy between the
severely affected subcortical white matter and the relatively spared
Clinical presentation central white matter, at least frontally.
Reproduced with permission from Kölker et al. 2002.
Canavan’s disease mostly manifests at age 2 to 4 months with delayed
development. Hypotonia with prominent head lag, epilepsy, loss of
previously acquired skills, as well as progressive megalencephaly are
regularly found. Seizures and optic nerve atrophy develop during clinical changes were not pronounced and were relatively tran-
the second year of life. As the disease progresses, affected children sient. The prognosis of infantile Canavan’s disease is rapidly fatal,
develop pyramidal signs, and finally decerebration. whereas milder disease has been described with survival beyond the
Neuroimaging reveals characteristic symmetrical leukodystrophic teenage years.
changes with loss of arcuate fibres; histology demonstrates spongi- Ethylmalonic encephalopathy
form degeneration, in particular of the cortex and subcortical white
matter (Fig. 12.2.12) with less involvement in the cerebellum and Aetiology/​pathophysiology
brainstem. In infancy, changes may be subtle and misinterpreted Ethylmalonic encephalopathy is a devastating, infantile, autosomal
as delayed myelination or periventricular leukomalacia. Variant recessive neurometabolic disorder affecting the brain, gastrointes-
Canavan’s disease has been described and partially been proven to tinal tract, and peripheral veins. The underlying metabolic defect was
be caused by the same metabolic defect. identified in a β-​lactamase-​like, iron-​coordinating metalloprotein
of the mitochondrial matrix encoded by the ETHE1 gene. Only re-
Diagnosis cently, it was elucidated using Ethe1-​deficient mice that the deficient
Muscular hypotonia, head lag, and progressive megalencephaly in protein is a mitochondrial sulphur dioxygenase which is involved
infancy are the classic clinical triad of Canavan’s disease. in the catabolism of sulphide in ethylmalonic encephalopathy. As
The identification of the accumulating N-​acetylaspartic acid by a consequence, toxic levels of sulphide and thiosulphide are found
GC/​MS analysis and confirmation of the suspected diagnosis by en- causing powerful inhibition of cytochrome c oxidase, short-​chain
zyme analysis (skin fibroblasts) or mutation analysis has obviated fatty acid oxidation, and exerting vasoactive and vasotoxic effects.
the need for brain biopsy for the diagnosis of Canavan’s disease. This explains deficient mitochondrial energy metabolism, the ab-
Prenatal diagnosis is possible by quantitative GC/​MS analysis of normal accumulation short-​chain organic acids, acylglycines and
N-​acetylaspartic acid in amniotic fluid or by mutation analysis. In acylcarnitines, as well as microangiopathy.
contrast, enzyme activity is unsuitable for reliable prenatal diagnosis.
Clinical presentation
Treatment and outcome Ethylmalonic encephalopathy is characterized biochemically by
Management is symptomatic (antiepileptics) and palliative. Special ethylmalonic aciduria and methylsuccinic aciduria, lactic acidaemia,
care is needed to prevent recurrent aspirations. Many patients need and clinically by severe psychomotor retardation, acrocyanosis, pe-
tube or gastrostomy feeding. Dietary therapies have not been shown techiae, and chronic diarrhoea.
to be beneficial and are potentially harmful. A promising protocol Newborns present with muscular hypotonia followed by pro-
for gene therapy was published in 2002 involving the transfer of gressive neurological deterioration, especially pyramidal dys-
human aspartoacylase cDNA intraventricularly; however, the function, learning difficulties, orthostatic acrocyanosis with distal
1970 SECTION 12 Metabolic disorders

1* 2*
Phenylalanine Tyrosine Dihydroxyphenylalanine

BH4 BH2 BH4 BH2

3* 3*
4*
Phenyl p-Hydroxyphenyl Dopamine
pyruvate pyruvate

Homogentisate Noradrenaline
5*

Maleylacetoacetate
Adrenaline

Phenylacetate Fumarylacetoacetate

6*
Fig. 12.2.13 Patient with ethylmalonic encephalopathy. Phenylacetylglutamine

Fumarate
swelling, chronic diarrhoea, and recurrent petechiae (Fig. 12.2.13). +
acetoacetate
Haematuria is often present. MRI scans show signal changes in cere-
3*
bellar white matter and lesions in the basal ganglia, the latter ap- BH4 BH2
pearing suddenly.
5OH
Diagnosis Tryptophan Tryptophan 5-Hydroxytryptamine
7*
The biochemical hallmark is increased urinary excretion of Fig. 12.2.14 The metabolism of phenylalanine and tyrosine and the
ethylmalonic and methylsuccinic acids associated with abnormal role of tetrahydrobiopterin. The asterisked enzymes are 1, phenylalanine
excretion of C4-​and C5-​(n-​butyryl-​, isobutyryl-​, isovaleryl-​, and 2-​ hydroxylase; 2, tyrosine hydroxylase; 3, dihydrobiopterin reductase;
methylbutyryl-​) acylglycines and acylcarnitines as well as intermit- 4, tyrosine aminotransferase; 5, homogentisic acid oxidase; 6, fumaryl
tent lactic acidosis. Since primary mitochondrial disorders are an acetoacetate hydrolyase; and 7, tryptophan hydroxylase.
important differential diagnosis, enzymatic analyses of respiratory
chain enzymes in muscle biopsy specimen have been performed in Aetiology/​pathophysiology
some patients revealing secondary cytochrome c oxidase deficiency. PKU is an autosomal recessive disorder caused by a severe defect
Mutation analysis of the ETHE1 gene provides the definitive diag- of phenylalanine hydroxylase which converts phenylalanine into
nosis including prenatal diagnosis. Increased ethylmalonate in urine tyrosine (Fig. 12.2.14). Tetrahydrobiopterin is required as a cofactor
is also found in multiple-​and short-​chain acyl-​CoA dehydrogenase and thus hyperphenylalaninaemia may also be caused by inappro-
deficiencies, primary respiratory chain deficiencies, and Jamaican priate generation of tetrahydrobiopterin. Through mechanisms still
vomiting sickness. not completely understood, the excess phenylalanine is toxic to the
Treatment and outcome central nervous system. Phenylalanine competes with the transport
of large neutral amino acids through the blood–​brain barrier using
No effective treatment is known. The prognosis is poor and the sodium-​independent system L and induces cerebral depletion
ethylmalonic encephalopathy is usually lethal in early childhood. of these amino acids and, subsequently, reduced synthesis of pro-
Defects of phenylalanine and tyrosine metabolism teins and neurotransmitters (large neutral amino acid hypothesis of
PKU). In addition, phenylalanine competes with glycine and glu-
Phenylketonuria tamate at their binding sites in N-​methyl-​d-​aspartate and α-​amino-​
The hyperphenylalaninaemias are a group of disorders characterized 3-​hydroxy-​5-​methyl-​4-​isoxazolepropionic acid receptors, thus
by defective hydroxylation of phenylalanine to tyrosine resulting in impairing glutamate signalling and, subsequently, synapse forma-
plasma phenylalanine values above the normal fasting range of 40 tion and cognitive function. Furthermore, phenylalanine inhibits
to 80 µmol/​litre. PKU was first identified by the Norwegian Asbjørn the rate-​limiting enzyme of cholesterol biosynthesis, 3-​hydroxy-​3-​
Følling in 1934 in several severely disabled individuals. Følling de- methylglutaryl-​CoA reductase, and switches forebrain oligodendro-
termined the urinary excretion of phenylpyruvic acid which led cytes to a nonmyelinating state.
to the previously used term ‘phenylpyruvic oligophrenia’. In 1947,
Jervis localized the metabolic error as an inability to oxidize phenyl- Clinical presentation
alanine to tyrosine. In 1953, Bickel and colleagues demonstrated Untreated, PKU almost invariably causes severe learning difficulties.
that a phenylalanine-​restricted diet was beneficial, and was thus the Newborns with PKU are asymptomatic since fetal phenylalanine is
first successful treatment of an inborn error of metabolism and one metabolized by the mother’s liver. On regular intake of natural pro-
which led the way to early diagnosis by newborn screening and treat- tein, phenylalanine levels quickly rise. Constitutional abnormal-
ment. The worldwide overall incidence of PKU is approximately 1 in ities (80–​100% of patients) such as hypopigmentation of the skin
10 000, with a large national and ethnic variability. and hair (fair) and iris (blue) develop rapidly because synthesis of
 12.2 Protein-dependent inborn errors of metabolism 1971

melanin from tyrosine is impaired. Elevated phenylacetate excretion growth spurts in childhood and adolescence the requirement for
gives the urine an odour reminiscent of mice and can cause an ec- phenylalanine may transiently increase.
zematous skin eruption. When a very strict diet is begun early and is well maintained,
Delayed psychomotor development may become evident from affected children can expect normal development. Regression of
the third month of life. It has been estimated that one IQ point is IQ and development of neurological symptoms when diets were
lost for each week of delay in diagnosis and treatment. Cognitive stopped in later childhood have led to continuation of dietary treat-
function is severely compromised in untreated children (IQ ment into the teenage years and adulthood. Patients generally have
<40). Microcephaly and movement disorders are frequent, as are not suffered when the diet was stopped at or after 15 or 16 years of
hyperexcitability as well as hypoexcitability and seizures; some pa- age. However, there is no follow-​up with respect to IQ change of
tients develop autistic behaviour or aggressiveness. Most patients a substantial number who have been off diet for 20 years or more.
with untreated PKU cannot be managed by their families and re- Most recommendations and centres have adopted a philosophy of
quire institutional care. ‘diet for life’. However, the urgent need for more detailed informa-
tion remains.
Diagnosis
Maternal PKU
In many countries, newborns are screened for increased phenyl-
In 1980, Lenke and Levy reported the severe effects of maternal
alanine levels in dried blood spots during the first days of life (new-
hyperphenylalaninaemia in the fetus (Table 12.2.5). The clinical
born screening). Originally, newborn screening of phenylalanine
features are similar to the fetal alcohol syndrome, and the severity
was performed by a bacterial inhibition assay (Guthrie test). The
of manifestations depends on the maternal phenylalanine level. In
implementation of MS/​MS techniques has, however, significantly
addition to learning difficulties and behavioural disorders, the ad-
improved the early identification of affected individuals by new-
verse effects include malformations such as cardiac defects (usu-
born screening. Confirmation of a positive screening result is per-
ally conotruncal), microcephaly, dysmorphic features, intrauterine
formed by quantitative amino acid analysis and mutation analysis.
growth retardation, neuronal migration disorders, and agenesis of
Liver biopsy and subsequent determination of the hepatic activity of
the corpus callosum.
phenylalanine hydroxylase is not indicated.
Defects in the metabolism of tetrahydrobiopterin (BH4), the Treatment and outcome
cofactor of phenylalanine hydroxylase, have to be differentiated Because of active placental transport, the ratio of fetal to maternal
from classic PKU by urinary pterin analysis and enzyme ana- phenylalanine plasma levels is 1.5 to 1.7. Maternal phenylalanine
lysis of dihydropteridine reductase in dried blood spots. In many values should be between 120 and 360 µmol/​litre, which requires a
centres, an oral dose of 20 mg/​kg BH4 is administered. To per- strict diet and very careful monitoring twice weekly. Microcephaly
form this test accurately, the initial plasma phenylalanine con- and congenital heart disease in the offspring of mothers returning
centration should be greater than 400 µmol/​litre (6.7 mg/​dl). to diet at the seventh or eighth week emphasizes the need for pre-
Following BH4 administration, plasma samples are collected for conception diet and training. Lowering maternal plasma phenyl-
phenylalanine and tyrosine analysis at defined time points as well alanine concentrations during pregnancy to a level between 120 and
as urine samples for pterin analysis. Notably, BH4 normalizes 360 µmol/​litre results in a favourable outcome in virtually all cases.
phenylalanine concentrations in patients with a primary disorder
of BH4 (see ‘Defects of biopterin metabolism’). This test has the Defects of biopterin metabolism
advantage that it may also identify BH4-​responsive individuals In the hydroxylation of phenylalanine, the cofactor BH4 is con-
with PKU. sumed and must be regenerated. BH4 is formed in a three-​step
pathway from guanosine triphosphate. The first and rate-​limiting
Treatment and outcome reaction is catalysed by guanosine triphosphate cyclohydrolase and
The most important therapeutic intervention in PKU is leads to the production of dihydroneopterin triphosphate. A defi-
phenylalanine-​restricted dietary treatment. Regular phenylalanine ciency of BH4 does not only impair phenylalanine hydroxylase in
determinations are used for monitoring. Unfortunately, recom- the liver, resulting in hyperphenylalaninaemia, but also tyrosine
mendations for PKU treatment differ considerably with regard to hydroxylase, tryptophan hydroxylase, as well as nitric oxide syn-
cut-​off levels to begin dietary treatment, age-​dependent recom- thases (Fig. 12.2.15). Tyrosine hydroxylation is needed for the
mendations for phenylalanine concentrations, frequency of clinical synthesis of noradrenaline and dopamine, and tryptophan hydrox-
examinations, and phenylalanine monitoring (Table 12.2.4). There ylation for the production of serotonin. BH4 is therefore crucial to
is no rational explanation for this. the production of neurotransmitters. The supply of this coenzyme is
The concept of dietary treatment has four components: (1) com- impaired in five recessively inherited enzyme defects. Most produce
plete avoidance of food containing abundant phenylalanine (e.g. hyperphenylalaninaemia, which may not be marked. All but pterin-​
meat, fish, milk, etc.); (2) calculated intake of natural food with a 4α-​carbinolamine dehydratase deficiency cause progressive neuro-
low phenylalanine/​protein ratio (e.g. vegetables and fruit) and low-​ logical disease. In less than 1% of newborns a raised phenylalanine
protein products; (3) adequate intake of energy substrates; and value detected by newborn screening is due to a defect of biopterin
(4) calculated intake of phenylalanine-​free amino acid supplements, metabolism.
vitamins, minerals, and trace elements. During catabolic states The enzyme defects lead to reduced levels of BH4 within the cen-
phenylalanine concentrations may increase, which is counteracted tral nervous system without significantly affecting phenylalanine
by dietary reduction of phenylalanine intake. In contrast, during metabolism in the liver (normal plasma phenylalanine). However,
 1972

Table 12.2.4 Guidelines for treatment and monitoring of PKU: international comparison

Germany 1999 UK 1993 USA 2014

Indication for dietary treatment >600 µmol/​litre >400 µmol/​litre >360 µmol/​litre
Start of dietary treatment As soon as possible ≤ day 20 of life ≤ day 7 of life
Recommendations for phenylalanine levels and frequency of phenylalanine monitoring
Germany 1999 UK 1993 USA 2014 Age Germany 1999 UK 1993 USA 2014
40–​240 µmol/​litre 120–​360 µmol/​litre 120–​360 µmol/​litre 0 2–​4×/​month 4×/​month 4×/​month
(0.7–​4 mg/​dl) (2–​6 mg/​dl) (2–​6 mg/​dl)
1 1–​2×/​month 2×/​month
2
SECTION 12 Metabolic disorders

3
4
5 2×/​month
School age: 6
120–​480 µmol/​litre 7
(2–​8 mg/​dl)
8
9
40–​900 µmol/​litre (0.7–​15 mg/​dl) 10 1×/​month 1×/​month
11
Adolescence and adulthood Adolescence and adulthood 12
120–​700 µmol/​litre 120–​360 µmol/​litre 13 1×/​month
(2–​11.7 mg/​dl) (2–​6 mg/​dl)
14
15
40–​1200 µmol/​litre 16 4–​6 ×/​year
(0.7–​20 mg/​dl)
17
120–​360 µmol/​litre 18+
(2–​6 mg/​dl)
Recommendations for clinical monitoring
Germany 1999 Germany 2004 UK 1993 USA 2000
Dietary training Amino acid profile Nutrition No details
Anthropometric data Blood count Growth
Health status Minerals, trace elements General health status
Neurological status Calcium and phosphorus metabolism
Psychological development Enzymes: AP, GOT, GPT
Vitamins and serum lipid status
 12.2 Protein-dependent inborn errors of metabolism 1973

Table 12.2.5 Incidences (%) of abnormalities in the offspring kidney development and function. Mutations in PCBD1 have re-
of mothers affected with classical PKU cently been reported to cause early-​onset nonautoimmune diabetes
mellitus highlighting that PCBD1 activity is required for early pan-
Congenital abnormalities Maternal PKU Unaffected mothers
creatic development. In addition, adult patients with PCBD1 defi-
Mental disability 92 5
ciency and hypomagnesaemia due to renal magnesium wasting have
Microcephaly 73 4.8 been identified demonstrating that PCBD1 also plays an important
Intrauterine retardation 40 9.6 role in the kidney, in particular in the distal convoluted tubule.
Congenital heart defects 12 0.8 In later infancy and childhood, defects in the metabolism of the
biogenic monoamines may be suspected in patients with (fluc-
Source data from Lenke R, Levy HL (1980). Maternal PKU and hyperphenylalaninemia:
an international study of treated and untreated pregnancies. N Engl J Med, 303, 1202–​8. tuating) extrapyramidal disorders, in particular parkinsonism
dystonia or more general ‘athetoid cerebral palsy’, and vegetative
disturbances. A severe epileptic encephalopathy and progressive
turnover of serotonin and the catecholamines in the brain can still learning difficulties may be present.
become severely compromised. Fasting plasma phenylalanine levels
are always normal in the dominantly inherited guanosine triphos- Diagnosis
phate cyclohydrolase deficiency (Segawa’s disease) and the auto- Every infant with hyperphenylalaninaemia detected in a population
somal recessive sepiapterin reductase deficiency. newborn screening programme or in the course of other diagnos-
tics later in life must be carefully investigated for possible defects of
Clinical presentation
biopterin metabolism (see also ‘Phenylketonuria’). Differential diag-
Except for pterin-​ 4α-​carbinolamine dehydratase (PCBD1) defi- nosis requires the analysis of pterins in urine or from Guthrie cards
ciency, autosomal recessive defects of biopterin metabolism re- as well as the determination of enzyme activity of dihydropteridine
sult in severe encephalopathies. Common but variable symptoms reductase in dried blood spots. If the initial plasma phenylalanine
are progressive learning difficulties, dystonia, chorea, oculogyric concentration is above 400 µmol/​litre (6.7 mg/​dl), oral loading with
crises, convulsions, tremor, spasticity, microcephaly, growth re- BH4 (20 mg/​kg) will result in normalization of phenylalanine values
tardation, swallowing difficulties, and depressive and aggressive be- within 4 to 8 h. Urinary biopterin and neopterin values are low in
haviour. Diurnal variation is often present. Onset of symptoms is the guanosine triphosphate cyclohydrolase deficiency, whereas 6-​
in the first months of life with hypotonia; sometimes affected new- pyruvoyltetrahydrobiopterin synthase deficiency has high neopterin
borns have difficulties in postnatal adaptation. Signs of autonomic values and low biopterin values. In patients with dihydropteridine
dysfunction include hypersalivation, temperature instability, leth- reductase deficiency, neopterin is normal or slightly elevated and
argy, hypersomnolence, and episodes of sweating and pallor. Less biopterin very high. After the biochemical diagnosis, all defects
frequently reported are ‘bulbar’ signs (drooling, dysarthria, ab- should be ascertained enzymatically and, if available, by mutation
normal tongue movements), ‘ataxia’, probably not cerebellar ataxia analysis. Following a diagnosis of a defect of biopterin metabolism, a
or sensory ataxia but dystonic gait, and Gower’s sign. PCBD1 is lumbar puncture becomes necessary for analysis of the neurotrans-
a bifunctional protein that acts as an enzyme in the regeneration mitter metabolites 5-​hydroxyindoleacetic acid and homovanillic
of BH4 and as a dimerization cofactor of the transcription factors acid as well as neopterin, biopterin, and 5-​methyltetrahydrofolic
HNF1A and HNF1B, which are important in liver, pancreas, and acid. This allows differentiation between severe and mild forms
of BH4 deficiencies and sets the indication for treatment with the
neurotransmitter precursors l-​dopa and 5-​hydroxytryptophan.
GTP In patients with suggestive encephalopathies and normal phenyl-
GTPCH alanine values, analysis of neurotransmitters in cerebrospinal fluid
is the only way of diagnosis.
Neopterin
PTPS
Treatment and outcome
SR Blood phenylalanine concentrations should be more rigidly con-
trolled than in classic PKU patients. In patients with guan­osine triphos-
phate cyclohydrolase deficiency and 6-​pyruvoyl­tetrahydrobiopterin
BH4 PAH, deficiency, administration of BH4 appears to be the most efficient
DHPR TYH, therapy in controlling blood phenylalanine levels. Patients with
TPH,
BH2 PCD dihydropteridine reductase deficiency need a low-​phenylalanine
NOS
Biopterin diet as in PKU.
Fig. 12.2.15 Biopterin metabolism. BH4 is synthesized and regenerated Deficiency of neurotransmitters requires treatment with the
by five enzymes. BH4 is consumed as a cofactor in the hydroxylation neurotransmitter precursors l-​dopa (3–​15 mg/​ kg per day) and
of tyrosine and tryptophan as well as phenylalanine (see also PKU) and 5-​hydroxytryptophan (2–​9 mg/​kg per day) in combination with
nitric oxide synthase (NOS). BH2, dihydrobiopterin. Relevant enzyme carbidopa (10 or 25% of l-​dopa). Lumbar punctures must be repeated
defects: DHPR, dihydropteridine reductase; GTPCH, GTP cyclohydrolase; regularly to adjust doses. In patients revealing l-​dopa-​induced peak-​
PCD, pterin carbinolamine dehydratase; PTPS, 6-​pyruvoyl-​
tetrahydropterin synthase; SR, sepiapterin reductase. dose dyskinesia slow-​release forms of drugs can be used, and reaching
Source data from Zschocke J, Hoffmann GF (2011). Vademecum metabolicum. the upper therapeutic limits of l-​dopa may be an indication for the
Manual of metabolic paediatrics, 3rd edition. Schattauer, Stuttgart. use of monoamine oxidase and/​or catechol-​O-​methyltransferase
1974 SECTION 12 Metabolic disorders

inhibitors. Patients with dihydropteridine reductase deficiency, in hepatomegaly, fever, oedema, and epistaxis; by the end of the first
addition, need administration of folinic acid to restore normal cere- year of life 90% have developed symptoms. The disease can progress
brospinal fluid folate concentrations. rapidly and death from hepatic failure often occurs in infancy.
Normal long-​term psychomotor development can be achieved A milder more chronic presentation is compatible with survival
but outcome strongly depends on the age when the diagnosis is for several years with chronic liver disease, a renal tubular Fanconi’s
made and how rigidly therapy is followed, especially in early life. syndrome with hypophosphataemic rickets, and episodic abdom-
inal pain and neuropathy suggestive of acute porphyria. The most
Dominantly inherited guanosine triphosphate serious complication is hepatocellular carcinoma which develops in
cyclohydrolase deficiency early childhood in one-​third of untreated patients.
Clinical presentation
Diagnosis Raised plasma tyrosine (often together with methio-
Dominantly inherited guanosine triphosphate cyclohydrolase nine), succinylacetone, and 5-​aminolaevulinic acid excretion as
deficiency, often called Segawa’s disease, is an eminently treat- well as renal Fanconi’s syndrome are the biochemical markers of
able condition. Early recognition is therefore of crucial import- tyrosinaemia type I caused by a deficiency of fumarylacetoacetate
ance. Presentation in children usually occurs within the first hydrolyase, the last enzyme in the pathway of tyrosine degradation
decade of life with a mean age of onset of symptoms being about (Fig. 12.2.14). Serum α-​fetoprotein is usually strikingly elevated.
7 years (range 16 months to 13 years). The first symptom is usu- Succinylacetone, formed from fumarylacetoacetate, is the most spe-
ally postural dystonia of one leg with progression to all limbs cific diagnostic metabolite. Plasma tyrosine values may be normal,
followed by action dystonia and hand tremor within the next resulting in insufficient specificity of this parameter for newborn
10 to 15 years, during which time cognition remains intact. screening.
Occasionally, in older children, the first signs may start in the Fumarylacetoacetate hydrolyase can be assayed in lymphocytes
arms with torticollis or writer’s cramp (focal dystonia). The dys- or fibroblasts. It is nonspecifically depressed in the liver in a var-
tonia is frequently asymmetrical and accompanied by reduced iety of liver diseases. The measurement of succinylacetone in amni-
facial expression or slowing of fine finger movements. Diurnal otic fluid and activity of fumarylacetoacetate hydrolyase in cultured
fluctuation is often present, with symptoms improving after night-​ amniocytes or chorionic villus samples forms the basis of prenatal
time sleep or bed rest. The variation in presenting symptoms is diagnosis, if informative mutations are not available.
large. Penetrance is reduced and many carriers of a mutant gene
Treatment and outcome Restricted intake of tyrosine and phenyl-
are asymptomatic.
alanine may reduce the excretion of succinylacetone and produce
Diagnosis regression of the Fanconi tubular defects, but does not cure the liver
disease. The risk of hepatocellular carcinoma remains and early
In classic cases with prominent dystonia of the lower limbs, marked
liver transplantation was the treatment of choice until nitisinone
diurnal variation, as well as worsening of the symptoms after ex-
(2-​(2-​nitro-​4-​trifluoromethylbenzoyl)1–​3-​cyclohexanedione) was
ercise, the clinical diagnosis of the deficiency is easily made, in
introduced by Lindstedt and colleagues in 1991. Nitisinone almost
particular in the presence of dramatic and sustained response to
completely blocks 4-​ hydroxyphenylpyruvate dioxygenase thus
l-​dopa. However, the diagnosis can be a real challenge in atypical
turning tyrosinaemia type I into tyrosinaemia type III and redu-
cases, in which it can be ascertained by determining BH4, and de-
cing the production of toxic metabolites. Treatment with nitisinone
creased levels of neopterin and homovanillic acid in cerebrospinal
should start as soon as the diagnosis is made with a dose of 1 mg/​
fluid. Confirmation of the diagnosis can be achieved by enzyme ana-
kg per day. In most patients there is a rapid improvement in liver
lysis in cultured skin fibroblasts or by mutation analysis.
and renal function; succinylacetone should disappear from the urine
Treatment and outcome within 1 week of treatment. Patients need to be treated with a diet
low in phenylalanine and tyrosine at the same time as introducing
Treatment relies on l-​dopa in combination with 10 to 25% carbidopa.
nitisinone. Plasma levels of tyrosine should be kept between 250 and
Amounts administered have varied between 3 and 10 mg/​kg per day
500 µmol/​litre.
divided into one to four doses with the effectiveness of treatment
The long-​term results of nitisinone treatment are encouraging
being monitored by the clinical outcome. The long-​term prognosis
with greatly reduced incidence of liver damage and hepatic car-
is usually excellent.
cinoma. Liver transplantation remains the treatment of choice for
Tyrosinaemias a few patients who do not respond to nitisinone and if there is any
suggestion of malignant change.
The steps in tyrosine metabolism starting with the rate-​limiting
step—​the conversion to p-​hydroxyphenylpyruvic acid by tyrosine
aminotransferase—​are outlined in Fig. 12.2.14. Intermediates of Tyrosinaemia type II (tyrosine aminotransferase deficiency)
this tyrosine metabolism are used for production of catecholamines, Clinical presentation Corneal erosions and dendritic ulcers may
dopamine, and the principal pigment of hair and skin, melanin. form within a few months of birth with later scarring, nystagmus,
and glaucoma. Skin lesions may begin after the eye lesions with blis-
Tyrosinaemia type I (fumarylacetoacetase deficiency) tering, painful palms and soles, and hyperkeratosis. Tongue changes
Clinical presentation Tyrosinaemia type I is also known as have been described. Learning difficulties are an inconstant feature
hepatorenal tyrosinosis. About one-​ third of patients present in about 50% of patients, but language defects may be more common
acutely in the early weeks of life with failure to thrive, vomiting, with possible impaired coordination and self-​mutilation.
 12.2 Protein-dependent inborn errors of metabolism 1975

Diagnosis Tyrosine aminotransferase, which is deficient, cata- Diagnosis

lyses the formation of p-​hydroxyphenylpyruvic acid (Fig. 12.2.14). Homogentisic acid can be demonstrated by urinary organic acid
Plasma tyrosine values reach 20 times normal (normal 40–​100 µmol/​ analysis. Enzymatic as well as molecular confirmation is possible.
litre) in younger patients and 10 times normal in others. There is Plasma tyrosine concentrations are normal.
increased excretion of tyrosine, N-​acetyltyrosine, tyramine, and of
phenolic acids; there is no Fanconi’s syndrome and no increase in Treatment and outcome
succinylacetone. So far no treatment has been shown to prevent the long-​term com-
The clinical features and amino acid analyses are usually sufficient plications. The prognosis for the joints is poor. By the fifth decade,
for diagnosis, which may be confirmed either by measuring the en- the lumbar spine is likely to be rigid and other joints will be ser-
zyme activity in liver or by molecular genetic studies. iously affected. Patients often require large amounts of analgesic and
Treatment and outcome A low-​tyrosine, low-​phenylalanine diet risk the complications of long-​term consumption of nonsteroidal
has been used to produce rapid improvement of skin and eye mani- anti-​inflammatory agents, which may exacerbate incipient coronary
festations. Corneal transplants can be valuable. The neurological heart disease.
symptoms appear to improve less. The degree of dietary control Homogentisic acid can be decreased by a low-​protein diet. It is
needed to sustain clinical improvement is uncertain. Plasma tyro- very probable that specifically designed low-​phenylalanine and low-​
sine concentrations less than 500 μmol/​litre are considered desirable. tyrosine diets would lower the production still further. Nitisinone,
the triketone inhibitor of 4-​hydroxyphenylpyruvate dioxygenase
Tyrosinaemia type III (4-​hydroxyphenylpyruvate introduced by Lindstedt in 1991, greatly reduces overproduction
dioxygenase deficiency) of homogentisic acid in alkaptonuria. Early studies from Gahl’s
4-​Hydroxyphenylpyruvate dioxygenase deficiency (Fig. 12.2.14) ap- group at the National Institutes of Health, United States of America,
pears to be very rare and possibly without clinical pathology, that is, showed that in adults of both sexes with alkaptonuria, an oral dose
a nondisease. It may be associated with learning difficulties and pos- of 1.05 mg twice daily reduced urinary homogentisic acid excretion
sibly other neurological complications. The biochemical findings from a mean of 4 g to 0.2 g per day. More than 220 patients with her-
are similar to those in tyrosinaemia type II, but the plasma values editary tyrosinaemia type I have received the drug at daily doses of
of tyrosine are usually less than 1200 µmol/​litre. Enzyme and mo- 0.5 to 2.0 mg/​kg body weight and even at these doses it is generally
lecular genetic studies can prove the diagnosis. Most patients are well tolerated, apart from mild blood cytopenias. In alkaptonuria
treated with a low-​tyrosine, low-​phenylalanine diet. nitisinone, as predicted, may elevate the plasma tyrosine concentra-
tions (in the early trial from c.70 to 760 μmol/​litre) and there is thus
Alkaptonuria a theoretical risk of lens opacities, which can be avoided by careful
Clinical presentation slit-​lamp monitoring, plasma amino acid measurement, and dietary
adjustment. In alkaptonuria, the outcome of nitisinone treatment
In 1902, alkaptonuria was the first disorder to be recognized as an
will take many years to evaluate fully, but comprehensive therapeutic
inborn error of metabolism by Garrod. It is caused by a deficiency
study is justified by the clear relationship between overproduction
of homogentisate dioxygenase resulting in the accumulation of
of a single metabolite and life-​shortening tissue manifestations with
homogentisic acid and its oxidized derivative benzoquinone acetic
disabling joint disease.
acid. The latter can then be polymerized to form a dark pigment
which is deposited in connective tissue. The disorder is extremely Neurotransmitter diseases and related disorders
rare in most populations but occurs with greatly increased fre-
Monogenic defects of neurotransmission have become recog-
quency in the Dominican Republic and in Slovakia. Presentation in
nized as a cause of early-​onset, severe, progressive, and often treat-
infancy occurs only if discoloration of the urine is noticed. It is usu-
able encephalopathies. The diagnosis is based on the quantitative
ally normal when passed but darkens on standing (more rapidly at
determination of the neurotransmitters or their metabolites in
alkaline pH) to deep brown or almost black. Back pain begins in the
cerebrospinal fluid, that is, glycine, serine, and GABA, the acidic me-
second and third decade with increasing stiffness due to interverte-
tabolites of the biogenic monoamines, and individual pterin species
bral disc degeneration. Involvement of the hips, knees, and shoul-
(Box 12.2.6). Determinations of metabolites in blood or urine are
ders follows. Greyish discoloration of cartilage is seen in the pinna,
neither sensitive nor specific. In contrast to inborn errors in cata-
and pigment is deposited in the sclera. Abnormal pigmentation is
bolic pathways, neurotransmitter defects are determined by the
seen in the heart valves and joint cartilages, and pigmented stones
are common in the prostate. Valvular calcification is prominent, es-
pecially in the coronary arteries. Recent studies of the natural course
of alkaptonuria indicate that it is associated with premature heart Box 12.2.6 Cerebrospinal fluid: investigation
disease and premature death with long-​standing impairment of for neurotransmitter disorders
quality of life. Pigment deposition with involvement of the fibrolipid • Cells, protein, immunoglobulin classes, and glucose (plus plasma glu-
components of atherosclerotic plaques cause calcific stenosis of the cose and evaluation of blood–​brain barrier)
aortic valve. In 58 patients studied by Phornphutkul and colleagues • Lactate and pyruvate
(2002), life-​table analysis showed that joint replacement occurred • Amino acids (plus plasma obtained simultaneously)
• Biogenic monoamine metabolites
at a mean age of 55 years, renal stones at 64 years, and cardiac valve
• Individual pterin species
involvement at 54 years; coronary calcification occurred at a mean
• 5-​Methyltetrahydrofolate
age of 59 years.
1976 SECTION 12 Metabolic disorders

interplay of biosynthesis, degradation, and receptor status. Even l-​dopa-​responsive dystonia due to haploinsufficiency of guanosine
borderline abnormalities can be diagnostic and their recognition triphosphate cyclohydrolase I, often neither the neurological status
requires a strictly standardized sampling protocol and adequate age-​ nor the catecholamine levels in cerebrospinal fluid can be com-
related reference values. pletely normalized in most patients.
At the severe end of the spectrum, virtually no movements are
Disorders of monoamine metabolism observed, not even dystonic movements. Some patients are more
Defects in the metabolism of the biogenic monoamines affect sero- severely affected and present with a progressive neurometabolic
tonin and/​or catecholamine (dopamine and noradrenaline) metab- disorder from early infancy with a progressive infantile enceph-
olism (Fig. 12.2.16). They present from infancy or childhood with alopathy characterized by abnormal extrapyramidal movements
(fluctuating) extrapyramidal disorders, in particular parkinsonian and affecting several cerebral and possibly cerebellar systems. It is
dystonia or more general ‘athetoid cerebral palsy’, and vegetative important to stress that such patients also show symptoms of sig-
disturbances, most noticeably hypoglycaemia. A severe epileptic en- nificant catecholamine deficiency, such as hypoglycaemia and in-
cephalopathy and progressive learning difficulties may be present. adequate stress responses. There is an obvious tendency to preterm
birth with troublesome cardiorespiratory perinatal adaptation.
Tyrosine hydroxylase deficiency Most infants with tyrosine hydroxylase deficiency develop sur-
prisingly normally until an arrest of motor development with
Tyrosine hydroxylase catalyses the hydroxylation of l-​tyrosine to
a characteristic combination of neurological symptoms later in
l-​dopa, the rate-​limiting step in the biosynthesis of the catechol-
infancy. Hypokinesia, marked truncal hypotonia, a mask face,
amines dopamine, noradrenaline, and adrenaline (Fig. 12.2.16). The
oculogyric crises, myoclonic jerks, and an extrapyramidal tremor
iron-​containing mixed function oxidase requires molecular oxygen
can progressively develop. The last three symptoms can be mis-
and the cofactor BH4. Tyrosine hydroxylase is expressed only in
taken as epileptic phenomena. Oculogyric crises are present but, as
catecholaminergic neurons and the adrenal medulla.
with the miosis, may go undiagnosed because of prominent ptosis.
Tyrosine hydroxylase deficiency has become incorporated into
Contractures, failure to thrive, and immobilization may develop.
concepts and classifications of dystonias as the cause of reces-
It appears likely that life expectancy is significantly reduced; (dys-
sive l-​dopa-​responsive dystonia, but can also present as l-​dopa-​
tonic) cerebral palsy is a likely descriptive (mis-​)diagnosis. Some
nonresponsive dystonia or progressive early-​onset encephalopathy.
patients did not develop extrapyramidal symptoms in the first
Clinical presentation Clinical symptoms often develop between year of life, were able to walk independently, and followed a clin-
3 and 7 months of age. Most patients show a substantial clin- ical course best summarized as spastic paraplegia. Their symptoms
ical improvement already on low doses of l-​dopa together with fully resolved following l-​dopa supplementation, and they are now
the decarboxylase inhibitor carbidopa, although in contrast to healthy adults living independently.

5-HIAA

MAO

TR + BH4 AADC + B6
tryptophan 5-OH-tryptophan serotonin

TH + BH4 AADC + B6 DβH PNM

tyrosine L -DOPA dopamine noradrenaline adrenaline

COMT MAO COMT COMT COMT

3-O-methyldopa DOPAC 3MT NM M

COMT COMT
COMT MAO ALD
MAO + aldd. MAO + alcd.

vanillyllactic acid HVA MHP G VMA

Fig. 12.2.16 Metabolism of biogenic monoamines. 5-​HIAA, 5-​hydroxyindolacetic acid; AADC, aromatic l-​aminoacid decarboxylase; alcd.,
alcohol dehydrogenase; ALD, intermediate aldehyde (3-​methoxy-​4-​hydroxyphenyl-​hydroxyacetaldehyde); aldd., aldehyde dehydrogenase;
BH4, tetrahydrobiopterin; COMT, catechol-​ortho-​methyltransferase; DbH, dopamine-​b-​hydroxylase; DOPAC, 3,4-​dihydroxyphenylacetic acid;
HVA, homovanillic acid; M, metanephrine; MAO, monoaminooxidase; MHPG, 3-​methoxy-​4-​hydroxy-​phenylglycol; MT, 3-​methoxytyramine;
NM, normetanephrine; PNM, phenylethanolamine-​N-​methyltransferase; TH, tyrosin hydroxylase; TR, tryptophan hydroxylase; VMA,
vanillylmandelic acid; . . ., several steps involved.
 12.2 Protein-dependent inborn errors of metabolism 1977

Diagnosis The diagnosis of tyrosine hydroxylase deficiency can guarded. About half of the patients improve on individual treatment
only be made via cerebrospinal fluid analysis following a stand- regimens and acquire different degrees of motor and psychosocial
ardized lumbar puncture protocol. A characteristic metabolite skills. Others do not show any improvements.
constellation is found: low concentrations of metabolites of dopa-
minergic neurotransmission homovanillic acid and 3-​ methoxy-​ Dopamine β-​hydroxylase deficiency
4-​
hydroxyphenylethyleneglycol in the presence of normal Clinical presentation Recessively inherited mutations in the dopa-
concentrations of metabolites belonging to the serotonin neurotrans- mine β-​hydroxylase gene lead to lowered levels of noradrenaline
mission system such as 5-​hydroxyindoleacetic acid (Fig. 12.2.16). within central and autonomic noradrenergic neurons (Fig. 12.2.16).
Urinary determinations of catecholamines and homovanillic acid The disorder is characterized by sympathetic noradrenergic de-
turned out to be inconclusive in several affected individuals. nervation and adrenomedullary failure. The central consequences
Enzyme analysis is not possible in tyrosine hydroxylase deficiency appear minimal. Syndromes become obvious in adolescence with
because tissues expressing enzyme activity—​ brain and adrenal noradrenergic failure, severe orthostatic hypotension, and ptosis
medulla—​are difficult to obtain. Thus mutation analysis is the only of the eyelids. During childhood fatigue, episodes of fainting, syn-
way to confirm the diagnosis. copes, and exercise intolerance are generally present. Physical and
cognitive function is normal. In males, autonomic neuropathy leads
Treatment and outcome Therapeutic interventions with l-​dopa
to retrograde ejaculation.
together with the decarboxylase inhibitor carbidopa and selegiline
were able to improve and/​or even normalize the clinical picture in Diagnosis Dopamine β-​hydroxylase deficiency is classified as a pri-
most patients but not all. Despite all therapeutic interventions, the mary autonomic neuropathy. Conditions that lead to chronic failure
disease course can be lethal. of the autonomic nervous system are, therefore, the primary differ-
Treatment with l-​dopa has to be started slowly and carefully, with ential diagnosis. Biochemically, dopamine β-​hydroxylase deficiency
doses as low as 0.5 mg/​kg per day in two to six divided doses to avoid is different from other conditions with orthostatic hypotension or
dyskinesias due to hypersensitivity and up-​regulation of dopamine autonomic dysfunction. Failure to produce noradrenaline and the
receptors in dopamine-​deficient patients. In such patients, l-​dopa consequent lack of end-​product inhibition of tyrosine hydroxylase
can only be increased very slowly, sometimes over several years. leads to a noradrenaline/​dopamine ratio of less than 0.1, and such
Slow-​release preparations may be useful to ensure constant l-​dopa a finding is pathognomonic for the disease. An increase in blood
levels. In general, incremental steps of l-​dopa/​carbidopa should not pressure and correction of the orthostatic hypotension in response
be more than 1 mg/​kg per day. to dihydroxyphenylserine is also diagnostic. Some 3 to 4% of the
normal adult population have near zero levels of the enzyme in
Aromatic l-​amino acid decarboxylase deficiency plasma, therefore plasma enzyme determination alone cannot be
Aromatic l-​amino acid decarboxylase deficiency is caused by used to confirm the diagnosis, it requires mutation analysis.
autosomal recessively inherited mutations in the DDC gene. The
Treatment and outcome Dopamine β-​hydroxylase deficiency
enzyme is required for the synthesis of both serotonin and the
is treated with dihydroxyphenylserine. This compound is decarb-
catecholamines.
oxylated by l-​amino acid decarboxylase to form noradrenaline.
Clinical presentation Clinical symptoms are indistinguishable Administration of 250 to 500 mg twice daily results in an increase
from those of patients with tyrosine hydroxylase deficiency. The se- in blood pressure and sustained relief of the orthostatic symptoms.
verity seems to fall into two groups. About half of the patients pre- Without appropriate treatment postural hypotension can lead to sig-
sent with feeding difficulties, autonomic dysfunction, and hypotonia nificant injuries or even death.
in the neonatal period. In the first few months of life dystonia or
intermittent limb spasticity, axial and truncal hypotonia, extreme Disorders of pyridoxine metabolism
irritability, oculogyric crises, and psychomotor retardation be- In 1954, Hunt and colleagues described a patient with a seizure dis-
come obvious. More mildly affected patients may initially develop order that was successfully treated solely by administration of pyri-
unremarkably or only slightly delayed and present with motor re- doxine (vitamin B6) and coined the term ‘pyridoxine dependency’.
tardation, hypokinesia, rigidity, and truncal hypotonia from early It became good clinical practice to test for pyridoxine responsive-
childhood. ness in every child with ‘difficult-​to-​treat’ seizures starting before
2 years of age. Later, a similar therapeutic response was described in
Diagnosis The enzyme deficiency leads to accumulation of 3-​
the same clinical constellation for folinic acid. Finally, the enzymatic
O-​methyldopa, 5-​hydroxytryptophan, and l-​dopa together with
defect has been pinpointed to the α-​aminoadipic semialdehyde de-
low concentrations of the end products homovanillic acid and 5-​
hydrogenase located in the lysine degradation pathway in the brain,
hydroxyindoleacetic acid (Fig. 12.2.16). 3-​O-​Methyldopa is formed
which results in the accumulation of the intermediate piperideine-​6-​
by methylation of l-​dopa. Confirmation of the diagnosis is by en-
carboxylate scavenging pyridoxal phosphate. A similar pathogenic
zyme assay in plasma and finally by mutation analysis.
mechanism again leading to intractable seizures is responsible for
Treatment and outcome Different approaches using dopamine pyridoxal deficiency in hyperprolinaemia type II and during treat-
agonists (pergolide, pramipexole, bromocriptine, and ropinirole) ment with the tuberculostatic drug isoniazid.
and/​or nonselective monoamine oxidase inhibitors (tranyl­ Another monogenic defect in humans is directly located within the
cypromine, phenelzine) have been attempted. Response to treat- synthesis of pyridoxal 5′-​phosphate: pyridox(am)ine 5′-​phosphate
ment is variable but outcome appears to be better in more mildly oxidase deficiency resulting in pyridoxal phosphate-​responsive seiz-
affected and later-​
presenting patients. The overall prognosis is ures (Fig. 12.2.17).
1978 SECTION 12 Metabolic disorders

Pyridoxine Pyridoxal Pyridoxamine onset with initially negative, but a later sustained positive response
to pyridoxine.
PK PK PK
Folinic acid-​sensitive seizures have been an enigmatic clinical and
Pyridoxine-P
PNPO
Pyridoxal-P
PNPO
Pyridoxamine-P
biochemical entity until it has been elucidated recently that they are
alleic to pyridoxine-​dependent epilepsy. Patients present with myo-
Membrane-associated phosphatases
clonic or clonic seizures, apnoea, and irritability within 5 days after
Cellular uptake
birth. The electroencephalogram shows a discontinuous background
pattern with multifocal spikes and sharp waves. Without specific
PK
treatment seizures will only be partially controlled. Psychomotor
Intracellular pyridoxal-phosphate development will become severely impaired. It is therefore recom-
mended that all patients with ‘difficult-​to-​treat’ seizures starting be-
fore 2 years should have a trial of pyridoxine and folinic acid (usually
Fig. 12.2.17 Pyridoxine metabolism. Pyridoxal phosphate (PALP;
vitamin B6) is cofactor of transamination and decarboxylation reactions given orally in this circumstance).
in various pathways including serotonin and dopamine biosynthesis.
It is synthesized from dietary pyridoxal, pyridoxamine, and pyridoxine; Diagnosis
enzymes involved include pyridoxal kinase (PK) and pyridox(am)ine The diagnosis of pyridoxine-​dependent epilepsy and folinic acid-​
5-​phosphate oxidase (PNPO). responsive seizures should be suspected clinically in patients with
Source data from Zschocke J, Hoffmann GF (2011). Vademecum metabolicum.
Manual of metabolic paediatrics, 3rd edition. Schattauer, Stuttgart. neonatal epileptic encephalopathy or ‘difficult-​ to-​
treat’ seizures
starting before 2 years of age who respond to pyridoxine and/​
or folinic acid. Because it is a treatable condition, a high index of
Each newborn with severe neonatal/​infantile epileptic enceph- suspicion is warranted. Both pyridoxine and pyridoxal phosphate
alopathy should have a lumbar puncture and then immediately may cause apnoea and prolonged cerebral depression after the ini-
receive consecutive therapeutic trials with vitamin B6, pyridoxal tial dose, and resuscitation equipment and intensive care facilities
5′-​phosphate, and folinic acid. should be available.
The suspected diagnosis can be confirmed by measurement of α-​
Aetiology/​pathophysiology aminoadipic semialdehyde in body fluids. Elevated CSF and plasma
Pyridoxine-​dependent epilepsy and folinic acid-​responsive seiz- pipecolic acid is also used as a biomarker. Furthermore, CSF analysis
ures are treatable causes of neonatal epileptic encephalopathy. may reveal a monoamine pattern similar to l-​amino acid dehydro-
The genetic base of both conditions is autosomal recessive inher- genase deficiency, elevated glutamate, and decreased GABA concen-
itance of pathogenic mutations in the ALDH7A1 (antiquitin) gene trations. Enzyme assay and mutation analysis of the ALDH7A1 gene
causing deficiency of the enzyme α-​aminoadipic semialdehyde is the most definitive proof of diagnosis.
dehydrogenase located in the pipecolic acid pathway, the major
route of cerebral lysine oxidation. As a consequence of accumu- Treatment and outcome
lating α-​aminoadipic semialdehyde and the cyclic compound ∆1-​ Treatment requires 5 to 30 mg/​kg body weight per day of pyridoxine
piperideine 6-​carboxylate, which spontaneously forms an adduct in one dose. Successful treatment with folinic acid can be achieved
with pyridoxal phosphate via a Knoevenagel reaction, pyridoxal with 3 to 5 mg/​kg body weight per day of folinic acid given in three
phosphate is inactivated resulting in cerebral depletion of pyridoxal doses. Doses need to be increased and adjusted to body weight
phosphate. Pyridoxal phosphate-​dependent enzymes such as glu- during growth. Breakthrough seizures are an obvious criterion for
tamate dehydrogenase, GABA transaminase and aromatic l-​amino increasing the dose. There is evidence that lower doses of pyridoxine
acid dehydrogenase are inactivated by pyridoxal phosphate deple- and folinic acid, while controlling seizures, may still not prevent the
tion causing significant disturbance in the metabolism of the neuro- development of cognitive impairment. High doses of pyridoxine
transmitters dopamine, serotonin, glutamate and GABA and thus a carry the risk of developing skin photosensitivity as well of a per-
severe epileptic encephalopathy. The conversion of pyridoxine, pyri- ipheral sensory neuropathy. Doses up to 1 g/​day can be regarded
doxal, and pyridoxamine to pyridoxal phosphate however remains as safe in older children. Serial cognitive assessment is therefore
unaffected. recommended. If there is a positive family history of pyridoxine-​
dependent seizures, maternal treatment in utero is indicated.
Clinical presentation Since pyridoxine-​dependent epilepsy and folinic acid-​sensitive
Pyridoxine-​dependent epilepsy can be heterogeneous in its presen- seizures appear to be genetically and biochemically identical, this
tation, and sometimes idiopathic epilepsies respond to treatment new understanding requires a re-​evaluation of optimal strategies
with high-​ dose pyridoxine. Classical patients with pyridoxine-​ such as the combined use of pyridoxine and folinic acid as well as of a
dependent epilepsy present with an intractable seizure disorder low-​lysine diet aiming to reduce the accumulation of α-​aminoadipic
within the first 2 days of life, and at the latest within 28 days. In semialdehyde and ∆1-​piperideine 6-​carboxylate.
some patients intrauterine convulsions are reported. There is no
consistent electrographic pattern. Continuous and discontinuous Hyperprolinaemia type II: l-​Δ -​pyrrolines-​5-​carboxylate
1

backgrounds, suppression burst-​like patterns, and hypsarrhythmia dehydrogenase deficiency

have all been observed. There are additional atypical presentations: Clinical presentation For a long time hyperprolinaemia type
(1) late onset, that is, later than 28 days; (2) neonatal onset but with an I, which has no clinically relevant phenotype, was not separ-
initial response to conventional anticonvulsant therapy; (3) neonatal ated from hyperprolinaemia type II. Also, as individuals with
 12.2 Protein-dependent inborn errors of metabolism 1979

hyperprolinaemia type II often have no clinical manifestations, Glycine CO2 + H2O

hyperprolinaemia was considered a nondisease. However, on inves-
tigation of larger cohorts of affected individuals it became obvious Tetrahydrofolate Methylene
tetrahydrofolate
that hyperprolinaemia type II can lead to epilepsy in more than 50%
of patients. The epilepsy usually disappears in adulthood. Serine Glycine + H2O

Diagnosis Plasma concentrations of proline are highly elevated, ex- 3-Phosphoserine

ceeding 1500 μmol/​litre. Whereas proline is the only amino acid ele-
vated in plasma and cerebrospinal fluid, glycine and hydroxyproline 3-Phosphohydroxypyruvate 3-Phosphoglycerate
are also found elevated in urine as these three amino acids share
Fig. 12.2.18 Reversible glycine cleavage to carbon dioxide and water
a common renal tubular transport system. Hyperprolinaemia type is illustrated together with reversible interconversion of serine and
II must be distinguished from hyperprolinaemia type I by demon- glycine. These reactions also serve to generate one-​carbon units.
stration of elevated levels of l-​Δ1-​pyrroline-​5-​carboxylate and/​or by 3-​phosphoglycerate (glycolysis) is the ultimate source.
enzyme assay or molecular analysis.
Treatment and outcome Unless a seizure disorder is present, no deficient activity of the glycine cleavage system which represents the
specific treatment is required. In a child with a seizure disorder, main catabolic route of glycine (Fig. 12.2.18) and is present at high
treatment with 5 to 30 mg/​kg body weight per day of pyridoxine in levels in liver, brain, and placenta. In brain, it keeps glycine levels
one dose should be started. There are usually no adverse sequelae. very low, resulting in a typically low cerebrospinal fluid to plasma
glycine ratio.
Pyridoxal phosphate-​responsive seizures: pyridox(am)ine Glycine is connected to multiple biochemical pathways. Most im-
5′-​phosphate oxidase deficiency portant is the generation of methylenetetrahydrofolate. The glycine
Clinical presentation Pyridoxal phosphate responsive seizures due cleavage system is made up of four mitochondrial proteins, P, H, T,
to pyridox(am)ine 5′-​phosphate oxidase deficiency (Fig. 12.2.17) and L. The P protein is a decarboxylase requiring pyridoxal phos-
result in a most severe early neonatal encephalopathy with con- phate. The heat-​resistant H protein contains lipoic acid and carries
vulsions, myoclonus, rotatory eye movements, and sudden clonic the aminomethyl moiety. Both proteins are needed to generate CO2
contractions. Seizures are resistant to conventional anticonvulsant from the carbon-​1 of glycine. The T protein requires tetrahydrofolate
therapy. Many patients are born prematurely, and fetal distress is and produces methylenetetrahydrofolate from carbon-​2 of glycine.
common, including ‘signs of asphyxia’ and low Apgar scores. Early The fourth protein (L protein) is needed to transfer hydrogen from
(lactic) acidosis and hypoglycaemia may be observed. Thus pyri- the lipoic acid moiety of the H protein to nicotinamide adenine
doxal phosphate-​ responsive seizures must enter the differential diphosphate.
diagnosis of hypoxic–​ ischaemic encephalopathy in prematurely Clinical presentation Symptoms of nonketotic hyperglycinaemia
born infants. are exclusively neurological. Pregnancy and delivery are generally
Diagnosis The deficiency of pyridox(am)ine 5′-​phosphate oxidase uneventful. Hiccupping in utero maybe recognized retrospectively.
results in combined deficiencies of l-​amino acid decarboxylase, Lethargy, convulsions, anorexia, poor feeding, and vomiting pro-
threonine dehydratase, ornithine δ-​aminotransferase, and the gly- gress to coma and unresponsiveness 24 to 48 h after birth. Patients
cine cleavage enzyme with the concomitant biochemical findings. are severely hypotonic. Seizures with hiccupping and myoclonic
In addition, some patients display variable lactic acidaemia as well spasms are prominent, and there is a burst suppression pattern on
as a tendency to hypoglycaemia. However, no biochemical abnor- electroencephalography. Apnoea worsens during the third day of
mality is 100% specific or sensitive, and a positive response to the life, mostly requiring ventilation. The mortality rate at this stage is
drug remains the most reliable indication of pyridoxal phosphate-​ high, especially, if the children are not ventilated. After 2 to 3 weeks
responsive seizures. The diagnosis is confirmed by mutation analysis. the patients improve slightly and no longer require intensive care.
However, intellectual development does not occur in survivors, seiz-
Treatment and outcome Pyridoxal 5′-​phosphate given by nasogas- ures persist, and tendon reflexes are increased. Microcephaly, poor
tric tube is dramatically effective in stopping seizures and improving head control, profound retardation, and a picture of spastic cerebral
the appearances of the electroencephalogram. Long-​term treat- palsy develop.
ment requires 30 to 60 mg/​kg body weight per day of pyridoxal 5′-​ Up to 15% of patients with neonatal presentation have a better
phosphate in four doses. Doses need to be increased and adjusted recovery after the neonatal period. They have a milder seizure dis-
to body weight during growth. Patients probably require lifelong order, usually controlled by benzoate therapy or by a single anticon-
supplementation. Breakthrough seizures are an obvious criterion vulsant. Most of these patients make some developmental progress,
for increasing the dose. So far many questions remain open with but they are still mentally disabled with developmental quotients
regards to prognosis. Serial cognitive assessment is recommended. varying between 10 and 60.
Defects of glycine and serine metabolism Variant forms of nonketotic hyperglycinaemia present in later in-
fancy or childhood with severe seizures, spastic paraparesis, clonus,
Nonketotic hyperglycinaemia and extensor plantar responses with modestly raised plasma and
Nonketotic hyperglycinaemia is the second most common dis- cerebrospinal fluid glycine values. Optic atrophy with cerebellar
order of amino acid metabolism, second to PKU, with an overall signs has also been described. The outcome is similar to that of pa-
worldwide frequency estimated at 1 in 60 000 births. It is caused by tients with the severe form of neonatal nonketotic hyperglycinaemia.
1980 SECTION 12 Metabolic disorders

Diagnosis Confirmation of diagnosis by enzyme assay and/​or mo- Clinical presentation Patients with serine deficiency due to 3-​
lecular analysis is highly advisable and should be pursued to facili- phosphoglycerate dehydrogenase deficiency have congenital micro-
tate future prenatal diagnosis. cephaly. They develop severe psychomotor retardation with spastic
Biochemically, nonketotic hyperglycinaemia is characterized by tetraparesis and severe microcephaly. Seizures usually start in in-
elevated glycine in plasma and in cerebrospinal fluid, with glycine fancy as West’s syndrome with hypsarrhythmia. The MRI scan is
being more elevated in cerebrospinal fluid than in plasma. Plasma characterized by striking delayed or absent myelination, with subse-
glycine is elevated to values of 600 to 1200 µmol/​litre but may vary quent cortical and subcortical atrophy. Variable symptoms include
throughout the day, and can be normal at times. Normal values for cataract, hypogonadism, megaloblastic anaemia, and nystagmus.
cerebrospinal fluid levels of glycine are around 4 to 5 µmol/​litre, the
Diagnosis Serine deficiency in 3-​phosphoglycerate dehydrogenase
normal cerebrospinal fluid to plasma ratio being less than 0.04. In
deficiency is most reliably diagnosed in cerebrospinal fluid with
nonketotic hyperglycinaemia patients, the cerebrospinal fluid to
values less than 14 µmol/​litre (normal cerebrospinal fluid serine
plasma glycine ratio is between 0.07 and 0.30.
42–​86 µmol/​litre in infancy). Serine values in fasting plasma are also
Great care must be taken to obtain simultaneous plasma and cere-
reduced (28–​64 µmol/​litre, controls 70–​187 µmol/​litre). However,
brospinal fluid samples. Diagnostic pitfalls can arise due to postpran-
nonfasting plasma levels can be normal.
dial blood sampling, blood contamination of the cerebrospinal fluid,
profound liver dysfunction, and treatment with valproate. Urine or- Treatment and outcome l-​Serine should be administered orally
ganic acids must be determined to exclude propionic aciduria and until normalized (300–​500 mg/​kg per day). If seizures persist, gly-
methylmalonic aciduria, as well as glyceric aciduria. Activity of the cine should be added up to 300 mg/​kg per day. A very satisfactory
glycine cleavage system can only be reliably measured on liver biop- outcome was achieved by antenatal treatment in one patient.
sies and in direct uncultured chorionic villi for prenatal diagnosis.
So far the molecular structures of the P protein, the T protein, and Defects of γ-​aminobutyric acid metabolism
the H protein have been elucidated, allowing molecular diagnosis of GABA is formed from glutamate in the brain by the cytosolic en-
defects of these three proteins. Molecular studies have demonstrated zyme glutamate decarboxylase, which requires pyridoxal phos-
a defect of the P protein in about 50 to 60% of patients and in the T phate (Fig. 12.2.19). Glutamate can be regenerated from GABA by
protein in about 30% of patients; a few patients were found to have transamination with ketoglutarate (GABA transaminase), which is
mutations in the GLDC gene leaving approximately 15% of patients also pyridoxal phosphate dependent. The other product is succinic
with no mutations found after all three genes had been analysed. semialdehyde, which is dehydrogenated to succinate and enters the
citric acid cycle. Deficiency of succinic semialdehyde dehydrogenase
Treatment and outcome Therapeutic interventions are unsatisfac-
leads to formation and excretion of 4-​hydroxybutyric acid.
tory. Some damage to the central nervous system may be prenatal.
Withdrawal of artificial ventilation and intensive care support should GABA transaminase deficiency
be discussed with the parents of neonates in the apnoeic phase. Once
Some patients with GABA transaminase deficiency presented with a
breathing resumes, most patients survive for many years.
fatal neonatal encephalopathy, characterized by seizures, hypotonia,
Plasma glycine can be lowered by exchange transfusion or peri-
hyperreflexia, a high-​pitched cry (cat cry), and accelerated growth.
toneal dialysis but without clinical improvement. Low-​protein diets
The diagnosis can be suspected from significantly elevated levels of
have only a limited effect on decreasing plasma glycine concentra-
GABA (both free and total), as well as β-​alanine and homocarnosine
tions. Supplying one-​carbon units in the form of methionine or
N-​formyltetrahydrofolate has not helped. The combination of so-
dium benzoate to increase glycine excretion and diazepines, which
compete for inhibitory glycine receptors in the central nervous
system, has lowered plasma and cerebrospinal fluid levels of glycine
and reduced seizures. Doses up to 600 to 750 mg/​kg per day may
be required to lower glycine sufficiently to values between 120 and
280 µmol/​litre. At such high, potentially toxic doses monitoring of
benzoate levels is advised, nevertheless gastric irritation is very fre-
quent and gastric protection with H2-​antihistamine or proton pump
inhibitors is preventively recommended.
Most patients need gastric tube feeding or gastrostomy. Gastro-​
oesophageal reflux develops frequently, and many patients benefit
from a Nissen fundoplication. Recurrent bronchitis is a major
problem and bronchopneumonia is frequently the cause of death.
For patients with mild nonketotic hyperglycinaemia, management
of the hyperactivity can be a major challenge.
Fig. 12.2.19 Synthesis and catabolism of 4-​aminobutyric acid (GABA).
3-​Phosphoglycerate dehydrogenase deficiency The enzymes recognized for known monogenic disorders in humans are
shown in boxes: GAD, glutamic acid decarboxylase deficiency, GT, GABA
Serine is synthesized from the glycolytic intermediate
transaminase deficiency, SSADH, succinic semialdehyde dehydrogenase
3-​phosphoglycerate by 3-​phosphoglycerate dehydrogenase yielding deficiency. The cofactor vit. B6 (vitamin B6) is underlined.
3-​phosphohydroxypyruvate (Fig. 12.2.18). Deficiency of this en- Source data from Zschocke J, Hoffmann GF (2011). Vademecum metabolicum.
zyme leads to serine deficiency. Manual of metabolic paediatrics, 3rd edition. Schattauer, Stuttgart.
 12.2 Protein-dependent inborn errors of metabolism 1981

in cerebrospinal fluid. Plasma levels of these amino acids are also Betaine Methionine
increased, but not as significantly. The diagnosis must be confirmed
by enzyme assay and possibly mutation analysis, both of which
can also be used for prenatal diagnosis. Unfortunately, there is no Dimethyl S-adenosyl
rational treatment available. Recently, in a family suffering from glycine methionine
4*
–CH3
encephalomyopathic mitochondrial DNA depletion syndrome, the –CH3
–CH3
underlying molecular defect was detected in GABA transaminase 3*
encoded by 4-​aminobutyrate aminotransferase (ABAT). Apparently, S-adenosyl
GABA transaminase connects GABA and nucleoside metabolism homocysteine
resulting in a neurometabolic disorder including mitochondrial
Methyltetrahydrofolate
DNA depletion.
Homocysteine
Succinic semialdehyde dehydrogenase deficiency **1
(4-​hydroxybutyric aciduria)
Clinical presentation The clinical presentation of succinic 2* Tetrahydrofolate Cystathionine
semialdehyde dehydrogenase deficiency is highly heterogeneous, Serine
even within sibships. The cardinal manifestations are complex and
rather nonspecific: hypotonia and delay of motor, mental, and fine CH2 Cysteine
motor skills and language. Ataxia and/​or seizures occur in about half
Glycine
of the patients. Hyperkinesis and aggressive and autistic behaviour Methylene
SO4
tetrahydrofolate
are additional features. MRI studies show bilateral globus pallidus
abnormalities but again not constantly. Fig. 12.2.20 The trans-​sulphuration pathway from methionine to
cysteine is shown on the right and the remethylation of homocysteine
Diagnosis Diagnosis is usually suspected by demonstrating in- on the left. Asterisked enzymes are: 1, cystathionine β-synthase; 2,
creased levels of γ-​hydroxybutyrate by organic acid analysis. It is methylene tetrahydrofolate reductase, 3, methionine synthase; and 4,
confirmed by enzyme assay and preferentially additional mutation betaine methyltransferase.
analysis.
Classic homocystinuria: cystathionine β-​synthase deficiency
Treatment and outcome A common treatment for succinic
semialdehyde dehydrogenase deficiency is the antiepileptic drug Clinical presentation
vigabatrin. The results have been encouraging in some patients, but Untreated classic homocystinuria is a slowly progressive, devastating
of little value or even detrimental in others. Seizures respond to con- multiorgan disorder. First symptoms in childhood are a rapidly pro-
ventional anticonvulsants. A ketogenic diet shows promise. Succinic gressive myopia and lens dislocation. Lens dislocation usually oc-
semialdehyde dehydrogenase deficiency is a slowly progressive en- curs in preschool years, but later dislocation is well recognized in
cephalopathy in childhood; it eventually stabilizes in most patients. pyridoxine-​responsive patients, and a few have not developed it
even in adult life. Monocular and binocular blindness has been rela-
Defects of trans-​sulphuration and remethylation tively frequent due to secondary glaucoma, staphyloma formation,
The trans-​sulphuration pathway transfers the sulphur of methio- buphthalmos, and retinal detachment.
nine to serine, thus generating cysteine (Fig. 12.2.20). Methionine In the older child, skeletal abnormalities and learning difficul-
adenosyltransferase, with widely distributed isoenzyme forms, ties become obvious. Genu valgum and pes cavus are usually the
produces S-​adenosylmethionine, the donor in a variety of methy- first signs of skeletal changes, which include osteoporosis and spon-
lation reactions. S-​Adenosylhomocysteine is cleaved to homocyst- taneous crush vertebral fractures. The common abnormalities seen
eine, the sulphydryl compound that exists in reversible equilibrium in Marfan’s syndrome—​high-​arched palate, pectus excavatum or
with its disulphide homocystine. Half of the homocysteine formed carinatum, genu valgum, pes cavus or planus, scoliosis—​are all well
goes through the trans-​sulphuration pathway and the other half recognized in homocystinuria. Arachnodactyly is less common
takes a methyl group from betaine (betaine methyltransferase) or and the fingers not infrequently (and elbows occasionally) show
5-​methyltetrahydrofolic acid (methionine synthase). The latter is a mild flexion contractures. Skeletal disproportion with a crown–​
cobalamin-​dependent enzyme which is functionally impaired in de- pubis length less than the pubis–​heel length is usual (Fig. 12.2.21).
fects of vitamin B12 metabolism. In addition, methionine synthase Learning difficulties affect two-​thirds of patients. Patients responsive
reductase is necessary to keep the methionine synthase-​bound co- to pyridoxine (vitamin B6) (see following ‘Treatment and outcome’
balamin in a functional state. The remethylation of homocysteine subsection) have generally higher IQ values than nonresponsive
is also impaired if the activity of the reductase that generates 5-​ patients. Seizures affect about one-​fifth of patients and a few show
methyltetrahydrofolate is inadequate. When accumulation of homo- extrapyramidal features, sometimes with severe involuntary move-
cysteine and its products homocystine and the also formed mixed ments. Psychiatric disturbances have also been described.
disulphide results from defects of homocysteine remethylation, Thromboembolism is a major cause of morbidity and the main
plasma methionine concentrations are low. They are high when cause of high premature mortality. Thromboses have been described
homocystine accumulates from impaired activity of cystathionine in a wide variety of arteries and veins: cerebral, coronary, mesen-
β-​synthase. teric, renal, and peripheral.
1982 SECTION 12 Metabolic disorders

normal range and supplementation should be considered. Both

folic acid (5–​10 mg/​day) and betaine (up to 12 g/​day) can further re-
duce plasma homocysteine levels but may produce large elevations
of plasma methionine. Low red-​cell folate values occur and even
megaloblastic anaemia. Low serum vitamin B12 values also occur
and should be corrected. Treatment started early can prevent or re-
duce the clinical sequels and lower the incidence of vascular events
throughout life; many patients have a normal life expectancy.

Methylene tetrahydrofolate reductase deficiency

Clinical presentation
Neurological features predominate with psychomotor retardation,
seizures, abnormalities of gait, and psychiatric disturbance. The age
of symptom development varies widely from infancy with a pro-
gressive encephalopathy with apnoea, seizures, and microcephaly to
adulthood with ataxia, motor abnormalities, psychiatric symptoms,
subacute degeneration of spinal cord, and cerebrovascular events.
Demyelination occurs and the changes may resemble the classic
Fig. 12.2.21 A patient with cystathionine synthase deficiency. Note the findings of subacute combined degeneration seen in vitamin B12 de-
kyphosis and disproportionate short trunk. ficiency. The risk of vascular disease is high.

Diagnosis
Diagnosis Plasma methionine concentrations are below normal and plasma
Elevated plasma methionine values between 100 and 500 µmol/​ homocysteine concentrations are in the range 20 to 200 µmol/​litre
litre (sometimes higher) are seen with plasma total homocysteine with an elevated excretion of 15 to 600 µmol/​day. As homocysteine
values of 50 to 200 µmol/​litre. A mixed disulphide (half homocyst- is easily missed on amino acid analysis, quantitative determination
eine, half cysteine) is always present at concentrations somewhat of total homocysteine by HPLC is the most important clue to diag-
below those of homocystine. Diagnosis requires the determination nosis. There is no megaloblastic anaemia. The enzyme can be as-
of fasting quantitative plasma amino acids, as well as plasma total sayed in liver, leucocytes, lymphocytes, or fibroblasts also allowing
homocysteine. Total homocysteine measured by HPLC includes prenatal diagnosis.
both homocysteine moieties of homocystine, the homocysteine
moiety of the mixed disulphide, and the homocysteine bound to Treatment and outcome
plasma proteins. The urine gives a positive nitroprusside test (it is Betaine in large doses (20–​150 mg/​kg per day) effectively lowers
also positive in cystinuria). However, this test can be falsely negative. plasma homocysteine and raises plasma methionine. Other treat-
Unfortunately, methionine elevation is unreliable in the early days ments tried alone or in combination include folinic acid, vitamin
of life, hampering the possibility of newborn screening. This can be B12, pyridoxine, and methionine. Some have suggested a cocktail of
reliably performed by screening for homocystinuria but still exclu- all these treatments. It is difficult to be sure of clinical success.
sively detects the more severely pyridoxine nonresponsive patients.
Confirmation of the diagnosis can be performed by enzyme assay Deficiencies of methionine synthase reductase (cobalamin E
using cultured skin fibroblasts and/​or mutation analysis, which al- defect) and methionine synthase (cobalamin G defect)
lows prenatal diagnosis. Clinical and biochemical findings of methionine synthase reduc-
tase (cobalamin E defect) and methionine synthase (cobalamin
Treatment and outcome G defect) deficiencies are virtually identical. Characteristic find-
Optimal outcome of treatment depends on its earliest possible intro- ings are developmental delay and megaloblastic anaemia, but the
duction. Treatment is focused on correcting homocysteine levels; onset may be in later in childhood with dementia and spasticity.
lifelong monitoring is essential. In about one-​half of the patients, Retinal degeneration, cardiac defects, and haemolysis have been
oral pyridoxine rapidly reduces methionine and homocysteine to described.
near-​normal values. The first treatment should be to try using doses Megaloblastic anaemia occurs in almost all patients. Biochemical
from as low as 50 mg in infants to 1000 mg/​day in older children or findings include low plasma methionine and raised homocysteine
adults and reducing the dose if a response is achieved; 5 to 10 mg/​ as well as homocystine in plasma and urine. Methylmalonic acid
day of folic acid should also be given. Very large sustained doses should be measured in urine to exclude other cobalamin defects
(1000 mg/​day or more) in adults can cause peripheral neuropathy. (see ‘Methylmalonic aciduria’). Methionine synthase can be as-
Those responding only partially or not at all to pyridoxine require sayed in liver or fibroblasts and antenatal diagnosis has been carried
a very low-​protein diet supplemented with a methionine-​free amino out on cultured amniocytes. Cells with the cobalamin E defect re-
acid supplement, minerals, and vitamins. Biochemical control may quire specific reducing conditions to demonstrate the deficient en-
only be achieved in older children and adults on natural protein in- zyme activity. Molecular diagnosis is possible for both conditions.
takes of 5 to 10 g/​day. Plasma cystine should be maintained in the Treatment involves large doses of hydroxocobalamin with betaine
 12.2 Protein-dependent inborn errors of metabolism 1983

and possibly folinic acid. Success of therapy and outcome is variable

isovaleric acidemia diagnosed by newborn screening. Am J Hum
and often unfavourable.
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mitochondrial nucleoside metabolism. Cell Metab, 21, 417–​27. investigations for neurometabolic disorders. Neuropediatrics,
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Baumgartner MR, et al. (2014). Proposed guidelines for the diag- acid disorders. Eur J Pediatr, 153 Suppl 1, S94–​100.
nosis and management of methylmalonic and propionic acidemia. Hörster F, et al. (2007). Long-​ term outcome in methylmalonic
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J Med, 347, 2111–​21. cholesterol trafficking and cause dystonia and deafness. Nat Genet,
Posset R, et al. (2019). Impact of Diagnosis and Therapy on Cognitive 44, 797–​802.
Function in Urea Cycle Disorders. Ann Neurol, 86, 116–28. Wortmann S, et al. (2013). 3-​Methylglutaconic aciduria—​lessons from
Prietsch V, et al. (2002). Emergency management of inherited meta- 50 genes and 977 patients. J Inherit Metab Dis, 36, 913–​21.
bolic disease. J Inherit Metab Dis, 25, 531–​46. Zschocke J, Hoffmann GF (2011). Vademecum metabolicum. Manual
Salomons GS, et al. (2007) Clinical, enzymatic and molecular charac- of metabolic paediatrics, 3rd edition. Schattauer, Stuttgart.
terization of nine new patients with malonyl-​coenzyme A decarb- Zschocke J, et al. (2000). Progressive infantile neurodegeneration
oxylase deficiency. J Inherit Metab Dis, 30, 23–​8. caused by 2-​methyl-​3-​hydroxybutyryl-​CoA dehydrogenase defi-
Schaefer F, et al. (1999). Dialysis in neonates with inborn errors of me- ciency: a novel inborn error of branched chain fatty acid and isoleu-
tabolism. Nephrol Dial Transplant, 14, 910–​18. cine metabolism. Pediatr Res, 48, 852–​5.
12.3
Disorders of carbohydrate metabolism

CONTENTS polyglucosan body disease and Lafora’s disease, have been shown
to result from abnormal glycogen structures in diverse cell types,
12.3.1 Glycogen storage diseases 1985
Robin H. Lachmann and Timothy M. Cox including neurons.
Formerly, diseases of glycogen metabolism were diagnosed by
12.3.2 Inborn errors of fructose metabolism 1993 showing excess storage of glycogen in the tissue of interest, accom-
Timothy M. Cox
panied by reduced activity of particular glycogen-​metabolizing en-
12.3.3 Disorders of galactose, pentose, and zymes. Currently, where available, molecular analysis of genomic
pyruvate metabolism 2003 DNA is the preferred method for providing a definitive diagnosis.
Timothy M. Cox The mainstay of treatment of glycogen diseases affecting the liver
is dietary, including pre-​emptive management of hypoglycaemia that
is readily provoked by fasting. In infants and children, continuous
provision of carbohydrate by the nasogastric route may be required
to maintain euglycaemia. Adults can usually be managed by a com-
bination of frequent sugary snacks and the use of uncooked corn-
starch as a slow-​release source of glucose. Dietary interventions may
12.3.1 Glycogen storage diseases also ameliorate some of the glycogen diseases that affect muscle,
Robin H. Lachmann and Timothy M. Cox and weakness and pain after exertion can be improved by graduated
exercise programmes in some patients.

ESSENTIALS
Glycogen is a highly branched glucose polymer with a compact Introduction
structure found predominantly in liver and muscle. Liver glycogen is
important in the maintenance of euglycaemia during fasting; muscle Maintenance of blood glucose is an essential homeostatic func-
glycogen is an immediate source of glucose for energy production tion: profound hypoglycaemia causes encephalopathy and car-
during exercise. Genetic disorders affecting proteins that regulate diac arrhythmias and is rapidly fatal if not treated promptly.
glycogen synthesis and breakdown cause marked accumulation of Two processes are involved in maintaining normal blood glu-
glycogen in diverse tissues, and pathological glycogen often has an cose during periods of fasting: de novo synthesis of glucose
abnormal macromolecular structure. Depending on the enzyme (gluconeogenesis) and the release of glucose from carbohydrate
system involved, diseases of glycogen metabolism principally affect stores (glycogenolysis). The body stores carbohydrate in the form
liver and muscle. of glycogen, a branched polymer of glucose. Glycogen stores in
Clinical features are related to accumulation of glycogen in tissues the liver are used to maintain normoglycaemia, but muscle also
and/​or failure to release glucose. Glycogen storage is associated with stores glycogen for its own use as an energy source during exer-
organomegaly and tissue injury: this usually affects the liver and/​or cise. In this chapter, we will discuss the metabolism of glycogen
muscles, including the heart, but in severe cases other organs may be and the inherited metabolic disorders which affect its synthesis
involved. Fasting hypoglycaemia occurs where hepatic breakdown and breakdown.
of glycogen is impaired. Hyperlipidaemia, hyperlactataemia and
hyperuricaemia leading to gout occur in those disorders with a major
liver component, and poor metabolic control is associated with de-
velopment of hepatic adenomas and frank liver cancers. Glycogen Glycogen
diseases that affect muscle usually present with rhabdomyolysis, ex-
ercise intolerance, and muscle pain or weakness. Recently, several Glycogen allows for the compact storage of glucose in a form that has
inherited multisystem disorders with neurodegeneration, such as a minimal osmotic effect but which is readily accessible and meta-
bolically active. The core of a glycogen molecule is a small protein,
1986 SECTION 12 Metabolic disorders

(a)

(b)
CH2OH CH2OH CH2OH
O O O
OH OH OH
...O O O
OH OH OH

CH2OH CH2OH CH2O CH2OH CH2OH

O O O O O
OH OH OH OH OH
...O O O O O O Glycogenin
OH OH OH OH OH

Fig. 12.3.1.1 (a) A cross-​sectional view of glycogen, showing the core glycogenin protein surrounded by branches of
glucose units, up to 60 000 of which can be contained within a glycogen granule. (b) Linear chains of glucose are formed
by α-​1,4 glycosidic bonds, with α-​1,6 bonds at the branch points.

glycogenin. Branched chains of polymerized α-​d-​glucose units are

Glycogen synthesis
covalently attached to this at their reducing termini (Fig. 12.3.1.1).
The glucose molecules in glycogen chains are linked to each
A glycogen molecule starts life with the autoglycosylation of a
other by α-​1,4 glycosidic bonds with α-​1,6 bonds at the branch
glycogenin molecule at a specific tyrosine residue. This primer
points (Fig. 12.3.1.1b). Glycogen molecules can contain up to
molecule is then acted on by glycogen synthase which uses uridine
60 000 glucose molecules, have a molecular weight of several mil-
diphosphoglucose molecules to form the α-​1,4 linkages of the nas-
lion daltons, and are visible to the electron microscope. The liver
cent sugar chain. The α-​1,6 branch points required for the complex
and muscle contain between 200 and 300 g of glycogen. The arbor-
structure of glycogen are formed by ‘branching enzyme’ (amylo-​(1,4
ization of the molecule, with large numbers of long outer chains
→ 1,6) transglucosidase). It transfers a minimum of six α-​1,4-​linked
that terminate in nonreducing glucose residues means that the en-
glucose units from the distal ends of glycogen chains to a 1,6 pos-
zymes of glycogen degradation can rapidly release large quantities
ition on the same or a neighbouring chain.
of glucose.
Glycogen synthase is a highly regulated enzyme complex that
Glycogen storage diseases (GSDs) can be caused by defects in
exists in distinct isoforms in muscle and liver. Glycogen synthase is
glycogen synthesis or glycogen breakdown (Fig. 12.3.1.2). The stored
subject to phosphorylation control that inhibits its activity: the phos-
glycogen may have a normal or an aberrant structure. Depending on
phorylation of at least nine serine residues is brought about by pro-
the enzymatic defect, glycogen metabolism in the liver, muscle, or
tein kinases and reversed by protein phosphatase I. This inhibition
both tissues may be affected.
can be overcome by the allosteric activator, glucose 6-​phosphate.
 12.3.1 Glycogen storage diseases 1987

Acid α-1,4 glucosidase

(lysosomes)

GLYCOGEN GLYCOGEN

Glycogen synthase (cytosol)

Branching enzyme
amylo 1,6-glucosidase
Glycogenin primer
Phosphorylase
Debranching enzyme
Uridine diphosphoglucose

UDP-glucose pyrophosphorylase

Glucose 1-phosphate Glucose 1-phosphate

Phosphoglucomutase Phosphoglucomutase

Glucose 6-phosphate GLUCOSE Glucose 6-phosphate

Hexokinase/ Glucose
Phosphohexose glucokinase 6-phosphatase Phosphohexose
isomerase isomerase

Fructose 6-phosphate Fructose 6-phosphate

Phosphofructokinase
Fructose diphosphatase

Fructose 1,6-diphosphate Fructose 1,6-diphosphate

(glycolysis)
(gluconeogenesis)

SYNTHESIS BREAKDOWN

Fig. 12.3.1.2 The synthesis and degradation of glycogen.

Regulation of glycogen synthase is important in maintaining glycolysis, gluconeogenesis, glycogenolysis, and the pentose phos-
blood glucose. Glucagon and adrenaline indirectly inhibit glycogen phate pathway, but cannot be transferred outside the cell. However,
synthase by maintaining protein phosphatase I in its inactive con- after conversion to glucose 6-​phosphate by phosphoglucomutase,
figuration and promoting phosphorylation of glycogen synthase. free glucose is formed by the action of glucose 6-​phosphatase.
Insulin stimulates glycogen synthase by activating protein phos- Glucose 6-​phosphatase exists as a multicomponent complex in the
phatase I and promoting its dephosphorylation. endoplasmic reticulum of hepatocytes and, to a lesser extent, in renal
tubular cells—​it is not found in muscle. The complex contains glu-
cose 6-​phosphatase, several proteins that facilitate the transport of
Glycogen breakdown glucose, glucose 6-​phosphate, and phosphate, as well as other stabil-
izing and regulatory units. Hepatic activity of glucose 6-​phosphatase
Two enzymes are involved in the breakdown of glycogen in the cyto- is the predominant metabolic source of blood glucose.
plasm: phosphorylase and debranching enzyme. Other enzymes are In muscle, glucose 6-​phosphate obtained from the breakdown
required to then produce free glucose. of glycogen is used directly as an energy source via glycolysis.
Phosphorylase sequentially removes glucose 1-​phosphate units Glycolytic defects can also affect glycogen metabolism in muscle
from the α-​1,4-​linked chains of glycogen. Debranching enzyme pos- (e.g. phosphofructokinase-​1 deficiency).
sesses transferase and α-​1,6-​glucosidase activities. When phosphor- Phosphorylase in liver and skeletal muscle is activated by phos-
ylase has degraded glycogen chains to within four α-​1,4-​glucosyl phorylation in response to hormonal or neural stimulation—​a com-
units of an α-​1,6 linkage, three glucose residues are transferred to the plex process that is mediated by the hepatic and muscle isoforms
end of another chain by the glycosyltransferase activity. Debranching of phosphorylase kinases. Phosphorylase kinase is in turn regulated
enzyme then hydrolyses the remaining α-​1,6 bond to release free by protein kinase A (cAMP-​dependent protein kinase), calcium and
glucose using its amylo-​1,6-​glucosidase activity. Debranching en- kinase activation of calmodulin, and protein phosphatases 1 and 2A.
zyme also cleaves the unique glucosyl–​tyrosine linkage that anchors Another enzyme, acid α-​1,4-​glucosidase (otherwise known
the terminal reducing glucose unit to glycogenin. as acid maltase), also has an important role in the metabolism of
The main product of glycogen breakdown in muscle and liver is glycogen, but in the lysosome not the cytoplasm. This lysosomal
glucose 1-​phosphate. Glucose 1-​phosphate is a key intermediate of hydrolase is present in all cells except erythrocytes. It has no role in
1988 SECTION 12 Metabolic disorders

glycolysis, but hydrolyses the glycogen which is constantly entering glycogen storage in the liver had normal glucose-​6-​phosphatase
the lysosome via autophagy. This pathway seems to be particularly activity, and were later shown to have glucose-​6-​phosphate trans-
important in muscle. porter defects (GSD Ib).
Other patients were described who stored abnormal forms of
glycogen (GSD IV), or who accumulated glycogen in muscle as well
Discovery and classification of glycogen as (GSD III), or instead of (GSD V), liver, or where the primary site
storage diseases of glycogen storage was the lysosome rather than the cytoplasm
(GSD II). More recently, the recognition of polyglucosan bodies has
The study of patients with GSDs has played an essential part in led to the description of new diseases which involve glycogen me-
elucidating the biochemical pathways described in the previous tabolism, as well as expanding the phenotype of classical GSD IV.
sections. In 1929, von Gierke described ‘hepatonephromegalia A summary of GSDs, their enzymology, and principal features
glykogenica’ with glycogen storage in the liver and kidney. is given in Table 12.3.1.1. Although GSDs have traditionally been
Twenty years later, the husband and wife team of CF and GT split into those that affect the liver and those that affect muscle,
Cori showed that this disease was due to deficiency of glucose-​ many are in reality multisystem disorders. The most important
6-​phosphatase activity (GSD Ia). However, some patients with clinical features, however, remain fasting hypoglycaemia and

Table 12.3.1.1 The glycogen storage disorders: genetic and enzymatic defects and principal clinical features

GSD Gene Locus Common term/​implicated Supplementary Clinical features

designation protein
0 (L) GYS1 12p12.1 Glycogen synthase Liver isozyme Hepatomegaly, hypoglycaemia
0 (M) GYS2 19q13.33 Glycogen synthase Muscle isozyme Cardiomyopathy
Ia G6P6 17q21.31 Von Gierke’s disease Glucose 6-​phosphatase Hypoglycaemia, hyperlacticaemia, hyperuricaemia,
Ib SLC37A4 11q23.3 Glucose 6-​phosphatase hypertriglyceridaemia
translocase Hepatomegaly, hepatic adenomas
Renal failure
GSD Ib also has neutropenia and colitis
II GAA 17q25.3 Pompe’s disease Lysosomal (α-​glucosidase) Cardiomyopathy (infantile form)
Proximal myopathy, hypoventilation
III AGL 1p21.2 Cori–​Forbes disease Debranching enzyme Hypoglycaemia, hepatomegaly, cardiomyopathy,
(Limit dextrinosis) myopathy
IV GBE1 3p12.2 Andersen’s disease Branching enzyme Infantile liver failure. Cardiomyopathy, myopathy
(Amylopectinosis) Adult polyglucosan body disease (neurogenic
bladder, spastic paraparesis and peripheral
neuropathy)
V PYGM 11q12–​q13.3 McCardle’s disease Glycogen phosphorylase Exercise intolerance, rhabdomyolysis
(muscle)
VI PYGL 14q22.1 Hers’ disease Glycogen phosphorylase Hypoglycaemia, hepatomegaly (very
(liver) rare—Mennonite)
VII PFKM 12q13.3 Tarui’s disease Phosphofructokinase Exercise intolerance, rhabdomyolysis
(muscle) Haemolytic anaemia
[VIII] N/​A N/​A [See Hers’ disease] N/​A (obsolete)
IX a1 PHKA1 Xq12–​q13.1 Phosphorylase kinase α1 subunit Muscle (regulatory) Exercise intolerance, rhabdomyolysis
IX a2 PHKA2 Xp22.13 Phosphorylase kinase α2 subunit Liver (regulatory) Hypoglycaemia, hepatomegaly
IX b PHKB 16q12.1 Phosphorylase kinase β subunit Liver and muscle Liver and muscle involvement
IX c PHKG2 16p12.2–​11.2 Phosphorylase kinase γ subunit (regulatory) Liver and testis
Liver (catalytic subunit)
X PGAM2 7p13 Phosphoglycerate mutase-​2 Muscle isozyme
XI LDHA 11p15.1 Lactate dehydrogenase A (M Muscle isozyme,
subunit) desquamation
XII ALDOA 16p11.2 Aldolase A (ubiquitous and Associated with haemolysis
muscle)
XIII ENO3 17p13.2 Enolase-​β Extremely rare—​muscle
XIV PGM1 1p31.3 Phosphoglucomutase 1 Also disordered protein
glycosylation (CDG1T)
XV GLYG1 3q24 Glycogenin (absent glycogen) Reduced or absent Cardiac and skeletal myopathy
GLYG1 3q24 Glycogenin (abnormal glycogen glycogen
-​ polyglucosan) Polyglucosan body
myopathy-​2
(proximal)
 12.3.1 Glycogen storage diseases 1989

myopathy and it can still be useful to distinguish between hepatic due to hepatomegaly. Hypoglycaemic encephalopathy is often ac-
and muscle GSDs. companied by seizures and can be fatal: recurrent episodes lead
The overall incidence of GSDs has been estimated at 1 in 20 000 to permanent neurodisability. Children have impaired growth
with the commonest being GSD IX, followed by GSD I, II, and III. and increased subcutaneous fat deposition leading to a ‘doll’s face’
The clinical features of the commoner disorders are described in the appearance.
following sections. With aggressive dietary management (see following subsection
on ‘Management’), the immediate life-​threatening complications
can be avoided. With improved survival, the chronic, multisystem
complications of GSD I have emerged (Fig. 12.3.1.3).
Glycogen storage disease type I There is persistent hepatomegaly, with glycogen storage accom-
(von Gierke’s disease) panied by gross infiltration with fat. Cirrhosis and portal hyper-
tension are, however, rare. Short stature, often combined with
Biochemistry obesity, is common. The kidneys are enlarged by glycogen depos-
GSD I is due to glucose-​6-​phosphatase deficiency. GSD Ia is caused ition. Progressive focal glomerulosclerosis and proximal tubular
by defects in subunits of the endoplasmic reticular enzyme com- injury with a secondary Fanconi’s syndrome may also occur. Short
plex that enable production of glucose from glucose 6-​phosphate. periods of fasting, or other metabolic stressors such as infection,
In GSD Ib, the endoplasmic reticular transmembrane protein provoke hypoglycaemia and lactic acidosis. In the longer term, poor
glucose-​6-​phosphate translocase is deficient. In both forms, the metabolic control causes growth arrest; hyperuricaemia and gout;
production of glucose from both glycogenolytic and gluconeogenic marked hypertriglyceridaemia (which can lead to acute pancreatitis)
pathways is blocked, resulting in profound fasting hypoglycaemia. and hypercholesterolaemia with raised very low-​density lipoprotein
Accompanying this, there is a build-​up of glucose 6-​phosphate. This and normal low-​density lipoprotein cholesterol concentrations in
is then metabolized by the pentose phosphate shunt, or transferred the plasma; and prolonged bleeding time related to an acquired von
back into glycogen which is stored in the liver and, to a lesser extent, Willebrand-​like defect affecting the platelet. Hepatic adenomas are
the kidney. The products of glucose-​6-​phosphate metabolism have seen in adults. These can regress with improved metabolic control,
an important role to play in the other metabolic consequences of GSD but there is a risk of transformation to hepatocellular carcinoma, and
I: hyperlactataemia, hyperuricaemia, and hypertriglyceridaemia. all patients need to be carefully monitored with regular liver MRI.
The hypoglycaemia is somewhat mitigated by the fact that small Patients with defects of the glucose-​ 6-​
phosphate translocase
quantities of free glucose can be liberated by the α-​1,6-​glucosidase system (type 1B) also have a neutropenia with impaired neutrophil
activity of the secondary action of debranching enzyme. Residual migration and chemotaxis and are prone to recurrent bacterial in-
production of glucose probably also occurs by lysosomal hydrolysis fections. These patients are also at risk of developing granulomatous
of glycogen. colitis with clinical features similar to ulcerative colitis.
Lactic acidaemia results from stimulation of glycolysis at the Partial deficiencies of the glucose-​6-​phosphatase system lead to
level of phosphofructokinase by high concentrations of glucose 6-​ variable clinical expression: in Japan, a milder form of GSD Ia oc-
phosphate (and hence fructose 6-​phosphate); lactate cannot be re- curs due to the common G727T mutation that is prevalent in that
cycled in the liver to form new glucose and lactic acidosis results. country. GSD I should be considered in patients presenting with
Failure to dephosphorylate glucose 6-​ phosphate stimulates glucagon-​unresponsive hypoglycaemia with or without liver en-
substrate cycling and increases the activity of the pentose phos- largement in adult life.
phate pathway, with enhanced production of the reduced form of
nicotinamide-​adenine dinucleotide phosphate (NADPH), ribose Management
5-​phosphate, and purines. Degradation of purine nucleotides by Historically, GSD I (and the other GSDs presenting with hypogly-
AMP-​deaminase and the coordinated action of xanthine oxidase caemia in infancy) were associated with a very poor outcome. This
on inosine phosphate and hypoxanthine leads to overproduction of has been transformed by the introduction of aggressive dietary man-
uric acid in the liver. The deaminase is activated when the concentra- agement aimed at maintaining a constant exogenous supply of glu-
tion of free phosphate falls as a result of sequestration in sugar phos- cose to meet basal requirements. Regular oral carbohydrate during
phate esters. Lactate competes with urate for excretory pathways in the day and continuous overnight pump feeding with glucose, de-
the kidney and this also contributes to the hyperuricaemia. livered either by nasogastric or gastrostomy tube, clearly improves
Enhanced flux through glycolysis and underutilization of clinical and biochemical parameters. Subsequently, fasting tolerance
gluconeogenic precursors leads to increased production of the re- has been improved with the use of uncooked cornstarch (obtained
duced form of nicotinamide-​adenine dinucleotide (NADH) and from the supermarket and suspended in water): this acts as a ‘slow-​
NADPH, glycerol, and acetyl coenzyme A, and these in turn in- release’ form of glucose and, particularly in older patients, allows for
duce hypertriglyceridaemia. Malonyl coenzyme A, derived from more time between meals during the day and for some patients to
acetyl coenzyme A, inhibits the carnitine acyltransferase system and discontinue overnight feeds. Modified cornstarches have now been
blocks the oxidation of fatty acids; thus marked ketosis does not usu- produced with the aim of increasing fasting tolerance further, al-
ally develop. though it is not yet clear that they offer a significant benefit over
shop-​bought cornflour. Maintaining normoglycaemia requires a
Clinical presentation diet with about 65% of dietary energy as carbohydrate. Continuous
Patients typically present in infancy with symptomatic hypogly- glucose monitoring can be useful in adjusting doses of uncooked
caemia and failure to thrive, accompanied by a swollen abdomen cornstarch and concentrations of overnight feeds. Regular dietetic
1990 SECTION 12 Metabolic disorders

Neurology dependent on duration

and severity of hypoglycaemia and
acidosis
Acute—coma
Low IQ
Seizures
Epistaxis
White matter parencyhmal loss
Mouth ulcers
(GSD Ib)
Acute pancreatitis
Insulin resistance

Pulmonary hypertension
(rare)

Splenomegaly (GSD Ib)

Hypersplenism
Gross hepatomegaly in infancy
—improves with metabolic control
Hepatic steatosis
Hepatic adenoma Nephromegaly
Hepatocellular carcinoma (rare) Hyperfiltration in childhood
Hypofiltration in adult life
Tubulointerstitial disease
Proteinuria
Renal failure
Diarrhoea Renal calculi
Inflammatory bowel disease (GSD Ib)

Polycystic ovaries
Delayed puberty

Chronic anaemia
Osteopenia
Platelet dysfunction
Neutropenia (GSD Ib)
Neutrophil dysfunction
Other
Growth failure / delay
Myopathy
Gout

Fig. 12.3.1.3 Complications of GSD I.

review is important to minimize excessive weight gain and insulin cases improving biochemical parameters can lead to adenoma re-
resistance, and ensure the diet is nutritionally complete. gression. Spontaneous regression is also seen (Fig. 12.3.1.4).
Intercurrent illness can rapidly provoke hypoglycaemia and pa- The occurrence of hepatic adenomas is concerning because they
tients with GSD I are given an ‘emergency regimen’ to use in times can progress to hepatocellular carcinoma: predicting this pro-
of metabolic stress. This consists of frequent oral glucose polymer. gression is difficult. Blood markers such as α-​fetoprotein have not
If for any reason patients can’t tolerate oral intake, 10% dextrose proved useful. A rapid increase in size or number of adenomas,
should be given intravenously at a rate of 2 ml/kg per hour. changes in vascularization, and bleeding should lead to a multidis-
Hyperlipidaemia and hyperuricaemia need to be treated. ciplinary team review to discuss surgical intervention, including
Hyperfiltration or albuminuria indicates renal involvement and liver transplantation.
angiotensin-​converting enzyme inhibitors or angiotensin receptor Human granulocyte colony-​stimulating factor is often required in
blockers should be introduced. Hypocitraturia may contribute to the patients with GSD Ib to increase the neutrophil count and control
increased incidence of nephrolithiasis and citrate supplementation mouth ulcers, recurrent infections, and inflammatory bowel disease.
may be useful. Iron supplementation is often needed. Osteopenia Long-​term use of granulocyte colony-​stimulating factor is associ-
is common and calcium and vitamin D supplementation should be ated with a number of complications and should be supervised by a
considered. haematologist.
Surveillance for hepatic adenomas is important. MRI with the use Due to the dangers of fasting and the bleeding tendency associ-
of intravenous contrast is the preferred method. About 70 to 80% ated with GSD I, surgery must be managed carefully. Patients should
of adult patients have been reported to have at least one lesion, and be admitted the day before so that fasting can be covered with intra-
these progress in size or number in 50% of cases. The occurrence venous glucose. Platelets should be available in case of postoperative
of adenomas seems to be related to metabolic control and in some haemorrhage.
 12.3.1 Glycogen storage diseases 1991

Fig. 12.3.1.4 Hepatic adenoma (white arrow) in left lobe of liver of a

young woman with GSD Ia. Fig. 12.3.1.5 A 42-​year-​old woman with GSD III and myopathy. She
has myopathic facies and a scoliosis.

Pregnancy in women with GSD I is now relatively routine. With

careful planning, close attention to glycaemic control, and increased
is less severe than GSD I and even in historic cohorts, most patients
carbohydrate requirements, especially in the second half of preg-
survived to adulthood.
nancy, and a well-​managed labour, outcomes are good.
In adults, fasting tolerance improves and on the whole
With optimal medical management, patients with GSD I now lead
hypoglycaemia can be prevented with dietary management.
relatively normal lives, but for some patients, good metabolic con-
Hepatic adenomas have only rarely been reported, although pa-
trol is never obtained. For these patients, liver transplantation offers
tients can occasionally develop cirrhosis, and the kidneys are not
a long-​term ‘cure’ for many features of the disease. Where there is
affected.
also end-​stage renal failure, combined liver and renal transplant-
Patients do, however, develop muscle symptoms and complain of
ation can be performed.
exercise intolerance, although rhabdomyolysis is not a recognized
feature. Some patients develop a progressive, disabling myopathy
with pronounced distal weakness and myopathic facies. Cardiac
Glycogen storage disease type II
muscle is also involved and hypertrophic cardiomyopathy can result
(Pompe’s disease)
in arrhythmias or heart failure (Fig. 12.3.1.5).
GSD II causes hypertrophic cardiomyopathy in infants and a pro- Management
gressive skeletal myopathy in older patients. It is primarily classified
The management of hypoglycaemia in childhood is as in GSD I. In
as a lysosomal storage disorder and is discussed in Chapter 12.8.
adult patients, it is important not to overtreat: with home glucose
monitoring it is often possible to reduce the dietary content of com-
plex carbohydrate.
Glycogen storage disease type III It has been suggested that the skeletal myopathy and cardiomy-
(Forbes–​Cori disease) opathy seen in GSD III is not solely due to glycogen storage and
that energy deficit may also have a role to play. In theory, this might
Biochemistry be addressed by providing alternative sources of energy. Ketone
GSD III is due to deficiency of debrancher enzyme. This results bodies can be provided directly as d,l-​3-​OH butyrate or by use of a
in the storage of structurally abnormal glycogen, with short outer ketogenic diet. A high-​protein diet should enhance gluconeogenesis.
chains, called limit dextrin, in both liver and muscle. Although To date, there have been isolated case reports of improvements in
glycogenolysis is blocked, gluconeogenesis is unaffected and cardiomyopathy and skeletal myopathy but no systematic studies of
fasting hypoglycaemia is milder than that seen in GSD I and these approaches have been done.
accompanied by ketosis rather than lactic acidosis. The sec- Although left ventricular hypertrophy occurs in many patients,
ondary metabolic consequences are mostly confined to a mild its clinical significance is not clear. To date, there are very few case
hyperlipidaemia. reports of heart failure or significant arrhythmia in adults. This may
change as patients age and periodic echocardiography and ECG
Clinical presentation monitoring is probably prudent.
GSD III affects both liver and muscle. Hypoglycaemia and the hep- The incidence of clinically significant hepatic fibrosis and cir-
atic consequences of storage dominate the clinical picture in chil- rhosis may also increase with age and liver imaging can be used to
dren, with fasting hypoglycaemia and poor growth. The condition monitor this as well as the occurrence of hepatic adenomas.
1992 SECTION 12 Metabolic disorders

Polyglucosan body disease (glycogen storage Clinical presentation

diseases types IV, VII, XV, and 0) Typically patients develop painful muscle cramps soon after the
start of exercise. Continued high-​intensity exercise leads to rhabdo-
Biochemistry myolysis and acute kidney injury (which is normally fully revers-
ible). However, if patients continue to exercise at lower intensities,
Polyglucosan body disease (PBD) is characterized by the storage
symptoms resolve and they are able to continue. This ‘second wind’
of aggregates of abnormal polysaccharides which are less branched
phenomenon is useful diagnostically and is due to the switch from
than normal glycogen. Polyglucosan has a fibrillar structure and, un-
glycolysis to alternative energy sources in aerobic exercise.
like glycogen is at least partially resistant to digestion with amylase.
Polyglucosan is seen in the heart and parts of the brain as a product Management
of normal ageing, but in PBD, aggregates occur at an earlier age and
No drug or dietary treatment has been shown to be effective in GSD
in a wide variety of different tissues.
V. There is some evidence that aerobic physical training is safe, and
PBD is not a single genetic entity: more than seven different mo-
may improve exercise tolerance. This is probably due to an increased
lecular causes of polyglucosan body formation have been recognized
capacity for fatty acid oxidation.
to date. Some of these are known GSDs (glycogenin deficiency (GSD
Treatment of rhabdomyolysis-​ induced acute kidney injury is
XV), branching enzyme deficiency (GSD IV), glycogen synthase de-
the same as for other more common causes of rhabdomyolysis (see
ficiency (GSD 0), and phosphofructokinase deficiency (GSD VII))
Chapter 21.5).
but other involved proteins do not seem to have a direct role in
glycogen metabolism (i.e. RBCK1, a ubiquitin ligase which regulates
the NF-​κB pathway and AMP-​activated protein kinase (AMPK)).
The biogenesis of polyglucosan bodies is not fully understood, but
Glycogen storage disease type IX
experimental work suggests that, at least in some cases, an imbal-
ance between the activities of glycogen synthase and debranching Biochemistry
enzyme may be important. GSD IX is due to deficiency of phosphorylase kinase. Phosphorylase
kinase consists of four subunits, two of which have tissue-​specific
Clinical presentation isoforms. The commonest form of GSD IX, and the commonest
Branching enzyme deficiency (GSD IV) is the best characterized GSD, is X-​linked and due to mutations in PHKA2.
of the PBDs. The classical form of GSD IV presents with progres-
sive liver failure in the first years of life. If these children are given Clinical presentation
liver transplants they go on to develop myopathy. Some patients GSD IXa is a hepatic GSD presenting early in life with hepatomegaly
present with isolated skeletal or cardiomyopathy. This can be of and fasting hypoglycaemia and ketosis. It is milder than GSD I and
early onset, in which case it can progress quickly to respiratory symptoms generally resolve in adulthood. Liver fibrosis has, how-
failure and death, but other patients present as adults with slowly ever, been reported as a long-​term complication.
progressive disease. The other forms of GSD IX are much rarer and can lead to muscle
The term adult PBD refers to a form of branching-​enzyme defi- as well as liver disease.
ciency which presents between the ages of 40 and 60 with a com-
bination of neurogenic bladder, spastic paraparesis, and peripheral Management
neuropathy. Imaging shows leukodystrophy. Polyglucosan bodies Management of hypoglycaemia is as for GSD I, but adult patients
are found throughout the central and peripheral nervous system. have normal fasting tolerance and do not need uncooked cornstarch.
The condition is progressive and patients usually die within 20 years
of diagnosis.
The other causes of PBD are rarer and generally present as hyper- Diagnosis of glycogen storage disease
trophic cardiomyopathy with or without skeletal myopathy in chil-
dren or adolescents. Most patients with hepatic GSDs present with hypoglycaemia in
early life. Historically, definitive diagnosis relied on demonstrating
glycogen storage and assaying enzyme activity in the affected
Glycogen storage disease type V tissue: many adults with GSD I still bear the scars of liver biopsies
(McArdle disease) performed in infancy. This was invasive and technically difficult, and
has to a large extent been superseded by new techniques.
Biochemistry In infants with suggestive symptoms, biochemical profiling,
McArdle described a patient who suffered exercise-​induced my- with measurements of glucose, lactate, and ketones, can suggest
algia in whom lactate fell during ischaemic exercise rather than the correct diagnosis. In some cases (e.g. GSD III), this can be con-
rising, suggesting a defect in glycogenolysis. Enzymology sub- firmed by enzymology using leucocytes, but in GSD I, molecular
sequently showed a deficiency of muscle phosphorylase activity. genetic analysis is required as the enzymes are only expressed in
Patients are asymptomatic during low intensity, aerobic exer- liver (Table 12.3.1.2).
cise, when muscle depends on fatty acid oxidation for energy, but Some patients present with hepatomegaly without biochemical
during anaerobic exercise patients rely on glycolysis and develop features suggesting GSD. In these cases, histological examination re-
symptoms. veals glycogen storage. If frozen tissue has been kept, enzymology
 12.3.2 Inborn errors of fructose metabolism 1993

Table 12.3.1.2 GSDs where enzyme activity can be assayed and

tissues needed for assay Kishnani PS, et al. (2010). Glycogen storage disease type III diagnosis
and management guidelines. Genet Med, 12, 446–​63.
Disease Enzyme Tissue Kishnani PS, et al. (2014). Diagnosis and management of glycogen
GSD I Glucose 6-​phosphatase Liver
storage disease type I: a practice guideline of the American College
of Medical Genetics and Genomics. Genet Med, 16, e1.
GSD II α-​1,4-​glucosidase Whole blood or dried blood spot
Lomako J, Lomako WM, Whelan WJ (2004). Glycogenin: the primer
GSD III Glycogen debrancher Whole blood, muscle or liver for mammalian and yeast glycogen synthesis. Biochim Biophys Acta,
GSD IV Glycogen brancher Whole blood, muscle or liver 1673, 45–​55.
Mayorandan S, et al. (2014). Glycogen storage disease type III: modi-
GSD V Phosphorylase Muscle
fied Atkins diet improves myopathy. Orphanet J Rare Dis, 9, 196.
GSD VI Phosphorylase Whole blood or liver Mochel F, et al. (2012). Adult polyglucosan body disease: natural his-
GSD VII Phosphofructokinase Muscle tory and key magnetic resonance imaging findings. Ann Neurol, 72,
GSD IX Phosphorylase b kinase Whole blood or liver 433–​41.
Olpin SE, et al. (2015). The investigation and management of meta-
GSD IX Fructose 1,6-​bisphosphatase Whole blood or liver
bolic myopathies. J Clin Pathol, 68, 410–​17.
Preisler N, et al. (2015). Skeletal muscle metabolism is impaired during
exercise in glycogen storage disease type III. Neurology, 84, 1767–​71.
may then confirm the diagnosis of a GSD. Electron microscopy can Quinlivan R, et al. (2010). McArdle disease: a clinical review. J Neurol
also be helpful if structurally abnormal glycogen is present. A diag- Neurosurg Psychiatry, 81, 1182–​8.
nostic fast, with measurement of glucose, lactate, and ketones can Quinlivan R, Martinuzzi A, Schoser B (2014). Pharmacological and
also provide useful information. Hepatomegaly with glycogen nutritional treatment for McArdle disease (glycogen storage disease
storage is not, however, always due to a GSD: hepatic glycogenosis type V). Cochrane Database Syst Rev, 11, CD003458.
is a well-​recognized complication of poorly controlled diabetes Quinlivan R, et al. (2011). Physical training for McArdle disease.
mellitus. Cochrane Database Syst Rev, 12, CD007931.
Muscle GSDs either present as exercise-​induced muscle pain or Raben N, et al. (2012). Autophagy and mitochondria in Pompe dis-
rhabdomyolysis, or progressive skeletal myopathy or cardiomyop- ease: nothing is so new as what has long been forgotten. Am J Med
athy. For patients who have exercise intolerance, and in whom de- Genet C Semin Med Genet, 160C, 13–​21.
fects of energy metabolism are suspected, the ischaemic forearm Valayannopoulos V, et al. (2011). Successful treatment of severe
cardiomyopathy in glycogen storage disease type III with D,L-​3-​
exercise test has traditionally been the diagnostic test of choice,
hydroxybutyrate, ketogenic and high-​protein diet. Pediatr Res, 70,
demonstrating a rise in ammonia but not lactate in GSD V. This test
638–​41.
is always unpleasant for the patient, and can precipitate rhabdo-
myolysis, and is now seldom performed. A 12-​min walking test,
monitoring speed and heart rate, can be used to demonstrate the
second wind effect in patients with GSD V. A number of the en-
zymes involved can be assayed in leucocytes, but for others muscle
is needed (Table 12.3.1.2).
Testing for individual enzymes is laborious and expensive and,
increasingly, molecular genetics is becoming the diagnostic test of 12.3.2 Inborn errors of
choice. Next-​generation sequencing allows large arrays of genes to fructose metabolism
be sequenced at the same time, and genetic panels to screen for all
causes of rhabdomyolysis, or all known GSDs, are now available. Timothy M. Cox

FURTHER READING ESSENTIALS

Boers SJB, et al. (2014). Liver transplantation in glycogen storage dis- Most people in developed countries ingest 50 to 100 g fructose
ease type I. Orphanet J Rare Dis, 9, 47. equivalents daily in their diet, arising from fructose itself, sucrose,
Brambilla A, et al. (2014). Improvement of cardiomyopathy after high-​ and sorbitol. After rapid carrier-​mediated absorption across the in-
fat diet in two siblings with glycogen storage disease type III. JIMD testinal epithelium, fructose is metabolized (mainly in the liver) by the
Rep, 17, 91–​5. enzymes ketohexokinase (fructokinase), aldolase B, and triokinase,
Dagli A, Sentner CP, Weinstein DA (2010). Glycogen storage ­ eventually being converted into glucose or glycogen. Dietary
disease type III. In: Pagon RA, et al. (eds) GeneReviews®. sugars—​burgeoning constituents in food and drinks worldwide—​
University of Washington, Seattle. http://​www.ncbi.nlm.nih.gov/​
have undesirable effects on those with limited capacity to metabolize
books/​NBK26372/​
fructose, including severe illness or death in young patients.
Derks TGJ, Smit GPA (2015). Dietary management in glycogen storage
‘Fructose malabsorption’ describes incomplete absorption of
disease type III: what is the evidence? J Inherit Metab Dis, 38, 545–​50.
Hedberg-​Oldfors C, Oldfors A (2015). Polyglucosan storage myop- fructose that is associated with abdominal symptoms and diarrhoea
athies. Mol Aspects Med, 46, 85–​100. reminiscent of intestinal disaccharidase deficiency. Symptoms occur
Julián MT, et al. (2015). Hepatic glycogenosis: an underdiagnosed after ingestion of fructose-​or sorbitol-​rich foods and drinks such as
complication of diabetes mellitus? World J Diabetes, 6, 321–​5. apple juice, but as yet a convincing genetic cause for this condition
1994 SECTION 12 Metabolic disorders

mutations in ALDOB (encoding the specific aldolase B isozyme)

has not been found. Symptoms improve when the offending sugars
which cause hereditary fructose intolerance are widespread and
are avoided.
shared in different populations, indicating ancient origins.
Three inborn errors of fructose metabolism are recognized and
Given the primacy of fructose and sucrose in the phenotypic ex-
these disorders are vivid examples of gene–​environment interactions:
pression of these disorders, an understanding of the driving forces
1. Essential or benign fructosuria due to fructokinase deficiency—​a responsible for the disease is of central importance for holistic clin-
very rare disorder with apparently no ill effects. ical management. Certainly, the relatively rare conditions that are
2. Hereditary fructose intolerance (fructosaemia)—​
an autosomal due to disturbance of fructose metabolism share features with en-
recessive disease caused by deficiency of aldolase B. Typically vironmentally driven syndromes of obesity, nonalcoholic hepatic
presents at weaning when most fatalities occur. May come to steatosis, and hyperlipidaemia. In the background, a succession of
light at any age with postprandial abdominal pain and vomiting, regrettable historical events led to the introduction of sugar pri-
symptomatic hypoglycaemia (which may induce seizures), marily into the modern European diet. Insatiable demands for sugar
hypophosphataemia, acidosis, and other metabolic disturbances obtained in plantations by foreign slave labour in New World col-
after consumption of offending foods and drinks. Unrecognized onies has left many painful consequences, for example, the wide geo-
disease causes failure to thrive/​growth retardation, a Fanconi-​like graphic dissemination of sickle cell disease and other effects such as
renal syndrome with nephrocalcinosis, and jaundice with lethal economic deprivation and social injustice.
liver injury. Parenteral infusion of fructose or its congeners may
cause death from acute hepatorenal injury. Diagnosis formerly
depended on a controlled intravenous fructose challenge test or Consumption of fructose and sucrose
demonstration of deficient aldolase B isozyme activity in liver or
small intestinal biopsy material; currently molecular analysis of The sugar trade expanded during the 16th to 19th centuries ce as
the aldolase B gene is preferred and usually decisive. Treatment the mass capture and trading of slaves took hold. Partially modelled
requires institution of a strict sugar-​exclusion diet supplemented on earlier Arabic trading in Africa, the use of slave labour in the
by folic acid and vitamin C. Early diagnosis and dietary modifica- sugar plantations in New World and other colonies has a haunting
tion are critical for well-​being and normal development. legacy. Nowadays, however, this history has an ironic payback in the
3. Fructose-​ 1,6-​
diphosphatase deficiency—​ a very rare disease consequential effects of sugar on global health. The mass industri-
of infancy and childhood associated with failure of hepatic alization of sugar production declares the nature of the human ap-
gluconeogenesis causing bouts of severe hypoglycaemia, ke- petite for sweet flavours, and exogenous sugar is added to food and
tosis, and lactic acidosis provoked by infection and starvation. drinks in modern societies across the world. Disorders of fructose
Metabolic decompensation is provoked by dietary fructose, metabolism and its assimilation mirror the ubiquity of sucrose and
related sugars, and/​or ketogenic fat. Diagnosis depends on en- fructose in the diet.
zymatic assay of fructose 1,6-​diphosphatase in fresh liver biopsy Consumption of free sugars varies greatly by age and country.
samples or molecular analysis of the cognate gene. Treatment Most people in developed countries ingest 50 to 100 g fructose
requires a fructose-​exclusion diet containing abundant carbohy- equivalents daily in the diet. The top cane and beet sugar (sucrose)-​
drate energy, restricted fat, and protein. Acute episodes of acidosis consuming countries are shown in Table 12.3.2.1. Global production
or hypoglycaemia are controlled by intravenous glucose infu- of sugar (sucrose from cane and beet) continues to rise, but over the
sions, with bicarbonate if required. last three decades, novel manufacture of fructose as a high-​fructose
corn syrup, enzymatically derived from starch in maize (corn), has
also burgeoned. This intensely sweet sugar, first enzymatically pro-
duced commercially from excess maize in the early 1970s, mainly
Introduction from United States mid-​Western agriculture, has been popular in
the United States of America, Mexico, and China, but is now manu-
Fructose is an important and burgeoning component of the modern factured and used in the European Union and Australia.
diet; it occurs as a free monosaccharide in fruit, nuts, honey, and
some vegetables but is now abundant and practically ubiquitous in Sugar manufacture—​a challenge for global health
popular, mass-​produced drinks. Free fructose is released from the World manufacture of sugar and sweeteners is growing; the global
disaccharide sucrose in the gut lumen by the sucrase–​isomaltase 2017 market was about $97 billion, representing an estimated
complex at the brush-​border membrane of the mucosal epithelium; 184 million metric tons of sugar as sucrose. Until recently, all large-​
in modern times, sucrose is the principal source of fructose for most scale sugar production came from sugar beet and sugar cane, which
persons. Finally, the sugar alcohol, sorbitol (a constituent of medi- in modern times yield products that are indistinguishable in taste
cines and tablets, as well as diabetics), is converted quantitatively to and composition. Cane sugar, principally from tropical countries,
fructose in the liver and intestine. represents about 80% of the global market and is generally cheaper
Inborn errors of fructose metabolism provide unique ex- to manufacture than beet sugar, which has enjoyed political and eco-
amples of gene–​environment interactions in recent economic his- nomic support from local farming systems, generally in nontropical
tory. Emergence of these conditions reflects revolutionary dietary countries. Direct market competition of beet with cane sugar had
changes resulting from the mass industrialization of sugar farming occurred in postcolonial times because beet sugar-​producing coun-
and manufacture. Were it not for the sugar industry, it is unlikely tries mitigated losses on exports by high revenue in domestic mar-
that these disorders would have come to light, even though several kets, thus allowing expansion of domestic beet cultivation.
 12.3.2 Inborn errors of fructose metabolism 1995

Table 12.3.2.1 Daily sugar consumption (grams per capita) production is never traded on the open market. Brazil, one of the
first since its early Portuguese colonization, and still the largest pro-
1 United States 126.4
ducer, controls half the global market but pays subsidies measured in
2 Germany 102.9 billions annually to its sugar industry. Until very recently, a complex
3 Netherlands 102.5 tariff rate system providing direct support of domestic sugar pro-
4 Ireland 96.7 duction was used in the United States of America, which maintained
5 Australia 95.6 the price there up to 90% higher than the world market price at an
annual charge of 3.7 billion dollars to American consumers. As of
6 Belgium 95.0
August 2018, a ‘zero-​for-​zero’ policy is poised for legislation to end
7 United Kingdom 93.2
domestic sugar subsidies after other major international producers
8 Mexico 92.5 such as Brazil and India agree reciprocally to cease sugar industry
9 Finland 91.5 subsidies. Strong subsidies also operated in the European Union,
10 Canada 89.1 but with a ruling from the World Health Organization some quotas
were abolished in 2015. Perhaps reflecting former colonial respon-
Data from the World Agricultural Outlook Board—​United States Department of
Agriculture USDA https://​public.govdelivery.com/​accounts/​USDAFAS/​subscriber/​new sibilities, in 2009 the European Union granted Least Developed
and Statista: https://​www.statista.com/​statistics/​496002/​sugar-​consumption-​worldwide/​ Countries zero-​tariff access status to the European market as part of
(accessed 26 August 2018).
its ‘Everything but Arms’ initiative.

High-​fructose corn syrup is now used extensively as a sweetener Control of sugar consumption
in drinks and processed foods. In 2017, the global market for this The World Health Organization and American Heart Association
preparation alone was $4.5 billion dollars (c.5% of cane and beet recommend that women consume less than six teaspoons of sugar
sugar) and this continues to rise by more than 2% annually. In 1970, per day, which amounts to 25 g; men are recommended to ingest no
the average per capita daily consumption in the United States of more than nine teaspoons of sugar per day (38 g). The American
America of 105 g calorific sweetener contained only 0.5 g from high-​ Academy of Pediatrics recommends that children between 2 and
fructose corn syrup, but by 2004 this had risen to 52.4 g of the 124.8 18 years take in no more than six teaspoons (25 g) per day. It is note-
g of the sweetener ingested on average each day. worthy that none of these recommendations apply to sugar that oc-
As the World Health Organization emphasizes—​and as patients curs naturally in foods, such as the fructose present in fruits, nuts,
who are genuinely intolerant realize—​many of the sugars consumed and honey.
today are ‘hidden’ in processed foods and drinks; they are neither Given the increasing awareness of the growth of sugar consump-
overtly present nor declared as sweeteners. An average portion of tion, the food and beverage industry is replacing sugar or corn syrup
ketchup sauce contains about 4 g of free sugar; a single can of soda with non-​nutritive sweeteners in a range of products that tradition-
contains up to 40 g sucrose and/​or fructose. Depending on the re- ally contained sugar. Aspartame has been a popular artificial sweet-
gional manufacturing and local distribution, the most popular ener in the US food industry, and its price dropped after expiry of the
international carbonated drinks obtained from one long-​established relevant patent in 1992. However, since 2008, sucralose has become
company based in the United States of America contain 100 to 140 the most popular nonsugar sweetener, replacing aspartame to artifi-
g/​litre sugar, mostly as fructose. cially sweeten foods and beverages.
Food and drink labels are often deceptive: a popular mint-​ Hidden practices also operate in the United States of America,
flavoured confection in the United Kingdom is described as con- where it has until recently been possible to mislabel foods and
taining several grams of carbohydrate but ‘sugar-​free’. In fact, all greatly minimize their apparent sugar content. From 2018, in a con-
the carbohydrate is present as sorbitol—​a direct source of fructose. tested mandate, the Food and Drug Administration required all food
These mints, peppery rather than sweet to the taste, caused seizures manufacturers to identify and explicitly list all ‘added sugars’ in their
and nephrocalcinosis in a strictly controlled and food-​conscious Nutrition Facts labels. This new food labelling regime clearly regards
mathematician with hereditary fructose intolerance (whose affected sugar as a major public enemy. As in many other countries, previ-
brother had died in infancy). While a popular carbonated mixer ously these sugars were concealed under the ‘Total Carbohydrates’
drink flavoured with quinine contains 80 g/​litre sugar, its ‘naturally section of the label, and only naturally occurring sugars were em-
light’ alternative contains nearly 30 g/​litre. phasized. Given the strong influence of food labels on the public, the
In Europe, sugar intake in adults ranges from about 8% of total new regulation is likely to have a salutary effect, and particularly for
energy intake in Hungary and Norway, to more than twice this pro- patients with disorders of fructose metabolism. Some consider that
portion in Spain and the United Kingdom. Intake is relatively greater sugar sales and promotion will soon be on the wane, but while this
among children, ranging from about 12% in Denmark, Slovenia, seems to be a premature judgement, sugar is starting to rival tobacco
and Sweden, to nearly 25% in Portugal. Generally, consumption of in perception as a major public ill in some quarters.
additional sugar is greater in urban compared with rural commu-
nities, but this may not hold in countries where production of cane
sugar is still a dominant industry, such as Brazil. Biochemistry of fructose metabolism
Changes in the sugar economy and mitigating factors The pathways of fructose metabolism are summarized in Fig. 12.3.2.1.
Production of sugar from cane, beet, and increasingly from cereal Phosphorylated forms of fructose are critical intermediates in
starch is a massive global industry, but more than 70% of world sugar the glycolytic and gluconeogenic metabolic pathways in all cells.
1996 SECTION 12 Metabolic disorders

Sucrose Sorbitol GLYCOGEN as a result of triokinase activity, glyceraldehyde is phosphorylated

so that the two triose phosphates may be condensed by aldolase
Glucose 1-phosphate A to form the glycolytic and gluconeogenic intermediate fructose
FRUCTOSE
1,6-​diphosphate.
Glucose 6-phosphate GLUCOSE
Fructokinase
Fructose malabsorption
Fructose 6-phosphate
Fructose
diphosphatase The occurrence of abdominal symptoms and diarrhoea, reminiscent
Fructose 1-phosphate Fructose 1,6-diphosphate of intestinal disaccharidase deficiency, in response to ingested fruc-
ALDOLASE B ALDOLASE A
tose is well recognized by gastroenterologists and often attributed
Glyceraldehyde dihydroxyacetone glyceraldehyde 3-phosphate to incomplete absorption of fructose: it is therefore called ‘fructose
phosphate
malabsorption’. The symptoms occur in adults and children after in-
triose phosphate isomerase pyruvate gestion of fructose-​rich or sorbitol-​rich foods and drinks such as
apple juice, and usually recede when the sugars are excluded from
triokinase
Krebs’ cycle
the diet. Many such individuals, as well as a high proportion of
healthy control subjects, have findings suggestive of fructose malab-
Fig. 12.3.2.1 Fructose metabolism. Gluconeogenesis from triose sorption based on hydrogen breath tests, but definitive evidence of
phosphates, lactate, glycerol, amino acids, and Krebs cycle intermediates
such as oxaloacetate, requires reversal of the committed reactions of
true malabsorption is usually lacking.
glycolysis. It is the enzyme fructose 1,6-​diphosphatase that releases the The molecular basis of this syndrome and of the wide variation
glucose precursor fructose 6-​phosphate from fructose 1,6-​diphosphate. of tolerance to dietary fructose and its congeners is not known.
Thus, when the remaining reactions of glycolysis are reversed, exogenous Moreover, in several patients complaining of fructose-​ related
fructose provides a source of glucose or glycogen. Fructose 1,6-​ intestinal symptoms, molecular analysis of the human GLUT5
diphosphatase is active in the liver, kidney, and intestine, and is a key
gene, which encodes a major intestinal fructose transporter, has
enzyme of gluconeogenesis.
so far failed to identify causal mutations. Recently, mice lacking
the action of a critical glucose-​activated transcription factor—​
Fructose is absorbed by a carrier mechanism that facilitates trans- carbohydrate-​ responsive element-​ binding protein (ChREBP)—​
port across the intestinal epithelium; this process is mediated by the that regulates glucose and lipid metabolism develop diarrhoea
glucose transporter isoforms GLUT5 and GLUT2, the latter prob- and weight loss after administration of diets high in sucrose or
ably contributing to efflux across the basolateral membrane of the fructose, but not high-​glucose diets. These effects are associated
enterocyte. Uptake of fructose is rapid and notable for its lack of with poor induction of the fructose carrier, GLUT5, in the small
dependence on insulin. intestine. Given these findings, it is conceivable that genetic vari-
Fructose is then conveyed via the portal bloodstream to the ation in the activity of this nutritional regulatory pathway in the
liver, where it is assimilated. The jejunal mucosa and proximal tu- intestine accounts for dietary idiosyncrasy to fructose and sucrose
bule of the kidney are subsidiary sites of fructose metabolism. in humans. While no information about ChREBP in patients com-
Assimilation of fructose depends on the concerted activities of the plaining of fructose malabsorption is yet available, the field is one
enzymes ketohexokinase (fructokinase), aldolase B, and triokinase, of great interest for large-​scale investigations that extend to obesity
which are expressed specifically in these tissues. Uptake of fructose and the metabolic syndrome.
occurs independently of insulin and its incorporation into inter- Other studies have suggested that the distal small intestine and
mediary metabolism bypasses the regulation of glycolysis at the colon of patients who experience abdominal flatulence and diar-
level of phosphofructokinase-​1. For these reasons, solutions of fruc- rhoea after ingesting fructose-​containing foods contain a bacterial
tose or sorbitol were advocated and, in the past, extensively used population with enhanced uptake and anaerobic metabolism of
for parenteral nutrition, particularly in German-​speaking countries. fructose. No conclusive evidence has yet been provided to support
However, the occurrence of lactic acidosis, hyperuricaemia, and these observations and more investigative studies are needed in
other serious consequences has led to their withdrawal from hyper- those patients who experience symptoms attributed to malabsorp-
alimentation regimens in most, if not all, regions. tion of this sugar, including measurement of intestinal fructose ab-
Fructokinase rapidly phosphorylates fructose at the 1-​carbon sorption, metabolism, and transport.
position. This enzyme has a high affinity for its substrates and the
intestinal mucosa and liver rapidly convert fructose to fructose
1-​phosphate; in other tissues, the capacity of hexokinase to phos- Essential (benign) fructosuria (OMIM 229800)
phorylate fructose at the 6-​carbon position is limited. Similarly, the
fate of fructose 1-​phosphate in the fructose-​metabolizing tissues is This is a rare disorder (estimated birth frequency 1 in 130 000) of
dependent on a specific isozyme of aldolase, aldolase B. This has little clinical consequence. The abnormality is transmitted as an
greater activity towards fructose 1-​phosphate than does its ubi- autosomal recessive condition and is demonstrated by the pres-
quitous counterpart aldolase A, the natural substrate of which is ence of a reducing sugar in the blood and urine, especially after
fructose 1,6-​diphosphate. Cleavage of fructose 1-​phosphate gen- meals rich in fructose. The abnormality is caused by the defi-
erates glyceraldehyde and dihydroxyacetone phosphate. These tri- ciency of fructokinase activity in the liver and intestine, signifi-
oses enter the intermediary pools of carbohydrate metabolism, and, cantly reducing the capacity to assimilate this sugar. Mutations in
 12.3.2 Inborn errors of fructose metabolism 1997

the human ketohexokinase gene on chromosome 2p23.3–​p23.2 Infants who survive the stormy period of weaning develop a strong
have been identified in patients with essential fructosuria, thus aversion to sweet-​tasting foods, vegetables, and fruits. This usually
confirming the suspected molecular defect in this condition. affords protection against the worst effects of fructose and sucrose,
Fructose metabolism occurs slowly in essential fructosuria as a re- but abdominal symptoms with bouts of tremulousness, irritability,
sult of conversion to fructose 6-​phosphate by hexokinase in adi- and altered consciousness due to hypoglycaemia usually continue.
pose tissue and muscle, but, while plasma concentrations remain It has become clear that many cases escape diagnosis in infancy
high postprandially, large amounts of fructose appear in the urine. and childhood, but the risk of illness related to dietary indiscretion
Essential fructosuria may be confused with diabetes mellitus if the remains throughout life. Characteristically, children and adults with
nature of the mellituria is not defined; with the use of glucose oxi- hereditary fructose intolerance show a striking reduction in, or ab-
dase strips in preference to the older chemical methods for urin- sence of, dental caries. They usually have notable preferences for
alysis, such confusion is now unlikely in the routine clinical testing foods and drinks, with striking dietary peculiarities. As explained in
of urine worldwide. No treatment beyond recognition and explan- relation to the growth of the sugar industry, nutritional behaviours
ation appears to be necessary. are changing worldwide, and increasingly it is found that hidden or
undeclared sugars are the culprit in patients with fructose intoler-
ance who remain unwell despite attempts to modify food and drink
Hereditary fructose intolerance (fructosaemia) intake. A syndrome of chronic sugar intoxication has been identi-
(OMIM 229600) fied in older children and adolescents with hereditary fructose in-
tolerance and may persist in the adult. General lack of vigour and
This disorder, first recognized in 1956, is the most common in- developmental retardation are prominent features. Hypoglycaemia,
herited defect of fructose metabolism with an estimated frequency though obvious after heavy fructose loading, may be insignificant
of about 1 in 20 000 births in Europe. Determination of aldolase B after chronic low-​level exposure in older children. Similarly, tests
mutation frequency in DNA obtained from neonatal blood spots in- of hepatic and renal function may be only mildly abnormal. The
dicated a frequency of 1 in 18 000 live births in the United Kingdom. intermittent presence of reducing sugar in the urine may indicate
The disease has been reported in populations throughout the world, fructosuria; amino aciduria may also be present.
including China and Israel. Persistent ingestion of fructose and sucrose is toxic to the kidney
Hereditary fructose intolerance is transmitted as an autosomal re- and liver, so that renal tubular acidosis (occasionally with calculi)
cessive trait and, although it manifests itself first in early infancy, the as well as hepatosplenomegaly occur in younger patients. Severe
effects of clinical disease may not be recognized until late childhood growth retardation may be accompanied by rachitic bone disease
or even adult life. Provided the diagnosis is made before visceral that complicates the Fanconi-​ like syndrome of proximal renal
damage occurs, hereditary fructose intolerance responds completely tubular disturbance with bicarbonate wasting. Growth retardation
to a strict exclusion diet and patients can survive to old age. The first responds to dietary treatment and is usually accompanied by regres-
patient ever reported (as a young adult) was healthy and an active sion of the other disease manifestations.
grandparent at well over 80 years of age.
Metabolic defect
Clinical features Hereditary fructose intolerance is caused by a deficiency of aldolase
The cardinal features of this illness are vomiting, diarrhoea, upper B in the liver, small intestine, and proximal renal tubule. These tis-
abdominal pain, and hypoglycaemia that are induced by the con- sues experience injury as a result of persistent exposure to fructose
sumption of foods, drinks, or medicines containing fructose, or the in patients affected by the disorder. In the absence of the fructose-​
related sugars, sucrose or sorbitol. The infant is first exposed to the 1-​phosphate-​splitting activity of aldolase B, the intracellular pool of
offending sugars at weaning or on first transfer from breast milk inorganic phosphate is depleted. Studies in vivo by 31P magnetic res-
to artificial feeds, and—​with continued exposure to the harmful onance spectroscopy show that 80% of hepatic free phosphate is se-
foods—​a generalized metabolic disturbance with lactic acidosis, questrated as sugar phosphates after the infusion of small quantities
hyperuricaemia, and hypophosphataemia develops. of fructose (250 mg/​kg body weight). The secondary metabolic dis-
Hypoglycaemia causes trembling, irritability, and cognitive im- turbances are initiated by the accumulation of fructose 1-​phosphate
pairment. Attacks are associated with pallor, sweating, and, when in a milieu where free inorganic phosphate is reduced: there is
severe, result in loss of consciousness, sometimes accompanied competitive inhibition of aldolase A and inhibition of phosphor-
by generalized seizures. These episodes typically occur within 30 ylase activity so that glycogenolysis and gluconeogenesis are im-
min of meals that contain large quantities of fructose or sucrose. paired. Thus, challenge with fructose leads to hypophosphataemia
Continued ingestion of noxious sugars is associated with renal and hypoglycaemia that is refractory to glucagon or the infusion of
tubular disease, liver injury with jaundice, and impaired blood co- gluconeogenic metabolites such as glycerol or dihydroxyacetone.
agulation. In children and infants, there is marked failure to thrive; During challenge with fructose, high concentrations of fructose
growth retardation becomes apparent and the child becomes listless 1-​phosphate cause feedback inhibition of fructokinase, thereby
and miserable. Persistent exposure to fructose and the related in- limiting the incorporation of fructose in the liver. As a result,
jurious sugars in feeds and drinks given to infants leads to structural fructosaemia occurs and, when the blood concentration exceeds
liver injury with cirrhosis, aminoaciduria, coagulopathy, and coma about 2 mmol/​litre, fructosuria is apparent. Although the assimila-
leading to death. Survival is dependent on recognition of the effects tion of fructose by the specialized pathway is blocked, only a small
of fruit and sugar by the mother or, especially in older infants, by fraction of the fructose load is recovered in the urine. Studies show
vomiting or forcible rejection of food by the patient. that 80 to 90% of the fructose is taken up under these circumstances
1998 SECTION 12 Metabolic disorders

by adipose tissue and muscle, where it can serve as an alternative The genetic basis of aldolase B deficiency has been studied inten-
substrate for hexokinase with conversion to fructose 6-​phosphate. sively and numerous mutations responsible for hereditary fructose
Electrolytic disturbances occur during challenge with fructose. intolerance have been identified. The human aldolase B gene maps
Hypokalaemia results from acute renal impairment with defective to chromosome 9q22.3. Several point mutations affecting the func-
urinary acidification. There is a defect of proximal tubule function tion of the enzyme are sufficiently widespread in patients of European
with bicarbonate wasting and acidosis. Occasionally, acute flaccid origin to merit focused diagnostic investigation. One particular mu-
weakness due to hypokalaemia accompanies the other effects of tation, originally termed Ala149→Pro, which disrupts residues in a
fructose exposure. In patients with hereditary fructose intolerance, substrate-​binding domain of aldolase B, is prevalent in populations of
the administration of fructose reproducibly increases serum magne- European descent. This mutation accounts for most alleles r­ esponsible
sium concentrations. This is probably explained by the breakdown for fructose intolerance, but others, including those originally named
of magnesium–​ATP complexes, releasing intracellular magnesium Ala174→Asp, Asn334→Lys, and a four-​base deletion in exon 4, are suf-
ions as a result of nucleotide degradation by adenosine deaminase. ficiently frequent and widespread to merit initial examination in a
Significant ingestion of fructose is thus also accompanied by marked specialized molecular diagnostic laboratory (see following ‘Molecular
hyperuricaemia in patients with hereditary fructose intolerance. diagnosis’ subsection). The intragenic deletion has also been reported
In the absence of acute exposure to fructose, only minor ab- from China. Biochemical and structural studies of the expressed mu-
normalities of blood analytes are detectable and the blood glucose tant enzymes reveal two main classes of aldolase B in hereditary fruc-
concentration is normal, even after prolonged fasting. Often trivial tose intolerance, active tetrameric variants which are unstable and
elevation of serum transaminase activities occur; red cell folate and readily lose their quaternary structure and mutant aldolases that re-
white cell ascorbate concentrations may be reduced as a result of re- tain their normal tetrameric structure but are catalytically impaired.
strictive dietary habits.
Differential diagnosis
Pathology and molecular genetics In infancy and childhood, presentation of persistent vomiting, with
Persistent ingestion of fructose and related sugars in hereditary fruc- failure to thrive, acidosis, hypoglycaemia, and/​or jaundice suggest
tose intolerance causes hepatic injury; there is diffuse fatty change a wide differential diagnosis, but fructose intolerance may be indi-
and increased glycogen deposition. Hepatocyte necrosis with cated by the nutritional history and feeding difficulties. Possibilities
intralobular and periportal fibrosis occurs and fully developed cir- include surgical diseases such as pyloric stenosis and even biliary
rhosis results from continued exposure to fructose. After acute ex- atresia, but particularly inborn errors of metabolism, including
perimental challenge, electron microscopy has shown irregular galactosaemia, Reye’s syndrome, hepatitis, renal tubular disease,
electron-​dense material surrounded by membranous structures, sug- Wilson’s disease, mitochondrial DNA depletion syndrome, con-
gesting a florid lysosomal reaction to intracellular deposits of fruc- genital defects of glycosylation, hereditary tyrosinaemia type 1,
tose 1-​phosphate. Parenteral administration of fructose or sorbitol long-​chain 3-​hydroxyacyl-​CoA dehydrogenase deficiency, classic
may induce the abrupt onset of hepatorenal failure associated with methylmalonic aciduria, and citrullinaemia type 1.
bleeding. Histological examination shows hepatic necrosis in these A carbohydrate-​deficient glycoprotein syndrome may be sus-
cases (Fig. 12.3.2.2). Loss of cellular functions (e.g. in the proximal pected on the basis of biochemical screening tests carried out in
renal tubule) is probably caused by depletion of ATP resulting from paediatric investigations, since untreated patients with hereditary
the arrested metabolism of fructose by the specialized pathway. The fructose intolerance almost invariably show a type I pattern of
source of the severe abdominal pain that follows ingestion of fructose carbohydrate-​deficient serum transferrin on isoelectric focusing;
is unknown, but stimulation of visceral afferent nerves by the local this is corrected within a few weeks of fructose exclusion and is due
release of purine nucleotides or lactate may be responsible. to transient inhibition of phosphomannose isomerase implicated in
glycoprotein processing and biosynthesis. In older infants and chil-
dren, poisoning might have occurred, and this will mainly reflect
inadvertent exposure to toxins, of which paracetamol in paediatric
elixir preparations and suspensions is a prominent accidental risk.
If fructose intolerance is considered, then sucrose, sorbitol, and
fructose should be excluded completely and immediately before de-
finitive diagnosis. Striking improvement, suggestive of hereditary
fructose intolerance, may be seen on institution of the appropriate
exclusion diet (including fluids) within a few days, and this can be
life-​saving in infants and children.

Diagnosis
Formerly, diagnosis of fructose intolerance required the demon-
stration of fructose-​1-​phosphate aldolase deficiency in tissue (liver
or small intestinal mucosa), but increasingly demonstration of
the presence of two causal mutant alleles of ALDOB is employed.
Fig. 12.3.2.2 Post-mortem needle liver aspirate (Mallory’s trichrome stain).
Molecular analysis of the ALDOB gene in genomic DNA from an
Reproduced from Ali M, Rosien U, Cox TM (1993). DNA diagnosis of fatal fructose
intolerance from archival tissue. Q J Med 86, 25–30 with permission from Oxford oral swab or blood sample can be carried out as soon as the diagnosis
University Press. is suspected.
 12.3.2 Inborn errors of fructose metabolism 1999

Molecular diagnosis of 0.25 g/​kg (0.2 g/​kg in infants) of d(+)-​fructose as a 20% solution
Direct genetic diagnosis of hereditary fructose intolerance is now over a few minutes; blood samples for potassium ions, magnesium
possible and is the preferred method, particularly (but not exclu- ions, phosphate ions, and glucose are taken before the administration
sively) for patients of European ancestry, from whom most of the and at regular intervals over a 2-​h period. In fructose intolerance,
widespread causal mutant alleles of ALDOB hitherto have been re- epigastric and loin pain usually accompany the infusion, and hypo-
ported. The nomenclature currently adds one to the mutated residue glycaemic coma may occur; hypophosphataemia is characteristic.
that occurs in the aldolase B protein (A149P is currently pAla150Pro Characteristically, since gluconeogenesis is blocked during exposure
or more conveniently A150P). Widespread founder mutations have to fructose or its congeners, the acute hypoglycaemia fails to respond
been reported from regions elsewhere, including North India. to glucagon and therefore glucose for parenteral injection must be
While molecular analysis of aldolase B genes for the presence of available. Responses differ between individuals, and hypoglycaemia
common mutations responsible for the disease can be carried out is usually milder in adults; typical responses in hereditary fructose in-
by specialized laboratories equipped for genetic testing, the rapid tolerance and a control subject are shown in Fig. 12.3.2.3. The toler-
spread of DNA diagnostic methods worldwide is greatly improving ance test should not be carried out in patients with overt signs of liver
recognition of the disease and its severity. Some specialized diag- disease where it may occasionally yield misleading results, and in a
nostic facilities, usually based in hospital laboratories offering patient with hereditary fructose intolerance the challenge will dan-
paediatric services, have reported useful practical protocols for hier- gerously aggravate the disease—​particularly in infants and children.
archical ALDOB mutation screening. Failure to identify two of the The ability to identify disease alleles by analysing genomic DNA
more frequent mutant alleles in patients with suspected hereditary obtained from very small samples of blood or tissue may not only be
fructose intolerance should encourage a systematic approach to mo- beneficial for the investigation of infants with this disorder but also
lecular diagnosis, if necessary to include definitive sequencing of for neonatal testing before dietary exposure occurs. There is a strong
the entire human aldolase B gene (ALDOB). It is obvious that this case for trials in which the utility of mass population screening for
stratagem obviates invasive or hazardous investigations using tissue fructose intolerance, a preventable nutritional disease, is investigated
biopsy procedures, or cumbersome parenteral challenge with sugar but despite much effort this apparently justifiable course has yet to
solutions, and ultimately is likely to reduce overall healthcare costs. be adopted.
The diagnosis has important consequences for relatives of the
propositus and will provide information critical for the introduction (a)
of a rigorous and life-​long exclusion diet.
5.0 2.0

Enzymatic analysis
4.0 1.6
Aldolase B deficiency may be demonstrated definitively by enzym-
atic analysis of biopsy samples obtained from the liver or small intes-
tinal mucosa. Biochemical assay of fructaldolases characteristically 3.0 1.2
demonstrates markedly reduced or absent fructose 1-​phosphate
cleavage activity with a partial deficiency of fructose 1,6-​diphosphate 2.0 0.8
aldolase. Since fructaldolase deficiency may accompany other par-
enchymal disease of the liver, and because liver biopsy for biochem-

Serum phosphate (mmol/l)

ical analysis is invasive, these assays are of limited value in the acutely 1.0 0.4
Blood glucose (mmol/l)

ill or jaundiced patient.

Intravenous fructose tolerance test (see Fig.12.3.2.3) (b)

The intravenous fructose tolerance test was previously useful for
diagnosis, particularly in adults; however, preparations of fructose 4.0 1.6
suitable for intravenous use are now difficult to obtain and direct
diagnosis by molecular analysis of ALDOB is preferred. In any event, 3.0 1.2
failure to obtain fructose solutions suitable for parenteral use should
not encourage the administration of fructose or sucrose orally, since
administration by this route may induce catastrophic effects with 2.0 0.8
severe pain, acidosis, and even shock. A child or adult is unlikely to
return for further care after such a casual toxic exposure to a highly 1.0 0.4
offensive sugar load given orally, usually against their will. Even in
recent times, critical illness polyneuropathy has occurred in at least
one affected child after misconceived diagnostic oral challenge with –10 0 10 20 30 40 50 60 70 80 90
fructose (hereditary fructose intolerance was formally diagnosed by Time (min)
retrospective molecular analysis of the aldolase B gene). Fig. 12.3.2.3 (a) Intravenous fructose tolerance tests in a 39-​year-​old
If no other method for investigating the patient is available, then woman with hereditary fructose intolerance proved by fructaldolase
the intravenous tolerance test should be carried out under controlled assay and DNA analysis. (b) An age-​matched and sex-​matched control
conditions with medical personnel at hand. It requires the infusion subject with alcohol-​related episodic hypoglycaemia.
2000 SECTION 12 Metabolic disorders

Treatment toxicity. Occasionally, patients are unable to tolerate certain foods

Provided that organ failure and serious tissue injury do not super- that are permitted on their diet sheets; in doubtful cases it is advis-
vene, patients with hereditary fructose intolerance recover rapidly able to avoid the offending item or to have it analysed.
when the toxic sugars are withdrawn. Children who survive by ac- Patients with hereditary fructose intolerance may lack folic acid
quiring a protective pattern of eating behaviour avoid foods which and vitamin C. Supplements of these vitamins in particular are re-
provoke abdominal symptoms. The aversion extends to most sweet-​ commended, especially during pregnancy, but, as with other medi-
tasting items of food and drink as well as fruits and vegetables; it re- cines, care has to be taken to avoid harmful sugars contained in the
mains lifelong and consumption of fructose (and sucrose) is usually preparation. Although the use of fructose-​containing or sorbitol-​
reduced to less than 5 g daily. It has been shown that normal growth containing preparations for intravenous nutritional supplementation
and development can be assured in growing children and adoles- has now been stopped, in the era before fructose and sorbitol infu-
cents if less than 40 mg/​kg fructose equivalents are ingested daily. sions were banned in Europe, at least 16 patients developed toxicity
Dietary treatment of fructose intolerance mitigates the disorder but and died (Fig. 12.3.2.2). Some medicines that are given parenterally
requires the almost complete exclusion of sucrose, fructose, and sorb- are still reconstituted in solutions containing harmful quantities of
itol. A changing and notable feature of the disease is the increasing con- sorbitol or fructose. Hepatorenal failure has recently been reported
tribution of added sweeteners and additives to the diet and present in after the administration of amiodarone in a polysorbate solution to a
drinks. The daily consumption of sugar should be reduced to less than patient with hereditary fructose intolerance, with dire consequences.
40 mg fructose equivalents per kilogram of body weight (i.e. 2–​3 g for Prognosis
an adult) in order to reverse the disease manifestations and establish
normal development in affected infants and children. The ubiquity of Untreated hereditary fructose intolerance is a potentially fatal disease
fructose and its congeners in the Western diet presents serious diffi- in infants and young children in whom it ultimately causes irreversible
culties. Not only are fructose and its congeners present in unexpected liver disease, renal tubular impairment, and episodic, life-​threatening
foods, such as certain types of potato, but the sugars are added to foods hypoglycaemia. The proportion of infants that die of unrecognized fruc-
unexpectedly and deceptively. Adult patients have usually restricted tose toxicity is unknown but given the discrepancy between the preva-
their consumption of fructose to less than 20 g daily and the source of lence of mutant aldolase B alleles and the apparent rarity of the disease,
the residual sugar may be difficult to establish. For this reason, the ad- the author estimates this to be at least one half of all those born with the
vice of an experienced dietitian should be sought (Box 12.3.2.1). condition. Occasionally, adolescents and adult patients may succumb to
Particular care needs to be taken with sugar-​coated pills and espe- the inadvertent use of parenteral fructose or sorbitol, but this practice,
cially with liquid medications for paediatric use, as large amounts of which until recently was popular in German-​speaking countries, is now
fructose, sucrose, and sorbitol are frequently present. obsolete. With the introduction of a strict exclusion diet, the disorder is
Children and adults with hereditary fructose intolerance may tol- compatible with a normal quality and duration of life.
erate the taste of confectionery that contains large quantities of nox-
ious sugars but in which the sweetness is masked by other flavours,
such as peppermint, which they enjoy. This behaviour may lead to Fructose diphosphatase deficiency
unexplained hypoglycaemic symptoms and other signs of sugar (OMIM 229700)
Box 12.3.2.1 Food items not allowed for patients with hereditary Clinical features
fructose intolerance and fructose diphosphatase deficiencya
This very rare, recessively inherited disorder presents with hypo-
• Table sugar
glycaemia, ketosis, and lactic acidosis in early infancy. Fewer than
• Fruit sugar, all fruit and fruit products, including tomatoes
100 cases have been reported since its original description in 1970.
• Sorbitol—​often used in confectionery (especially), as an excipient or
stabilizer in medication or diabetic foods Severe, sometimes fatal, acidosis is associated with infection and
• Honey, syrup, treacle, and molasses starvation, and most cases present within the first few days of life or
• Diabetic foods in the neonatal period. Onset during the first year of life is the rule.
• Chocolate and sherbet In newborn infants, the severe metabolic disturbance shows it-
• Preserves, jams, and marmalade self by acidotic hyperventilation, which may be accompanied by ir-
• Frankfurters, honey-​roast ham, and sweet-​cured ham ritability, disturbed consciousness, seizures, or coma. The unusual
• Processed cheese spreads combination of ketonaemia, lactic acidaemia, and hypoglycaemia
• Cream and cottage cheese with chives, pineapple, etc. is induced by fasting, the administration of fructose, sorbitol, and
• Flavoured milks and yoghurts glycerol, and by ingestion of a diet rich in fat. Episodes in the neo-
• Wheatgerm, brown rice, and bran natal period respond well to infusions of glucose and bicarbonate
• Breakfast cereals but, after an interval, further attacks occur, often provoked by inter-
• Coffee essence and powdered milk
current infection. Lethargy accompanied by hyperventilation is fol-
• Carbonated sweet drinks
lowed abruptly by prostration, coma, and seizures. Investigations
• Allspice, nuts, coconut, carob, and peanut butter
• Mayonnaise, pickles, salad dressings, and sauces
reveal hypoglycaemia, ketosis, and profound lactic acidosis; there
• Some potatoes (especially stored, new potatoes) is also hyperuricaemia, aminoaciduria, and ketonuria. If the infant
• Most legumes survives, hepatomegaly due to fatty infiltration may be detected but
a
overt clinical disturbances of hepatic or renal tubular function are
More information is provided in ‘Further reading’.
not seen. The untreated disease is associated with growth retardation.
 12.3.2 Inborn errors of fructose metabolism 2001

The first infant to be affected by fructose diphosphatase deficiency hypoglycaemia associated with episodes of infection. The combination
in a given family may succumb before the diagnosis is established of ketosis and lactic acidosis with hypoglycaemia is highly suggestive of
and in any case fares worse than siblings for whom the appropriate a disorder affecting the gluconeogenic pathway, including deficiency of
diet and prompt control of the condition are instituted. The response glucose 6-​phosphatase, pyruvate carboxylase, pyruvate dehydrogenase,
to treatment is favourable, however, and fructose diphosphatase and phosphoenolpyruvate carboxykinase. The absence of abdominal
deficiency is ultimately compatible with a benign course and with distress, haemolysis, jaundice, coagulopathy, and disturbances of the
normal growth and development. proximal renal tubule differentiates the condition from hereditary fruc-
tose intolerance, tyrosinosis, and Wilson’s disease. Confusion may arise
Metabolic defect with disorders associated with secondary defects in gluconeogenesis, es-
Deficiency of fructose 1,6-​ diphosphatase causes failure of pecially the Reye’s-​like syndrome caused by deficiencies of long-​chain,
gluconeogenesis in the liver, although the abnormality may be de- medium-​chain, and short-​chain acyl coenzyme A dehydrogenase activ-
tected in intestinal mucosa, kidney, and in cultured mononuclear ities, as well as defects of carnitine metabolism. Organic acidaemias are
cells from peripheral blood. The muscle isozyme of fructose 1,6-​ also readily distinguished by biochemical screening methods.
diphosphatase is not affected. Provocative tests using food deprivation and the administration of
Between meals, blood glucose is maintained by glycogenolysis and infusions of fructose, sorbitol, or glycerol should be avoided in the
hence the onset of disturbed metabolism in fructose diphosphatase acutely ill infant or child with suspected deficiency of fructose 1,6-​
deficiency depends on the availability of hepatic glycogen. Since fe- diphosphatase (or fructose intolerance). The definitive diagnosis
brile illnesses accelerate the consumption of liver glycogen, the accom- depends on the demonstration of selectively decreased fructose
panying anorexia with or without vomiting may deplete glycogen stores diphosphatase activity in tissue samples. Most frequently, the enzym-
critically. Acidosis results from the accumulation of gluconeogenic atic defect will be identified by biochemical assay of a freshly obtained
precursors including lactate, pyruvate, and alanine as well as ketone liver biopsy specimen, which allows other metabolic disorders and
bodies, which cannot be utilized. Hypoglycaemia that is unresponsive gluconeogenic defects to be confidently excluded. The defect may also
to glucagon and associated with exhaustion of glycogen stores occurs; be demonstrated in biopsy samples of jejunal mucosa and in cultured
it does not respond to normal gluconeogenic substrates (e.g. glycerol, monocyte-​ derived macrophages obtained from peripheral blood.
amino acid solutions, dihydroxyacetone, sorbitol, or fructose); indeed, However, the presence of fructose 1,6-​diphosphatase in these tissues
administration of these aggravates the metabolic disturbance. is metabolically inconsequential and, although useful for confirm-
The pathogenesis of hypoglycaemia and accompanying disturbances ation of the diagnosis where it is strongly suspected, in practice, de-
in fructose diphosphatase deficiency is complex and not completely cisive identification of this disorder normally depends on a systematic
explained by exhaustion of hepatic glycogen stores. Well-​fed patients biochemical analysis of liver tissue in an experienced laboratory. The
have a normal response to glucagon but are intolerant of high-​fat diets, human fructose-​1,6-​diphosphatase (FBP1) gene maps to chromo-
as well as fructose, sorbitol, alanine, glycerol, and dihydroxyacetone some 9q22.2–​q22.3, and inactivating mutations have been identified
administration. Challenge with these nutrients induces hypogly- in the disease. Unlike fructose intolerance, however, these mutations
caemia, hyperuricaemia, and hypophosphataemia, accompanied tend to be private and thus individually of less diagnostic significance
by an exaggerated rise in blood lactate levels. The hypoglycaemia is for routine laboratory use in this disorder since mutational heterogen-
then unresponsive to glucagon, indicating a secondary inhibition of eity appears to be the rule. However, a minor exception to this occurs
phosphorylase activity in the liver, which results from the build-​up in the Japanese population, where one mutation (960–​961insG) ap-
of phosphorylated sugar intermediates that cannot be further metab- pears to account for almost one-​half of mutant FBPI alleles.
olized in the context of reduced intracellular free inorganic phosphate.
Adenosine deaminase is activated primarily because of reduced phos- Treatment
phate concentrations, so that purine nucleotides are broken down to Dietary control and avoidance of starvation with rapid relief of fe-
uric acid. Failure to utilize glucogenic amino acids and metabolites brile illnesses are the mainstays of management. Minor infections
such as dihydroxyacetone and glycerol appears to stimulate trigly- and injuries require prompt attention, and intravenous glucose
ceride formation in the liver, which induces steatosis. Unlike heredi- therapy should be instituted early in acute episodes to avoid hypo-
tary fructose intolerance (discussed previously), high concentrations glycaemia and acidosis. Fasting should be avoided as far as possible,
of hepatic fructose 1-​phosphate do not occur, and profound disturb- while night-​time feeding may be needed in infants during recovery
ances of blood coagulation or hepatic or renal tubule function with from injuries or infections, and after strenuous exercise in older chil-
progressive structural damage are absent in fructose diphosphatase dren. The habit of taking meals at regular 4-​h intervals is best incul-
deficiency. Similarly, aversion to foods that aggravate the disorder does cated when the patient is young. The diet should exclude excess fat;
not develop in affected infants and children; this may be explained by sorbitol, sucrose, and fructose must be strictly avoided. Breast milk
the absence of pain and abdominal symptoms in the condition. is rich in lactose, which is readily assimilated, but difficulties arise on
transfer to artificial feeds during weaning. In addition, medications
Diagnosis and syrups containing fructose, sucrose, or sorbitol present a special
The importance of establishing the diagnosis of fructose diphosphatase danger to patients with fructose diphosphatase deficiency. A diet
deficiency cannot be overemphasized. Proper dietary control and excluding these sugars but containing 56% calories as carbohydrate,
protocols for the institution of appropriate therapy depend on recog- with 32% calories as fat and 12% as protein, has produced normal
nizing the complex disturbance that underlies this disease. growth and development. Acute episodes of acidosis or hypogly-
Fructose diphosphatase deficiency should be considered in other- caemia are controlled rapidly by intravenous administration of glu-
wise normal infants who develop unexplained severe acidosis or cose with or without bicarbonate as required.
2002 SECTION 12 Metabolic disorders

Hunter RW, Hughey CC, Lantier L, et al. (2018). Metformin re-

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Ananth N, et al. (2003). Two cases of hereditary fructose intolerance. tolerance: frequency of the most common mutant aldolase B allele
Indian J Clin Biochem, 18, 87–​92. (A149P) in the British population. J Med Genet, 33, 837–​41.
Baerlocher K, et al. (1978). Hereditary fructose intolerance in early Kelishadi R, Mansourian M, Heidari-Beni M (2014). Association of fruc-
childhood: a major diagnostic challenge. Survey of 20 symptomatic tose consumption and components of metabolic syndrome in human
cases. Helv Paediatr Acta, 132, 605–​8. studies: a systematic review and meta-analysis. Nutrition, 30, 503–10.
Baker L, Wingrad AI (1970). Fasting hypoglycaemia and metabolic Kikawa Y, et al. (2002). Diagnosis of fructose 1,6-​bisphosphatase defi-
acidosis associated with deficiency of fructose-​1,6-​diphosphatase ciency using cultured lymphocyte fraction: a secure and noninvasive
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editary fructose intolerance. J Inherit Metab Dis, 24, 523–​6. Steinmann B, Gitzelmann R, Van den Berghe G (2001). Disorders of
Elpeleg ON, Hurvitz H, Branski D (1989). Fructose-​1,6-​diphosphatase fructose metabolism. In: Scriver CR, et al. (eds) The metabolic and
deficiency: a 20-​year follow-​up. Am J Dis Child, 143, 140–​2. molecular bases of inherited disease, 8th edition, vol. II, pp. 1489–​520.
Gibson PR, et al. (2007). Review article: fructose malabsorption and McGraw-​Hill, New York. http://​www.ommbid.com.
the bigger picture. Aliment Pharmacol Ther, 25, 349–​63. Softic S, et al. (2017). Divergent effects of glucose and fructose on hep-
Greenwood J (1989). Sugar content of liquid prescription medicines. atic lipogenesis and insulin signaling. J Clin Invest, 27, 4059–​74.
Pharm J, 243, 553–​7. Thabet F, et al. (2002). Severe Reye syndrome: report of 14 cases managed
Gruchota J, et al. (2006). Aldolase B mutations and prevalence of in a pediatric intensive care unit over 11 years. Arch Pediatr, 9, 581–​6.
hereditary fructose intolerance in a Polish population. Mol Genet Valadares ER, et al. (2015). Hereditary fructose intolerance in Brazilian
Metab, 87, 376–​8. patients. Mol Genet Metab Rep, 15, 35–​8.
 12.3.3 Disorders of galactose, pentose, and pyruvate metabolism 2003

Yang TY, et al. (2000). Hereditary fructose intolerance presenting as Disorders of pyruvate metabolism
Reye’s-​like syndrome: report of one case. Acta Paediatr Taiwan, 41, Deficiency of the pyruvate dehydrogenase complex is the most
218–​20.
common inherited disorder with lactic acidaemia, most often due
Wasserman D, et al. (1996). Molecular analysis of the fructose trans-
to deficiency of the E1α subunit inherited as a dominant X-​linked
porter gene (GLUT5) in isolated fructose malabsorption. J Clin
Invest, 98, 2398–​402. character. Presentation is with overwhelming neonatal acidosis;
World Health Organization (WHO) (2015). Sugars Intake for Adults moderate lactic acidosis with progressive neurological features; or—​
and Children. WHO/​NMH/​NHD/​15.2 (Executive summary). in male children and young adults—​an indolent neurological course
WHO, Geneva. without overt acidosis but with episodes of cerebellar ataxia induced
by carbohydrate administration.
Pyruvate carboxylase deficiency causes lactate/​pyruvate acidosis with
a necrotizing encephalopathy resembling Wernicke’s encephalopathy.
Hypoglycaemia may complicate intercurrent infections and starvation.

12.3.3 Disorders of galactose,

Disorders of galactose metabolism
pentose, and pyruvate metabolism
Timothy M. Cox Metabolism of galactose
Galactose is derived from exogenous sources but constitutively de-
rived de novo by metabolic interconversion from endogenous glu-
ESSENTIALS cose. The chief exogenous source is the disaccharide, lactose, which
Inborn errors of galactose metabolism is present in milk and dairy products, following the action of mu-
cosal lactase in the small intestine.
Galactose is principally found as free lactose in dairy products.
The concentration of lactose in human breast milk is approximately
Three inborn errors of galactose metabolism are recognized:
70 g/​litre (200 mM); this explains the relative sweetness of human
Galactokinase deficiency (‘galactose diabetes’)—​a very rare con-
breast milk, compared with cows’ milk. Newborn infants obtain
dition which impairs the assimilation of dietary galactose such
about one-​fifth of their dietary energy supply in the form of galactose,
that the free sugar and its metabolites appear in plasma and
which is obtained by digestion of lactose to galactose and glucose in
urine. Conversion of galactose to osmotically active galactitol in
equimolar amounts. Galactose occurs as a free sugar in certain fruits
tissues causes premature bilateral cataracts and (occasionally)
such as tomatoes and avocados, as well as legumes, brassicas, and
pseudotumour cerebri in infants, which are prevented by early in-
other vegetables. It is also complexed with other molecules present in
stitution of a galactose-​and lactose-​free diet.
food and is a component of membrane glycoproteins, glycosamino-
Classical galactosaemia (galactose-​ 1-​
phosphate uridylyltransferase
glycans, and glycosphingolipids abundant in nervous tissue.
deficiency)—​the commonest (1/​47 000 births) and most important
Assimilation of galactose from dietary sources and the de novo
disorder. High concentrations of galactose in the plasma and tissues
biosynthesis of metabolically active galactose nucleotides share
lead to aberrant glycosylation of glycoproteins and other
reactions involving the interconversion of galactose and glucose
glycoconjugates, including lipids. The principal manifestations are a bac-
common to the Leloir pathway. This pathway utilizes nucleoside (uri-
tericidal defect associated with neonatal Escherichia coli sepsis; failure to
dine) diphosphate sugar intermediates that interact with galactose
thrive; and—​in older patients—​growth retardation, mental retardation,
1-​phosphate which directly enters mainstream carbohydrate me-
renal Fanconi’s syndrome, jaundice, and hepatosplenomegaly: without
tabolism (Fig. 12.3.3.1). High-​energy uridine diphosphate (UDP)-​
exclusion of lactose and galactose, death with cirrhosis is the rule.
sugar intermediates, especially UDP-​glucose, UDP-​galactose, and
Diagnosis is made by plasma galactose, galactose 1-​phosphate, and
their nitrogen-​containing derivatives such as UDP-​galactosamine,
red cell transferase determinations in blood spots obtained after birth
are critical building blocks in the formation of glycoproteins and
and refined by molecular analysis of the GALT gene. Prompt institution
glycolipids, including glycosphingolipids. Intracellular concentra-
of an appropriate diet allows survival into late adult life, but disabling
tions of these metabolites reflect the activity of the Leloir pathway.
cognitive and language defects and other neurological manifestations
The Leloir pathway employs four enzymes that catalyse essen-
persist. Attenuated nonacute galactosaemia presents in adult life with
tial reactions for the metabolic incorporation of galactose derived
cataracts and progressive neurological disease; premature ovarian
from dietary sources and by de novo biosynthesis. By their actions,
failure is the rule in affected women.
hexose units derived from galactose enter glycolysis, are incorp-
Uridine diphosphate galactose-​4´-​epimerase deficiency—​a rare but
orated into glycogen, and used for key biosynthetic processes. The
often harmless disorder which may be identified by neonatal screening.
enzymes are (1) galactose mutarotase—​which facilitates intercon-
Rarely, cataract, sensorineural deafness, and impaired psychomotor
version of the α-​and β-​d-​galactose anomers to maintain the source
development with hepatorenal features of classical galactosaemia
of galactose in the alpha conformation necessary for its further
occur, with favourable responses to the galactose exclusion diet.
assimilation. (2) Galactokinase—​which catalyses the rapid phos-
Pentosuria phorylation of β-​d-​galactose to form galactose 1-​phosphate in the
Essential pentosuria is an asymptomatic, autosomal recessive trait liver and renal proximal renal tubule. (3) Galactose 1-​phosphate
affecting glucuronate metabolism, principally found in Ashkenazi uridyltransferase—​responsible for the conversion of galactose 1-​
Jews. phosphate and UDP-​glucose to glucose 1-​phosphate and UDP-​gal-
actose. (4) UDP-​galactose-​4´-​epimerase—​which reversibly catalyses
2004 SECTION 12 Metabolic disorders

Dietary lactose De novo synthesis

UDP-​galactose-​4´-​epimerase enables the galactose moiety to be
Intestinal lactase
generated from glucose for the synthesis of complex glycoconjugates,
providing a de novo supply of UDP-​galactose that is independent
Glucose
of exogenous galactose from milk and other dietary components.
Galactose The pathway is most active in the growing fetus. While the Leloir
pathway is the main route of galactose metabolism in humans, minor
pathways also operate: reduction of galactose to galactitol and oxi-
Galactokinase dation to galactonic acid can occur, but these only partially mitigate
the metabolic block at the level of the transferase that causes classic
galactosaemia. A major source of endogenous galactose is the recyc-
Galactose 1-phosphate ling of galactose-​containing glycosaminoglycans, glycoproteins, and
UDP-glucose glycosphingolipids in the lysosomal compartment.
Galactitol appears at high concentrations in the blood and urine in
Galactose 1-phosphate
UDP 4-epimerase classic galactosaemia, galactokinase deficiency, and epimerase defi-
uridyltransferase
UDP-galactose ciency. If the transferase is markedly deficient or absent, galactose, gal-
actose 1-​phosphate, galactitol, and gluconate accumulate in the tissues.
Glucose 1-phosphate
Galactokinase deficiency: ‘galactose diabetes’
Failure to phosphorylate galactose in the liver and other tissues
impairs its clearance from the blood so that the free sugar mainly
derived from lactose in the intestine, as well as its metabolites,
Glycogen galactonic acid and galactitol, appear in the urine.
Glucose 6-phosphate
Fig. 12.3.3.1 Galactose metabolism. Genetics
The human gene for galactokinase maps to chromosome 17q24, with a
regeneration of UDP-​g lucose and allows formation of UDP-​ putative second locus on chromosome 15. Numerous mutations respon-
galactose from UDP-​glucose. UDP-​galactose is a critical building sible for galactokinase deficiency have been identified in the GALK1
block for the biosynthesis of essential glycoconjugates, includ­ gene at its chromosome 17 locus. Many of these are private, but the so-​
ing glycosaminoglyans, glycoproteins, and glycosphingolipids. called Osaka variant, a missense mutation (p.A198V), was first identi-
Inherited defects in the interconversion of these metabolites in- fied through mass neonatal screening and has a prevalence of 4.1% in
crease blood and tissue concentrations of galactose—​ especially Japanese individuals and 2.8% in Koreans; it is uncommon among indi-
when the diet contains milk or dairy products. viduals of Taiwanese and Chinese ancestry. The Osaka GALK1 variant
has been reported to occur in 7.8% of Japanese adults with bilateral cata-
Exogenous pathway racts, in whom it may represent a true population risk factor.
Free galactose is released from lactose (β-​d-​galactopyranosyl-​ Homozygous deficiency of galactokinase is exceptionally rare,
(1→4)-​d-​glucose) in the diet by the action of lactase at the intestinal occurring with an approximate frequency of 1 in 1 000 000 live
brush-​border membrane. Lactase preserves in the reaction products, births. However, galactokinase deficiency occurs in East central
galactose and glucose, the anomeric β-​configuration of the galactose Europe with a high incidence among the Roma (‘Gypsies’), in whom
moiety in the substrate. After intestinal uptake of these monosac- a founder Romani GALK1 mutation, p.P28T, has been found in
charides by the sodium-​dependent hexose transporter (SGLUT1), Spain, Bulgaria, Bosnia and Hungary. The carrier frequency in these
galactose enters the portal bloodstream by facilitated diffusion across groups is about 1 in 50, predicting a birth frequency of about 1 in
the basolateral membrane via GLUT2, and this low-​affinity, high-​ 10 000 and justifying institution of a screening programme that is
capacity transporter also brings about the uptake by hepatocytes. culturally acceptable to and actionable within this population group.
Metabolic incorporation of galactose occurs only as its α-​d-​
galactose anomeric form, which is supplied by the action of the Clinical features
ubiquitous bidirectional enzyme, mutarotase, that maintains the Precocious formation of cataracts in infants and children is charac-
conformational equilibrium of the α-​ and β-​anomers of d-​galactose. teristic, and some heterozygotes develop cataracts before the age of
Intracellular incorporation of exogenous d-​galactose that is se- 40 years. When blood concentrations are high, galactose is taken up by
lective for the α-​anomer involves an endergonic reaction catalysed by the lens and converted to the end product, the sugar alcohol, galactitol,
galactokinase; phosphate-​bond energy from ATP drives the reaction by the action of aldose reductase: subsequent toxic or osmotic effects
thermodynamically. After rapid phosphorylation of free galactose lead to swelling and irreversible damage to lens fibres. Several infants
at the 1-​carbon position to form galactose 1-​phosphate, principally have presented with benign intracranial hypertension (pseudotumour
in the liver, the high-​energy sugar nucleotide, UDP-​galactose, is cerebri), possibly as a result of comparable osmotic effects of galactitol
generated by the action of galactose-​1-​phosphate uridyltransferase. in the brain. Patients with galactokinase deficiency persistently excrete
UDP-​glucose can be regenerated by the action of UDP-​galactose-​4´-​ reducing sugar in their urine, but, apart from possible confusion with
epimerase, which promotes flux through the Leloir pathway. diabetes mellitus, this has no apparent significance.
 12.3.3 Disorders of galactose, pentose, and pyruvate metabolism 2005

Diagnosis and treatment the normal enzyme activity in erythrocytes but remain asymptom-
Galactokinase deficiency should be suspected in infants or chil- atic; premature ovarian failure does not occur in women harbouring
dren with cataracts, and ideally reducing sugar (which will not this variant. Galactosaemia is rare in Japan.
react with glucose oxidase test strips) should be sought in the The human galactosyl-​1-​phosphate uridylyltransferase gene, GALT,
urine. Definitive diagnosis is by enzymatic assay of galactokinase maps to human chromosome 9p13 and encodes a protein of molecular
in erythrocytes or cultured fibroblasts, which differentiates the dis- weight 43 kDa, which exists as a functional homodimer. Molecular
order from classic galactosaemia and hypergalactosaemia due to analysis indicates that most patients with classic galactosaemia har-
vascular disease in the liver. bour missense-​type mutations and are compound heterozygotes.
In populations with newborn surveillance for high blood gal- Numerous variant transferase enzymes are known, and more than
actose concentration, the deficiency may be detected as a result of 330 disease-​associated mutations are reported. There are several wide-
finding an abnormal blood galactose concentration with normal spread mutations: p.Q188R accounts for about two-​thirds of mutant
transferase and epimerase activities. Definitive enzymatic meas- alleles in white Europeans, with a strong North-​West dominance, and
urements can be conducted on amniocytes and cultured skin fibro- greater than 90% of mutant alleles in patients from Ireland. In Eastern
blasts. Neonatal screening that depends on tests for galactose in the and Central Europe, the mutant GALT p.K285N accounts for about
blood will not detect galactokinase deficiency. for 30% of galactosaemic alleles and has a strong association popula-
Lifelong treatment with a lactose-​and galactose-​exclusion diet tions of Slavic origin. The so-​called Duarte transferase mutation that
prevents cataract formation, and early cataract formation in infants is most frequent in persons of African ancestry has been identified
may even be reversed; otherwise surgical removal may be required. as p.N314D. Molecular analysis of the transferase gene, GALT, now
Urinary galactitol concentrations, which have been reported to ex- renders prenatal diagnosis of at-​risk pregnancies possible.
ceed 2500 mmol/​mol creatinine, fall to within the reference range for Pathogenesis
healthy subjects (<3 mmol/​mol creatinine) after some weeks of dietary
Although the exact mechanism of toxicity is unknown, the accumu-
treatment. Although there are numerous reports of bilateral cataracts in
lation of galactose 1-​phosphate in a milieu with depleted inorganic
heterozygotes for galactokinase deficiency, it remains unclear whether
phosphate probably inhibits other enzymatic reactions involving phos-
any propensity to cataract formation in later life is prevented by dietary
phorylated intermediates and may cause purine nucleotide depletion.
restriction; some authors have suggested that cataracts are more fre-
Aldose reductase is responsible for the direct reduction of gal-
quent in otherwise healthy individuals who consume abundant dairy
actose to galactitol, which is not metabolized further in the polyol
products, but have no galactokinase deficiency. In the face of this con-
pathway and accumulates in tissues where it contributes to the
troversy, it appears to be most prudent to recommend modest restric-
pathophysiology of galactosaemia, resembling sorbitol in its ability
tion of lactose intake in heterozygotes for galactokinase deficiency.
to cause rapid-​onset cataract formation, and with potential effects
in the induction of cerebral oedema and pseudotumour cerebri.
Galactose-​1-​phosphate uridyltransferase
Sustained excess of d-​galactose as well as relative deficiency or
deficiency: galactosaemia
distribution of high-​energy sugar nucleotides that are required
Unlike individuals in whom galactokinase is deficient, when patients for key glycosylation reactions is likely to have effects on the brain
who lack galactose-​1-​phosphate uridyltransferase ingest lactose, lipids and countless glycoproteins, including circulating hor-
there is a significant rise in intracellular galactose 1-​phosphate as mones. It appears plausible that the deficiency of UDP-​galactose
well as blood galactose concentrations. The severe consequences of will affect the biosynthesis of key galactosphingolipids by UDP-​
classic galactosaemia are attributed to the toxic effects of galactose 1-​ galactosylceramide transferase in neural cells.
phosphate, principally in the liver, proximal renal tubule, and brain. A toxic effect on the fetal ovary due to maternal hypergalactosaemia
Three main forms of galactosaemia are readily recognized: has been postulated to account for the hypergonadotropic hypo-
they may be termed classical, adult (variant), and mild—​most pa- gonadism in affected women and girls, but abnormal glycosylation
tients present in the neonatal period with the classical variant. of follicle-​stimulating hormone and Müllerian factor have also been
Increasingly, patients with strongly predictive galactose-​1-​phos- suggested.
phate uridyltransferase deficiency, enzymology and/​or GALT geno-
type for this acute disease are identified by neonatal screening. Clinical features
Classical galactosaemia
Genetics
Classical galactosaemia is associated with absent or near absent
Galactosaemia is transmitted as an autosomal recessive trait with galactose-​1-​phosphate uridyltransferase activity, and typically with
an overall estimated frequency of 1 in 47 000 in liveborn infants. the GALT p.Q188R/​Q188R genotype accompanied by severe clin-
It is more frequent in some isolated groups, most notably in the ical features in the neonatal period.
modern Traveller population of Ireland, where there is a birth fre- Affected infants nearly always appear normal at birth, but vomiting
quency of 1 in 480 compared with 1 in 30 000 in the non-​Traveller or diarrhoea, jaundice, and hepatomegaly usually occur in the first
Irish population. In African American patients from the United few weeks. There is failure to gain weight, spontaneous bruising, and
States of America, a relatively mild disorder has been reported that progressive enlargement of the liver. Cataracts may be apparent at
is probably due to an unstable enzyme variant; uridylyltransferase 1 month of age, by which time abdominal distension with ascites
activity is absent from the red cells of these patients but amounts to has developed. Pseudotumour cerebri, often presenting with prom-
some 10% of normal in samples of liver and small intestinal tissue. inent anterior fontanelle presumably related to the osmotic effects of
Patients with the so-​called Duarte variant possess about one-​half of galactitol, may be apparent shortly after birth.
2006 SECTION 12 Metabolic disorders

Learning difficulties do not become apparent until later in the prominent and decompensated liver disease does not occur. About
first year of life and vary greatly in severity. Many patients with 85% of women with this condition have premature ovarian failure
galactosaemia develop severe infections with Escherichia coli during reflected in delayed menarche, amenorrhoea, oligomenorrhoea,
the neonatal period: Gram-​negative bacterial sepsis may be the first and/​or secondary amenorrhoea/​premature menopause.
indication of this disorder in young infants. A bactericidal defect
in circulating leucocytes has been postulated. In adult patients after Mild galactosaemia
reversal of the acute galactose toxicity syndrome, the most obvious Mild, or biochemical, galactosaemia arises from biochemical
sequelae are growth failure, neurological deficit, and, in women, pri- screening in at-​risk or targeted populations: the subjects harbour
mary ovarian failure with infertility. GALT mutations with modest effects on galactose-​ 1-​
phosphate
A few patients with galactosaemia remain asymptomatic while uridyltransferase activity and/​or stability (c.25%), of which the com-
ingesting milk, but eventually fail to gain weight. Such patients pound heterozygous genotype, p.N314D/​Q188R, the so-​called Duarte
may come to light during childhood or even adult life with varying 2 variant, is characteristic. These individuals are asymptomatic.
degrees of learning difficulties and cataracts. Hepatomegaly and
intermittent galactosuria are usually present, and often there is a his- Diagnosis
tory of feeding difficulties on institution of modified formula feeds Recognition of hereditary galactosaemia in early infancy is of
during the neonatal period. paramount importance since the acute effects of galactose poi-
The neurological manifestations of classic galactosaemia are soning may be reversed by the institution of a lactose-​exclusion
highly variable but, despite prompt institution of dietary therapy, a diet. Nearly all infants with classic galactosaemia or clinical variant
degree of intellectual disability is common in affected children and galactosaemia can be identified in newborn screening that includes
adults. Characteristic learning difficulties in mathematics and spa- testing for galactosaemia. However, clinical variant galactosaemia
tial relationships with behavioural deficits have been observed, and may be missed if total blood galactose is analysed without deter-
children with galactosaemia have a particularly high risk for lan- mining red cell transferase activity.
guage impairment. Neurological manifestations, despite induction Definitive diagnosis relies on the determination of galactose-​
of a galactose-​free diet, can include seizures, apraxia, extrapyram- 1-​phosphate uridylyltransferase activity and other galactose-​
idal disorders with tremor and dystonia, and cerebellar deficits. metabolizing enzymes in red cells, skin fibroblasts, or leucocytes
Histological examination of the brain shows nonspecific signs of in- by means of a specific enzymatic assay. This procedure is required
jury with gliosis and Purkinje cell loss in the cerebellum. to confirm the results of initial screening tests conducted on dried
Serum tests of liver function are nonspecifically deranged but blood spots (Beutler assay). The transferase activity in patients
histological examination of the liver shows lobular fibrosis, fatty with classic galactosaemia is generally less than 1% of the normal
change, bile ductular proliferation, and progression to frank cir- reference range. In classical galactosaemia, red cell galactose-​1-​
rhosis. Involvement of the proximal renal tubule is shown by gen- phosphate is usually greater than 0.4 mmol/​litre (10 mg/​dL) and red
eralized aminoaciduria and occasionally a full-​ blown Fanconi’s cell transferase activity is absent or just detectable.
syndrome with vacuolation of tubular epithelial cells. It is important to realize that in many patients with attenuated
Follow-​up studies of female patients with galactosaemia have shown (‘mild’ or asymptomatic) clinical variants of galactosaemia, trans-
a high incidence of gonadal failure with ovarian atrophy. Although ferase activity is much higher in brain and intestinal tissue (c.10%
this complication appears to be more common in patients in whom of healthy reference values), even though it may be absent or barely
dietary therapy was delayed, no clear cause-​and-​effect relationship has detectable in the red cell assay. Individuals with attenuated, clin-
been established. Men with galactosaemia have been reported to have ical variant galactosaemia may have erythrocyte activity close to or
a higher than expected prevalence of cryptorchidism and low semen above 1% of reference values, but very rarely greater than 15%.
volumes, but the specificity of these findings in patients with this Reliable enzymatic or genetic testing for heterozygotes can be
chronic metabolic disease is unclear. In the clear-​cut case of women conducted in the parents of a child who died before the diagnosis
and adolescent females, hypogonadism and premature ovarian failure was confirmed. In particular populations, neonatal screening for
has more obvious effects on health, well-​being, and potential parental elevated blood galactose and galactose-​ 1-​
phosphate concentra-
fulfilment. However, pregnancies occur in a few women with classic tions is carried out routinely. Molecular analysis of the GALT gene
galactosaemia and usually result in the birth of healthy infants with encoding galactose-​1-​phosphate uridylyltransferase in at-​risk preg-
no evidence of teratogenic effects. Lactation and breastfeeding pro- nancies is useful and can usually be requested for advising affected
ceed normally. Since most females develop premature ovarian failure families (see following ‘Pregnancy’ subsection).
with hypergonadotropic hypogonadism, the hypogonadism and the
imposed nutritional factors for metabolic control contribute to osteo- Differential diagnosis
porosis, which occurs at high frequency, even in young adults. Hereditary fructose intolerance and hereditary tyrosinaemia type 1
are credible differential diagnoses in infants and young children with
Adult or variant galactosaemia the acute, classical form of galactosaemia. Transient galactosaemia
Adult or variant galactosaemia is a relatively indolent but important with mixed glycosuria also occurs in the Fanconi–​ Bickel syn-
disease that often defies prompt conventional diagnosis. Residual drome, now known to be due to biallelic mutations in the GLUT2
galactose-​1-​phosphate uridyltransferase activity (c.10% of healthy glucose–​galactose carrier, which is the facilitative glucose trans-
reference mean) is detectable and the homozygous GALT p.S135L/​ porter in hepatocytes, pancreatic β-​cells, enterocytes, and proximal
S135L missense mutation is typically present. The condition presents renal tubular cells. Studies in infants have shown that persistent
with neurological disease and early cataracts; hepatomegaly is not hypergalactosaemia can also be explained by portosystemic venous
 12.3.3 Disorders of galactose, pentose, and pyruvate metabolism 2007

shunts that are often associated with patent ductus venosus or other Management of complications
congenital vascular abnormalities in the liver. Doppler ultrasonog- Hypogonadism is a considerable problem for young girls and
raphy is a convenient noninvasive investigation to search for such women with galactosaemia: it affects self-​perception, physical devel-
shunts. opment, life quality, self-​confidence—​and where relevant—​family
Treatment life and expectations. Most women with galactosaemia develop
oligomenorrhoea and secondary amenorrhea within a few years of
Without strict dietary treatment, most patients with classical their first period. In one series, only 5 out of 17 women older than
galactosaemia die in early infancy, although some may survive with age 22 years had normal menstruation. Women and adolescent girls
liver disease and learning difficulties beyond childhood. The course with galactosaemia benefit from the ability to discuss matters related
of galactosaemia is strikingly altered on withdrawal of lactose (and to their reproductive health and fertility, this enable them to obtain
galactose), although the outcome of neurological disease is often the necessary referrals for gynaecological and endocrinological
disappointing and it appears that the galactose-​free diet fails to treatment with safe hormone supplementation.
confer benefit on mental development when instituted beyond the Review allows for regular metabolic monitoring and serial evalu-
age of 2 years. An international guideline was set out in 2017 with ation of bone mineralization density and vitamin D status, with
practical recommendations for the management and follow-​up of opportunities to intervene where appropriate to avoid the risk of
patients with this disease. fragility fractures, particularly in women with this disease who are a
Dietary exclusion great risk of osteoporosis.

Lactose is present in many nondairy foods, hence advice from an Pregnancy

experienced dietician, as well as meticulous attention to detail, In pregnancies of heterozygous mothers who have had affected chil-
is required to eliminate it satisfactorily. Free galactose is found in dren, there is evidence that premature cataracts can be avoided in
fruits and vegetables, especially avocados, peas and beans, as well the fetus if the maternal intake of lactose is restricted. In late preg-
as other legumes. In infants, soybean milks or commercial casein nancy, lactosaemia and lactosuria are common findings and result
hydrolysates are used as milk substitutes, and therapy is monitored from the physiological induction of lactose biosynthesis in mam-
by periodic assay of red cell galactose-​1-​phosphate concentrations. mary tissue. In rare cases, there is a potential risk of self-​intoxication
Soya milk contains galactose equivalents complexed to other mol- when women with homozygous deficiency of the transferase be-
ecules (about 15 mg/​litre) and there is a trend to adopt a completely come pregnant and breastfeed, so that scrupulous dietary precau-
galactose-​free artificial formula in the treatment of affected infants, tions are needed to maintain metabolic control during lactation.
but there is no proof that this biochemically successful strategy in-
duces better long-​term outcomes. Organization of care
To avoid other potential vegetable sources of bound galactose Maintaining appropriate lifelong care for patients with galactosaemia
in complex oligosaccharides is challenging and of uncertain value. in specialist clinics shows benefits in the provision of dietary man-
However, even with high fruit and vegetable consumption, daily ex- agement with expert advice as well as developmental monitoring
posure to galactose from such sources is unlikely to exceed 70 mg and assessment of cognitive function that is matched to educa-
(<0.4 mmol). This compares with the endogenous daily de novo syn- tional needs. Regular review in paediatric, transitional, and then
thesis of galactose in healthy adults, which approaches 6 mmol (1 g). adult metabolic specialist centres is critical for many patients who
A comprehensive retrospective study that examined more than have overt or hidden difficulties with speech or cognition, to which
230 children and adults with classical galactosaemia found no as- should be added apraxia and the compounding effects of sensineural
sociation between rigorous nondairy galactose restriction in early deafness.
childhood and five key long-​term outcomes. It thus appears un-
necessary to take an extreme view of dietary measures and forbid Prognosis
fruit and vegetable intake once recovery from metabolic decompen- The acute manifestations of galactosaemia and growth failure re-
sation has occurred. spond quickly to dietary therapy and cataract formation is prevented;
Lifelong adherence to the exclusion of lactose and foods con- in the early phases in the neonatal period, prompt intervention can
taining free galactose should be advocated. However, after challenge lead to complete regression of cataracts. Unfortunately, some pa-
studies conducted in the Netherlands, the United Kingdom, and tients have significant neurological deficits despite prompt and con-
elsewhere, avoidance of fruits and vegetables is no longer standard scientious treatment.
practice. An international survey reported the long-​term outcome in 350
patients receiving dietary therapy. The presence of ovarian failure
Monitoring metabolic control and elevated galactose-​1-​phosphate concentrations in patients ap-
In the untreated state, the concentration of red cell galactose 1-​ parently ingesting no lactose or galactose emphasized the import-
phosphate is above 5 mmol/​litre, but with close adherence to the diet ance of the endogenous pathway and may also explain the emergence
it falls within a few months to less than 0.25 mmol/​litre. Although of neurological disease in treated patients.
biochemical monitoring has not been shown closely to predict out- Several pregnancies have been reported in women with classic
comes, as a rule, expert centres recommend that the desired long-​ galactosaemia, including subjects homozygous for the p.Q188R mu-
term target for blood galactose-​1-​phosphate concentrations should tation. In such pregnancies, high concentrations of galactitol were
be about 0.15 mmol/​litre of erythrocytes; monitoring two to three found in amniotic fluid, but cord blood values were within the range
times per year in the first decade is usually practised. found in galactosaemic patients receiving strict dietary therapy.
2008 SECTION 12 Metabolic disorders

Thus, although galactitol present in maternal plasma can traverse based on delivering a codon-​ optimized version of the human
the placenta, it probably does not harm the heterozygous fetus. galactose-​1-​
phosphate uridylyltransferase gene to express func-
tional GALT protein. Using recombinant adeno-​associated viral
Prevention vectors, abundant synthesis of the wild-​type transferase has been
Genetic counselling obtained in cells from patients with galactosaemia. It seems likely
As a recessive condition, the diagnosis of galactosaemia has conse- that the clinical development of this project will involve attempts to
quences for members of the affected pedigree. Appropriate genetic deliver a vector with suitable tissue tropisms to allow adequate trans-
counselling is required. duction of the liver as well as the brain, with sustained expression of
the therapeutic protein sufficient to alleviate the disease.
Screening
Uridine diphosphate-​4´-​epimerase deficiency
Several retrospective studies indicate that neonatal screening pre-
The gene for human UDP-​galactose-​4´-​epimerase has been mapped
vents early death; in one survey, 80% of patients who underwent
to chromosome 1p36–​p35, and numerous mutant alleles have been
newborn screening were diagnosed by 14 days of age, compared with
identified. Epimerase deficiency is a very rare autosomal reces-
only 35% of patients who were not tested but who had manifest dis-
sive condition that may be identified during screening for classic
ease. A Cochrane review in 2017 concluded that there were no ran-
galactosaemia. In most cases there are no symptoms attributable
domized controlled studies or controlled clinical studies, published
to galactosaemia, and follow-​up studies have confirmed the usu-
or unpublished, comparing the use of any newborn screening test to
ally benign nature of this anomaly. However, a few cases of more
diagnose infants with galactosaemia and presenting a comparison
marked deficiency of UDP-​4´-​epimerase have been discovered in
between a screened population compared with a nonscreened popu-
patients otherwise manifesting the classic features of galactosaemia.
lation. No studies of newborn screening for galactosaemia were
The autosomal recessive nature of this inherited disorder has been
found. However, neonatal screening for galactosaemia is available
confirmed by demonstrating a partial epimerase deficiency in the
in the United States of America and in Europe, but only a small per-
healthy parents of an affected infant. The condition may be con-
centage of newborns in the United Kingdom are tested.
trasted with the transferase deficiency that allows the formation of
Future prospects small amounts of endogenous galactose in the presence of an intact
epimerase.
Galactokinase inhibitors—​restriction of exogenous substrate
In the absence of epimerase activity, the individual is dependent
One approach to advance this field would be to embrace the toxicity on exogenous sources of galactose, since this cannot be derived
hypothesis and target the overproduction and raised intracellular from glucose. As a complete deficiency of the epimerase would lead
concentrations of galactose 1-​phosphate in classical galactosaemia. to an absolute lack of UDP-​galactose for galactosphingolipid syn-
The immediate reaction target is galactokinase because this en- thesis, the ingestion of very small quantities of galactose has been
zyme catalyses the first committed step for the metabolic incorp- recommended so that brain development and biosynthesis of es-
oration of α-​d-​galactose, upstream of the transferase in the Leloir sential galactosides can proceed. Because of the dual activity of the
pathway. At least one ‘lead’ candidate small-​molecule inhibitor has epimerase towards UDP-​acetyl glucosamine as well as UDP-​glucose,
been identified for this potential therapeutic development, but con- it has been suggested that small supplements of the aminoacetyl gal-
cerns include (a) it would in effect generate systemic galactokinase actosamine should also be provided.
deficiency, a recognized metabolic disease; (b) this would block all
acquisition of exogenous galactose and, in combination with the
severe transferase deficiency, may well have unforeseen effects on Pentosuria
the endogenous galactose pathway; (c) it would fail to address the
neurological and other effects of the disease that almost certainly Pentosuria is caused by the excessive renal excretion of l-​xylulose.
depend on de novo synthesis of galactose and essential biosynthetic This has no clinical significance except that it may lead to the incor-
pathways; and (d) as a kinase, galactokinase will have numerous rect diagnosis of diabetes mellitus should tests for reducing sugar be
homologies with hundreds of critical kinases affecting metabolic carried out on the urine. Xylulose does not react with urinary test
regulation, hence securing adequate safety and proven selectivity of strips based on the glucose oxidase method.
any inhibitor will be a formidable challenge. The disorder has historical significance as one of the five original
‘inborn errors of metabolism’ investigated by Archibald Garrod in
Enhancement of residual galactose-​1-​phosphate
his seminal work. Although pentosuria is a rare autosomal reces-
transferase activity
sive trait, its frequency in Ashkenazi Jews may be as high as 0.05%.
Several promising small molecules that serve as potential pharma- It is caused by deficiency of l-​xylulose reductase, a nicotinamide
cological chaperones have been identified, but the clinical target ex- adenine dinucleotide phosphate-​dependent enzyme in the oxida-
tends beyond the liver to the brain, and the need to deliver the drug tive pathway of glucuronate metabolism, resulting in the daily ap-
at sufficiently high concentrations to secure safe long-​term efficacy pearance of 1 to 4 g xylulose and l-​arabitol in the urine. Output is
after traversing the blood–​brain barrier remains challenging. continuous throughout life but greatly enhanced by the ingestion of
glucuronic acid or drugs that are excreted as glucuronides.
Gene therapy l-​xylulose reductase is present in many cells including red cells
At the time of writing, investigators at Nationwide Children’s and hepatocytes. Several reactions remove the carboxyl carbon atom
Hospital and the University of Utah have announced a stratagem of d-​glucuronic acid to generate the pentose l-​xylulose, which is
 12.3.3 Disorders of galactose, pentose, and pyruvate metabolism 2009

converted to its stereoisomer, d-​xylulose. d-​Xylulose is phosphor- Pyruvate dehydrogenase is a multienzyme complex of five enzyme
ylated to d-​xylulose 5-​phosphate, which can be converted to hexose proteins: three (E1, E2, and E3) are catalytic, and two (pyruvate de-
phosphates in the reactions of the pentose phosphate shunt. hydrogenase phosphatase and pyruvate dehydrogenase kinase) are
The diagnosis is made definitively by confirming the enzymatic regulatory. The combined molecular mass of the pyruvate dehydro-
defect in erythrocytes, but pentosuria is most readily confirmed by genase complex is about 8.5 million daltons and the complex com-
paper chromatographic analysis of urine using n-​butanol, ethanol, prises 30 units of E1, 60 units of E2, and 6 units each of E3 and X
and water (50:10:40) as the partitioning solvent and orcinol-​ (which is required to anchor E3 to E2). The whole complex of poly-
trichloroacetic acid as a detection agent; the sugar has a high mo- peptides is the product of 10 distinct genes and requires three cofac-
bility (RF 0.26) and is identified by its red colour on development. tors (thiamine pyrophosphate, lipoic acid, and coenzyme A) as well
Contemporary methods of mass spectrometric analysis of urine are as the binding protein for one of the catalytic subunits (E3BP).
likely to detect the copious quantities of pentose directly and could The E1 catalytic protein is a heterotetramer of two α subunits and
give rise to temporary confusion in a child under investigation for two β subunits. It is activated by dephosphorylation through the ac-
unrelated illness. tion of pyruvate dehydrogenase phosphatase and catalyses the rate-​
Long-​term monitoring of 40 individuals with pentosuria over limiting reaction of pyruvate oxidation, for which it requires the
more than 16 years showed no decrease in life expectancy. activated form of thiamine (vitamin B1), thiamine pyrophosphate.
Phosphorylation of the E1 complex is down-​regulated by pyruvate
dehydrogenase kinase, which orchestrates reciprocal allosteric con-
Inborn errors of pyruvate metabolism trol of pyruvate oxidation.
The second and third catalytic proteins, E2 (dihydrolipoamide S-​
The organic acids, pyruvate and lactate, are key interconvertible acetyltransferase) and E3 (dihydrolipoamide dehydrogenase), are
intermediates in energy metabolism. Pyruvate is mainly generated linked by co-​binding to E3-​binding protein and have shared func-
from glucose, but also by oxidative deamination of alanine, from the tions and combine functionally with the Krebs cycle dehydrogenases,
other 3-​carbon amino acids, cysteine and serine, and indirectly from namely the α-​ketoglutarate dehydrogenase and branched-​chain α-​
other amino acids. Breakdown of pyruvate proceeds by oxidation, ketoacid dehydrogenase complex.
first by pyruvate dehydrogenase, then the Krebs cycle, and finally the Genetics
respiratory chain; anabolic assimilation of pyruvate is mediated by
pyruvate carboxylase. E1α-​subunit mutations
Pyruvate is at the cross roads of energy metabolism: after entering While all the genes that encode components of the pyruvate de-
the mitochondrion it generates acetyl coenzyme A and enters the hydrogenase complex map to the nuclear genome, the most
Krebs cycle, by which it is oxidized. Pyruvate contributes the back- common cause of pyruvate dehydrogenase deficiency is due to mu-
bone in the formation of amino acids including alanine, and con- tations in the E1α subunit, a protein encoded on the short arm of the
tributes critically to gluconeogenesis after the action of pyruvate X chromosome (Xp22.12). Although the disease is characteristically
carboxylase and phosphoenolpyruvate carboxykinase. Pyruvate as more severe in males, manifestations in the heterozygous female are
a source of coenzyme A is used in lipogenesis. unusually frequent for an X-​linked disease and probably reflect the
Lactate is the product of anaerobic glycolysis and is generated en- low functional reserve of the enzyme complex in the brain and the
tirely from reduction of pyruvate by lactate dehydrogenase, and it is adverse cell-​intrinsic effects of lyonization in the mosaic situation.
disposed of by the reversal of this reaction. Defective metabolism of Only one-​quarter of the mothers of male patients harbour a causal
pyruvate therefore readily leads to the accumulation of lactate, the mutation, thus most patients arise by new germline mutations and
development of lactic acidaemia and the build-​up of alanine. recurrence in further offspring in the same pedigree is uncommon.
An important function of the Krebs (tricarboxylic acid) cycle
is the generation of reduced nicotinamide adenine dinucleotide Mutations in other subunits
(NAD), which is used to generate chemical energy in the form of Pyruvate dehydrogenase deficiency can be caused by mutations in
ATP by the action of the electron transport chain. When the metab- the E1β subunit, E1 phosphatase deficiency, E2 (dihydrolipoamide
olism of pyruvate or the related α-​ketoacid dehydrogenases in the acetyltransferase deficiency), E3 (dihyrolipoamide dehydrogenase
mitochondria is disrupted, it is not surprising that the high energy-​ deficiency), and E3BP (E3 binding protein)
requiring tissues of nervous system are almost invariably implicated.
Biochemical defect
Pyruvate dehydrogenase deficiency The pyruvate dehydrogenase complex catalyses the conversion of
Deficiency of pyruvate dehydrogenase, a mitochondrial enzyme pyruvate to acetyl CoA within mitochondria and is rate limiting for
complex which generates acetyl coenzyme A from pyruvate, is the aerobic metabolism of glucose in the brain. Daily glucose consump-
most common cause of lactic acidosis in newborn infants and chil- tion is 125 g in the adult brain, hence the pyruvate dehydrogenase
dren, but it is also associated with neurodegenerative syndromes in complex is critical for brain metabolism since this is normally en-
adults. Coenzyme A is one of the critical substrates for the formation tirely dependent on the oxidative breakdown of glucose. Where
of citrate and without the feed-​forward delivery of pyruvate into the the activity of the complex is impaired, accumulated pyruvate may
Krebs cycle, the cycle would be arrested and mitochondrial oxida- either be reduced to lactate or transaminated to alanine, so that
tive phosphorylation coupled to energy production would be mark- hyperalaninaemia and varying degrees of lactic acidaemia occur.
edly depressed. Very rare defects in dihydrolipoyl dehydrogenase are associated
2010 SECTION 12 Metabolic disorders

with deficiency of branched-​chain ketoacid dehydrogenase, pre- In boys, episodic cerebellar ataxia may be induced by feeding
sumably because of the shared molecular function. carbohydrate-​rich foods or medicinal glucose. In these patients,
Failure to carry out oxidative reactions in regions of the cortex some of whom are otherwise unimpaired and have normal intelli-
and midbrain causes neuronal death; deficiency of four-​carbon gence, blood lactate concentrations may only be trivially elevated,
intermediates may critically impair synthesis of neurotransmitter and they do not normally exceed 10 mmol/​litre in this condition.
molecules and lead to a Parkinsonian phenotype. In contrast, in other patients a progressive brainstem disorder oc-
There are three main activities associated in the complex: (1) pyru- curs, characteristic of Leigh’s disease, with haemorrhagic necrosis
vate dehydrogenase, a thiamine pyrophosphate-​dependent complex and symmetrical spongiform appearances in the periventricular
(E1); (2) dihydrolipoyl transacetylase (E2); and (3) dihydrolipoyl grey matter, thalami, midbrain, pons, medulla, and spinal cord; the
dehydrogenase, a flavoprotein (E3). Also associated are a pyruvate mammillary bodies are spared.
dehydrogenase-​ specific kinase and phosphatase (both involved There are fascinating similarities between pyruvate dehydro-
in overall metabolic regulation of the complex) as well as an es- genase complex deficiency and diseases related to thiamine defi-
sential lipoate-​containing protein other than dihydrolipoamide ciency, with or without induction by exposure to alcohol (ethanol).
transacetylase in the pyruvate dehydrogenase complex (X-​lipoate), About one-​third of patients with pyruvate dehydrogenase complex
which possesses an acyl transfer function. deficiency have facial appearances reminiscent of the fetal syndrome
due to maternal consumption of excess alcohol. This dysmorphism
Clinical features and prognosis is characterized by a narrow head, retroussé nose, flared nostrils,
The extent of clinical expression of the enzymatic defect is highly and an elongated philtrum; there is frontal bossing of the skull and
variable, but three principal patterns of pyruvate dehydrogenase a broad nasal bridge. In the acquired syndrome, acetaldehyde from
complex defects are recognizable: (1) neonatal lactic acidosis, fre- the maternal circulation is believed to inhibit pyruvate dehydro-
quently associated with agenesis or dysgenesis of the corpus cal- genase in the fetus, and Robinson and colleagues have suggested
losum; (2) Leigh’s encephalopathy in infants and children up to the that low endogenous activity of the pyruvate dehydrogenase com-
age of 5 years; and (3) intermittent ataxia in adults. In females, mu- plex due to genetic deficiency in the fetus is responsible for the de-
tations in the E1α subunit cause more homogeneous but severe dis- velopmental abnormalities.
ease with dysmorphism, microcephaly, spastic paraplegia, and mild/​ A striking connection between agenesis of the corpus callosum,
moderate cognitive impairment. usually in patients with neonatal pyruvate dehydrogenase defi-
There may be fulminant disease in the newborn infant: intra- ciency, has been made with the Marchiafava–​Bignami syndrome, a
uterine development is impaired, marked acidosis (blood lactate condition characterized by degeneration of the corpus callosum and
>10 mmol/​litre) is present at birth, and the condition is rapidly associated with longstanding abuse of alcohol.
fatal. In other cases, lactic acidaemia may not be apparent and the Finally, in Wernicke’s encephalopathy, the effects of thiamine de-
disease comes to light because of intrauterine growth failure, neo- ficiency and deficiency of the pyruvate dehydrogenase complex on
natal hypotonia/​asphyxia and feeding difficulty, and the principal the brain occur principally in the regions of the greatest metabolic
abnormality is progressive psychomotor retardation often accom- activity, especially in the brainstem and basal ganglia. Diminished
panied by brainstem injury and disease of the basal ganglia. There is activity of the pyruvate dehydrogenase complex is caused by thia-
dysgenesis with structural abnormalities of the olivopontocerebellar mine pyrophosphate deficiency, possibly combined with inhibition
tract and periventricular grey matter. Cortical atrophy and agenesis by the ethanol metabolite, acetaldehyde, as a plausible common
of the corpus callosum have also been reported in association with factor in neuropathogenesis.
spastic quadriplegia, especially in patients presenting with neonatal Hereditary spinocerebellar degeneration appearing in early adult
acidosis. In patients who present with severe acidosis at birth, sub- life has been attributed to deficiency of pyruvate dehydrogenase, but
acute necrotizing encephalomyelopathy of the Leigh type has been there is no direct relationship to Friedreich’s ataxia.
confirmed at necropsy with cystic appearances principally in the
cerebral cortex, basal ganglia, and brainstem. Mutations in other subunits
Without intensive treatment, death usually occurs in infancy; E1β subunit Very rare patients with mutations in the E1β subunit
however, should feeding by gavage be instituted, there is a protracted have early-​onset disease, delayed development, but moderate pro-
course with failure of neurological development, microcephaly, gression of neurological disease, later with involvement of the basal
quadriplegia, seizures, and blindness due to the development of ganglia and brainstem nuclei; patients with features of Leigh’s syn-
optic atrophy. Intermittent cerebellar ataxia or torsion dystonia have drome has been reported.
been recorded, and choreoathetoid movements occur. Peripheral
E1 phosphatase regulatory protein Mutations in the E1 phos-
neuropathy with onset in infancy has been observed. Involuntary
phatase regulatory protein have been shown to cause hypotonia and
eye movements in children are associated with a progressively
feeding difficulties with psychomotor retardation, and at least one
deteriorating course.
case with an acute neurological disease with lethal lactic acidosis in
E1α subunit mutations infancy has been described. Two mildly affected adult brothers of
Turkish origin have been reported to be living in their twenties after
A milder form of the disorder occurs in defects of the X-​linked E1α
treatment with a ketogenic diet.
gene (PDHA1), but because pyruvate dehydrogenase deficiency is
of key importance in brain metabolism, expression of disease is ob- E2 (dihydrolipoamide acetyltransferase) deficiency E2
served in females and affected males, hence this form of pyruvate de- (dihydrolipoamide acetyltransferase) deficiency is an exception-
hydrogenase complex deficiency is an X-​linked dominant disorder. ally rare disease, the principal manifestations of which are dystonic
 12.3.3 Disorders of galactose, pentose, and pyruvate metabolism 2011

episodes together with less prominent typical features of pyruvate de- evaluation of enzymatic assays of fibroblasts obtained from obligate
hydrogenase deficiency, such as hypotonia and ataxia. Radiological carriers or female patients in whom the diagnosis is suspected.
examination reveals discrete lesions restricted to the globus pallidus.
Investigation and diagnosis
E3 (dihydrolipoamide dehydrogenase) deficiency E3
The diagnosis is suspected from the presence of severe acidosis at
(dihydrolipoamide dehydrogenase) deficiency is an autosomal re-
birth. It may also emerge during the investigation of neurological
cessive condition due to mutations in E3 dihydrolipoyl dehydro-
deficits, especially where they are associated with intrauterine
genase, common to the action of the pyruvate dehydrogenase
growth failure.
complex and the α-​ketodehydrogenase complex and the branched-​
Measurement of glucose, lactate, pyruvate, 3-​hydroxybutyrate,
chain α-​ ketoacid dehydrogenase complexes. Clinical manifest-
and acetoacetate in whole blood, as well as plasma amino acid
ations range from an acute disease in infants with fatal metabolic
concentrations, should be carried out. Hyperammonaemia with
crises and decompensation associated with early-​onset neurological
citrullinaemia, hyperlysinaemia, and hyperalaninaemia may be
manifestations, to isolated liver disease appearing first in adoles-
found. The NADH/​NAD+ ratio is informative when within the
cence or adult life. Hepatic decompensation, heralded by nausea
healthy reference range because use of NADH is unimpaired in
and vomiting, progresses rapidly to portosystemic encephalopathy
pyruvate dehydrogenase deficiency, whereas in respiratory electron
which is accompanied by coagulation failure, hypoglycaemia, and
chain defects with defective complexes I, III and IV there is an ele-
bleeding. Liver failure can result in death, even in those with late-​
vated lactate/​pyruvate ratio and NADH is typically elevated.
onset disease.
Routine screening of urine samples for organic acids may identify
The biochemical defect in dihydrolipoyl dehydrogenase defi-
excessive pyruvate and lactate. Urine organic acid analysis requires
ciency interferes with the Krebs cycle as well as the decarboxylation
the assistance of a specialized laboratory equipped for gas chro-
of pyruvate. The diagnosis is confirmed by the presence of patho-
matography, and mass spectrometry is increasingly used in major
genic mutations in the DLD gene, but recently it has been proposed
centres.
that the appearance of citrullinaemia is an important biomarker.
Determination of lactate and pyruvate concentrations in cerebro-
A variant presentation has recently been described with a late-​
spinal fluid are of critical value and require special conditions for
onset mitochondrial myopathy and limited evidence of liver dis-
collection, transport, and storage before assay. In patients without
ease. One well-​documented 19-​year-​old patient had lactic acidosis,
clinically evident acidosis, cerebral disease is accompanied by
a complex amino-​and organic aciduria, and progressive exertional
striking elevations of lactate and pyruvate in the cerebrospinal fluid.
fatigue. Muscle biopsy showed mitochondrial proliferation and lack
Muscle biopsy for mitochondrial studies and determination of
of cross-​reacting dihydrolipoamide dehydrogenase. Empirical ribo-
the redox state in cultured skin fibroblasts using the lactate:pyruvate
flavin supplementation induced a complete resolution of exercise
ratio may also be valuable, but further specialized studies will re-
intolerance with the partial restoration of the protein and resolution
quire advice from a biochemical and genetics service with experi-
of pathological mitochondrial proliferation in the muscle. Oral ad-
ence in the diagnosis of inborn errors of metabolism. Given that
ministration of lipoic acid has been reported to correct the organic
these measurements can show wide fluctuations in acutely ill pa-
acidaemia with clinical improvement in other patients. These find-
tients, several samples should be examined as recovery occurs so
ings prompt more systematic use of all the relevant vitamin cofactors
that the steady-​state abnormalities are reflected.
in the pyruvate dehydrogenase complex, here illustrating a classical
Glucose challenges are not critical for diagnosis, but pyruvate
chaperone effect elsewhere familiar in adult metabolic practice (e.g.
rises markedly in pyruvate dehydrogenase deficiency.
in attenuated pyridoxine-​responsive homocystinuria).
Neuroradiological imaging reveals ventricular dilatation and
E3BP (E3 binding protein) More than 20 patients with E3BP de- cerebral atrophy. In several infant girls with pyruvate dehydrogenase
ficiency have been reported. It appears generally to be less severe deficiency, MRI showed hypoplasia of the corpus callosum as well
than pyruvate dehydrogenase deficiency due to mutations in the as loss of normal white matter signal intensity. Proton magnetic
E1α subunit. A few have shown neonatal onset with lactic acidosis, resonance spectroscopy revealed high-​abundance signals for brain
the survivors of which had a clinical course similar to the late-​onset lactate with decreased intensity of N-​acetylaspartate, while phos-
patients who suffer psychomotor retardation and encephalopathy—​ phorus magnetic resonance spectroscopy of skeletal muscle showed
pyramidal spasticity, in some cases with microcephaly. abnormally low muscle phosphorylation potentials, in keeping with
Neonatal lactic acidosis is more frequent in males. For prenatal the predicted biochemical disturbance. Pathological examination of
testing, diagnosis by molecular analysis of DNA is essential—​and is previously affected siblings shows shrinkage of gyri, with involve-
also valuable for the identification of the other defects such as E1β-​ ment of the medulla shown by loss or hypoplasia of the pyramids.
subunit deficiency. The pathological features of Wernicke’s encephalopathy may be pre-
An auxiliary gene for the E1α subunit is localized as a result of sent. The corpus callosum may be absent.
retroposition from the X chromosome to the long arm of chromo- Definitive diagnosis depends on genetic and enzymatic studies
some 4, but is expressed only during spermatogenesis; its presence, in skin fibroblasts or blood leucocyte samples. This should in-
however, indicates the critical need for activity of the complex in clude indirect measurement of the activity of the whole complex
nearly all tissues. Causal mutations in the PDHA1 gene on the X by determining release of 14CO2 from [1-​14C pyruvate] from cul-
chromosome have been described; most appear to be short deletions tured cells in the presence or absence of high thiamine pyrophos-
or duplications and, at present, are not generally applicable for diag- phate to explore vitamin responsiveness, and in the presence or
nosis. However, analysis of X-​chromosome inactivation patterns, absence of dichloroacetate which activates the enzyme in intact
by determination of methylation status, has proved useful for the cells by inhibiting the regulatory E1 kinase. Mutation analysis of
2012 SECTION 12 Metabolic disorders

the X-​linked PDHA1 gene or other PDH-​related genes permits de- resemble those caused by deficiencies of pyruvate dehydrogenase
cisive diagnosis. While chorionic villus biopsy tissue or cultured activity and appear to be determined by the degree of residual pyru-
amniocytes can be used for prenatal diagnosis, prior studies of ma- vate carboxylase activity.
terial obtained from previously affected probands is often invaluable.
Genetics
Treatment This disorder is transmitted as an autosomal recessive trait. In se-
Institution of a high-​ fat, low-​ carbohydrate, ketogenic diet may verely affected patients with hyperammonaemia, pyruvate carb-
ameliorate the biochemical abnormalities, but—​given the degree oxylase protein and its mRNA are absent in the liver. A partially
of neurological impairment that is normally present at diagnosis—​ inactive variant enzyme is detectable in other patients.
only very modest clinical improvement can be expected in those pa-
tients with established disease. Biochemical defect
Therapeutic responses to the administration of high-​dose thia- Pyruvate decarboxylase is a biotin-​dependent enzyme of the mito-
mine (500 mg daily) have been reported in patients with partial chondrial matrix which catalyses the first step in the formation of
enzymatic deficiency, notably where ataxia and abnormal eye move- oxaloacetate from pyruvate and carbon dioxide and is activated allo-
ments reminiscent of Wernicke’s encephalopathy or features indica- sterically by acetyl coenzyme A. It is critical enzyme for the produc-
tive of Leigh’s disease are conspicuous. tion of glucose by gluconeogenesis: this is achieved by carboxylation
Dichloroacetate, which is a structural analogue of pyruvate, is an of pyruvate to form oxaloacetate, which is shuttled to the cytosol
inhibitor of the regulatory E1α-​subunit kinase and has been used where it is acted upon by phosphoenol pyruvate carboxykinase to
for the treatment of primary lactic acidaemia, particularly in pa- generate the glucose precursor phophoenolpyruvate, which is the
tients with pyruvate dehydrogenase deficiency. Clinical trials in- first committed step in de novo glucose formation. Thus, in pyru-
dicate that correction of the biochemical abnormality depends on vate carboxylase deficiency, hypoglycaemia would be expected after
the molecular defect, and heterogeneity in patient selection may ex- glycogen stores are depleted.
plain the equivocal clinical responses observed in long-​term studies. Pyruvate carboxylase as a source of lipids is explained by its
Nonetheless, dichloroacetate appears to be well tolerated and de- intramitochondrial proximity: acetyl coenzyme A condenses with
serves consideration in patients who fail to respond to other meas- pyruvate to generate citrate. Impaired synthesis of lipids explains the
ures, including the recommended ketogenic diets with high-​dose often widely distributed loss of white matter in pyruvate carboxylase
thiamine supplementation. deficiency.
In patients with mutations in the multifunctional flavoprotein Krebs cycle intermediates may become depleted so that syn-
E3 dihydrolipoyl dehydrogenase, oral administration of lipoic thesis of neurotransmitters is impaired. There may also be a reduced
acid has been reported to correct the organic acidaemia with clin- supply of aspartate for the arginosuccinate synthase reaction of the
ical improvement. More striking has been the report of high-​dose urea cycle, hence the association with hyperammonaemia.
riboflavin supplementation in a young adult with a mitochondrial
myopathy and lactic acidosis producing salutary metabolic, histo- Clinical features
logical, and functional reversal, plausibly due to a chaperone effect Three broad clinical types of pyruvate carboxylase have been
of this critical enzyme cofactor. Given the severe nature of these recognized.
diseases, and in the absence of clinical trial data, there may be
justification for empirical clinical use of the vitamin cofactors in Type A (infantile form)
selected cases. The North American form of the disease is associated the onset
In patients with seizures, the use of sodium valproate cannot be of vomiting, metabolic acidosis (lactate is 2–​10 mmol/​litre), and
recommended by the author: the agent is an inhibitor of mitochon- collapse in infants aged 2 to 6 months and associated with intercur-
drial metabolism and has been implicated in unmasking and aggra- rent infection. The patients develop ataxia, pyramidal tract signs,
vating several mitochondrial diseases. Other anticonvulsants affect and nystagmus: severe mental retardation and seizures develop
mitochondrial metabolism, including carbamazepine, phenytoin, rapidly. An enlarged liver is present and neuroradiological imaging
oxcarbazepine, ethosuximide, zonisamide, topiramate, gabapentin, shows subdural fluid, lesions resembling antenatal ischaemia-​like
and vigabatrin. Where possible in disorders of pyruvate-​driven brain lesions, and periventricular haemorrhagic cysts accom-
oxidative phosphorylation, it would seem prudent to avoid these panied by cortical atrophy. Myelination is retarded and the patient
agents, but valproate probably should be avoided altogether in pa- relentlessly deteriorates to die, almost always in infancy or early
tients with defective activity of the mitochondrial pyruvate dehydro- childhood.
genase complex.
Type B (severe, neonatal form)
Pyruvate carboxylase deficiency The so-​called French form, with severe prostration within the first
Inborn defects in pyruvate carboxylase, a biotin-​ dependent 48 h of life. There is vomiting, hypotonia, lethargy, hypothermia, and
gluconeogenic enzyme, cause hypoglycaemia or profound meta- rapid neurological deterioration with tremor, rigidity, poor move-
bolic acidosis with neurodegenerative features. The neuronal loss is ment, and abnormal ocular movements. The disease is rapidly fatal
prominent, although the enzyme is principally expressed in astro- in most cases; those who survive the early days are unresponsive and
cytes and other non-​neuronal cells, suggesting impairment of the die from respiratory infection before the age of 6 months. There is a
supply of nutrients derived from metabolic activity in astroglia marked lactate acidosis with concentrations of 10 to 20 mmol/​litre
that are essential for neuronal survival. The manifestations closely (normal is <2.2 mmol/​litre).
 12.3.3 Disorders of galactose, pentose, and pyruvate metabolism 2013

Type C (intermittent/​benign form)

Cornblath M, Schwartz R (1991). Disorders of galactose: metabolism.
A rare third subtype is compatible with survival to adult life with In: Cornblath M, Schwartz R (eds) Disorders of carbohydrate me-
episodic lactic acidosis and ketosis (<10 mmol/​litre), these epi- tabolism in infancy, 3rd edition, pp. 295–​324. Blackwell Scientific,
sodes resolve with supportive measures and parenteral fluids. While Boston.
subcortical leukodystrophy has developed in some patients, many Demirbas D, et al. (2018). Hereditary galactosemia. Metabolism, 83,
develop normally and have cognitive ability and motor-​skill devel- 188–​96.
opment that is within the healthy reference range. Frederick AB, Cutler DJ, Fridovich-​Keil JL (2017). Rigor of non-​dairy
galactose restriction in early childhood, measured by retrospective
Diagnosis survey, does not associate with severity of five long-​term outcomes
quantified in 231 children and adults with classic galactosemia.
The condition is suspected when acidosis and neurological dis-
J Inherit Metab Dis, 40, 813–​21.
ease occur in infants, especially in the presence of hypoglycaemia. Frey P (1996). The Leloir pathway: a mechanistic imperative for three
Specific diagnosis requires enzymatic assay in fibroblasts, which can enzymes to change the stereochemical configuration of a single
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12.4
Disorders of purine and
pyrimidine metabolism
Anthony M. Marinaki, Lynette D. Fairbanks, and Richard W.E. Watts†

ESSENTIALS extending from hyperuricaemia alone to hyperuricaemia with profound

neurological and behavioural dysfunction (Lesch–​Nyhan syndrome).
These disorders are due to abnormalities in the biosynthesis, inter- Phosphoribosyl pyrophosphate synthetase superactivity presents with
conversion, and degradation of the purines—​adenine and guanine—​ uric acid lithiasis or gouty arthritis in childhood or early adult life.
and of the pyrimidines—​ cytosine, thymine, and uracil. All are Acute attacks of gout are treated with nonsteroidal anti-​
heterocyclic bases which exist in tri-​, di-​, and monophosphorylated inflammatory drugs, colchicine, or steroids. First-​line treatment to
forms, and as either deoxyribosylated or ribosylated derivatives (de- prevent acute attacks or manage chronic tophaceous gout is with
oxyribose and ribose are pentose carbohydrates). The phosphor- the xanthine oxidase inhibitor, allopurinol.
ylated deoxyribosylated and ribosylated derivatives are termed Hypouricaemia may be caused by inherited disorders of uric acid
‘nucleotides’, and the purely ribosylated derivatives, which lack the biosynthesis (e.g. xanthine oxidase deficiency) or may be due to in-
phosphate group, are ‘nucleosides’. herited or acquired renal tubule transport defects.
The purine nucleotides, their cyclic derivatives (cAMP and cGMP), Other diseases of purine metabolism cause diverse abnormalities
and their more highly phosphorylated derivatives have functions in and are generally the result of single gene defects, for example, ad-
many aspects of intermediary metabolism. Purine compounds also enosine deaminase and purine nucleoside phosphorylase catalyse
function as signal transducers, neurotransmitters, vasodilators, and sequential steps in the metabolism of purine ribonucleosides and
mediators of platelet aggregation. deoxyribonucleosides and are highly expressed in lymphoid cells;
The polynucleotide deoxyribonucleic acid (DNA) contains their deficiency causes lymphotoxic metabolites to accumulate and
equimolar amounts of adenosine monophosphate (adenylic acid, leads to lymphopenia and severe combined immunodeficiency.
AMP), guanosine monophosphate (guanylic acid, GMP), thymidine
monophosphate (thymidylic acid, TMP), and cytidine monophosphate Disorders of pyrimidine metabolism
(cytidylic acid, CMP). Uridine monophosphate (uridylic acid, UMP) re- The de novo synthesis of pyrimidine nucleotides involves a series of
places TMP in the polynucleotide ribonucleic acid (RNA). six reactions beginning with the formation of carbamyl phosphate
and concluding with orotidine monophosphate, which then under-
Disorders of purine metabolism
goes a series of interconversion and salvage reactions. The inherited
The end point of purine metabolism in humans is uric acid. When disorders of pyrimidine metabolism (e.g. orotic aciduria), which have
uric acid levels become supersaturated in body fluids, uric acid diverse presentations, are much less common and/​or much less
and sodium urate monohydrate crystallize, causing gout. This re- easily recognized than disorders of purine metabolism.
sults from either overproduction or underexcretion of urate, or
from a combination of these defects. Decreased net tubular urate
secretion is most often due to genetic polymorphism in uric acid
transporters and is the most common cause of primary (‘idiopathic’) Disorders of purine metabolism
gout. Gout may be secondary to a wide variety of renal disorders,
ranging from simple reduction in glomerular filtration rate (chronic Purine metabolism
kidney disease) to specific defects, for example, the autosomal dom- Biosynthesis, interconversion, degradation, and salvage
inant tubulointerstitial kidney diseases caused by mutations in the
genes encoding uromodulin (UMOD), hepatocyte nuclear factor-​1b The purine nucleotides are built up in a stepwise manner (de novo
(HNF1B), renin (REN), and mucin-​1 (MUC1). synthesis) and undergo a series of interconversion and salvage re-
Gout is also a consequence of enzymatic defects that accel- actions and a final degradative process to yield uric acid, as shown
erate de novo purine synthesis. X-​ linked hypoxanthine-​
guanine in Fig. 12.4.1. The dietary intake of nucleoproteins contributes to
phosphoribosyltransferase deficiency results in a clinical spectrum uric acid formation. Ingested adenine and guanine nucleotides are
degraded to free purine bases and, hence, to uric acid by enzymes

†
It is with great regret that we report that Richard W.E. Watts died on 11 February, 2018.
2016 SECTION 12 Metabolic disorders

Ribose-5-Phosphate Phospho-D-ribosyl -1- 5-Phosphoribosyl-1-amine + Glycine-ATP

+ATP pyrophosphate + Fumarate
PRPS glutamine GAR
Glutamine ATP
FGAR
ATP
FGAM HCO3
AIR Aspartate ATP
CAIR
H2O
DNA SAICAR
Fumarate DNA
ADSL AICAR
dGMP dGDP dGTP
FAICAR ATIC
dATP dADP dAMP RNA
ADSL
ATP ADP AMP sAMP IMP XMP GMP GDP GTP

NT NT
ADA
RNA APRT Deoxyadenosine Deoxyinosine HPRT Deoxyguanosine
Adenosine Inosine Guanosine

PNP PNP
Polyamine metabolism Adenine
Hypoxanthine
Guanine
XO

8-OH Adenine Xanthine Guanase

XO

2-8-OH Adenine Uric acid

Fig. 12.4.1 Pathways of purine metabolism in humans. ADA, adenosine deaminase; ADSL, adenylosuccinate lyase; APRT adenine
phosphoribosyltransferase; ATIC, AICAR transformylase/​IMP cyclohydrolase; HPRT, hypoxanthine-​guanine phosphoribosyltransferase; NT,
5′-​nucleotidase; PNP, purine nucleoside phosphorylase; PRPS, phosphoribosylpyrophosphate synthetase; XO, xanthine oxidase. De novo
synthesis intermediates: AICAR, 5-​phosphoribosyl-​5-​amino-​4-​imidazolecarboxamide; AIR, 5-​phosphoribosyl-​aminoimidazole; CAIR,
5-​phosphoribosyl-​5-​amino-​4-​imidazolecarboxylate; FAICAR, 5-​phosphoribosyl-​5-​formamido-​4-​imidazolecarboxamide; FGAM,
5-​phosphoribosyl-​N-​formylglycinamidine; FGAR, 5-​phosphoribosyl-​N-​formylglycinamide; GAR, 5-​phosphoribosyl-​glycinamide;
SAICAR, 5-​phosphoribosyl-​5-​amino-​4-​imidazole-​succinocarboxamide.

in the intestinal fluids and in the mucosa of the small intestine, The kidney handles urate by:
so that the products of their metabolism do not mix with the cor-
• glomerular filtration (virtually no hindrance to passage through
responding endogenous metabolic pools except at the final uric
the glomerular filtration barrier)
acid stage.
• proximal tubular reabsorption by urate anion exchangers, pre-
De novo synthesis contributes about 300 to 600 mg (1.8–​3.6 mmol/​
dominantly URAT1, OAT4, and OAT10 in the endothelial brush
day) and dietary purines about 600 to 700 mg (3.6–​4.2 mmol/​day)
border (99% of the filtered load)
to the dynamic urate metabolic pool of about 1200 mg (7.2 mmol)
expressed as uric acid. Each day about two-​thirds of the uric acid • reabsorption into the circulation at the basolateral membrane,
is excreted in the urine and about one-​third is excreted via the gut predominantly by the fructose–​ urate transporter GLUT9
where it is destroyed mainly by bacterial uricolysis. (SLC2A9)
• urate excretion at the apical membrane by MRP4, NPT1, NPT4,
Renal handling of urate and BCRP/​ABCG2.
The urate anion is freely filterable at the renal glomerulus, only The net renal clearance of uric acid is approximately 10% of the
5 to 10% being very loosely bound to the plasma proteins (α1–​2-​ filtered load and is in the range of 6 to 11 ml/​min per 1.73m2 (1.73
globulin fraction). The physiologically important pKa value of uric m2 = average body surface area of an adult).
acid is 5.75, so that it exists mainly as the monovalent urate anion Genome-​wide association studies have led to considerable ad-
in plasma (pH 7.4) and assumes more of the free acid form when it vances in the understanding of this complex process by identifying
passes into regions of the renal tubule, the contents of which are at genes in uric acid transport and genetic variants predisposing to
lower pH values. gout (Fig. 12.4.2).
 12.4 Disorders of purine and pyrimidine metabolism 2017

Basolateral Tubular cell Apical membrane

membrane (brush border)

URA11
Urate GLUT9 Urate OAT4 Urate
OAT10

Circulation Tubular lumen

Approximately Approximately
90% of filtered 10% of filtered
uric acid is uric acid is
reabsorbed excreted

ABCG2
OAT1
Urate Urate MRP4 Urate
OAT3
NPT1 and NPT4

Fig. 12.4.2 Proximal tubule uric acid anion transport. OAT1 and OAT3 mediate urate uptake from the basolateral
membrane. Secretion at the apical membrane into the tubule is via ABCG2, MRP4, NPT1, and NPT4. Tubular
reabsorption is via URAT1, OAT4, and OAT10. GLUT9 promotes reabsorption of urate back into the circulation.
Approximately 90% of urate filtered in the glomerulus is reabsorbed in the proximal tubule. This increases to
approximately 95% in patients with hyperuricaemia due to uric acid underexcretion.

URAT1, encoded by the gene SLC22A12, was the first uric acid by 13 exons. GLUT9b expression is restricted to liver and kidney,
transporter to be identified and is involved in urate reabsorption whereas GLUT9a has a broad tissue distribution including liver,
in the proximal tubule. It is expressed apically in the brush border kidney, intestine, leucocytes, and interestingly, chondrocytes. It is
epithelium and is an anion exchanger stimulated by an outwardly suggested that the functions of this urate anion transporter is to
directed chloride gradient. Lactate, pyrazinoate, and nicotinate are transport urate formed intracellularly by purine catabolism and
substrates for the antiporter activity of URAT1 thereby increasing so maintain intracellular urate concentrations below the solubility
urate reabsorption. The uricosuric agents benzbromarone, pro- limit and prevent intracellular crystallization. In the kidney, GLUT9
benecid, and losartan are inhibitors. OAT4 (SLC22A11) and OAT10 may be the principal pathway of basolateral urate transport from the
(SLC22A13) are also expressed in epithelial cells of the proximal tu- proximal tubule cell.
bule apical membrane and play a role in the reabsorption of uric acid
from the proximal tubule in exchange for dicarboxylates. Plasma urate concentration
The multidrug resistance protein MRP4 and the transporter
ABCG2 contribute to uric acid efflux into the tubular lumen. Reference range
ABCG2 is also expressed in the intestine and plays an important role The currently quoted overall reference range for plasma uric acid
in the extrarenal excretion of uric acid through the gut. An amino in adults is 3.5 to 8.1 mg/​dl (210–​480 µmol/​litre) for men and 2.5
acid substitution p.Q141K in ABCG2 is associated with significantly to 6.5 mg/​dl (150–​390 µmol/​litre) for women. The corresponding
increased plasma uric acid levels and an increased risk for gout in value for children is 1.0 to 4.0 mg/​dl (60–​240 µmol/​litre), with the
multiple ethnic backgrounds. The data suggests that at least 10% lowest values in infancy. It rises to adult values at puberty with values
of gout cases in individuals of European descent are attributable to being lower in women than in men. Extrinsic factors, particularly
this variant. The p.Q141K variant is unexpectedly also associated diet, plumbism, the prevalence of a high ethanol intake in the com-
with increased urinary uric acid output because of the decreased munity, and the prevalence of diseases such as malaria and thalas-
intestinal excretion associated with the variant. More recently, the saemia, which lead indirectly to either increased purine biosynthesis
ABCG2 p.Q141K variant has been associated with a poor response or decreased excretion (Table 12.4.1), affect the plasma urate distri-
to allopurinol therapy, although the mechanism for this is unclear. bution in different populations.
The urate fructose–​glucose transporter GLUT9 (SLC2A9) is a The plasma urate concentration decreases during pregnancy,
voltage-​dependent uric acid transporter. Alternative splicing leads the reference range being 1.7 to 4.5 mg/​dl (100–​270 µmol/​litre).
to two transcripts, GLUT9a encoded by 12 exons with 540 amino Hyperuricaemia is a characteristic and often an early feature of
acids and GLUT9b, a shorter protein of 512 amino acids encoded pre-​eclampsia, preceding proteinuria and hypertension, and is a
2018 SECTION 12 Metabolic disorders

Table 12.4.1 Causes of hyperuricaemia and gout 100

1989
1971
Increased uric acid synthesis Decreased renal clearance 80 1962

Cumulated frequency (%)

Increased uric acid production Genetic polymorphism in urate Women
due to HPRT deficiency or PRPS transporters URAT1, GLUT9, 60
synthase superactivity and ABCG2
Dietary sources including fructose Chronic kidney disease 40
Chronic haemolytic anaemia of Autosomal dominant tubulointerstitial
any cause kidney diseases 20
Myeloproliferative disorders Hyperparathyroidism
Malignancies Bartter’s syndrome 0 2 4 6 8 10 12
Psoriasis Hypothyroidism Serum uric acid (mg/dl)

Obesity Obesity
100 1989
Down’s syndrome Diabetes 1971
Glycogen storage diseases Lead poisoning 1962
80

Cumulated frequency (%)

Fructose intolerance Lactic acidosis
Men
Gaucher’s disease Drug administration (e.g. diuretics, 60
pyrazinamide, and ethambutol)
40

diagnostically valuable parameter. It results from a reduced renal 20

urate clearance and tends to be associated with hypocalciuria.
Epidemiological studies show significant variations in plasma urate
0 2 4 6 8 10 12
concentrations between different ethnic groups, for example, Maoris Serum uric acid (mg/dl)
and Polynesians have higher values than Western Europeans and
Fig. 12.4.3 Differences in the cumulative frequencies in urate levels in
Americans. This illustrates the genetic, presumably polygenic, aspects
female and male blood donors in Bavaria between 1962 and 1989. Urate
in the control of serum uric acid. Other epidemiological studies em- deposition in man and its clinical consequences.
phasize the importance of the environmental factors of purine, pro- Reproduced from Gresser U, Zöllner N (1991). Urate deposition in man and its clinical
tein, and alcohol intake. For example, Gresser and Zöllner showed consequences. With kind permission of Springer Science + Business Media.
that the cumulative frequency of plasma urate, expressed as uric acid,
rose from approximately 6.2 mg/​dl (370 µmol/​litre) to about 9.0 mg/​
dl (536 µmol/​litre) between 1962 and 1971 in association with the im- with urate-​lowering therapies carries a significant risk of toxicity and
proved nutritional state of the Bavarian population from the near star- in the absence of evidence for clear clinical benefit, recommenda-
vation conditions following the Second World War (Fig. 12.4.3). This tions are that asymptomatic hyperuricaemia should not be treated.
effect was not apparent in the female population. Similarly, the plasma The evidence for a causal association between hyperuricaemia
urate levels of immigrant communities with low values in their home- and hypertension, cardiovascular disease, metabolic syndrome, and
lands rise towards the values prevailing in the host country as they an increased risk of renal failure is contradictory. If indeed causal,
adopt the lifestyle and dietary habits of that country (e.g. Filipinos any association is likely to have a small effect of limited clinical
migrating to the United States of America). Migrants with genetically significance compared to other comorbidities. A few studies have
determined high urate levels become even more hyperuricaemic. compared measures of renal function in patients with asymptom-
The frequency distribution of plasma urate values based on atic hyperuricaemia treated with allopurinol to those in patients not
asymptomatic populations is only approximately Gaussian, with treated for hyperuricaemia, and although there is some evidence
an excess of higher values due to the inclusion of some asymptom- for an improvement in estimated GFR with treatment, these small
atic hyperuricaemic subjects. Although plasma is saturated with studies have had a duration of a few months rather than years. There
monosodium urate at a concentration of 7.0 mg/​dl (420 µmol/​litre), is also little evidence that asymptomatic hyperuricaemia increases
higher concentrations of urate can remain in a stable supersaturated the risk of gouty arthritis. However, although there is currently
solution in plasma without producing any symptoms. Ignoring the insufficient evidence to suggest that treatment of asymptomatic
slight asymmetry of the frequency distribution and defining nor- hyperuricaemia is beneficial, lifestyle advice on diet and exercise
mality as the mean value ±2 standard deviations about the mean, should be given to the patient and may be of benefit in lowering uric
normal values of 7.0 mg/​dl (420 µmol/​litre) for men and 6.0 mg/​dl acid levels as well as improving other comorbidities.
(360 µmol/​litre) for women have been widely adopted and this has
led to considerable overtreatment of patients with quite innocuous Gout
plasma urate concentrations. (For further discussion see Chapter 19.10.) The incidence of gout
has been estimated at about 0.2 to 0.35 per 1000. The incidence in-
Asymptomatic hyperuricaemia: to treat or not to treat? creases with age and is higher in men than in women, although the
Routine biochemical screening frequently identifies patients with incidence in women rises with age. In men the first attack has usually
hyperuricaemia. The treatment of asymptomatic hyperuricaemia occurred by 50 years of age and in women by 70 years of age.
 12.4 Disorders of purine and pyrimidine metabolism 2019

I
Gout due to urate under-​excretion is characterized by a reduced
1 2 fractional excretion of urate defined as the ratio of urate clearance to
the GFR. In the presence of normal overall renal function, this can
be measured on a timed urine sample with a simultaneous plasma
II
sample. The equation simplifies to:
1 2 3 4 5

Fractional clearance of urate = U [urate] × P [creatinine]/​P [urate]

III 3 × U [creatinine]
4 5 6 7 8 9

where U and P represent urate and plasma concentrations. The

IV fractional clearance can be used to assess the role of renal tubular
1 2 3 6 7 8 9 dysfunction in the production of hyperuricaemia provided that the
overall renal function is normal. An elevated urinary urate to cre-
V atinine ratio is indicative of purine overproduction.
1 2 3 4 5 6 Associations of hyperuricaemia and gout are shown in Box 12.4.1.
Hyperuricaemia may be a marker of coincident cardiac disease.
Elevated plasma uric acid concentrations are observed in patients
VI * *
1 2 with ischaemic cardiac disease, however there is no evidence that
uric acid is directly toxic to the myocardium. Increased urate levels
Fig. 12.4.4 Pedigree chart of a family showing autosomal dominant
could arise from up-​regulated vascular adenosine synthesis associ-
inheritance of gout complicated in some cases by renal failure (autosomal
dominant tubulointerstitial kidney disease). ■, ●, male and female ated with ischaemia and subsequent degradation of adenosine to uric
subjects, respectively, with hyperuricaemia and renal failure; ■, ●, male acid. Plasma uric acid accounts for 60% of the free-​radical scavenging
and female subjects not known to be affected; ■, ●, deceased male and activity in human plasma, for example, it interacts with peroxynitrile
female subjects; ↗, propositus; ↘, subjects whose rates of mononuclear to form a stable nitric oxide donor, so promoting vasodilatation and
cell de novo purine synthesis were measured and shown to be normal; *, reducing the potential for peroxynitrile-​induced oxidative damage.
babies who were examined clinically but not further investigated.
Conversely, it could have an adverse effect on endothelial function by
Reproduced with permission from McDermott, et al. (1984). Clin Sci, 67, 249–​58.
© Biochemical Society and Medical Research Society (http://​www.clinsci.org). promoting leucocyte adhesion to the endothelium.

Clinical features
Gout is a classic example of a multifactorial disease in which there
is an interplay of genetic and environmental factors. The overall ef- Acute gouty arthritis
fects of this interplay are wide, extending from cases where there Acute gout is a sodium urate monohydrate-​induced crystal in-
is a clear-​cut family history with autosomal dominant inheritance flammation of joints, bursae, and tendon sheaths. Clinically the
(Fig. 12.4.4) to those where environmental factors may be major de- affected structures—​classically the first metatarsophalangeal joint
terminants, although often against a genetic background that may is the first joint affected—​become acutely inflamed, exquisitely
be either unifactorial or multifactorial. Gout per se does not shorten tender, warm to the touch, and the overlying skin becomes red,
life, although some of its complications may do so in the absence of shiny, and itchy and may desquamate as the inflammation subsides
treatment. spontaneously over the course of 5 to 15 days in the absence of
Gout is defined as the syndrome brought about by the crystalliza- treatment (Fig. 12.4.5). Inflammation is usually maximal within
tion of monosodium urate monohydrate in vivo from body fluids 24 h of onset and is accompanied by pyrexia and malaise.
supersaturated with this salt. This results from either overproduc- The American College of Rheumatology criteria for the clinical
tion or underexcretion of urate, or from a combination of these de- diagnosis of acute gout are shown in Box 12.4.2. The presence of 6
fects (Table 12.4.1). The underlying causes of hyperuricaemia and
gout are as follows:
• Decreased net tubular urate secretion: this occurs in those cases Box 12.4.1 Associations of hyperuricaemia and gout
of gout previously described as being idiopathic (or primary), and The following abnormalities (features of the ‘metabolic syndrome’) are
the hereditary predisposition is often compounded by environ- commonly associated with, but not causally related to, hyperuricaemia
mental factors (e.g. high dietary purine and alcohol intake). and gout:
• Obesity
• Identifiable enzymatic defects that accelerate de novo urate syn-
• Dyslipidaemia (usually type 4) with raised very low-​density lipopro-
thesis: X-​linked hypoxanthine-​guanine phosphoribosyltransferase teins and normal cholesterol levels, and sometimes hypercholester-
(HPRT) deficiency, if complete or virtually complete, causes olaemia with elevated low-​density lipoprotein cholesterol and low
Lesch–​Nyhan syndrome. Lesser degrees of deficiency cause X-​ high-​density lipoprotein cholesterol
linked recessive hyperuricaemia, gout, and uric acid stones with • Hypertension
minor neurological abnormalities in some cases. • Insulin resistance with hyperinsulinaemia and impaired glucose
tolerance
• Phosphoribosylpyrophosphate (PRPP) synthetase superactivity:
• Ischaemic heart disease
this also presents as X-​linked recessive hyperuricaemia, gout, and
uric acid stones and, in some cases, neurological manifestations Thus, these patients may display the features of the ‘metabolic
syndrome X’.
(e.g. deafness).
2020 SECTION 12 Metabolic disorders

Box 12.4.3 Drugs and dietary supplements causing

hyperuricaemia and gout
• Thiazide diuretics (including bendroflumethiazide, chlortalidone,
cyclopenthiazide, indapamide, metolazone, and xipamide)
• Loop diuretics (including furosemide, bumetanide, and torasemide)
• Pyrazinamide and ethambutol
• Low-​dose aspirin
• Nicotinic acid
Reproduced with permission from Gibson TJ (2013), Hypertension, its treat-
ment, hyperuricaemia and gout. Curr Opin Rheumatol, 25, 217-22. Copyright
© 2013 Lippincott Williams.

The spontaneous resolution of an attack of acute gouty arthritis

depends on the differentiation of monocytes to macrophages that ef-
ficiently phagocytose crystals. This conclusion is based on studies of
Fig. 12.4.5 Gout presenting in the metatarsophalangeal joint of the big the changing pattern of proinflammatory cytokines tumour necrosis
toe. Note the slight redness of the skin overlying the joint (arrow). factor (TNF), interleukin-​1 (IL-​1), and interleukin-​6 (IL-​6) secreted
Image by James Heilman, MD ((CC BY-SA 3.0 (http://creativecommons.org/licenses/ by monocyte/​macrophage cells at different degrees of differentiation
by-sa/3.0)).
and their ability to phagocytose monosodium urate crystals in vitro.
The crystals are removed by mature phagocytes. It is proposed that
of the 11 criteria has a 95% specificity in differentiating gout from
this mechanism prevents the development of acute gouty arthritis
pseudogout (calcium pyrophosphate gout) and an overall sensi-
in stable asymptomatic hyperuricaemic patients. TNFα, IL-​1β, and
tivity of 85%.
IL-​6 secretion promote E-​selectin expression and secondary neutro-
Although acute gouty arthritis is typically a monoarthritis, some
phil capture. Differentiation over 3 to 5 days leads to development of
patients have short, recurrent, mild attacks of discomfort and
a noninflammatory phenotype with lack of proinflammatory cyto-
swelling of other affected joints. Some 10% of attacks affect more
kine secretion, lack of endothelial cell activation, and lack of sec-
than one joint, and typical attacks may provoke migratory attacks in
ondary neutrophil recruitment. Acquisition of the noninflammatory
other joints. Multiple, simultaneous attacks are rare. Some attacks are
phenotype correlates with expression of macrophage antigens but
triggered by trauma, intercurrent illness, surgery, alcohol, dietary ex-
not with dendritic cell marker or activation marker.
cess, diuretics, and other medications (Box 12.4.3). An acute septic
Monocytes and macrophages are similarly phagocytic and control
arthritis is the most important differential diagnosis of acute gouty
particle, zymosan-​elicited secretion of all the cytokines in both cell
arthritis. The joint fluid contains negatively birefringent sodium urate
types. Coincubation with monosodium urate suppressed zymosan-​
monohydrate (Fig. 12.4.6) as opposed to the positively birefringent
induced TNFα secretion from macrophages but not monocytes. In
crystals of calcium pyrophosphate in pseudogout and is diagnostic.
summary, differentiated macrophages provide the mechanism for
Attacks of acute gouty arthritis usually occur when the plasma urate
removal of sodium monohydrate crystals.
is rising or falling. The cells in the joint fluid are a mixture of mono-
cytes, macrophages, and polymorphonuclear leucocytes.

Box 12.4.2 American College of Rheumatology criteria for the

diagnosis of acute gouty arthritis
• More than one attack of acute arthritis
• Maximum inflammation developing within 1 day
• Monoarthritis
• Redness over the affected joint
• The first metatarsophalangeal joint is painful and swollen
• Unilateral first metatarsophalangeal joint involved
• Unilateral tarsal joint attack
• Tophus (proven or suspected)
• Hyperuricaemia
• Asymmetrical swelling of a joint on radiography
• Subcortical cysts with an erosion on radiography
• Joint fluid culture negative for microorganisms during an attack
The patient must have at least six of the listed criteria or have either
proven sodium urate monohydrate crystals in the joint fluid or a proven
tophus. Fig. 12.4.6 Negatively birefringent uric acid crystals in synovial fluid.
Reproduced with permission from Hochberg MC (2001). Gout. In: Silman Under polarized light, horizontal crystals appear as yellow.
AJ, Hochberg MC (eds) Epidemiology of the rheumatic diseases, 2nd edition, Reproduced from Dalbeth, N. Laboratory testing in gout diagnosis and management.
pp. 230–​42. Oxford University Press. In (Ed.), Gout (Oxford Rheumatology Library). Oxford, UK: with permission from
Oxford University Press.
 12.4 Disorders of purine and pyrimidine metabolism 2021

Gout due to autosomal dominant tubulointerstitial

kidney disease
Rare cases of familial gout, presenting in early adulthood or before,
have been identified for a long time in families with a history of
renal failure. It is now known that familial (juvenile) hyperuricaemic
nephropathy is associated with at least four gene defects, and these
disorders are more accurately known as the autosomal dominant
tubulointerstitial kidney diseases (ADTKD).
ADTKD-​ UMOD is due to defects in the gene encoding
uromodulin (UMOD) and a specific syndrome ‘medullary cystic
kidney disease: familial juvenile hyperuricaemic nephropathy’
(MCKD/​FJHN) is now recognized. These patients show impaired
Fig. 12.4.7 Thiazide or loop diuretic treatment for hypertension urine concentrating ability, hyperuricaemia and hypouricosuria due
are frequent causes of hyperuricaemia and gout. Tophus overlying a
to a reduced net tubular excretion of uric acid, cysts (specifically at
Heberden’s node in an elderly patient taking bendroflumethiazide for
hypertension. the corticomedullary junction), interstitial fibrosis, and ultimately
Reproduced with permission from Gibson TJ (2013), Hypertension, its treatment, renal failure. These cases are associated with mutations in the gene
hyperuricaemia and gout. Curr Opin Rheumatol, 25, 217–​22. Copyright © 2013 directing the synthesis of the glycoprotein uromodulin, also known
Lippincott Williams.
as Tamm–​Horsfall protein, which occurs in the cells of the thick, as-
cending segment of Henle’s loop, and in renal collecting tubule cells.
Chronic tophaceous gout Uromodulin excretion is diminished. Heterozygous missense gene
Large deposits (tophi) containing monosodium urate monohydrate mutations or small insertion/​deletion events in the gene encoding
crystals produce firm nodules over affected joints on the extensor uromodulin have been demonstrated, and it is proposed that these
surfaces of the fingers (Box 12.4.3, Fig. 12.4.7), hands, olecranon produce changes in the tertiary structure with conformational
bursas (commonly bilateral), extensor surfaces of the forearm, changes in the protein due to reduction in the intramolecular disul-
Achilles tendon, the helix of the ear, and in the renal parenchyma. phide bonding, which alters the folding pattern of the protein and
Tophi may discharge white chalky material, containing sodium urate glycosylation. Uromodulin is an 85-​kDa glycoprotein which also has
monohydrate. They cause the bone erosions and joint destruction a role in preventing renal stone formation, the modulation of im-
with secondary degenerative arthritis that is seen on radiographs. mune responses, and urothelial cytoprotection.
Tophus formation can be regarded as an attempted, but disordered, Management
healing process in response to the presence of sodium urate monohy-
drate crystals in tissues. Acute attack
Full doses of any of the nonsteroidal anti-​ inflammatory drugs
Saturnine gout (NSAIDs) are effective in terminating attacks of acute gout.
The link between alcohol consumption, lead poisoning, and gout Indomethacin is particularly favoured by some clinicians.
should be considered in socioeconomic backgrounds where the il- Colchicine remains a very effective remedy. The American College
licit brewing of alcohol is commonplace. Lead solder and piping in of Rheumatology guidelines recommendation is that acute gout can
the equipment used for the illicit brewing and distillation of alcohol be treated with a loading dose of 1.2 mg of colchicine followed by
may be a source of lead contamination in the beverages produced. 0.6 mg 1 h later. This regimen can then be followed by prophylaxis
Lead toxicity and saturnine gout may also derive from occupational dosing of 0.6 mg once or twice daily 12 h later, until the gout at-
exposure, lead-​based paints (particularly in childhood), ceramic tack resolves. For countries where 0.5 mg tablets only are available,
glazes, additives to petrol, drinking water systems, and even nat- the advice is 1.0 mg colchicine as the loading dose, followed by 0.5
ural remedies. The association between lead and hyperuricaemia mg 1 h later, and then followed, as needed, after 12 h, by continued
remains poorly understood but is most likely to be a consequence of colchicine (up to 0.5 mg three times daily) until the acute attack re-
chronic kidney disease. solves. Lower total doses (1.5–​1.8 mg) have comparable efficacy to
In addition to the symptoms of gouty arthritis, symptoms of higher doses in acute gout but appear to be without the unwanted
lead poisoning are usually present. The condition occurs equally in gastrointestinal toxicity. High doses of colchicine can cause gastro-
both males and females, and often at a relatively young age of 40 to intestinal haemorrhage and favour the development of other severe
60 years, even younger in those where there has been excessive child- side effects, including profuse diarrhoea, rashes, renal and hep-
hood exposure to lead. These symptoms and signs include protein- atic damage, and (more rarely) peripheral neuropathy, myopathy,
uria and chronic kidney disease, as well as anaemia characterized by and alopecia in the long term. Intravenous colchicine is no longer
red cell basophilic stippling due to the inhibition of pyrimidine-​5ʹ-​ recommended.
nucleotidase. Burton’s lines, a bluish line on the gums, may be present. An attack of acute gout can be effectively terminated by the
Lead excretion in urine is elevated, and serum lead levels are ele- adrenocorticotropin analogue, tetracosactrin, by a single intra-
vated in cases with current lead exposure. Treatment includes limi- venous dose of hydrocortisone, with a short course of oral prednis-
tation of continued lead exposure, lead chelation therapies such as olone (typically 30 mg daily), or (for some joints) by steroid injection
EDTA, dimercaprol, and succimer, as well as xanthine oxidase in- into the affected joint. Rebound attacks of acute gout tend to occur
hibitors to lower blood urate levels. unless the situation is covered by either colchicine or an NSAID.
2022 SECTION 12 Metabolic disorders

Pharmacological doses of colchicine disrupt the microtubular Box 12.4.4 Hyperuricaemia detected on routine
function in inflammatory cells. This mode of action gives it the po- biochemical screening
tential to do more widespread damage. Short intensive courses of
• Search for an identifiable cause (e.g. dietary factors, myeloproliferative
colchicine should not be repeated at less than 3-​day intervals, al- disease, medications)
though lower doses (0.5–​2 mg/​day) can be used for longer periods, • Check renal function
as in the treatment of familial Mediterranean fever. • Imaging to detect the presence of uric acid urinary calculi
Rasburicase (dosage 20 mg/​kg per day, treatment for more than • Measure uric acid excretion after eliminating dietary and medication
5 days is not recommended) is a recombinant urate oxidase derived factors
from Saccharomyces cerevisiae. It catalyses the oxidation of urate to • Treat if:
allantoin which is five times more soluble than uric acid at urinary —​ more than one attack of acute gouty arthritis per year
pH values and is the purine metabolite excreted by nonprimate spe- —​ chronic joint damage attributed to gout
cies. Acute hypersensitivity reactions have been reported in 5% of —​ tophi
patients who do not have a history of allergy. It should not be used —​ hyperuricaemic nephropathy
—​ uric acid urolithiasis.
in pregnancy or in glucose-​6-​phosphate dehydrogenase deficiency.
It can be used to terminate an attack of acute gouty arthritis, but this
seems unnecessary with the availability of well-​established methods.
occasionally as much as 700 to 900 mg/​day given in divided doses.
However, it may have a place in the treatment of acute uric acid neph-
Between 10 and 20 mg/​kg body weight per day is an appropriate
ropathy in tumour lysis syndrome and in patients who are allergic
dosage for children.
to allopurinol and the other drugs used to treat hyperuricaemia
The incidence of adverse reactions to allopurinol is low but they
and gout. More recently, pegloticase a polyethylene glycol conju-
can be severe and occasionally fatal. Reactions include erythema
gate of a recombinant porcine uricase which is less immunogenic
multiforme progressing to Stevens–​Johnson syndrome and toxic
than rasburicase and therefore more suited for longer-​term therapy,
epidermal necrolysis (associated with the HLA B*5801 allele), ex-
has benefited patients with a severe gout disease burden and re-
foliative dermatitis, vasculitis, interstitial nephritis, eosinophilia,
fractoriness to oral urate-​lowering therapies, but has not been ap-
hepatocellular damage, polyneuropathy, bone marrow suppres-
proved for this purpose by the National Institute for Health and
sion, disturbances of vision and taste, as well as gastroenteropathy.
Care Excellence in the United Kingdom. The agent appears to have
Allopurinol potentiates the effect of coumarin anticoagulants (e.g.
powerful hypouricaemic effects with debulking of tophi in severely
warfarin), azathioprine, and 6-​mercaptopurine, and predisposes to
affected patients resistant to other therapies. Infusion reactions are
an ampicillin or amoxicillin rash. At high dosage and in the presence
frequent, although frank anaphylaxis appears to be uncommon.
of greatly increased purine synthesis, it may cause radiotranslucent
Rapid breakdown of plasma urate by uricase has been associated
xanthine and oxypurinol urinary stones. There is also an increased
with a high frequency of acute exacerbations of gout in the early
risk of toxicity with captopril (especially in the presence of renal
weeks after its introduction. Moreover, since all putative treatments
failure) and with ciclosporin.
of hyperuricaemia based on the action of uricases have the potential
Much of the overall toxicity of allopurinol is due to the metabolite
to generate abundant hydrogen peroxide and other oxidants, their
oxypurinol, which has a much longer half-​life in vivo than the parent
introduction for long-​term use carries with it an appreciable risk of
compound. Special care is necessary in the presence of advanced
tissue injury (see contraindication for use of rasburicase, in ‘Acute
chronic kidney disease and a dose of 100 to 150 mg is usually suffi-
uric acid nephropathy’). Although pegylated and other preparations
cient in this circumstance. Patients with hyperuricaemia due to renal
of uricases from various sources demonstrate clear efficacy in vivo
failure rarely develop gout, possibly due to their immunoparesis.
and remain attractive for therapeutic research, at the time of writing,
this approach does not yet have an established place for the treat- Treatment when allopurinol produces adverse reactions The
ment of severe chronic gout. specific xanthine oxidase inhibitor, febuxostat, has been ap-
proved by the European Commission, the National Institute for
Interval treatment Health and Care Excellence in the UK and by the Food and Drug
Asymptomatic hyperuricaemia should not be treated with urate-​ Administration in the United States of America, for the treatment
lowering drugs unless the patient experiences more than one acute of chronic gout in which it rapidly decreases serum urate concen-
attack of gout per year (Box 12.4.4). Allopurinol, a xanthine oxi- trations. Febuxostat is appropriate for patients hypersensitive to or
dase inhibitor, is effective in preventing acute gout by reducing the intolerant of allopurinol, those in whom allopurinol has failed to
serum urate concentration to a value below the solubility of sodium control symptomatic hyperuricaemia, and in patients with chronic
urate monohydrate in plasma so that tophaceous deposits are mo- kidney disease where uricosuric therapy is contraindicated. As with
bilized and healing occurs. This applies to the tophi in bones as well allopurinol, suitable prophylaxis against exacerbation of acute gout
as elsewhere. The drug should be introduced at a low level (e.g. 100–​ is indicated (e.g. with colchicine) when treatment with febuxostat
200 mg daily) and increased under cover of either colchicine or an is started.
NSAID, which should be continued until the serum urate concen- The drug is approved in European countries at 80 and 120 mg
tration has stabilized at a normal level. Allopurinol is then continued daily. In the United States of America, the label is for a daily dose of
indefinitely. 40 mg, increasing to 80 mg after at least 2 weeks if the serum urate
Initiating allopurinol without cover may cause attacks of acute concentration remains elevated. Febuxostat at a dose of 40 mg/​day
gout as the serum urate concentration falls. Moderately severe is associated with a higher likelihood of achieving a target serum
gout may require as much as 300 to 600 mg allopurinol daily and uric acid level of 6 mg/​dl (0.36 mmol/​L) than allopurinol given at
 12.4 Disorders of purine and pyrimidine metabolism 2023

the commonly used doses of 300 mg/​day. Nevertheless, a meta-​ Rasburicase has been licensed for use as a single-​course therapy
analysis dating from 2013 concluded that there was no evidence for hyperuricaemia in the acute paediatric and adult tumour lysis
that febuxostat is superior to allopurinol for clinically relevant out- syndrome. The enzyme has a plasma half-​life of 18 to 24 h and is
comes. Given the higher cost of febuxostat, the evidence suggests markedly antigenic, therefore having little application as an off-​
that febuxostat should not be routinely used as a first-​line treat- label agent in severe tophaceous gout and certainly not sustainable
ment for chronic gout. Since it is an inhibitor of xanthine oxidase, for more than a few months. On account of its capacity to induce
febuxostat, like allopurinol, has the potential for highly toxic drug oxidant injury and thus haemolysis in susceptible individuals,
interactions with azathioprine, 6-​mercaptopurine, and theophylline rasburicase is contraindicated in patients with glucose-​6-​phosphate
and its derivatives. dehydrogenase deficiency.
Patients for whom the treatment of hyperuricaemia and gout
is essential and in whom therapy with xanthine oxidase inhibi- Ethanol-​induced hyperuricaemia
tors have been ineffective present a special problem, especially if Ethanol is oxidized to acetaldehyde by the liver. This raises the
they have impaired overall renal function. The uricosuric drugs ratio of reduced nicotinamide adenine dinucleotide to nicotina-
sulphinpyrazone, probenecid, and benzbromarone, together with mide adenine dinucleotide, which in turn promotes the reduc-
a sufficiently high fluid intake to provide a measured urine output tion of pyruvate to lactate in the hepatocytes. Lactate competes
of at least 3 litres/​24 h and alkalization of the urine with sodium with urate in the renal tubular excretory mechanisms and thereby
or potassium bicarbonate or sodium or potassium citrate, are an promotes urate retention. There is often an element of starva-
approach to this problem, but may be inappropriate in the overall tion ketoacidosis in chronic alcoholics, with acetoacetate and
clinical context, for example, in patients with cardiac or renal β-​hydroxybutyrate also competing for the renal tubular excretory
failure. Only sulphinpyrazone is readily available in the United mechanisms which subserve urate tubular secretion. In addition,
Kingdom. Uricosuric drugs may be inefficient in the presence of there is increased urate production associated with ethanol intake,
renal failure and are contraindicated in the presence of uric acid first due to the high purine content of some alcoholic beverages
urinary stones. (e.g. beer) and second because the metabolism of alcohol involves
The uricosuric agent benzbromarone is sometimes effective in pa- increased dephosphorylation and degradation of adenine nucleo-
tients with renal failure when other uricosuric agents have lost their tides in the liver.
efficacy. The use of oxypurinol (at low dosage) has also been pro-
posed. Protocols are also available for the desensitization of patients Uric acid urolithiasis
who have experienced adverse reactions to allopurinol and in whom Pure uric acid stones account for 5% of all urinary stones in patients
the risk of uric acid stone formation, with the potential for further in the United Kingdom, but there is a much higher incidence else-
reduction of renal function, presents a problem. where (e.g. in the Middle East). In Israel, about 40% of urinary cal-
culi are composed of uric acid and 75% of patients with primary
Other hyperuricaemic conditions
gout develop renal calculus disease. Overall, uric acid urolithiasis
Acute uric acid nephropathy occurs in about 10% of patients with gout, more often in secondary
This complicates the treatment of widespread malignant disease, gout than in primary gout, and sometimes associated with an im-
particularly chemotherapy and/​or radiotherapy of leukaemias and paired ability to alkalinize the urine. Ileostomy predisposes to uric
lymphomas. The nephropathy is of multifactorial origin and may acid urolithiasis because of (1) chronic bicarbonate loss, which leads
form part of the acute tumour lysis syndrome with accompanying to a persistent acidification of the urine, and (2) a concentrated urine
tubular necrosis. These patients are usually underhydrated, acid- due to excessive water loss. Urinary uric acid concentrations close to
otic, and have high rates of uric acid production from nucleoprotein or more than those at which spontaneous crystallization begins are
degradation in the apoptotic tumours. Acute uric acid nephropathy frequent in these circumstances.
has occasionally been reported after extremely severe muscular ex- The genetic causes of uric acid urolithiasis are rare: (1) HPRT
ercise, after severe epileptic seizures, and in patients with gout due to deficiency, (2) PRPP superactivity, and (3) inherited renal
grossly increased rates of de novo purine synthesis. hyporuricaemia (congenital failure of the renal tubular reabsorp-
The renal lesion is the intratubular precipitation of uric acid crys- tion of urate).
tals. In addition, the renal pelvis and ureters may also be blocked The urinary uric acid concentration is the main determinant of
by crystal aggregates and/​or uric acid stones. Acute uric acid neph- uric acid stone formation. The concentration depends on the state of
ropathy can be avoided by giving allopurinol for several days be- hydration, the rate of de novo purine synthesis, the rate of metabolic
fore starting the chemotherapy or radiotherapy. The condition turnover of purine compounds, the dietary intake of purines and
presents as acute oliguric renal failure. Imaging techniques should alcohol, and the action of uricosuric drugs (e.g. sulphinpyrazone).
be used to exclude the presence of bilateral ureteric obstruction by Calcium oxalate stone formation is increased 30-​fold in patients
radiotranslucent uric acid stones. Treatment is by: with gout, and hyperuricosuria is common in nongouty stone-​
formers. Uric acid microcrystals may act as epitaxial nucleation sites
• induction of an alkaline diuresis for calcium oxalate crystallization. It is also possible that colloidal
• haemodialysis, peritoneal dialysis, or haemofiltration uric acid adsorbs urinary glycosaminoglycan inhibitors of crystal-
• percutaneous nephrostomy and/​or ureteric catheterization may lization and crystal growth.
be needed if there is an element of postrenal obstruction due to Uric acid stone disease is treated by hydration to maintain a urine
impacted aggregates of sodium urate crystals or uric acid stones volume of at least 3 litres/​24 h, alkalization of the urine, and allopur-
• disruption or removal of impacted stones. inol if there is hyperuricosuria. The use of sodium and potassium
2024 SECTION 12 Metabolic disorders

salts for alkalization has to be carefully reviewed in the light of con- of function mutations in URAT1 (SLC22A12) and type 2 due to
current diseases, particularly impaired renal and cardiac function. mutations in GLUT9 (SLC2A9). Inheritance is autosomal reces-
The standard imaging techniques (particularly ultrasonography) are sive. Hyperuricosuria is a feature and may amount to 1000 mg
required for the diagnosis of these radiotranslucent stones. Stones (5.9 mmol) per 24 h in homozygous patients, with a lesser degree
can be fragmented or removed by standard procedures. of hyperuricosuria in heterozygotes. Uric acid urolithiasis occurs
For further discussion of urinary stones, see Chapter 21.14. in about 25% of the homozygotes, most commonly in patients with
combined hyperuricosuria and hypercalciuria.
Hereditary renal hypouricaemia and uric acid stones Treatment with allopurinol has, counter-intuitively, been used to
The causes of hypouricaemia are summarized in Box 12.4.5. prevent the recurrence of renal stones in patients who have experi-
Renal hypouricaemia may be due to renal tubular damage by gen- enced acute renal injury after exercise. The rationale is to decrease
etic diseases or by toxic damage (Box 12.4.5), and this may be as- the generation of uric acid thereby decreasing the filtered uric acid
sociated with other features of Fanconi’s syndrome. Reduced net load and lowering the risk of precipitation in the renal tubules.
tubular reabsorption of urate occurs as an isolated renal tubular Reduced tubular urate reabsorption can occur in other inherited
reabsorption defect due to loss of function mutations in the genes or acquired renal tubule transport defects (Box 12.4.5).
directing the synthesis of the urate carriers. Type 1 is due to loss
Hypoxanthine-​guanine phosphoribosyltransferase
deficiency: Lesch–​Nyhan syndrome and its variants
Box 12.4.5 Causes of hypouricaemia Lesch–​ Nyhan syndrome results from mutations in the gene
Inherited disorders of uric acid biosynthesis
encoding HPRT, an enzyme which catalyses the salvage of hypo-
xanthine and guanine to inosine monophosphate (IMP) and guano-
• Genetic defects in the molybdoflavoprotein enzymes:
—​ Xanthinuria type I (isolated xanthine oxidase deficiency) sine monophosphate (GMP), respectively, as shown in Fig. 12.4.1.
—​ Xanthinuria type II (combined xanthine oxidase and aldehyde oxi- In affected male hemizygotes, the lack of HPRT results in increased
dase deficiencies) levels of PRPP due to failure to salvage hypoxanthine or guanine.
—​ Molybdenum cofactor deficiency (xanthine oxidase, aldehyde oxi- Elevated PRPP levels then act as a driver of de novo purine syn-
dase, and sulphite oxidase deficiency) thesis, resulting in purine overproduction. The clinical spectrum
• Purine nucleoside phosphorylase deficiency extends from hyperuricaemia alone to hyperuricaemia with pro-
Secondary reduction in uric acid biosynthesis found neurological and behavioural dysfunction. The biochemistry
• Allopurinol and oxypurinol medication and molecular genetics of this disorder have been studied exten-
• Hepatic failure sively. Functional assays of HPRT on cultured fibroblasts or intact
• Acute intermittent porphyria red cells, rather than erythrocyte lysates, give a better correlation
Inherited renal hypouricaemia (isolated renal tubule reabsorption between the degree of residual enzyme activity and clinical pheno-
defect) types. Mutation analysis is a valuable tool for genetic counselling,
• Loss of function mutations in urate transporters URAT1 (SLC22A12) the identification of carriers, and prenatal diagnosis.
and GLUT9 (SLC2A9)
• Inherited causes of Fanconi’s syndrome and its variants (the syndrome Pathophysiology
of multiple renal tubule reabsorption defects) Both the de novo purine synthesis and the HPRT-​catalysed purine
Acquired causes of Fanconi’s syndrome and its variants salvage pathways are present in all parts of the normal brain. HPRT
• Metal poisoning (Cd, Zn, Cu, Pb, Hg, Ur) activity is absent or defective but the de novo synthesis pathway
• Multiple myelomatosis remains active in patients with the Lesch–​Nyhan syndrome. The
• Nephrotic syndrome present view is that the neurological manifestations are brought
• Malignant disease (paraneoplastic syndrome) about by a neurotransmitter imbalance, probably mainly in the
• Autoimmune disease (i.e. Sjögren’s syndrome) basal ganglia. This imbalance is possibly due to a deficient supply
• Thermal burns of metabolic energy resulting from the nonsalvage of hypoxan-
• Primary hyperparathyroidism thine and guanine causing a deficiency of adenine nucleotides
• Acute renal tubular necrosis
that provide energy for short bursts of neurotransmitter syn-
• Renal transplant rejection
thesis. However, the positron emission tomography evidence of
Drugs dopamine receptor deficiency is the main concrete evidence for
• Drugs used either as uricosuric agents or to block other aspects of renal a neurotransmitter defect, either directly or indirectly because of
tubule excretion (sulphinpyrazone, probenecid, benzbromarone) guanosine triphosphate deficiency underlying the Lesch–​Nyhan
• NSAIDs with uricosuric properties
syndrome. There is increased excretion of the serotonin metabolite
• Phenylbutazone
5-​hydroxyindoleacetic acid and decreased levels of homovanillic
• Azapropazone
• Aspirin dosage greater than 4 g/​day
acid, a major metabolite of dopamine, in the cerebrospinal fluid.
• Coumarin anticoagulants (e.g. warfarin) Deficiency of basal ganglia dopamine systems emerging during the
• Outdated tetracycline (5α-​6-​anhydro-​4-​epitetracycline) first 2 months of life has been demonstrated in a mouse model of
Lesch–​Nyhan syndrome.
Nutritional deficiencies
Failure of pubertal development and testicular atrophy in HPRT
• Vitamins B12, C, and D
deficiency are attributed to an inadequate supply of purine nucleo-
• Kwashiorkor
tides to meet the increased metabolic energy requirement in the
 12.4 Disorders of purine and pyrimidine metabolism 2025

40
Box 12.4.6 Clinical manifestations of the Lesch–​Nyhan
syndrome (complete or virtually complete absence of HPRT
deficiency) 30
• X-​linked recessive inheritance

Weight (kg)
• Failure of overall growth
20
• Muscle hypotonia
• Delayed motor development
• Torsion dystonia 10
• Aggressive behaviour
• Dysarthria
• Variable degree of intellectual deterioration in later childhood 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
• Megaloblastic anaemia (in some cases only) Age (years)
• Hyperuricaemia and hyperuricaciduria with gout and tophus develop-
ment after puberty and urolithiasis occasionally during the first decade Fig. 12.4.8 Patterns of growth in the weight of 13 boys with the Lesch–​
of life Nyhan syndrome: each patient is shown by a different symbol. The 50th
• Failure of pubertal development and testicular atrophy at the age and 3rd centiles are shown.
when puberty would be expected to occur With kind permission from Springer Science+Business Media: J Inherit Metab Dis,
Lesch-​Nyhan syndrome: Growth delay, testicular atrophy and a partial failure of the
11β-​hydroxylation of steroids, 10, 3, 1987, 210–​223, R. W. E. Watts. Copyright ©
1987, SSIEM and MTP Press Limited.
testis at this time. A similar inability to meet energy requirements
may underlie the neurological manifestations. A partial defect in point accurately, leading to great frustration. The self-​injurious be-
adrenocortical 11β-​hydroxylation of steroids is demonstrable in haviour and dyskinesia are eliminated or much reduced when the
patients with the Lesch–​Nyhan syndrome after ACTH stimulation child is concentrating on a self-​selected activity, such as watching
and is thought to be linked with a failure to modulate mitochon- an interesting television programme. Self-​injury and dyskinesia are
drial function for this hydroxylation due to a deficiency of purine exacerbated by excitement, such as the arrival of a visitor, fear, frus-
nucleotides. tration, and unsuccessful attempts at volitional motor activity. The
children also appear to be aware of the value of this behaviour as an
Clinical features
attention-​seeking manoeuvre, and sometimes appear to use it in a
The clinical features of the most severely affected patients who are manipulative manner.
correctly referred to as having classic Lesch–​Nyhan syndrome or as Although learning difficulties have been stressed as a feature of
having ‘complete or virtually complete HPRT deficiency’ are sum- the Lesch–​Nyhan syndrome, they are of inconstant severity and are
marized in Box 12.4.6. In some cases, the enzyme has altered kin- neither marked nor specific. The apparent degree of intellectual dis-
etics or is unstable but has 1 to 5% residual activity. Patients with ability may be affected by the extensive disorder of expressive motor
partial enzyme defects of 0 to 5% HPRT activity in red cell lysates functions that exceeds the comprehension defect, by the lack of
but more than 8% activity in the fibroblast assays have gout and renal basic social and educational opportunities, and by the lack of intel-
complications but no neurological manifestations. The disease fre- ligence tests for older children who have lacked these opportunities.
quency is about 1 in 380 000 births. However, for whatever combination of reasons, there does appear to
Infants affected by HPRT deficiency have a lower than average be a decline of intellect from the age of 8 to 10 years.
birth weight, indicating some degree of intrauterine growth retard- Self-​injurious behaviour usually begins at about 2 years of age.
ation. The first clinical sign may be the presence of red grit (uric acid Its severity and the ingenuity with which the patients exploit new
crystals with absorbed urinary pigments) on the nappy. Affected in- ways of self-​injury exceed that encountered in any other clinical
fants are hypotonic from birth, although this is frequently not re- situation. It is not a constant feature and some patients never show
marked on before poor head control becomes apparent at the age of it; in most its severity waxes and wanes. Self-​injury can produce very
about 3 months. severe damage, such as complete destruction of the lower lip or trau-
Postnatal growth, which becomes more marked after the second matic amputation of a fingertip. The patients feel pain normally and
year of life, is also subnormal (Fig. 12.4.8) as indicated by sequential are aware of their compulsion; they are afraid of it but are unable
measurement of body weight, accurate assessment of body length to control it. Nyhan and his colleagues consider it to be the clinical
being impossible due to the dystonic posturing. The overall pattern hallmark of complete HPRT deficiency, as opposed to those patients
of weight growth follows centile lines for the first 2 years of life and with some residual enzyme activity (which may or may not be meas-
thereafter slows to about 1 kg/​year, or about half normal; a pubertal urable in erythrocyte lysates).
growth spurt is not observed. Head growth and bone development The severe dystonic spasms with violent extension of the neck
are less affected than weight. The poor weight gain cannot be attrib- can produce damage to the cervical spinal cord and produce motor
uted to either renal failure or malnutrition. pyramidal tract signs in the legs. The phenotypes associated with
Torsion dystonia, with its two components of abnormal pos- appreciable residual HPRT activity vary from the neurological def-
turing and episodic rigidity, is superimposed on the basic hypotonia icit described for the complete Lesch–​Nyhan syndrome but without
that is present between the dystonic episodes. Severe dysarthria self-​mutilation (Lesch–​Nyhan variant), to patients with only X-​
is associated with dyskinesia of the face, mouth, pharynx, and the linked gout and/​or urolithiasis and only very subtle, if any, neuro-
larynx, which greatly limits communication and even the ability to logical features.
2026 SECTION 12 Metabolic disorders

Investigation Patients with the Lesch–​ Nyhan syndrome are insensitive to

There are no structural or ultrastructural changes in the brain as punishing stimuli and do not learn when such stimuli are used to
judged by light and electron microscopy or on electroencephalog- reinforce the desired behaviour, which in this case is to refrain from
raphy. Reductions in the size of the caudate nucleus, the putamen, self-​injury, and their ability to learn from rewarding stimuli is also
and total cerebral volume have now been demonstrated by refined impaired. Psychotherapeutic techniques that are effective in elim-
MRI. Dopamine transporter reduction and hence dopamine defi- inating self-​injurious behaviour in other situations fail in patients
ciency has been demonstrated by positron emission tomography. with the Lesch–​Nyhan syndrome. They could be modified by a pro-
Imaging studies have supported the concept that HPRT defi- gramme of positive reinforcement of abstaining from self-​injury
ciency constrains brain development with particular emphasis on and ‘time out’, but this has proved difficult to achieve in the long
the basal ganglia, and defective function of dopaminergic neurons term. The reinforcement strategy was found to be unsuitable for use
is specifically involved. A more recent study of adult patients with at home because it involved apparently ignoring the self-​injury and
classic Lesch–​Nyhan syndrome showed larger reductions of white only paying attention to the child in the absence of self-​injurious
(26%) than grey (17%) matter volume relative to healthy controls. behaviour, which was misinterpreted by friends and relations as un-
These reductions were less marked in patients classified as Lesch–​ kindness or indifference.
Nyhan variant with reductions of white (14%) and grey (15%) Managing self-​injurious behaviour therefore requires teaching
matter volume. Both patient groups demonstrated reduced volume good communication skills, relaxation techniques, consistent hand-
in medial inferior white matter regions. Compared with the variant ling from all those involved in care, as well as physical restraints and
group, classic Lesch–​Nyhan syndrome patients showed larger re- specially designed equipment. Dental extraction, physical restraints
ductions in inferior frontal white matter adjoining limbic and tem- with splints and bandages, and strapping the patient into a specially
poral regions and the motor cortex. These regions likely include designed padded wheelchair fitted with a firm padded head support
such long association fibres as the superior longitudinal and un- to prevent cervical spine injury during violent opisthotonic spasms,
cinate fasciculus. are usually needed to limit the effects of compulsive self-​mutilation.
Patients with Lesch–​Nyhan syndrome whose hyperuricaemia has Children whose restraints have been temporarily released ask or
been controlled and who have not had renal damage, often live be- indicate their wish for the bandages, straps, etc. to be replaced so
yond their third decade, but may succumb to sudden death, usually that they are less able to damage themselves. Every effort should be
due to respiratory problems. made to exploit the intellect of these patients and to keep them in a
stimulating environment.
Management
Clinical genetic aspects
Control of hyperuricaemia
The Lesch–​Nyhan syndrome and its variants are inherited in a
Allopurinol should be administered to reduce the plasma urate
sex-​linked recessive manner. Clinical manifestations in the female
and urine uric acid concentration in order to prevent gouty arth-
carriers are rare, but subtle alterations in purine metabolism, with
ritis, urate nephropathy, and renal calculi. As HPRT deficiency
small increases in the rates of de novo purine synthesis and in-
leads to increased de novo purine synthesis and purine overpro-
creased uric acid excretion and occasionally mild asymptomatic
duction, allopurinol may lead to dramatically increased concentra-
hyperuricaemia, have been reported. There are extremely rare re-
tions of xanthine in urine and consequent xanthine nephropathy.
ports of female Lesch–​Nyhan cases which have been attributed to
Allopurinol treatment should be titrated against plasma uric acid
nonrandom inactivation of the X chromosome. Genomic analysis
as well as urinary uric acid and xanthine concentrations. The pa-
is preferred for the identification of carrier females. The demonstra-
tient should also be kept well hydrated to minimize the risk of
tion of mosaicism by HPRT+ and HPRT− hair roots due to random
xanthine stone formation. Allopurinol treatment from birth does
inactivation of the X chromosome is error prone and is not widely
not prevent the behavioural phenotype. All therapeutic attempts
available. Similarly, autoradiographic techniques to demonstrate
at neuropharmacological manipulation have been unsuccessful.
two cell populations (HPRT+ and HPRT−) in fibroblast cultures are
There are however anecdotal reports that intrathecal baclofen
rarely used.
ameliorated the motor symptoms and also improved behaviours.
Prenatal diagnosis is possible using chorionic villus samples
Oral S-​adenosylmethionine at doses of 20 to 25 mg/​kg per day has
obtained during the ninth week of pregnancy; this permits elective
been reported to dramatic reduce self-​injurious and aggressive be-
termination of an affected fetus before the end of the first trimester
haviour, as well as a milder reduction of dystonia in five Malaysian
of pregnancy. In vitro fertilization with enzymatic assay or geno-
patients.
typing on a cell removed at the four-​cell stage to ensure that only
Behavioural manifestations unaffected embryos are implanted is possible.
Following on from the discussion of pathophysiology, some aspects Other disorders of purine metabolism
of the Lesch–​Nyhan phenotype may be related to dysfunction of the
small central, but widely projecting, aminergic pathways involved in PRPP synthetase superactivity and PRPP synthetase deficiency
learning. It has been suggested that the self-​injurious behaviour in The enzyme PRPP synthetase (PRPS) catalyses the production of
the Lesch–​Nyhan syndrome is due to an imbalance between the ac- PRPP, which is required for the first specific and rate-​limiting re-
tivities of catecholaminergic neurons and 5-​hydroxytryptaminergic action in the de novo pathway of purine synthesis, is encoded by
neurons, the former being largely concerned with learning by re- the PRPS1 gene. It is subject to feedback inhibition by purine nu-
ward and the latter with learning by punishment. cleotides. Mutations associated with diminished sensitivity to this
 12.4 Disorders of purine and pyrimidine metabolism 2027

feedback inhibition, lead to increased PRPP production, which in many racial groups, the type II subtype has so far only been identi-
turn acts as a driver for increased de novo purine synthesis, leading fied in the Japanese population.
to hyperuricaemia, hyperuricosuria, and gout. The condition is in- This condition often presents in early life because of the extremely
herited in an X-​linked recessive fashion. low solubility of 2,8-​dihydroxyadenine in renal tubule fluid and
Affected males develop uric acid lithiasis or gouty arthritis in urine. Severe obstructive uropathy and renal failure may occur in
childhood or early adult life. Hyperuricaemia is often severe and infancy.
in the range 0.5 to 1 mmol/​litre, with uric acid excretion of 5 to Treatment is by hydration and xanthine oxidase inhibition with
15 mmol/​24 h. Heterozygous females are usually asymptomatic, al- allopurinol, and with standard measures to disrupt or remove the
though some degree of increased purine synthesis de novo and occa- stones and to manage urinary infections and renal failure.
sionally gout, may occur with nonrandom X-​inactivation.
In some families, the disorder presents in childhood with associ- Xanthinuria
ated neurological features such as motor retardation and learning Xanthine stones occur in patients with xanthinuria due to deficiency
difficulties, ataxia, deafness, hypotonia, disturbed speech, and of xanthine oxidase/​reductase deficiency and occasionally, in those
the development of polyneuropathy, intracerebral calcifications, who are being treated with the xanthine oxidase inhibitor, allopur-
and dysmorphic facial features. Carrier females may have mild inol. The latter is particularly likely in patients with accelerated de
hyperuricaemia and some degree of hearing impairment. The con- novo purine synthesis, as in patients with the Lesch–​Nyhan syn-
stellation of associated disorders varies in different families. drome. Xanthinuria is inherited in an autosomal recessive manner,
Carriers can be identified by mutation analysis and by studies in and hypoxanthine and xanthine accumulate behind the metabolic
cultured skin fibroblasts. Amniocentesis, prenatal diagnosis, and block. The plasma urate concentration and urine uric acid excretion
preventive termination of pregnancy are not justified in this condi- are typically less than 0.06 mmol/​litre (1.0 mg/​dl) and 0.30 mmol/​
tion, unless one of the unusually severe phenotypes is known to be 24 h (50 mg/​24 h), respectively, when the patient is taking an un-
segregating in the family. The hyperuricaemia, primary purine over- restricted diet. It is a rare, perhaps under-​recognized condition.
production, and uricosuria can be well controlled with allopurinol. Concentrations of urine oxypurines (hypoxanthine plus xanthine)
Mutations in PRPS1 can also lead to PRPP synthetase defi- are characteristically elevated. Normal subjects have plasma levels
ciency of varying degree and a broad spectrum of phenotypes between 0.00 and 0.15 mmol/​litre (0.00–​0.25 mg/​dl) and urine levels
including syndromic and nonsyndromic hearing loss comprising of 0.07 to 0.13 mmol/​24 h (11–​22 mg/​24 h); patients with xanthinuria
Charcot–​Marie–​Tooth, X-​linked recessive disease type 5 (CMTX5), typically have plasma levels between 0.03 and 0.05 mmol/​litre (0.00–​
nonsyndromic sensorineural deafness (DFN2), and Arts’ syndrome. 0.90 mg/​dl) and urine levels of 0.60 and 3.5 mmol/​24 h (100–​600
Hearing loss in affected males is bilateral and ranges from moderate mg/​24 h). Xanthine accounts for 60 to 90% of the total xanthine plus
to profound. Arts’ syndrome is characterized by profound sensori- hypoxanthine excreted, presumably reflecting the more active meta-
neural hearing impairment, early-​onset hypotonia, delayed motor bolic turnover of hypoxanthine and its efficient salvage by hypo-
development, mild to moderate mental retardation, ataxia, and optic xanthine phosphoribosyltransferase. Hypoxanthine and xanthine
atrophy. Oral supplementation with S-​adenosylmethionine (30 mg/​ are mainly derived from adenine and guanine nucleotides, respect-
kg per day) has provided significant clinical benefit to two brothers ively (Fig. 12.4.1). Hypoxanthine has a relatively high solubility and
diagnosed with Arts’ syndrome. This suggests that other patients causes no problems.
with PRPS synthetase deficiency, including mildly affected carrier At any age, about one-​third of cases present with radiotranslucent
females, may benefit from S-​adenosylmethionine supplementation. xanthine stones. These stones are usually smooth, soft, and yellow-​
Uric acid concentrations in patients with PRPS deficiency may be brown. Xanthinuric myopathy is a rare complication.
low or normal and levels cannot be used as a diagnostic marker. Type 1 xanthinuria is due to an isolated defect in xanthine oxi-
dase/​reductase, while type 2 xanthinuria is due to a defect in mo-
Adenine phosphoribosyltransferase deficiency and lybdenum sulphurase which catalyses the terminal step in the
2,8-​dihydroxyadeninuria synthesis of the molybdopterin cofactor necessary for the activity
These patients lack adenine phosphoribosyltransferase activity; of both aldehyde oxidase and xanthine oxidase. These patients
adenine accumulates behind the metabolic block and is oxi- present with xanthine stones and are detected by their inability to
dized by xanthine oxidase to the very insoluble compounds 2-​ convert allopurinol to oxypurinol, a reaction normally catalysed
hydroxyadenine and 2,8-​ dihydroxyadenine. These compounds by aldehyde oxidase. Xanthine stones also occur when there is a
are excreted in the urine along with adenine itself, where it forms combined deficiency of the three molybdoflavoprotein enzymes,
radiotranslucent stones that are white or pale fawn in colour. These xanthine oxidase, sulphite oxidase, and aldehyde oxidase, because
rough and friable calculi have, in the past, been widely misdiagnosed of defective molybdopterin cofactor synthesis. The clinical picture
as uric acid stones because 2,8-​dihydroxyadenine reacts as if it were in these patients is overshadowed by the sulphite oxidase defi-
uric acid in colorimetric assays. The use of enzymatic uric acid as- ciency that produces severe brain damage and dislocation of the
says has obviated this confusion. ocular lenses.
Adenine phosphoribosyltransferase deficiency has an autosomal
recessive pattern of inheritance and is clinically silent in hetero- Adenylosuccinase deficiency and ATIC deficiency
zygotes. There are two subtypes (I and II). Type I patients have no Adenylosuccinase (adenylate succinate lyase (ADSL)) catalyses the
detectable enzyme activity, being homozygotes or compound het- eighth step on the 10-​step de novo purine synthesis pathway and the
erozygotes for null alleles. Type II patients have between 5 and 25% second step in one of the purine nucleotide interconversion path-
residual enzyme activity. Whereas type I patients are encountered in ways, the formation of ATP from inosine monophosphate.
2028 SECTION 12 Metabolic disorders

The patients present in infancy with severe psychomotor dis- Myoglobinuria following strenuous exercise has been reported
abilities, autism, and axial hypotonia with normal tendon reflexes. in a few cases and hence the risk of rhabdomyolysis has led some
Self-​mutilation has been recorded in some cases and cerebellar authors to recommend the avoidance of vigorous exercise. Such ad-
hypoplasia is present on CT scans. vice is only appropriate if exertion-​related myoglobinuria has oc-
The presence of succinyl adenosine and succinyl aminoimidazole curred or been suspected. Oral ribose (2–​60 g/​day, or taking a dose
carboxamide riboside in plasma, cerebrospinal fluid, and urine before vigorous exercise) has been reported to produce symptomatic
confirms the diagnosis. There is gross purine overproduction improvement.
with high levels of purine ribosides in urine. Urine and plasma
uric acid levels are normal. Partial enzyme deficiencies have been Inborn errors of purine metabolism and immunodeficiency
demonstrated in liver, kidney, muscle, lymphocytes, and fibro- Adenosine deaminase and purine nucleoside phosphorylase catalyse
blasts, with mutations identified in more than 70 patients. Clinical sequential steps in the metabolism of purine ribonucleosides and
severity is variable and correlates with the ratio of succinyl ad- deoxyribonucleosides. These enzymes are highly expressed in the
enosine to succinyl aminoimidazole carboxamide riboside in the lymphoid cells and their deficiency, which causes the lymphotoxic
cerebrospinal fluid. substrates 2′-​deoxyadenosine or 2′-​deoxyguanosine to accumulate,
The bifunctional enzyme 5-​aminoimidazole-​4-​carboxamide leads to lymphopenia and immunodeficiency.
ribonucleotide formyltransferase/​IMP cyclohydrolase (ATIC) cata- Most patients with adenosine deaminase deficiency lack both
lyses the last two reactions of de novo purine synthesis. A deficiency cell-​mediated (T-​cell) and humoral-​mediated (B-​cell) immunity
of ATIC leads to the accumulation of the dephosphorylated sub- resulting in severe combined immunodeficiency disease. Although
strate of ATIC, aminoimidazol carboxamide riboside, as well as the purine nucleoside phosphorylase deficiency causes defective T-​
accumulation of succinylaminoimidazole carboxamide riboside and cell-​mediated immunity, these patients may possess either normal,
succinyladenosine in body fluids. hyperactive, or reduced humoral immunity. Most patients with these
Both deficiencies are inherited as autosomal recessive conditions. enzyme deficiencies present in infancy or early childhood, with se-
For ADSL deficiency, the growth retardation has been improved vere infections caused by pathogens or opportunistic organisms.
by adenine (10 mg/​kg) and allopurinol. The latter promotes purine
conservation by blocking hypoxanthine oxidation to xanthine and Adenosine deaminase deficiency
uric acid, and prevents the oxidation of administered adenine to About 85% of patients with adenosine deaminase deficiency present
2,8-​dihydroxyadenine. There is currently no effective treatment as infants with severe combined immunodeficiency disease. Among
for either enzyme deficiency. Oral S-​adenosylmethionine has been all severe combined immunodeficiency disease patients, adenosine
suggested as a purine replacement therapy in ADSL deficiency, but deaminase deficiency accounts for 10 to 15% of cases. Although ad-
showed no clinical benefit in a patient treated for 9 months. enosine deaminase deficiency classically presents in infancy (early
onset), a minority of patients have a clinically less severe variant with
Myoadenylate deaminase deficiency delayed onset presenting with severe combined deficiency between
Myoadenylate deaminase is the muscle-​specific isoenzyme of ad- the ages of 1 and 10 years. Very rarely, patients may presents in the
enylate deaminase which catalyses the deamination of adenosine second to fourth decade. The prevalence of adenosine deaminase
monophosphate nucleotide (AMP) to inosine monophosphate deficiency has been estimated at between less than 1 in 106 and 1 in
(IMP) during muscle contraction. This reaction is necessary for 2 × 105 live births.
normal muscle function. Myoadenylate deaminase deficiency may Adenosine deaminase deficiency is inherited in an auto-
be congenital, due to a mutation in the gene directing the syn- somal recessive fashion. The diagnosis is made by meas-
thesis of the protein, or associated with a wide range of muscle uring adenosine deaminase activity in erythrocytes and the
diseases including the muscular dystrophies, polymyositis, and presence of deoxyadenosine nucleotides in red cell nucleotide pro-
dermatomyositis. files. Heterozygote detection and prenatal diagnosis are best done by
Patients with congenital myoadenylate deaminase deficiency pre- genetic characterization.
sent at any age including early childhood with a syndrome of muscle In addition to immunoparesis, clinical feature include growth
weakness and muscle cramps during and after exertion. There is some failure, absent tonsils and lymph nodes, and absence of a thymus
decrease in muscle mass, some hypotonia, and a little muscle weak- shadow on radiography. Characteristic skeletal abnormalities in-
ness. There may be a modest rise in plasma creatine phosphokinase clude anterior rib cupping, scapular spurring, and are present at
levels and nonspecific electromyographic changes. The lack of am- diagnosis in about half of individuals. Sensorineural deafness and
monia and IMP occurs normally in the venous outflow from the af- other neurological symptoms have been reported, but may be sec-
fected muscles during exercise, and the enzyme deficiency can be ondary to infections, autoimmunity, or transplantation.
demonstrated histochemically. The pattern of inheritance is auto- The prognosis in untreated severe adenosine deaminase defi-
somal recessive, not all of the homozygotes have clinical symptoms, ciency is very poor with death due to multiple recurrent infections
and the heterozygous carriers are clinically silent. The nonsense during the first year of life.
variant c.34C>T, (p.Q34X) in exon 2 is polymorphic in Caucasian Adenosine and 2′-​deoxyadenosine, derived from the breakdown of
populations. Exon 2 is alternatively spliced and transcripts lacking DNA due to cell death, accumulate proximal to the metabolic block;
the c.34C>T, (p.Q34X) variant encode a functionally active protein. 2′-​deoxyadenosine is the primary lymphotoxic precursor in adeno-
The acquired disorder may be due to the coincidental disease arising sine deaminase deficiency and elevated levels are present in urine.
in a patient whose inherited myoadenylate deaminase deficiency Erythrocytes contain markedly raised levels of deoxyadenosine
would otherwise be silent. triphosphate and reduced activity of S-​adenosylhomocysteine
 12.4 Disorders of purine and pyrimidine metabolism 2029

hydrolase due to inactivation by 2′-​deoxyadenosine. Erythrocyte as well as guanosine and inosine. Paradoxically there is massive
ATP is reduced. The level of deoxyadenosine triphosphate in purine overproduction and excretion. Plasma uric acid may be low,
erythrocytes correlates with clinical expression and with the level of but not in all patients.
residual adenosine deaminase activity. Erythrocyte concentrations of deoxyguanosine triphosphate
There are several mechanisms by which adenosine deaminase are markedly raised in purine nucleoside phosphorylase-​deficient
deficiency can impair immune function. Accumulation of cells. T cells but not B cells appear to be particularly susceptible
deoxyadenosine triphosphate can induce apoptosis in lymphoid to 2′-​deoxyguanosine toxicity, probably as a result of accumula­
cells. This may be related to deoxyadenosine triphosphate-​induced tion of deoxyguanosine triphosphate, inhibition of ribonucleotide
inhibition of ribonucleotide reductase blocking DNA replication reductase, impairment of DNA synthesis, and eventually cell
in dividing cells and to deoxyadenosine triphosphate-​ induced death.
DNA strand breaks in nondividing lymphocytes. Deoxyadenosine There are few reports of successful bone marrow or stem trans-
triphosphate also activates the protease (caspase 9) involved plantation in purine nucleoside phosphorylase-​deficient patients,
in apoptosis. S-​ adenosylhomocysteine hydrolase blocks S-​ possibly reflecting an avoidance of high-​risk procedures in children
adenosylmethionine-​mediated transmethylation reactions. The for- with a later-​onset presentation than seen in adenosine deaminase
mation of deoxyadenosine triphosphate from 2′-​deoxyadenosine deficiency. There is, however, increasing evidence that early inter-
activates inosine monophosphate dephosphorylation thereby vention may be beneficial and may also prevent further neurological
leading to depletion of cellular ATP. It has also been suggested that deterioration.
lymphocyte function may be impaired by aberrant signal trans-
duction mediated by deoxyadenosine acting through G-​protein-​ Other conditions
associated receptors or from an altered costimulatory function of Adenosine kinase deficiency has been reported in patients from
T-​cell-​associated adenosine deaminase complexing protein CD26/​ three families presenting with severe developmental delay and liver
dipeptidyl peptidase IV. dysfunction. Biochemical finding suggested a block in the methio-
Treatment is based on enzyme replacement. Enzyme replace- nine cycle, with plasma methionine, S-​adenosylmethionine, and
ment therapy with pegylated bovine adenosine deaminase provides S-​adenosylhomocysteine all elevated.
a source of the enzyme to remove the toxic metabolites in the short A defect in deoxyguanosine kinase is associated with mitochon-
term until the patient can be transplanted. Allogeneic haemato- drial DNA depletion with a predominantly hepatocerebral pheno-
poietic stem cell transplant is done if a fully HLA-​matched sibling type. Liver transplantation may be beneficial in patients in whom
or family donor is available. Transplants from unrelated or haplo-​ neurological disease is absent or mild.
identical donors have been less successful. Haematopoietic stem Mutations in inosine monophosphate dehydrogenase type
cell gene therapy to insert a functional adenosine deaminase copy 1 (IMPDH1), which together with IMPDH2 catalyse the first
into the genetic material of the patient has recently become available step in the conversion of inosine monophosphate to guanosine
and has shown curative potential. Measurement of deoxyadenosine monophosphate, are associated with autosomal dominant retinitis
­triphosphate levels in red cells is useful for monitoring therapy. pigmentosa (RP10 form).
Inactivating mutations in the gene NT5C2 encoding cyto-
Purine nucleoside phosphorylase deficiency solic purine 5’-​nucleotidase (cytosolic nucleotidase II), AMPD2
Purine nucleoside phosphorylase deficiency occurs less frequently encoding adenosine monophosphate deaminase-​2, and ENTPD1
than adenosine deaminase deficiency. In addition to the clinical (ectonucleoside triphosphate diphosphohydrolase 1) are associ-
results of immunoparesis, more than 50% of these patients have ated with hereditary spastic paraplegias, neurodegenerative motor
neurological abnormalities including disorders of muscle tone, de- neuron diseases characterized by progressive age-​dependent loss of
layed motor and intellectual development, ataxias, tremors, spastic corticospinal motor tract function.
tetraparesis, and behavioural difficulties. Autoimmune haemolytic
anaemia and megaloblastic bone marrow changes have been occa-
sional associations. Disorders of pyrimidine metabolism
There appears to be a particular susceptibility to virus infection
such as varicella, vaccinia, and cytomegalovirus. The tonsils and The pathways of pyrimidine biosynthesis interconversion and deg-
the thymus are small or absent and the lymph nodes are deficient radation are shown in Fig. 12.4.9. The de novo synthesis of pyr-
in the thymus-​dependent areas. Circulating lymphocyte counts are imidine nucleotides involves a series of six reactions beginning
usually very low with a low percentage of T lymphocytes and de- with the formation of carbamyl phosphate and concluding with
pressed or absent responsiveness to mitogen-​induced transform- orotidine monophosphate, which then undergoes a series of inter-
ation. Serum immunoglobulin levels and antibody responses to conversion and salvage reactions. The first three steps in the de novo
pneumococcal polysaccharide and keyhole limpet haemocyanin synthesis pathway are encoded in a gene directing the synthesis of
are typically increased in these children with purine nucleoside the multifunctional protein that encompasses carbamyl phosphate
phosphorylase deficiency, and the occasional finding of mono- synthetase, aspartate transaminase, and dihydro-​orotase. The fourth
clonal IgM paraprotein strongly suggests that B-​cell hyperactivity step is catalysed by dihydro-​orotate dehydrogenase which is encoded
and changes in antibody production are secondary to T-​ cell in a single gene. The fifth and sixth steps are catalysed by the gene
dysregulation. directing the synthesis of the bifunctional protein encoding orotate
Purine nucleoside phosphorylase deficiency is associated with the phosphoribosyltransferase and orotidine 5′-​monophosphate de-
accumulation and excretion of 2′-​deoxyguanosine and deoxyinosine carboxylase, which reside in separate regions of the protein uridine
2030 SECTION 12 Metabolic disorders

radiotranslucent orotic acid urinary stones. Cardiac malformations,

mild intellectual impairment, and strabismus have been reported.
Orotic aciduria is inherited as an autosomal recessive defect. Patients
heterozygous for a UMPS mutation may have mildly elevated orotic
acid in urine and this may explain some cases of benign hereditary
orotic aciduria found on screening.
Enzyme assays on erythrocyte lysates may show low levels of
orotate phosphoribosyltransferase or orotidine 5′-​monophosphate
decarboxylase activity, or both, depending on the location and nature
of the underlying genetic defect. Administration of uridine (100–​
150 mg/​kg per day), which is converted to uridine monophosphate
(Fig. 12.4.9), produces a prompt haematological response in those
patients with a megaloblastic anaemia. Treatment needs to be started
as soon as the diagnosis is made during infancy in order to minimize
the possibility of persistent neurological deficits.
Orotic aciduria has been found in urea cycle defects, lysinuric
protein intolerance, purine nucleoside phosphorylase deficiency,
normal pregnancy, and during allopurinol administration.

Pyrimidine 5′-​nucleotidase deficiency (uridine 5’-​

monophosphate hydrolase)
Fig. 12.4.9 Pathways of pyrimidine metabolism in humans. 5′-​NT,
pyrimidine 5′-​nucleotidase; CPSH, carbamyl phosphate synthetase This autosomal recessive disorder leads to a life-​long nonspherocytic
II; DHPD, dihydropyrimidine dehydrogenase; NP, pyrimidine mild to moderate chronic haemolytic anaemia. Uridine tri-
nucleoside phosphorylase; ODC, orotidine decarboxylase (OPRT phosphate and cytidine triphosphate accumulate in the red cells
+ ODC form uridine monophosphate synthase); OPRT, orotate which show basophilic stippling and reticulocytosis. There is
phosphoribosyltransferase; TK, thymidine kinase; UK, uridine kinase; hepatosplenomegaly. The enzyme is assayed in erythrocytes
UPRT, uracil phosphoribosyltransferase.
and activities between 0 and 30% of normal have been reported.
Developmental delay and learning difficulties have been reported
monophosphate synthetase (UMPS). The pyrimidines are degraded in some patients. Treatment is supportive. Transfusions are rarely
to β-​alanine and β-​aminoisobutyrate. required and splenectomy is not indicated. Lead poisoning can also
The inherited disorders of pyrimidine metabolism are much less be associated with acquired erythrocyte pyrimidine 5′-​nucleotidase
common and/​or possibly much less easily recognized than disorders deficiency.
of purine metabolism.
Deficiency of dihydropyrimidine dehydrogenase
Dihydro-​orotate dehydrogenase deficiency This autosomal recessive disorder presents with a variable pheno-
(Miller’s syndrome) type ranging from microcephaly, hypertonia, epilepsy, learning dif-
Dihydro-​orotate dehydrogenase is located on the inner membrane ficulties, and autism, to mild behavioural abnormalities, even within
of mitochondria and catalyses the conversion of dihydro-​orotate the same family. Some cases have only been diagnosed during adult
to orotate, the fourth step in the de novo synthesis of pyrimidines. life when they have developed life-​threatening or fatal toxicity
A deficiency of dihydro-​orotate dehydrogenase causes Miller’s syn- ­following cancer chemotherapy with 5-​fluorouracil. Uracil and thy-
drome or postaxial acrofacial dysostosis syndrome which is charac- mine are elevated in the urine of completely deficient patients, but
terized by micrognathia, orofacial clefts, malar hypoplasia, aplasia not in carriers. Absent enzyme activities have been demonstrated
of the medial lower lid eyelashes, coloboma of the lower eyelid, and in leucocytes, liver, and fibroblasts. There is no effective treatment
cup-​shaped ears, combined with postaxial limb deformities. Miller’s for this condition and the prognosis for life is very variable. Partial
syndrome was the first Mendelian disorder whose genetic basis was dihydropyrimidine dehydrogenase deficiency due to a heterozygous
identified by whole-​exome sequencing. Dihydro-​orotate levels are variant genotype occurs in approximately 6% of Caucasian popu-
not reported to be elevated in urine. lations, is asymptomatic but is associated with severe toxicity to
fluoropyrimidine-​based chemotherapy.
Hereditary orotic aciduria
Orotic aciduria is due to point mutations in the gene UMPS directing Deficiency of dihydropyrimidinase
the synthesis of the bifunctional protein UMP synthase which cata- Dihydropyrimidinase catalyses the second step of the pyrimi-
lyses the last two steps on the pyrimidine biosynthetic pathway. dine degradation pathway. Patients present with neurological and
There is massive overproduction of orotic acid due to loss of feed- gastrointestinal abnormalities and markedly elevated levels of 5,6-​
back inhibition of carbamyl phosphate synthase, which is the first dihydrouracil and 5,6-​dihydrothymine in body fluids. There is con-
and rate-​limiting step on the metabolic pathway. siderable phenotypic variation, even within families. Patients with
Orotic aciduria presents during infancy with severe megaloblastic dihydropyrimidinase deficiency are also at risk of severe toxicity to
hypochromatic anaemia, orotic acid crystalluria, and occasionally, fluoropyrimidine chemotherapy.
 12.4 Disorders of purine and pyrimidine metabolism 2031

ß-​Ureidopropionase deficiency
Fam AG (2001). Difficult gout and new approaches for control of
Ureidopropionase catalyses the conversion of N-​carbamyl-​ß-​ hyperuricaemia in the allopurinol-​allergic patient. Curr Rheumatol
alanine and N-​carbamyl-​ß-​aminoisobutyric acid to ß-​alanine Rep, 3, 29–​35.
and ß-​aminoisobutyric acid, ammonia, and CO2. Patients pre- Ferraro PM, et al. (2015). A London experience 1995-​2012: demo-
sent mainly with neurological abnormalities (intellectual dis- graphic, dietary and biochemical characteristics of a large adult co-
abilities, seizures, abnormal tonus regulation, microcephaly). hort of patients with renal stone disease. QJM, 108, 561–​8.
N-​carbamyl-​ß-​alanine and N-​carbamyl-​ß-​aminoisobutyric acid Frampton JE (2015). Febuxostat: a review of its use in the treatment of
are markedly elevated in urine and blood. As with the other de- hyperuricaemia in patients with gout. Drugs, 75, 427–​38.
Harkness, et al. (1988). Lesch-​Nyhan syndrome and its pathogen-
fects of pyrimidine degradation, phenotypic variability of ß-​
esis: purine concentrations in plasma and urine with metabolite
ureidopropionase deficiency was demonstrated in one family in
profiles in CSF. J Inherit Metab Dis, 11, 239–​52.
which the index patient was clinically affected whereas the same
Hart TC, et al. (2002). Mutations of the UMOD gene are respon-
genotype did not lead to overt symptoms in the mother of the sible for medullary cystic kidney disease 2 and familial juvenile
patient. hyperuricaemic nephropathy. J Med Genet, 39, 882–​92.
Johnson RJ, et al. (2013). Uric acid and chronic kidney disease: which
Thymidine phosphorylase deficiency
is chasing which? Nephrol Dial Transplant, 28, 2221–​8.
Thymidine phosphorylase catalyses the conversion of thy- Khanna D, et al. (2012). 2012 American College of Rheumatology guide-
midine and deoxyuridine to thymine and uracil respectively. lines for management of gout. Part 1: systematic nonpharmacologic
A deficiency of the enzyme results in the accumulation of both and pharmacologic therapeutic approaches to hyperuricemia.
thymidine and deoxyuridine in blood and urine and results Arthritis Care Res (Hoboken), 64, 1431–​46.
in the mitochondrial depletion syndrome mitochondrial Khanna D, et al. (2012). 2012 American College of Rheumatology
neurogastrointestinal encephalomyopathy (MNGIE). The intra- guidelines for management of gout. Part 2: therapy and antiinflam-
cellular accumulation of these nucleosides leads to imbalances matory prophylaxis of acute gouty arthritis. Arthritis Care Res
(Hoboken), 64, 1447–​61.
of mitochondrial deoxynucleotide pools impairing mitochon-
Merriman TR (2015). An update on the genetic architecture of
drial DNA replication and leading to depletion of mitochondrial
hyperuricemia and gout. Arthritis Res Ther, 17, 98.
DNA. MNGIE is a multisystemic autosomal recessive disorder Mount DB (2013). The kidney in hyperuricemia and gout. Curr Opin
with onset typically before the age of 30 years, with most pa- Nephrol Hypertens, 22, 216–​23.
tients presenting as children, some within 5 months of birth. Rampoldi L, et al. (2003). Allelism of MCKD, FJHN, and GCKD
Symptoms include ptosis, progressive external ophthalmoplegia, caused by impairment of uromodulin export dynamics. Hum Mol
gastrointestinal dysmotility, cachexia, peripheral neuropathy, and Genet, 12, 3369–​84.
leukoencephalopathy. Rannou F, et al. (2015). Diagnostic algorithm for glycogenoses and
Allogeneic haematopoietic stem cell transplantation is reported myoadenylate deaminase deficiency based on exercise testing
to restore enzyme function and improve clinical manifestations in parameters: a prospective study. PLoS One, 10, e0132972.
the long term. Scriver CA, et al. (eds) (2001). The metabolic and molecular basis of
inherited disease, 8th edition. McGraw–​Hill, New York.
Thymidine kinase 2 deficiency Sperling O (2006). Hereditary renal hypouricaemia. Mol Genet Metab,
Mutations in TK2 encoding thymidine kinase 2, which catalyses 89, 14–​18.
Torres RJ, Puig JG (2007). Hypoxanthine-​ guanine phosopho­
the phosphorylation of deoxypyrimidine nucleosides in the mito-
ribosyltransferase (HPRT) deficiency: Lesch-​ Nyhan syndrome.
chondrial matrix, are mainly associated with the myopathic form
Orphanet J Rare Dis, 2, 48.
of mitochondrial depletion syndromes. The phenotypic spectrum van Kuilenburg AB, et al. (2010). Dihydropyrimidinase defi-
ranges from infantile myopathy with motor regression and early ciency: phenotype, genotype and structural consequences in 17 pa-
death to milder forms of myopathy with prolonged survival, my- tients. Biochim Biophys Acta, 1802, 639–​48.
opathy with liver involvement, or chronic progressive external oph- Van Kullenburg AB, et al. (2004). Beta-​ureidopropionase deficiency:
thalmoplegia in adults. an inborn error of pyrimidine degradation associated with neuro-
logical abnormalities. Hum Mol Genet, 13, 2793–​801.
Watts RWE, et al. (1987). Lesch-​Nyhan syndrome; growth delay, tes-
ticular atrophy and a partial failure of 11β-​hydroxylation of steroids.
FURTHER READING J Inherit Metab Dis, 10, 210–​23.
Cameron JS, Simmonds HA (2005). Hereditary hyperuricaemia and Woodward OM (2015). ABCG2: the molecular mechanisms of urate
renal disease. Semin Nephrol, 25, 9–​18. secretion and gout. Am J Physiol Renal Physiol, 309, 485–​8.
Dalvi SR, Pillinger MH (2013). Saturnine gout, redux: a review. Am J Zanella A, et al. (2006). Hereditary pyrimidine 5′-​nucleotidase defi-
Med, 126, 450.e1–​8. ciency from genetics to clinical manifestations. Br J Haematol, 133,
de Brouwer AP, et al. (2010). PRPS1 mutations: four distinct syn- 113–​23.
dromes and potential treatment. J Hum Genet, 86, 506–​18. Zhang W, et al. (2006). EULAR evidence based recommendations
Eckardt KU, et al. (2015). Autosomal dominant tubulointerstitial for gout. Part II: Management Report of a task force of the EULAR
kidney disease: diagnosis, classification, and management—​ a Standing Committee for International Clinical Studies Including
KDIGO consensus report. Kidney Int, 88, 676–​83. Therapeutics (ESCISIT). Ann Rheum Dis, 65, 1312–​24.
12.5
The porphyrias
Timothy M. Cox

ESSENTIALS haem shorten life-​threatening episodes and may be effective prophy-

laxis for recurrent porphyria in women with periodic attacks. Genetic
The porphyrias are a remarkable family of metabolic disorders char- counselling informed by molecular analysis of cognate genes, and
acterized biochemically by overproduction of haem precursors, lifetime management advice should be offered to first-​degree rela-
principally in the liver and bone marrow. The acute porphyrias are tives of patients in whom acute porphyria has been diagnosed.
inborn errors of varying penetrance that affect enzymatic steps in a Beyond comprehensive genetic characterization of the acute
tightly regulated biosynthetic pathway for haem; nonacute acquired porphyrias, promising developments in molecular therapy are
forms also occur in genetically predisposed individuals. coming to fruition, including RNA interference-​mediated silencing
Haem formation for erythropoiesis, while adaptable to physio- of the rate-​limiting biosynthetic enzyme, hepatic aminolaevulinate
logical and pathological changes, is generally constant, but hepatic synthase 1.
synthesis of haem undergoes extreme and rapid oscillations to meet
dynamic changes in various pathophysiological states, and this in- Nonacute porphyrias
fluences the clinical expression of porphyria, which is often latent. The nonacute porphyrias are photosensitivity syndromes caused by
excess photoactive macrocyclic porphyrins triggered especially by
Acute porphyrias
visible light in the blue–​violet range (380–​420 nm). In the most severe
Clinical presentation—​ life-​
threatening neurovisceral attacks occur form, manifestations are of severe blistering lesions on sun-​exposed
in four of the porphyrias: acute intermittent porphyria, varie- skin, particularly of the hands and face, with the formation of vesicles
gate porphyria, hereditary coproporphyria, and Doss’ porphyria and bullae that may become infected. Healing may lead to loss of
(5-​aminolaevulinate dehydratase deficiency). These present with ab- digits, scarring of the eyelids, nose, lips, and scalp, and occasionally
dominal pain, psychiatric symptoms, and signs of sympathetic and blindness due to corneal scarring.
hypothalamic autonomic overactivity, sometimes accompanied Protoporphyria, either autosomal due to impaired incorporation of
by convulsions and motor and sensory deficits. They typically de- iron or X-​linked due to overexpression of erythroid aminolaevulinate
velop on exposure to environmental or endogenous factors that synthase, causes burning pain and erythema with oedema; blistering
place a demand for hepatic haem biosynthesis, the most frequent is absent. Diagnosis is based on finding excess formed porphyrins in
being changes in reproductive steroid hormones either due to nat- blood and excreta. Sunlight exposure should be minimized until the
ural hormone cycles or the administration of exogenous gonadal porphyrin abnormality is corrected, for example, by phlebotomy to
steroids, starvation, intercurrent infection, alcohol, and drugs. Acute deplete iron excess that usually aggravates porphyria cutanea tarda,
porphyrias may also be associated with overproduction of photo- or by liver or haematopoietic stem cell transplantation in some (very
active metabolites and thus long-​term photosensitivity, which is ag- rare) cases. The approved synthetic analogue of α-​melanocyte-​
gravated during acute attacks. stimulating hormone, afamelanotide, increases skin pigmentation by
Diagnosis—​this is key to survival of an acute attack of porphyria, increasing melanin production and significantly improves sunlight
which can be suspected on the basis of the past history, in par- tolerance and quality of life in patients with at least one cutaneous
ticular of photosensitivity or the intermittent discoloration of urine, form of (nonacute) porphyria, namely protoporphyria.
and family history, and is confirmed by finding excess water-​soluble
haem precursors in urine. Enzymatic studies can later be used to
verify the exact type of suspected porphyria, with molecular analysis
of genes encoding relevant haem synthetic enzymes used to identify Introduction
at-​risk individuals in affected pedigrees.
Management—​treatment of an acute porphyric attack mandates The haem biosynthetic pathway holds great fascination for biochem-
immediate withdrawal of inappropriate drugs and other precipitating ists, who marvel at the evolution of ancient enzymes which interact
factors; infusions of haem arginate or other licensed preparations of to bring about the formation of the pigments of life, haemoglobin,
the cytochromes, chlorophyll, and the cobalamins (vitamin B12). It is
 12.5 The porphyrias 2033

unfortunate that, because of complexities in their chemical structure

and nomenclature, the important diseases associated with their dis-
turbed haem metabolism are perceived as obscure. These consider-
ations apply particularly to the acute porphyrias, which are rare but
distressing syndromes that mimic other acute illnesses but for which
recognition may be critical for the patient’s survival; too often their
inherited nature is overlooked and the diagnosis is not established
until permanent disability (or even death) supervenes.
The porphyrias are rare diseases caused by disturbances in the
multistep pathway for the formation of haem, a pigment essential for
oxygen transfer and the energy-​yielding reactions of electron trans-
port. The formation of haem is tightly regulated so that acquired or
hereditary defects of any of its component reactions lead to the over-
production of haem precursors. Potentially photoactive macrocyclic
compounds and toxic precursors of pyrroles thus accumulate.
Most of the human porphyria syndromes result from uncommon
genetically determined deficiencies of unitary enzymes of the haem Fig. 12.5.1 Main pathways for haem biosynthesis and degradation in
biosynthetic pathway, but certain toxins including lead, iron, and humans.
hydrocarbons influence the pathway and cause porphyria in sus-
ceptible individuals. Similarly, the metabolism of endogenous monoxide. Many tissues use this one-​way destructive route to dis-
molecules, including steroid hormones, and xenobiotics including pose of haem, formation of which in health is balanced by fastidious
alcohol and many therapeutic drugs, disturb the delicate biochem- control of de novo biosynthesis. The routes for the formation and deg-
ical equilibrium in asymptomatic patients with latent porphyria. radation of haem are distinct (Fig. 12.5.1). Unlike the biosynthesis
Catastrophic gene–​environment interactions in previously fit indi- of other essential building blocks (e.g. cholesterol and other sterols,
viduals may precipitate sporadic attacks of acute porphyria. purines and pyrimidines, sphingolipids, and glycosphingolipids),
once formed there is no means to recycle haem or recover its com-
plex macromolecular precursors through salvage reactions.
Haem metabolism
Functions and formation of haem
General perspective Haem serves as a key prosthetic group in haem proteins, including
In healthy adults, daily formation of haem requires the incorpor- cytochromes, myoglobin, and haemoglobin, by which it fulfils its
ation of about 25 mg of iron into protoporphyrin IX to generate ap- essential biological roles as a transporter of oxygen and electrons
proximately 275 to 300 mg of haem de novo. About 15% of haem in the respiratory chain. It is also essential for transcription fac-
biosynthesis occurs in the liver and 80% in the erythroid marrow, tors that regulate circadian activities, binding reversibly to a nuclear
with the main bulk of haem being biochemically coordinated in receptor (Rev-​erbα) which is a crucial regulator of the core clock
haemoglobin and, to a lesser extent, as myoglobin in the muscles. functions in biological rhythms. Haem suppresses the action of
The remaining haem is mostly present in enzyme proteins, including Rev-​erbα on expression of proteins involved in maintenance of glu-
catalase, tryptophan pyrrolase, nitric oxide synthase, guanylate cose homeostasis and gluconeogenesis. A molecular understanding
cyclase, prostaglandin synthase, nucleotide phosphodiesterases, of these recently discovered interactions holds much promise for
and cytochromes (in the endoplasmic reticulum cytochrome P450 elucidating how acute attacks of porphyria are induced by starva-
system as well as the mitochondrial electron transport chain). tion, sepsis, endogenous hormonal factors, and xenobiotics.
Hepatic synthesis of haem is subject to rapid and wide fluctu- Haem biosynthesis requires eight coordinated reactions that are
ations but haem formation in the erythropoietic bone marrow is, catalysed by cytoplasmic and mitochondrial enzymes which ex-
under most circumstances, constitutive and stable. However, haem change substrate intermediates between intracellular compartments
synthesis may be increased, either as the erythron expands and (Fig. 12.5.1).
proliferates to meet the demands of blood loss or haemolysis, or in
response to intrinsic disease of the bone marrow—​or conditions 5-​aminolaevulinate synthetase
where there is tissue hypoxia or inappropriate erythropoietic drive The first committed, essential, and rate-​ limiting precursor,
(see Chapters 22.6.2 and 22.6.4). 5-​
amino­ laevulinate, is generated by condensation of glycine
Very little free haem is present in the cytosol or plasma compart- and the Krebs cycle intermediate, succinyl coenzyme A. This re-
ment, in the latter of which it is avidly bound to the glycoprotein, action is brought about by one or other of the two isozymes of
haemopexin. Haem proteins undergo appreciable turnover and the 5-​aminolaevulinate synthetase (ALAS): the gene for the ‘hepatic’
haem component is rapidly degraded by distinct haem oxygenases enzyme, ALAS1, maps to the autosome chromosome 3 and is ubi-
in many tissues, especially those populated by macrophages. Haem quitously expressed; the gene for the distinct erythroid isoform,
oxygenases break open the porphyrin ring to liberate iron, thereby ALAS2, is found on the X chromosome and undergoes dosage
generating linear pyrroles that are metabolized further to biliverdin compensation in females by lyonization. These enzymes them-
and bilirubin pigments with the stoichiometric release of carbon selves are localized in the mitochondrial matrix. Expression of the
2034 section 12 Metabolic disorders

gene encoding ALAS1 is rate limiting for the formation of haem uro­porphyrinogen to yield coproporphyrinogen III, which is then
and is increased in response to a key regulator of mitochondrial reimported into the mitochondrion for further oxidative decarb-
biogenesis that stimulates activity of the Krebs cycle, the transcrip- oxylation. Coproporphyrinogen III oxidase modifies the two propi-
tion factor peroxisome proliferator-​activated receptor coactivator onate side chains to vinyl groups yielding protoporphyrinogen IX,
1α (PGC-​1α). To preclude the build-​up of toxic porphyrin inter- the penultimate precursor of haem. Protoporphyrinogen oxidase
mediates when the supply of iron is restricted, transcription of removes six hydrogen atoms to yield protoporphyrin IX, which is
aminolaevulinate synthase is regulated by the presence of iron-​ the substrate for the final step in haem biosynthesis. The insertion of
binding elements. ferrous ions into the porphyrin macrocycle to form ferroprotohaem
Terminal differentiation of erythroid cells depends upon tran- (haem) is catalysed by the mitochondrial enzyme ferrochelatase.
scriptional activation of ALAS2 by the erythroid factors, especially
GATA1, and activation of ALAS2 appears to be a prerequisite for in- Control of haem synthesis
duction of the other genes that encode the enzymes of haem biosyn- The highly regulated control mechanism of haem biosynthesis en-
thesis. ALAS2 mRNA harbours an iron-​response element that binds sures that the free concentrations of the toxic intermediates involved
iron-​regulatory proteins (IRP1 and -​2), thereby blocking translation in the pathway are kept low unless there is a metabolic arrest at one
of the ALAS2 mRNA; these iron-​sulphur binding proteins are de- of the biosynthetic reactions; under these circumstances, an over-
stabilized when iron is present and translation can proceed. These production of the intermediate compounds occurs which can be
elaborate molecular control processes serve to coordinate haem bio- used for diagnosis. This overproduction predisposes to the develop-
synthesis with iron availability in erythroid cells and in this way the ment of the particular clinical porphyric syndrome.
risk of toxic injury from the convergence of highly reactive biochem- A knowledge of the enzymatic steps and of the differential solu-
ical intermediates generated from different corners of the cellular bility of the haem precursors facilitates appropriate diagnostic testing
machinery can be minimized. for the precise identification of suspected porphyria. In general, over-
Pyridoxal 5-​phosphate (derived from vitamin B6) is an essential production of the early precursors such as 5-​aminolaevulinic acid is
cofactor for ALAS isozymes. Deficiency of pyridoxine or interfer- a common feature of those syndromes associated with neurovisceral
ence with its metabolism leads to sideroblastic anaemia. manifestations or acute attacks of porphyria. Aminolaevulinate, in par-
ticular, represents a common biochemical marker of such attacks and
5-​Aminolaevulinate dehydratase those syndromes that mimic the acute porphyrias, such as hereditary
After its formation, 5-​aminolaevulinate is exported to the cyto- tyrosinaemia type I and lead poisoning. In patients with cutaneous
plasm where the abundant cysteine-​rich (heavy metal-​sensitive) photosensitivity, overproduction of the formed porphyrin macro-
enzyme, 5-​aminolaevulinate dehydratase, catalyses the formation of cycles can also be detected in plasma, urine, and faeces in which they
hydroxymethylbilane (alternatively known as preuroporphyrinogen), are distributed according to their aqueous solubility (Table 12.5.1).
which spontaneously forms the monopyrrole porphobilinogen. The profile of molecules that are overproduced in a given syn-
5-​Aminolaevulinate dehydratase is a multimeric enzyme with re- drome may be predicted from the level at which the enzymatic ar-
active sulphydryl groups that are particularly sensitive to the toxic rest occurs as flux through the pathway is stimulated by diminished
effects of heavy metals, especially lead, so that activity of this enzyme negative feedback. In those porphyrias where the principal site of
is a sensitive measure of environmental and industrial toxicity. The production appears to be in the liver, including the acute porphyrias
enzyme is inhibited competitively by the metabolite succinylacetone, and porphyria cutanea tarda, fluctuations through the biosynthetic
concentrations of which rise to inhibitory levels in patients who pathway as a result of regulatory effects from environmental or en-
have the defect of aromatic amino acid degradation tyrosinaemia dogenous factors can occur very rapidly; indeed minute-​to-​minute
type I. Patients with tyrosinaemia type I and lead poisoning have oscillations in biosynthetic haem fluxes have been recorded in the
neurovisceral manifestations that resemble the acute porphyrias, liver. Thus, in starvation and on challenge with xenobiotic reagents
and it appears likely that overproduction of aminolaevulinate, as a (which place a demand for the production of haem to meet the needs
result of arrest at the 5-​aminolaevulinate dehydratase reaction, con- for new cytochrome formation), as well as with endogenous hor-
tributes to this effect. monal changes, enhanced flux through the pathway leads to toxic
overproduction of 5-​aminolaevulinic acid. By the same token, rapid
Porphobilinogen deaminase and uroporphyrinogen repression of the haem biosynthetic pathway in the liver can be in-
III synthetase duced by the administration of exogenous haem, a useful agent in
Four molecules of porphobilinogen are enzymatically condensed to the control of acute attacks and which rapidly corrects the disturbed
yield the macrocyclic tetrapyrrole uroporphyrinogen III in a com- metabolism (see next paragraph).
plex reaction brought about by porphobilinogen deaminase and
uroporphyrinogen III synthetase. These enzymes act coordinately Table 12.5.1 Solubility and routes of excretion of haem precursors
to reverse the orientation of one porphobilinogen molecule to yield
uroporphyrinogen III, an isoform member of the III series of por- Plasma Urine Faeces
phyrins that are the sole precursors of haem in biological systems. 5-​Aminolaevulinate ++ +++ −
Porphobilinogen ++ +++ −
Uroporphyrinogen III decarboxylase, coproporphyrinogen III
oxidase, protoporphyrinogen oxidase, and ferrochelatase Uroporphyrins I and III + ++ +
Coproporphyrins I and III + + +++
The cytoplasmic enzyme uroporphyrinogen III decarboxylase
decarboxylates the four acetate substituent side chains of Protoporphyrin IX + − +++
 12.5 The porphyrias 2035

Haem formation in the erythron is more rapid than that in the with genetic porphyrias from 11 European countries suggested an
liver but is not subject to sudden oscillations in synthetic rates. annual incidence for symptomatic acute porphyria of 0.2 per mil-
Nonetheless, in patients with erythropoietic porphyrias such as lion. The incidence of symptomatic acute intermittent porphyria
congenital porphyria, enhanced rates of red cell destruction when was similar in all countries (0.13 per million per year; 95% confi-
hypersplenism supervenes or in response to light exposure greatly dence interval 0.10–​0.14), excepting Sweden (0.51; 95% confidence
exacerbate the overproduction of porphyrin intermediates and interval 0.28–​0.86). Prevalence of overt acute intermittent porphyria
aggravate photosensitivity due to increased porphyrin release. was 5.4 cases per million. Higher figures have been reported in other
Short-​term experiments indicate that exogenous haem may par- studies: one in Norway gave the prevalence of acute intermittent
tially repress the endogenous haem biosynthetic pathway in eryth- porphyria to be approximately 4 in 100 000, with an overall annual
roid tissue, but this has not proved to be useful for long-​term relief incidence of 0.5 to 1 in 100 000, and the condition occurs in about
in the erythropoietic porphyrias. Blood transfusion to suppress 1 in 1000 of the Lapp population that is shared between Sweden,
erythropoiesis or definitive replacement of bone marrow by trans- Finland, and Norway.
plantation has, however, proved to be successful in controlling the Acute variegate porphyria is most common in the Afrikaner
devastating manifestations of congenital erythropoietic porphyria. population of South Africa: traced to a Dutch settler in the
17th century, it has a prevalence of about 3 in 1000 persons.
The condition has spread to all ethnic groups within the South
Classification and epidemiology of the porphyrias African population, molecular analysis of which confirms the
presence of a single dominant missense mutant allele of the
The porphyrias have been classified into hepatic and erythropoietic protoporphyrinogen IX oxidase gene (p.R59W). There are iso-
types depending on the main site of overproduction of haem pre- lated reports of high prevalence among the potters in the Bikaner
cursors. For clinical purposes, however, a useful operational defin- district of Rajasthan, India.
ition of the porphyric syndromes distinguishes the acute from the
nonacute porphyrias. Nonacute porphyrias
The most common condition in this category is porphyria cutanea
Classification
tarda, with an estimated prevalence of approximately 1 in 10 000 in
Acute porphyrias cause life-​threatening neurovisceral manifestations Norway. Protoporphyria, the second most frequent of the nonacute
which are typically precipitated by sporadic environmental factors. All porphyrias, in which systemic features with cholestatic liver disease
but one of these disorders is inherited as a dominant condition, but a are rare (5%), is estimated to have a frequency of 1 in 75 000 to 1 in
striking feature is their clinical heterogeneity with great variation in 200 000 births.
expressivity and penetrance—​the latter often termed ‘latency’. Tables 12.5.2 to 12.5.4 set out the individual defects that charac-
Nonacute porphyrias are characterized by photosensitivity syn- terize the clinical porphyrias and summarize the clinical features of
dromes due to overproduction of macrocyclic porphyrins which these hereditary syndromes.
cause light-​induced skin injury. Several of the acute porphyrias may
also cause overproduction of porphyrin intermediates that are either
intrinsically fluorescent or readily oxidized to become fluorescent.
These porphyrias may at times be accompanied by marked photo-
Table 12.5.2 The porphyria syndromes
sensitivity and blistering skin reactions, which are usually exacer-
bated during the acute attacks. Hereditary Acute porphyrias:
porphyria
Epidemiology • Acute intermittent porphyria
The frequency and epidemiology of the porphyrias are areas of con- • Variegate porphyriaa
tinued uncertainty: estimated prevalence of all porphyrias is from • Hereditary coproporphyriaa
1 in 300 to 1 in 200 000 in different populations. Difficulties arise • Doss’ porphyria—​aminolaevulinate dehydratase deficiency
because there are many types of porphyria and, being rare, often
Nonacute porphyrias:
episodic, and of low penetrance, they frequently escape formal
diagnosis. It is also regrettable that biochemical complexity and • Congenital erythropoietic porphyria—​Gunther’s disease
scientific nomenclature intimidates many practitioners. These con- • Protoporphyria
siderations also impede proper management, especially since costly • X-​linked protoporphyria
technological sophistication and specialist referral is often needed • Porphyria cutanea tardab—​sporadic or familial
for definitive diagnosis. Patients referred with skin manifestations • Hepatoerythropoietic porphyriac
to dermatologists are more readily identified, but the associated or
subsequent neurovisceral manifestations in underlying porphyrias
Acquired • Hexachlorobenzene porphyria
porphyria
such as variegate or coproporphyria are not always recognized in the • Lead poisoning (plumboporphyria)
nonacute clinical context. • Hereditary tyrosinaemia type 1
Acute porphyrias a
Acute syndromes also accompanied by long-​term skin photosensitivity.
b
Porphyria cutanea tarda is not a simple monogenic disorder; it is almost always provoked
There are regional variations in reported frequency of acute inter- by environmental agents such as hepatitis C, oestrogens, iron excess, or alcohol.
mittent porphyria. A prospective study of newly diagnosed patients c
Homozygous uroporphyrinogen III decarboxylase deficiency.
2036 section 12 Metabolic disorders

Table 12.5.3 Main biochemical abnormalities in the porphyrias

Disorder Enzyme defect Biochemical abnormality

Acute intermittent porphyria Porphobilinogen deaminase Increased urinary porphobilinogen and 5-​aminolaevulinate
Variegate porphyria Protoporphyrinogen IX oxidase Increased urine 5-​aminolaevulinate and porphobilinogen
(especially acute attacks)
Increased stool coproporphyrin III and protoporphyrin
Hereditary coproporphyria Coproporphyrinogen III oxidase Increased urine 5-​aminolaevulinate and porphobilinogen
(especially acute attacks)
Increased stool coproporphyrin III more than protoporphyrin
Doss’ porphyria Aminolaevulinate dehydratase Increased urinary 5-​aminolaevulinate
Faecal porphyrins normal
a
Porphyria cutanea tarda Uroporphyrinogen III decarboxylase Increased urine uroporphyrin I and III
Increased faecal hepatacarboxylic porphyrin and
isocoproporphyrin
Congenital erythropoietic Uroporphyrinogen III synthase Increased urine, plasma, and red cell uroporphyrin I and
porphyria coproporphyrin I
Normal 5-​aminolaevulinate and porphobilinogen
Increased faecal coproporphyrin I
Protoporphyria Ferrochelatase Increased protoporphyrin in stool and red cells (metal free)
Caseinolytic mitochondrial matrix peptidase chaperone Increased protoporphyrin in stool and red cells (metal free)
subunit (ClpXP)
X-​linked protoporphyria Aminolaevulinate synthase 2 Increased protoporphyrin in stool and red cells (heterozygous
females mosaic)
Hexachlorabenzene porphyria Uroporphyrinogen III decarboxylase Increased urinary uroporphyrin I and III and hepatocarboxylic
and other acetic acid substituents
Hereditary tyrosinaemia I Aminolaevulinate dehydrataseb (acquired deficiency) Increased urinary 5-​aminolaevulinate and succinylacetone
(toxic metabolite)
Lead poisoning Aminolaevulinate dehydratase, ferrochelatase ± impaired Increased urinary 5-​aminolaevulinate, raised red cell
iron delivery from transferrin protoporphyrin and zinc protoporphyrin
a
Homozygous deficiency also responsible for hepatoerythropoietic porphyria.
b
Inborn deficiency of fumarylacetoacetate hydrolase leads to excess formation of the 5-​aminolaevulinate hydratase inhibitor, succinyl acetone (4,6-​dioxoheptanoate).
Reference ranges: urine—​total porphyrins 20 to 320 nmol/​litre; 5-​aminolaevulinate <52 μmol/​litre (urine:creatinine porphobilinogen ratio <1.5); porphobilinogen <10.7 μmol/​litre.
Faeces—​total porphyrins 10 to 200 nmol/​g dry weight.
Red cell—​total porphyrins 0.4 to 1.7 μmol/​litre.
Laboratory ranges supplied by Porphyria Service, Department of Medical Biochemistry, University Hospital of Wales NHS Trust, Heath Park, Cardiff CF4 4XW (Professor G.H. Elder).

Table 12.5.4 Principal manifestations of the porphyrias

Acute intermittent porphyria Acute neurovisceral attacks

Variegate porphyria Acute neurovisceral attacks
Skin photosensitivity with fragility, scarring, hairiness, and pigment changes
Hereditary coproporphyria Acute neurovisceral attacks, blistering skin lesions, photosensitivity
Doss’ porphyria Acute neurovisceral attacks, susceptibility to lead exposure. (Only six confirmed cases reported)
Porphyria cutanea tarda Blistering skin lesions on light exposure, pigment changes, atrophy, and scarring—​also may be associated with
manifestations of iron storage disease, also hepatitis C
Congenital erythropoietic Haemolytic anaemia, hypersplenism, porphyrinuria, extreme photosensitivity with skin ulceration and injury; adult or
porphyria late onset reported
Hepatoerythropoietic porphyria Resembles congenital erythropoietic porphyria: blisters, photosensitive skin with scar formation, haemolysis, red urine
Protoporphyria and X-​linked Photosensitivity; early-​onset, characterized by burning pain, oedema—​scarring rare
protoporphyria X-​linked disease
Occasional cholestatic liver disease, protoporphyrin gallstones—​fulminant or subfulminant hepatic failure complicated
by neurovisceral syndrome, especially in perioperative state
Hexachlorobenzene porphyria Resembles sporadic porphyria cutanea tarda
Lead poisoning Neurovisceral manifestations with signs of disordered red cell haemoglobinization
Hereditary tyrosinaemia I Toxic neurovisceral disease
 12.5 The porphyrias 2037

3. Hereditary tyrosinaemia type 1 is an inborn error of tyrosine

Pathogenesis
metabolism due to the deficiency of fumarylacetoacetate hydro-
lase: there is liver disease (with a high risk of hepatocellular
Acute neurovisceral attacks
carcinoma), renal tubular disease, and neurological manifest-
These attacks occur in four of the porphyrias indicated in ations. Acute neurological crises, with abdominal symptoms,
Tables 12.5.2 to 12.5.4. In all but one, the very rare Doss’ porphyria painful extremities, and hypertension with hyponatraemia,
(aminolaevulinate dehydratase deficiency, a recessive disease), the occur episodically and may lead to fatal respiratory failure—​
inheritance is as an autosomal dominant trait. widely referred to as porphyria-​like syndrome. When man-
Clinical expression is characterized by recurrent acute, life-​ aged by dietary restriction of tyrosine and phenylalanine,
threatening attacks of neuropathy that include abdominal pain, psy- these episodes persist, but the illness is characterized by ele-
chiatric symptoms including anxiety, and signs of sympathetic and vation of the secondary metabolite succinylacetone (5,7-​
hypothalamic autonomic overactivity with tachycardia and systemic dioxoheptanoate) and 5-​ aminolaevulinate concentrations in
hypertension. The illness is sometimes accompanied by convulsions plasma and urine. Succinylacetone is a potent noncompeti-
and principally motor rather than sensory deficits; the neurological tive inhibitor of 5-​aminolaevulinic dehydratase (Ki 30 nM),
features may be confused with Guillain–​Barré syndrome. thus explaining the accumulation of 5-​ aminolaevulinate.
Acute decompensation is characteristically precipitated by drugs The neurological crises in tyrosinaemic patients resolve
which induce hepatic haem formation and are metabolized by the rapidly on introduction of nitisinone, an inhibitor of 4-​
hepatic cytochrome P450 system located in the endoplasmic re- hydroxyphenylpyruvate dioxygenase which catalyses conver-
ticulum. Neuropathological examination shows axonal degener- sion of 4-​hydroxyphenylpyruvate to homogentisic acid, thus
ation and central chromatolysis in anterior horn cells and in the blocking the proximal tyrosinaemia pathway and correcting
brain. Electromyography may reveal denervation compatible with the pathological generation of succinylacetone. If started early,
a primary axonal neuropathy of peripheral nerves. Although psy- the clinical manifestations are ameliorated but the long-​term
chiatric symptoms often accompany the attacks, there is conflicting neurocognitive outcomes are often impaired.
evidence that patients with acute porphyria have a greater risk of
chronic psychiatric illness than other patients with long-​standing The structure of aminolaevulinate is analogous to the inhibi-
episodic illnesses that affect the quality of life and are associated with tory neurotransmitters γ-​aminobutyric acid and l-​glutamate. It
physically disabling manifestations. seems likely that 5-​aminolaevulinate may interfere with the ac-
tion of the γ-​aminobutyric acidergic system, the best evidence for
Role of 5-​aminolaevulinic acid which appears to be its ability to inhibit melatonin production in
the rat pineal gland in vivo, as has been described in patients with
The porphyric crises of 5-​aminolaevulinate dehydratase deficiency
recurrent acute porphyric attacks. It has been further postulated
are associated with lone overproduction of 5-​aminolaevulinic acid,
that under the conditions of the acute attack there may be a de-
which is common to all porphyrias associated with acute manifest-
ficiency of essential haem proteins, such as the cytochrome P450
ations. It has been suggested that toxic effects of other factors may
isozymes in the liver, with further disturbances in secondary me-
contribute, but evidence supports the view that 5-​aminolaevulinic
tabolism; other possibilities include a decrease in the activity of
itself, or a direct metabolite of this critical precursor of porphyrin
hepatic tryptophan dioxygenase, leading to increased formation of
synthesis, has a causal role in the acute porphyric attack.
5-​hydroxytryptamine (serotonin).
1. Mutations in aminolaevulinate synthase 1 (ALAS1) have not been At present there is no clear resolution between combined or in-
causally associated with human diseases. Mutations in the erythroid dividual effects of acute porphyria on the production of neurotoxic
isozyme gene, ALAS2, cause two diseases: inactivating or low-​activity pseudotransmitters (aminolaevulinate) or secondary local deficiency
mutations, as with deficiency of the cofactor pyridoxal 5-​phophate, of haem. However, the beneficial results of liver transplantation in pa-
cause sideroblastic anaemia; mutations at the C-​terminus of the gene tients with disabling recurrent attacks of acute intermittent porphyria
are responsible for X-​linked nonacute protoporphyria, in which indicate that the principal cause of the acute syndrome is the hepatic over-
there is a common four-​nucleotide base deletion. production of toxic haem precursors. In any event, there is convincing
2. Acute, ‘nonsurgical’ abdominal pain, encephalopathy, and per- evidence of abnormal neurotransmitter function and increased sero-
ipheral motor mononeuropathy are typical features of toxic tonin production, as well as direct interference of γ-​aminobutyric acid
lead exposure, which is associated with specific acquired bio- receptors by toxic concentrations of 5-​aminolaevulinate. Supplying ex-
chemical abnormalities including elevated 5-​ aminolaevulinic ogenous haem during the acute attack, however, would be expected to
excretion together with elevated free protoporphyrin—​changes correct both arms of this disturbed metabolism, which may account
predicted by the effects on aminolaevulinate synthase and for the beneficial biochemical and clinical effects observed with its use.
ferrochelatase, respectively (both sulphydryl-​rich enzymes that The recent development of a mouse model of porphyrinogen
are readily susceptible to inhibition by lead). As an addendum to deaminase deficiency showing sensitivity to barbiturates serves as
these observations, it has been shown that individuals who are an authentic model of the biochemical and neuropathological mani-
otherwise asymptomatic heterozygotes, identified from studies festations of acute porphyria and may clarify much about the patho-
of pedigrees with 5-​ aminolaevulinate dehydratase deficiency genesis. Finally, decisive evidence for causal role of aminolaevuinate
(‘Doss’ porphyria’), are themselves exquisitely sensitive to en- or a related metabolite has emerged from the spectacular clinical and
vironmental lead exposure, thereby developing symptomatic biochemical success of short-interfering RNA molecules (siRNAs)
plumboporphyria. that are able to modulate synthesis and abundance of ALAS1.
2038 section 12 Metabolic disorders

The findings in mice that model acute intermittent porphyria have The final step in the haem biosynthetic pathway involves
been decisively translated into a human RNA interference agent insertion of ferrous iron into the protoporphyrin nucleus
(givosiran) that specifically targets hepatic ALAS1 gene expression. generated enzymatically from protoporphyrinogen IX by
Not only was this drug able to prevent the biochemical abnormal- protoporphyrinogen IX oxidase. This last step occurs in the
ities, it markedly reduced the paralysis associated with barbiturate mitochondrion. Ferrochelatase depends on the iron–​transferrin
challenge in affected animals and in humans. cycle for the delivery of iron from plasma transferrin. In the
bone marrow, when the iron supply is deficient, freely available
Photosensitivity zinc may be preferentially converted to zinc protoporphyrin ra-
In living cells, most of the macrocyclic precursors of the haem biosyn- ther than ferroprotohaem, thus offering a convenient means to
thetic pathway are present as their reduced porphyrinogen precursors monitor iron-​deficient erythropoiesis. Similarly, industrial lead
which are not photoreactive. However, when these tetrapyrroles exposure, which inhibits both iron delivery and the activity of the
(uroporphyrinogen, coproporphyrinogen, and proto­porphyrinogen) sulphydryl enzyme ferrochelatase, causes accumulation of zinc
are produced in excess, they diffuse into plasma and tissues where they protoporphyrin and free protoporphyrin in erythroid precursors
react with ambient oxygen to form their parent porphyrins, which are and reticulocytes. Deficiency of ferrochelatase leads to the accu-
spectacularly fluorescent. Porphyrins absorb light maximally in the mulation of free protoporphyrin in liver tissue, plasma, and the
Soret region (400–​420 nm) and between 500 and 600 nm (both within skin where it induces marked photosensitivity. The accumula-
the visible light range of 380–​700 nm); they re-​emit this light energy tion of excess protoporphyrin in red cell precursors leads to the
at lower wavelengths to give pink, orange, or red fluorescence. The characteristic fluorocytes (young red cells containing excess free
double-​bond resonance structure of these macrocyclic compounds protoporphyrin) that are the easily recognized hallmark of patients
promotes the formation of singlet oxygen by the transfer of absorbed with burning photosensitivity caused by protoporphyria.
energy to ground-​state oxygen through light activation, and it appears In protoporphyria, an adequate oxygen supply has been shown
that generation of singlet oxygen brings about the photodermatoses to be critical for the development of experimental phototoxicity
associated with the porphyrias. Porphyrias associated with overpro- in vivo. Singlet oxygen and other radicals may lead to lipid
duction of formed macrocyclic haem precursors are thus associated peroxidation and cross-​linking of membrane proteins with acti-
with photosensitivity. The particular skin reactions that develop differ vation of late complement components. In the more severe dis-
between the particular enzyme defects, which may be explained prin- ease, congenital erythropoietic porphyria, egress of uroporphyrin
cipally by the degree of hydrophobicity of the overproduced porphy- I from circulating erythrocytes, which may be destroyed within
rins and their solubility in cellular membranes. capillaries, leads to gross accumulation of porphyrin in dermal
The first tetrapyrrole that serves as an immediate precursor to haem tissue and juxtaposed epithelium. Exposure to light is known
is uroporphyrinogen III, formation of which requires coordinated to promote photohaemolysis, indicating that light of the visible
action of the two cytoplasmic enzymes uroporphyrinogen I synthase wavelength can penetrate the skin sufficiently to induce porphyrin
(porphobilinogen deaminase) and uroporphyrinogen III cosynthase. photoactivation in situ.
In the absence of adequate cosynthase activity there is a marked
overproduction of porphyrins of the I series, which do not form bio- Induction of acute porphyric attacks
logically active ferroprotohaem. Deficiency of uroporphyrinogen III Acute attacks of porphyria may be life-​threatening illnesses that occur
cosynthase leads to the very rare but disabling syndrome of Gunther’s in genetically predisposed individuals who usually remain asymp-
disease (congenital erythropoietic porphyria), characterized by ex- tomatic. The acute episodes develop on exposure to environmental
treme photosensitivity, haemolysis, and the passage of pink urine or endogenous factors that place a demand for hepatic haem biosyn-
containing abundant porphyrins of the I isoform. Persistently high thesis; this leads to the overproduction of porphyrin intermediates
concentrations of these toxic molecules in body fluids lead to staining and pyrrole precursors. The most frequent precipitating factors are
of the teeth and bones and extreme photosensitive damage, often changes in reproductive steroid hormones either due to natural hor-
with cruel and painful skin disfigurement and hair loss. mone cycles or the administration of exogenous gonadal steroids.
Porphyria cutanea tarda is caused by deficiency of uro­ Starvation, including that associated with surgical procedures and
porphyrinogen decarboxylase, defects of which involve complex anaesthesia, intercurrent infections, and many xenobiotics, including
interactions between heredity and environmental factors. The en- alcohol as well as prescription drugs, over-​the-​counter agents, and
zyme activity is markedly decreased in the presence of excess tissue chemicals present in health foods can precipitate acute porphyria.
iron and, although rare familial cases of porphyria cutanea tarda Boxes 12.5.1 and 12.5.2 list drugs that have been classified as
occur, most patients have a sporadic disease that is provoked by unsafe in patients with porphyria, either because they have been
exposure to environmental toxins such as alcohol, oestrogens, hy- shown to be porphyrinogenic in animals or in vitro studies, or have
drocarbons, iron (often associated with mutations in the haemo- been associated with acute attacks in patients with porphyria. These
chromatosis gene HFE), and hepatitis C. At the time of writing, tables are taken from the British National Formulary published
the pathogenic relationship between these external factors and the by the British Medical Association and the Royal Pharmaceutical
manifestations of uroporphyrinogen decarboxylase deficiency is Society of Great Britain. It is noteworthy that slight changes in the
unclear. Skin biopsies show subepidermal bullas and electron mi- chemical structure can lead to marked differences in the ability of
croscopy reveals vacuoles in the cells of the superficial dermal epi- the drug to induce attacks of porphyria. Inspection of contemporary
thelium. In this disease, as in protoporphyria, the endothelium of national and international websites provides up-​to-​date information
the dermal capillary is thickened and the vessels are surrounded by of immediate relevance and value, especially in relation to local pre-
complement and mucopolysaccharide deposits. scribing practice (see ‘Further reading’). A clinically more useful list
 12.5 The porphyrias 2039

Box 12.5.1 Classes of drug that are unsafe in acute porphyrias Clinical features of acute porphyria
• Anabolic steroids
• Antidepressants, monoamine oxidase inhibitors (contact the United The clinical manifestations of an acute attack are very diverse and
Kingdom Porphyria Medicines Information Service (UKPMIS) for the condition may be indistinguishable from many other disorders.
advice) The common neurovisceral symptoms of acute porphyric attacks
• Antidepressants, tricyclic and related (contact UKPMIS for advice) are listed in Box 12.5.4 and, of these, abdominal pain is the most
• Barbiturates (includes primidone and thiopental) common presenting symptom. The pain itself may be difficult to
• Contraceptives, hormonal (for detailed advice contact UKPMIS or a identify since it is usually constant but poorly localized and usually
porphyria specialist)
not associated with tenderness. Beyond severe myalgic pains, some-
• Hormone replacement therapy (for detailed advice contact UKPMIS
or a porphyria specialist) times affecting anterior abdominal muscles, there may be an associ-
• Imidazole antifungals (applies to oral and intravenous use; topical ated colicky component and later ileus with abdominal distension,
antifungals are thought to be safe due to low systemic exposure) which may mimic a surgical emergency. Constipation is a charac-
• Non-​nucleoside reverse transcriptase inhibitors (contact UKPMIS for teristic symptom but diarrhoea with increased borborygmi can also
advice) occur. The patient is usually markedly distressed with anxiety and
• Progestogens (for detailed advice contact UKPMIS or a porphyria tachycardia. Marked arterial hypertension (not always previously
specialist) noted), sometimes paroxysmal, is the rule
• Protease inhibitors (contact UKPMIS for advice)
Development of pain in the limbs is a frequent feature, particu-
• Sulphonamides (includes co-​trimoxazole and sulfasalazine)
larly in the upper thighs and also in other somatic muscles of the
• Sulphonylureas (glipizide and glimepiride are thought to be safe)
• Taxanes (contact UKPMIS for advice)
chest, lumbar region, shoulders, and neck. Ultimately, muscle weak-
• Triazole antifungals (applies to oral and intravenous use; topical ness and respiratory paralysis may occur. The patient, almost in-
antifungals are thought to be safe due to low systemic exposure) variably very anxious, becomes restless, frankly disturbed, or even
deluded as in a toxic confusional state. Prominent mental disturb-
For further information see UK Porphyria Welsh Medicines Information Service
(2017): https://​www.wmic.wales.nhs.uk/​specialist-​services/​drugs-​in-​porphyria.
ances are reported in patients with the posterior encephalopathy
syndrome and cerebral vasculopathy that accompanies the parox-
ysmal and severe systemic hypertension of untreated attacks. The
inability of attending medical personnel to identify the cause of the
is of safe drugs is provided in Box 12.5.3. For further information see pain and the distress associated with it often leads to alienation and
the ‘Complete 2018 List of Safe Drugs in Acute Porphyrias’ (http://​ an exaggeration of the complaints, which may be difficult to diag-
www.drugs-​porphyria.org/​), which provides an updated current list nose. Should a suggestion of psychiatric illness (typically some type
with informative notes. of somatic symptom disorder) be made by attending staff, this in-
Tolerance of alcohol varies greatly in patients with porphyria, many variably compounds the distress experienced by the patient. From
of whom appear to tolerate it in modest amounts. Alcohol is, however, every aspect, distressed patients with suspected porphyria should
best avoided, although at the same time it is wise not to implicate al- be treated attentively and every effort should be made to accelerate
cohol in an acute attack unless other causes have been excluded. the definitive diagnosis and treat accordingly It is a general rule that
There is emerging evidence that cigarette smoking, which induces the mental features of porphyria subside rapidly as the biochemical
enzymes of the haem-​rich cytochrome P450 system, is prevalent in disturbance resolves.
patients who have frequent acute attacks of porphyria. The author Hypertension, sweating, and tremor together with tachycardia
recommends that persuasive advice to stop smoking is given when- indicate marked sympathetic overactivity and cardiac arrhythmias
ever possible. may ensue. In about 10% of severe attacks, grand mal seizures de-
Acute attacks of porphyria occur in the four conditions known velop, treatment of which may prolong the attack since many anti-
as the hepatic porphyrias and particularly occur for the first time in convulsants are highly porphyrinogenic. With sustained attacks,
latent carriers who are aged between 15 and 40 years. Attacks have there may be signs of a peripheral neuropathy that is related to
been recorded in children before puberty but are very rare and usu- axonal degeneration, principally affecting motor nerves. Peripheral
ally occur during febrile illnesses or are precipitated by the use of neuropathy in its early stages may not affect the limb and tendon re-
porphyrinogenic drugs and over-​the-​counter remedies. Although flexes, but with time these will be decreased or absent. In prolonged
the porphyrias occur in a latent state in men with a frequency that porphyric attacks, an ascending muscle weakness rapidly affecting
is equal to that in women, women who have acute porphyria out- the respiratory muscles and diaphragm, and with bulbar paralysis,
number men by at least two to one. may lead to ventilatory failure and death if life-​saving cardiorespira-
The recent description of Rev-​erbα, a haem sensor involved in the tory resuscitation and intensive care measures are delayed.
coordination of metabolic pathways and circadian rhythms, as well In a full-​blown attack, mental symptoms including anxiety, sleep-
as PGC-​1α, a transcriptional coactivator involved in the regulation lessness, and depression are often prominent; the terrifying nature
of ALAS1 expression, offers the hope that a better understanding of the illness only aggravates distress in the patient. If the porphyric
of the mechanism by which environmental influences trigger acute attack is sustained as a result of failed diagnosis or inadequate man-
porphyria in susceptible individuals will be forthcoming. Genetic agement, progressive alienation, visual and auditory hallucinations,
variation in these pathways, particularly the cytochrome P450 and frank paranoia with homicidal outbursts may occur. Such dis-
system also may go some way to explain the immense variation that turbances are difficult to contain within the environment of the busy
individuals show in their susceptibility to the attacks. acute hospital.
2040 section 12 Metabolic disorders

Box 12.5.2 Individual drugs unsafe in acute porphyrias

• Aceclofenac • Methyldopa
• Alcohol • Metolazone
• Amiodarone • Metyrapone
• Aprepitant • Mifepristone
• Artemether with lumefantrine • Minoxidil (safety uncertain, contact UKPMIS for advice)
• Bexarotene • Mitotane
• Bosentan • Nalidixic acid
• Busulfan • Nitrazepam
• Carbamazepine • Nitrofurantoin
• Chloral hydrate (although evidence of hazard is uncertain, manufacturer • Orphenadrine
advises avoid) • Oxcarbazepine
• Chloramphenicol • Oxybutynin
• Chloroform (small amounts in medicines probably safe) • Pentazocine
• Clemastine • Pentoxifylline
• Clindamycin • Pergolide
• Cocaine • Phenoxybenzamine
• Danazol • Phenytoin
• Dapsone • Pivmecillinam
• Diltiazem • Pizotifen
• Disopyramide • Porfimer
• Disulfiram • Raloxifene
• Ergometrine • Rifabutin (safety uncertain, contact UKPMIS for advice)
• Ergotamine • Rifampicin
• Erythromycin • Riluzole
• Etamsylate • Risperidone
• Ethosuximide • Spironolactone
• Etomidate • Sulfinpyrazone
• Flutamide • Tamoxifen
• Fosaprepitant • Temoporfin
• Fosphenytoin • Thiotepa
• Griseofulvin • Tiagabine
• Hydralazine • Tibolone
• Ifosfamide • Topiramate
• Indapamide • Toremifene
• Isometheptene mucate • Trimethoprim
• Isoniazid (safety uncertain, contact UKPMIS for advice) • Valproate
• Ketamine • Verapamil
• Mefenamic acid (safety uncertain, contact UKPMIS for advice) • Xipamide
• Meprobamate

Although seizures may be a presenting sign of the acute attack, difficulties (see ‘Hyponatraemia and seizures’). Inappropriate use
they often occur in association with fulminant hyponatraemia re- of hypotonic dextrose will aggravate hyponatraemia and seiz-
sulting from the inappropriate secretion of antidiuretic hormone. ures and may induce fatal cerebral herniation due to severe brain
Treatment of hyponatraemia in the acute attack poses special oedema.

Box 12.5.3 Drug classes thought to be safe in acute porphyrias Box 12.5.4 Clinical manifestations of acute porphyria

• Antihistamines: cetirizine, chlorpheniramine, and cyclizine • Abdominal pain

• Diuretics: acetazolamide, amiloride, bumetanide, cyclopenthiazide, • Vomiting
and triamterene • Constipation
• Ergot derivatives: oxytocin is probably safe • Limb, head, neck, and chest pain
• Sulphonylureas: glipizide • Muscle weakness
• Analgesics: morphine, diamorphine, codeine, dihydrocodeine, fen- • Sensory loss
tanyl, and pethidine. • Hypertension
• Tranquillizers: chlorpromazine, and haloperidol • Tachycardia
• Local anaesthetics: bupivacaine and lignocaine can be used with • Convulsions
caution • Respiratory paralysis
• Antimicrobials: rifamycins have been used without ill effect in some • Fever
patients • Psychiatric symptoms
 12.5 The porphyrias 2041

Acute attacks of porphyria appear to be more common in women effects of the disease in patients with acute attacks have improved.
as a result of changes in sex steroids: many women who have peri- Reports from a single centre reported that about three-​quarters of
odic attacks do so in the 1 or 2 days before the onset of menstrual patients with acute intermittent porphyria or variegate porphyria
bleeding, but sometimes attacks lasting a day or two may have their were able to lead normal lives after an acute attack. Recurrent attacks
onset in the mid-​menstrual phase soon after ovulation. The pattern of pain occurred only in a minority during a period of prolonged
may worsen as the menopause approaches, but severe attacks usually follow-​up; these recurrent attacks were most likely to occur in the
cease with the onset of oligomenorrhoea or amenorrhoea. first 3 years.
Although it appears that progestogens are principally respon- The development of national centres for the treatment of por-
sible for cyclical or periodic attacks in women and are more phyria, the early detection of genetic predisposition in at-​risk first-​
porphyrinogenic than oestrogens, pregnancy itself is not invari- degree relatives, and the dramatic reduction in prescriptions of
ably associated with adverse outcomes in women at risk from acute porphyrinogenic drugs, such as barbiturates and sulphonamides,
attacks. Seizures and hypertension due to acute porphyria may be together with better treatment of acute attacks can undoubtedly
attributed erroneously to eclampsia. Drugs that provoke attacks, contribute to improved outcome. Nonetheless, acute porphyria re-
such as metoclopramide, may be used mistakenly to control gastro- mains potentially life-​threatening, and deaths or marked disability
intestinal symptoms in pregnancy and thus place the woman and due to prolonged, mismanaged, or undiagnosed attacks are all too
her unborn infant at risk. frequent.
Many mild attacks of porphyria resolve spontaneously within a
few days, either as a result of withdrawal of the precipitating factor Complications
or because of natural hormonal rhythms. Prolonged attacks are usu- Acute encephalopathy—​posterior reversible
ally the consequence of multiple factors and delays in the institution encephalopathy syndrome (reversible posterior
of definitive therapy. The ensuing neurological injury, accompanied leucoencephalopathy syndrome)
in severe attacks by bulbar and respiratory paralysis, may lead to
This syndrome has been reported in exceptionally ill patients with
prolonged or permanent disability. Experience shows that in many
acute porphyria. Clinically, the patient is confused and complains of
such cases inappropriate drugs have been given to counter the early
headache, visual phenomena, and field loss, often accompanied by
manifestations of the condition (e.g. analgesics, psychotropic drugs
generalized seizures. Ischaemia of the occipital cortex during acute
and anticonvulsants), hence the initiating medical interventions
attacks with severe hypertension has been associated, in several in-
ultimately prove to be critical determinants of outcome where the
stances, with failed recognition of colours or of human faces (proso-
diagnosis is not suspected or, if known, has been perilously ignored.
pagnosia) and cortical blindness.
Diagnosis of acute attacks Magnetic resonance imaging typically reveals bilateral symmet-
Diagnosis of the acute attack is often suspected from scrutiny of the rical and gyriform lesions in the cerebrum and cerebellar hemi-
past history, including episodes of photosensitivity with blistering spheres due to oedema. The lesions are initially hyperintense on
lesions or intermittent discolouration of urine. The passage of frank T2-​weighted images and prominent in the posterior regions of the
wine-​coloured or permanganate-​coloured urine is unusual, but if occiput and pons as well as parietal lobes. Should the patient make
present indicates a full-​blown established attack. The family history a neurological recovery with stabilization of blood pressure, the
is often informative, with a history of abdominal pain in first-​degree radiological changes are potentially reversible over a matter of 1 to
family members, with or without photosensitivity skin eruptions. 2 weeks. However, in some cases permanent neurological impair-
In all instances, it is the overproduction of haem precursors that ment including visual changes and seizures is the result. Though un-
characterizes the condition biochemically and this is the principal common, death may occur with progressive swelling due to cerebral
means by which a diagnosis can be made during an acute attack, oedema, compression of the brainstem, increased intracranial pres-
confirmation of which requires the demonstration of increased por- sure, or intracerebral haemorrhage.
phyrin precursors in the urine. Most commonly, increased excretion Posterior reversible encephalopathy syndrome may recur in about
of the monopyrrole, porphobilinogen, is accompanied by increased 5 to 10% of cases. This happens most commonly in cases accom-
excretion of urinary 5-​aminolaevulinate, but porphobilinogen ex- panied by hypertension, and where sustained or paroxysmal sys-
cretion is not increased in the extremely rare aminolaevulinate temic hypertension is difficult to control or escapes clinical attention.
dehydratase deficiency or in the pseudoporphyria of lead poisoning.
Other neurological complications
Without genetic characterization in a first-​degree relative, ‘cold’
diagnosis can be very challenging when the biochemical abnor- Rapidly recurrent attacks of porphyria may be associated with se-
malities have corrected themselves. Future developments in gen- vere motor neuropathy and sustained hypertension; postural hypo-
etic diagnosis may well improve the interval diagnosis of acute tension may result from autonomic neuropathy. Cranial nerve
porphyrias, but more work is needed before information from fo- palsies can occur in severe cases, typically affecting the facial and
cused sequencing of the responsible genes can be used appropriately vagus nerves.
to facilitate clinical diagnosis of these important conditions.
Chronic kidney disease
Prognosis Chronic kidney disease is frequently associated with hypertension
An early series showed that during the first acute attack of porphyria and a common long-​term comorbidity of the acute porphyrias, but es-
half the patients died. However, perhaps as a result of better hospital pecially acute intermittent porphyria. Nearly all patients with recur-
facilities to deal with severe or adverse outcomes, the mortality and rent acute attacks are or will be affected, as revealed in a large cohort
2042 section 12 Metabolic disorders

of 415 patients with confirmed deficiency of hydroxymethylbilane and an erythroid-​specific isozyme. Most mutations cause a decrease
synthase and acute intermittent porphyria. Chronic kidney dis- in the abundance as well as the activity of the porphobilinogen
ease arose over 10 years in nearly 60% of the symptomatic patients, deaminase enzyme in all tissues. A few mutations associated with
in whom an annual decline in the glomerular filtration rate of ap- lack of the detectable protein product from the mutant allele are as-
proximately 1 ml/​min per 1.73 m2 was documented; proteinuria was sociated with reduction of the housekeeping isozyme but normal
rarely observed. Renal histology showed a chronic tubulointerstitial enzymatic activity of the erythroid-​specific isozyme. Thus, in such
nephropathy associated with a fibrous intimal hyperplasia and focal patients, hepatic porphobilinogen deaminase activity may be re-
cortical atrophy. The effects of quasi-​pathological amounts of por- duced to approximately half normal values while the activity of the
phyrin precursors were examined and the investigators suggested easily accessed red cell enzyme is within the normal range.
that endoplasmic reticulum stress, apoptosis, and epithelial changes A few mutations lead to the synthesis of a catalytically impaired
reflected injury to proximal tubular cells. but stable porphobilinogen deaminase protein from the cognate
Chronic kidney disease associated with acute porphyria should be mutant allele, but these are a minority. Molecular analysis of the
considered in the presence of chronic tubulointerstitial nephropathy porphobilinogen deaminase gene in patients with acute intermit-
or focal cortical atrophy with severe proliferative arteriosclerosis. tent porphyria has been very valuable in establishing diagnosis of
latent heterozygotes at risk in the affected family, for the provision
Hepatic carcinoma of appropriate counselling, and for the introduction of preventative
There are multiple reports of primary liver carcinoma in the three strategies (see ‘Latency or genetic penetrance’).
most frequent acute porphyrias: acute intermittent porphyria, varie- Acute intermittent porphyria is characterized solely by acute
gate porphyria, and hereditary coproporphyria. Histological reports porphyric attacks and cutaneous photosensitivity does not occur. In
indicate that most of these tumours are hepatocellular carcinomas, most instances, the patients do not notice any change in their urine,
but cholangiocarcinomas are also found. Annual incidences of 0.16 but when the urine is allowed to stand, the increased excretion of
to 0.35% are reported in cohorts of patients followed. Tumours are pyrroles leads to the formation of coloured oxidation products of
associated with age over 50 years and undoubtedly more frequent in porphobilinogen (loosely called porphobilin), which may lead to
patient cohorts from Sweden and Norway, suggesting the presence obvious discoloration (Fig. 12.5.2). During the increased excretion
of additional genetic factors due to at least one high-​prevalence, of porphyrin precursors, water-​soluble porphyrins, formed as a re-
cosegregating modifying factor. No consistent environmental co- sult of nonenzymatic photochemical reactions, induce a pink discol-
factor (drug, hepatitis virus, or other features) has been identified. ouration. During severe acute attacks, copious excretion of pyrrole
Specificity in relation to the acute porphyrias may not be ab- precursors, including porphobilin, may occasionally give the urine
solute: the author has recently cared for an unusual patient, a 62-​ a striking appearance resembling blackcurrant juice or strong solu-
year-​old man with congenital erythropoietic porphyria and with no tions of potassium permanganate.
other frank toxicity, iron storage, or hepatitis infection: a cryptic but
ultimately fatal hepatocellular carcinoma developed at the time of Latency or genetic penetrance
splenectomy. The incidence and severity of acute attacks in acute intermittent por-
Regular radiological surveillance of the liver, typically by ultra- phyria and variegate porphyria are generally greater than in heredi-
sonography, is appropriate for older patients suffering from acute tary coproporphyria. Various estimates indicate between 1 in 10 to
porphyria. 1 in 5 of heterozygotes experience acute attacks of porphyria during
their lifetime; a study in France indicated penetrance of 23%. Recent
large-​scale studies using genomic/​exomic sequencing data in white
Individual acute porphyrias

These are, in a descending order of frequency: acute intermit-

tent porphyria, variegate porphyria, hereditary coproporphyria,
and Doss’ porphyria (5-​aminolaevulinate dehydratase deficiency).
The first three of these disorders occur in at-​risk heterozygotes for
a single mutant allele in the cognate gene as autosomal dominant
traits; 5-​aminolaevulinate dehydratase deficiency is inherited as a
very rare autosomal recessive trait.

Acute intermittent porphyria

This, the most frequent of the acute porphyrias, is caused by muta-
tions in the porphobilinogen deaminase gene that maps to human Fig. 12.5.2 Urine from a patient with acute intermittent porphyria
chromosome 11q23 in which well over 200 mutations have been around the time of an acute attack (left); control urine (right). A positive
identified. Several widespread mutations have been identified in cer- reaction with Ehrlich’s diazo reagent is shown in the patient’s urine
tain populations, but most are reported in only one or two pedigrees. following the addition of 50 µl urine to 1 ml of 2% acidic dimethyl
Two isozymes of the human porphobilinogen deaminase enzyme benzaldehyde. Subsequent tests showed that the pink diazo adduct
was insoluble in chloroform and other organic solvents indicating the
occur in the tissues: an erythroid mRNA variant and a nonerythroid presence of excess porphobilinogen. (Urobilinogen in excess may give
transcript that encodes 17 additional amino acid residues in its N-​ a positive reaction with the diazo reagent but the product is readily
terminus, leading to synthesis of a housekeeping ubiquitous isozyme extracted into organic solvents.)
 12.5 The porphyrias 2043

persons identified nonsynonymous and two consensus splice-​site alone, one-​fifth had acute neurovisceral disease, and a similar pro-
pathogenic variants for a combined prevalence of approximately portion had acute attacks as well as cutaneous disease.
0.00056. Since the estimated prevalence of acute attacks is approxi- Cutaneous photosensitivity resembles that seen in porphyria
mately 0.000005, and the estimated frequency of clinical pathogenic cutanea tarda and hereditary coproporphyria (see ‘Hereditary
variants is approximately 0.00056, the penetrance of acute intermit- coproporphyria’) with fragility, milia, hyperpigmentation, and hairi-
tent porphyria appears to be as low as 1% of all heterozygotes. Since ness of light-​exposed skin. During acute sunlight exposure, vesicles
the disease is monogenic, very low penetrance points to the exist- and even large bullas may form. Microscopic examination of the
ence of modifying factors (environmental or genetic) that either pre- affected skin shows deposits of immunoglobulin and hyaline ma-
dispose heterozygotes to the acute attack or suppress expression of terial (that stains positively with periodic acid–​Schiff reagent) in the
the disease. dermal capillaries with proliferation of the basal lamina. As with
More recent research into acute intermittent porphyria from porphyria cutanea tarda, ingestion of reproductive steroids (e.g. the
France has reconsidered the concept of autosomal dominant in- oral contraceptive pill) may induce the cutaneous manifestations of
heritance with incomplete penetrance. This work examined the variegate porphyria in otherwise latent heterozygotes.
prevalence, penetrance, and heritability in affected pedigrees with A few severely affected patients with variegate porphyria have
602 overt patients, 1968 first-​degree relatives, and control samples inherited mutations of the protoporphyrinogen oxidase gene (that
from the general population. The pathogenicity of the 42 missense maps to chromosome 1q22–​q23) from each parent, leading to
variants identified was assessed in silico, and also systematically in homozygous ‘dominant’ variegate porphyria. These individuals pre-
vitro by measuring residual enzyme activity of recombinant mutant sent in childhood with a severe phenotype associated with marked
hydroxymethylbilane synthases. The minimal estimated prevalence photosensitivity and a neurological syndrome as described briefly in
of acute intermittent porphyria in the general population was 1 in ‘Protoporphyrinogen oxidase’.
1299. Thus, 50 000 subjects would be expected to carry the gen-
etic trait in France, allowing penetrance to be estimated at 22.9% Hereditary coproporphyria
in affected families but in only 0.5 to 1% of the general population. This condition is an infrequent and often mild form of acute por-
Intrafamily studies showed correlations to be strong overall and phyria which may be associated with cutaneous manifestations. It is
modulated by kinship and the area in which the person was living, due to mutations in the coproporphyrinogen III oxidase gene that
immediately pointing to a combination of interacting and strong maps to chromosome 3q12 and is transmitted as an autosomal dom-
influences of genetic and environmental modifiers on the expres- inant trait of low penetrance. The condition usually presents with
sivity of the trait in pedigrees. Null alleles were associated with a acute attacks of abdominal pain, as with the other acute porphyrias,
more severe phenotype and a higher penetrance than for other mu- and about 30% of patients develop cutaneous photosensitivity.
tant alleles. The authors concludes that the striking difference in the As with some other porphyrias, several children presenting with
penetrance of the mutant hydroxymethylbilane synthases between marked photosensitivity in childhood have been shown to have in-
the general population and the French families affected by porphyria herited a mutant allele of the coproporphyrinogen III oxidase gene
indicates that the inheritance does not follow the classical autosomal from each parent giving rise to so-​called homozygous dominant her-
dominant model: expression of disease is modulated by strong en- editary coproporphyria. Particular mutations in the gene are usually
vironmental and genetic factors that are independent of the ‘causal’ restricted to individually infected pedigrees. As with the other acute
HMBS gene. porphyrias, molecular analysis of the coproporphyrinogen III oxi-
In practice, increasing use of molecular diagnostic methods for dase gene may be of value in identifying at-​risk heterozygotes for
screening at-​risk families, institution of appropriate avoidance, genetic counselling and provision of appropriate advice about the
and the careful dissemination of information to family members prevention and management of symptomatic disease.
and their medical advisers will further reduce the likelihood of dis-
ease in latent gene carriers. Latent carriers of acute intermittent 5-​Aminolaevulinate dehydratase deficiency
porphyria have a high frequency of hypertension and, although (Doss’ porphyria)
this should be treated, the potential for inducing attacks is in- Only a few affected homozygotes for this recessive condition have
creased by the uninformed prescription of antihypertensive drugs. been identified. Molecular analysis of the cognate gene has revealed
Some patients appear to have depression and other chronic mental the presence of compound heterozygosity and homozygosity for
symptoms, and at least one survey has reported an increased point mutations in the gene which map to chromosome 9q34. As
prevalence of acute intermittent porphyria in patients attending with the porphobilinogen deaminase gene, there are two promoter
long-​stay psychiatric facilities, which again puts them at risk from regions and alternative noncoding exons that allow for the synthesis
the ill-​considered use of porphyrinogenic neuroleptic and other of housekeeping and erythroid-​specific transcripts. Less than 10
psychoactive drugs. cases of this porphyria have been reported, but it seems likely from
the individual case histories of those identified that the disease will
Variegate porphyria be under-​recognized as the cause of acute abdominal crises, usually
Variegate porphyria is particularly frequent among white South presenting shortly after puberty and associated with neurological
African people and other ethnic groups within that country. The symptoms, including respiratory paralysis.
condition is associated with typical acute attacks of porphyria as The condition resembles acute lead poisoning. The urine contains
well as skin manifestations (the van Rooten skin). Acute attacks of an excess of 5-​aminolaevulinate but the excretion of porphobilinogen
porphyria occur very much as in acute intermittent porphyria. In and tetrapyrrolic haem precursors is normal. Heterozygotes for
a series of patients, more than one-​half presented with skin lesions aminolaevulinate dehydratase deficiency have been reported in at
2044 section 12 Metabolic disorders

least one lead worker in whom peripheral neuropathy was ascribed immediate haem precursor, protoporphyrinogen IX. These patients
to simple lead poisoning, but it may have resulted from the suscep- do not develop acute neurovisceral symptoms of acute porphyria.
tibility of the residual 5-​aminolaevulinate dehydratase to inhibition
by environmental lead. Protoporphyrinogen oxidase
Patients harbouring biallelic mutations of protoporphyrinogen
Unusual genetic variants of the acute porphyrias oxidase present in infancy or childhood with a severe phenotype
(homozygotes or compound heterozygotes) associated with disfiguring photosensitivity accompanied by soft
In the last 20 years, very rare homozygous forms of porphyria have tissue mutilation, evidence of digital bone loss (osteolysis), and
been recognized where the presence of two mutant alleles of the impaired cognitive development. Peripheral skeletal abnormal-
causative gene are responsible for severe clinical disease. Most in- ities include medially deviated and shortened fifth digits, known as
dividuals affected prove to be compound heterozygotes for two mu- clinodactyly, and slight growth retardation. A mild distal sensory
tant alleles of the cognate gene; true homozygotes are most likely to neuropathy has been reported. There is later development of gen-
occur only in consanguineous pedigrees. eralized seizures, usually during adolescence or early adulthood.
Cranial magnetic resonance imaging reveals a leucodystrophy
Porphobilinogen deaminase (hydroxymethylbilane synthase) with hypomyelination of long tracts. Biochemical investigation
Bialleic mutations in the third enzyme in the haem biosynthetic reveals striking elevation of red cell and plasma protoporphyrin
pathway led, in one well-​studied pedigree, to an unusual neurological which is predominantly zinc-​chelated, a feature of homozygous
syndrome with impaired cerebellar function and slowly progressive hepatic porphyrias. None of the patients so far reported has devel-
white matter disease with hypomyelination. There was also truncal oped attacks of acute porphyria.
muscle weakness and wasting, notably associated with ptosis, a clin-
ical sign compatible with mitochondrial disease. Biochemical tests Ferrochelatase
revealed excessive urinary porphobilinogen, 5-​aminolaevulinate, Although homozygous ferrochelatase deficiency (protoporphyria)
porphobilinogen, and uroporphyrin. Furthermore hepta-​, hexa-​, is not strictly related to an acute porphyria, patients who are com-
penta-​, and coproporphyrins I were highly increased in urine and pound homozygotes or true homozygotes have a severe photosensi-
typical of patients with acute porphyria during a metabolic crisis. tivity syndrome that is more frequently complicated by accelerated
The author suggests that these features indeed indicate a mitochon- cholestatic liver disease and pigment cirrhosis. However, the pos-
drial defect, probably due to impaired oxidative phosphorylation ition is etymologically complex, since generally only those who in-
related to the haem deficiency in critical cytochrome components herit a mutation on one FECH allele and a polymorphism in trans
of the electron transport chain, such as cytochrome c. Supportive on the other allele, which is common in general European popula-
evidence is provided by defective mitochondrial energetics in the tion and diminishes expression of the ferrochelatase, develop clin-
brain and skeletal muscle of mice generated as homozygous mutants ical manifestations. Such patients are not conventional compound
for the porphobilinogen deaminase locus, and by a patient having heterozygotes since the polymorphism is common in the apparently
consistently elevated plasma lactate concentrations and metabolic healthy population (c.11% of Europeans). However, rare individuals
acidosis. with biallelic inheritance of disabling FECH mutations appear to be
Intermittent hypoglycaemia was found in one patient who died at especially predisposed to the development of cholestatic liver dis-
the age of 20 years due to cardiorespiratory failure; their sibling had ease with cirrhosis that aggravates the photosensitivity and leads to a
died suddenly at 9 years of age of unknown causes. Despite greatly potentially fatal outcome unless liver transplantation is undertaken.
reduced hydroxymethylbilane synthase activity in these two sib-
lings due to compound heterozygosity for adjacent base transitions
in the same codon in exon 10 of the PBG deaminase gene, neither Individual cutaneous porphyrias
had any evidence of metabolic decompensation or the neurovisceral
manifestations of an acute porphyric attack; neither of the biological Congenital erythropoietic porphyria
parents had ever suffered acute porphyria. Congenital erythropoietic porphyria (Gunther’s disease) is a classic
but very rare syndrome now known to have an astonishing range
Coproporphyrinogen oxidase of presentation from severe haemolytic anaemia in utero or severe
This is a very rare syndrome principally dominated by haemato- photosensitivity presenting soon after birth (with excess porphyrins
logical (erythroid) features of haemolytic anaemia accompanied staining the teeth and urine) to mild late-​onset forms presenting
by hepatosplenomegaly and marked photosensitivity. The patients with skin lesions in adult life. Most patients have a mild to severe
thereby resemble those suffering from congenital erythropoietic haemolysis with increased reticulocytosis, circulating normoblasts,
porphyria (Gunther’s disease) due to biallelic mutations that induce decreased serum haptoglobin, and increased unconjugated bilirubin
marked deficiency of uroporphyrinogen III cosynthase. This presen- concentrations. Inclusion bodies are often seen in marrow, erythroid
tation is associated with expression of a missense mutation, p.K404E, cells, and circulating normoblasts. Splenomegaly develops in child-
in either homozygous or compound heterozygous form with a dis- hood, thereby causing pancytopenia as a result of hypersplenism;
abling splice-​site mutation in the COX gene. The hallmark of this this accelerates the haemolysis and leads to compensatory erythro-
disorder is the incomplete decarboxylation of the tetracarboxylic poiesis in the bone marrow. Under these circumstances, splenec-
coproporphyrinogen III to yield excess tricarboxylic intermediate tomy may help to control the condition.
harderoporphyrin rather than the principal product of wild type The classic skin manifestations are of severe blistering lesions on
coproporphyrinogen III oxidase, the dicarboxylic isomer and sunlight-​exposed skin, particularly of the hands and face, with the
 12.5 The porphyrias 2045

formation of vesicles and bullae that may become infected. There nose, lips, ears, and scalp, and occasionally blindness due to corneal
are pigmentary changes with greatly increased skin fragility. Healing scarring (Fig. 12.5.3). Examination of the teeth shows erythrodontia
of the lesions with or without consequential infection often leads and deformities, and exposure to ultraviolet light may reveal striking
to cutaneous deformities with loss of digits, scarring of the eyelids, dental fluorescence. The condition is associated with osteoporosis

(a)

(b)

Fig. 12.5.3 Congenital erythroid porphyria (Gunther’s disease). (a) Pinnae and hand showing porphyrin deposits and tissue destruction due
to photonecrosis. (b) Splenomegaly. (c) Successive urine samples before and after splenectomy showing progressive postoperative reduction in
porphyrinuria (uroporphyrin I and coproporphyrin I).
2046 section 12 Metabolic disorders

(c) Pre-operative Day of surgery Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7

1 2 3 4 5 6 7 8 9 10 11

Fig. 12.5.3 Continued

and resorption of long bones as a result of gross expansion of the accidents such as that which occurred in Turkey in the 1960s.
erythroid bone marrow. Occasional cases have been reported after exposure to other halo-
Mutations in the uroporphyrinogen III synthase gene that maps genated phenols, but under these circumstances it appears simply
to chromosome 10q25.3–​q26.3 have been shown to be respon- to be an environmental toxic syndrome which is separate from the
sible for this disease and thus may assist in the prenatal diagnosis sporadic porphyria cutanea tarda that is precipitated by other spe-
of mothers who have previously given birth to an affected infant cific environmental factors including increased hepatic storage iron,
and are harbouring an at-​risk pregnancy. Constitutive activation of excess ethanol consumption, administration of oestrogens, hepatitis
the haem biosynthetic pathway in erythroid cells leads to persistent C virus infection, human immunodeficiency virus infection, and
overproduction of uroporphyrinogen I and coproporphyrinogen (possibly) nutritional deficiencies including antioxidants such as
I as by-​products of the defective synthesis of uroporphyrinogen III, vitamin C.
the sole precursor of protoporphyrin IX and haem. These reduced Most individuals who develop sporadic porphyria cutanea tarda
and colourless metabolites become oxidized to the fluorescent tissue prove to have increased iron stores in association with the presence
and urinary porphyrins associated with the passage of pink urine of one or more mutant alleles for the HFE gene that also predispose
that characterizes this often devastating disease. to the development of hereditary adult haemochromatosis. Many
Several infants and children with congenital erythropoietic por- patients also consume excess alcohol and smoke. There is a clear as-
phyria have been successfully treated by haematopoietic stem cell sociation with renal impairment in which the development of the
transplantation (HSCT) and this remains a convincing option for disease can be explained by the presence of iron overload (as a result
treatment of this very severe and otherwise life-​shortening in- of defective iron utilization with or without routine iron supplemen-
born error of haem metabolism. Splenectomy is often required in tation, particularly in patients on haemodialysis) and failure to ex-
early childhood to reduce transfusion requirements and improve crete excess plasma porphyrins that do not readily diffuse through
cytopenias (Fig. 12.5.3). It has recently been identified that an ap- the peritoneal cavity or haemodialysis membranes.
proved antifungal agent, ciclopirox, binds allosterically to and In sporadic porphyria cutanea tarda, there is a partial defi-
stabilizes several naturally occurring uroporphyrinogen III syn- ciency of uroporphyrinogen III decarboxylase activity in the liver
thase human mutants and restores their activity. This may lead to an and no family history of the condition. The sequencing of the
innovative treatment for this severe and destructive disease, which human uroporphyrinogen decarboxylase gene that maps to human
currently lacks molecular therapy. chromosome 1p34 has not provided any evidence of mutations to
account for the tissue-​specific enzyme deficiency, and no isoforms
Porphyria cutanea tarda of the enzyme have yet been identified, hence the molecular patho-
This disease is the most common of the cutaneous porphyrias and, genesis of sporadic porphyria cutanea tarda remains unknown, but
unlike other hepatic porphyrias, is never associated with acute it is clear that iron and other environmental influences inactivate the
porphyric crises. It is characterized by skin blistering which is re- hepatic enzyme. The relationship between regulators of iron homeo-
lated to sunlight exposure. stasis and the demand for haem biosynthesis in the hepatocytes of
affected individuals is not understood, but it appears likely from
Aetiology studies in experimental animals that genetic variation in the ex-
Toxic cutaneous porphyria may result from environmental exposure pression and activity of cytochrome isozymes such as P450 IA2 may
to dioxin or to hexachlorobenzene, particularly after industrial be critical for disease expression. Irreversible inhibition of hepatic
 12.5 The porphyrias 2047

uroporphyrinogen decarboxylase may also explain the occurrence light, which may burst leaving ulcerated lesions that are slow to heal.
of toxic porphyria cutanea tarda after exposure to halogenated hy- Increased pigmentation, often accompanied by areas of decreased
drocarbons, metabolites of which cause experimental uroporphyria pigmentation, is a common feature combined with increased hair
in animals. growth, particularly on the face.
Less than one-​quarter of patients who have porphyria cutanea Patients with porphyria cutanea tarda do not always notice the
tarda show a familial susceptibility to the condition, when muta- photosensitivity and rarely experience marked pain unless exposed
tions in one allele of the human uroporphyrinogen decarboxylase to brilliant sunlight. Occasionally, there is evidence of dermal injury
gene lead to catalytic deficiency of the enzyme in all cells, including and loss of nails, damage to the conjunctivae, and hair loss. Careful
erythrocytes. In most instances, the genetic defect leads to par- examination of the affected areas shows small depigmented cuta-
tial reduction of the enzyme protein encoded by the mutant allele. neous scars and the formation of milia. If bacterial infection occurs
Studies of pedigrees affected by familial porphyria cutanea tarda and there is repeated exposure to sunlight, then severe and per-
indicate that expressivity of the trait is very low; less than 10% of manent scarring may result.
heterozygotes develop clinical disease. Conversely, a very few pa- Typically, porphyria cutanea tarda occurs in middle-​aged men
tients present with a syndrome that closely resembles congenital with a history of alcohol use and in women after institution of
erythropoietic porphyria with marked blistering skin lesions, excess oestrogen replacement therapy; in young persons, infection with
hair growth, and cutaneous scarring in association with the excre- hepatitis C or the immunodeficiency virus may precipitate dis-
tion of pink or red urine. These individuals represent a homozy- ease expression. Frank signs of hepatomegaly or iron overload are
gous form of uroporphyrinogen decarboxylase deficiency, termed rare in porphyria cutanea tarda but have been noted; as with adult
hepatoerythropoietic porphyria, associated with a variety of muta- haemochromatosis, there is a significantly increased frequency of
tions in the uroporphyrinogen III decarboxylase gene. hepatocellular carcinoma.
In hepatoerythropoietic porphyria, the activity of uro­ Occasionally patients with porphyria cutanea tarda may notice an
porphyrinogen decarboxylase is markedly deficient, although re- increase in urine excretion of formed porphyrins which, especially
sidual activity remains to preserve essential haem biosynthesis in after concentration overnight, may resemble the colour of tea or
the erythron and liver. Most patients ultimately develop spleno- cola. The stool and urine contain large quantities of coproporphyrins
megaly with accelerated haemolysis closely resembling con- and uroporphyrins that fluoresce intensely on exposure to long-​
genital erythropoietic porphyria. Molecular analysis of the human wavelength ultraviolet light when placed in a suitable vessel for its
uroporphyrinogen decarboxylase gene may assist the prenatal diag- transmission (namely silica rather than standard glass). Similarly,
nosis of at-​risk pregnancies in women who have already given birth examination of liver biopsy specimens under ultraviolet light reveals
to an affected infant. bright red/​orange fluorescence; microscopic examination may also
show coincidental hepatitis with or without excess deposits of stain-
Clinical features able tissue iron reflecting the increased iron storage of this disease.
The clinical features of porphyria cutanea tarda of whatever form In sporadic porphyria cutanea tarda, increased storage iron is re-
are very characteristic and are confined to light-​exposed skin flected by the modest elevations of serum ferritin that often occur
(Fig. 12.5.4). Usually, the only signs are of erosions resulting from in association with the presence of one or more copies of the C282Y
minor trauma in skin, with increased fragility as a result of light ex- allele of the HFE gene that maps to human chromosome 6 and which
posure, typically on the dorsum of the hands. Other changes include is associated with adult haemochromatosis.
the development of large subepidermal bullae after exposure to
Treatment
Sunlight exposure should be avoided as much as possible and sun-
block creams used until the porphyrin abnormality is corrected.
Care is needed to protect fragile skin from mechanical injury and
from infection. Patients should be advised to moderate or stop their
intake of alcohol and avoid the use of iron tonics and sex hormones,
especially oestrogens.
Screening should be undertaken for chronic infection with human
immunodeficiency virus and hepatitis viruses, especially hepatitis
C. Management should also include imaging or biopsy of the liver
if serum liver-​related tests are abnormal, as well as measurement of
serum α-​fetoprotein since there is a risk of hepatocellular carcinoma
in this disease.
Most patients with porphyria cutanea tarda respond to iron de-
pletion by phlebotomy and initial iron status should be determined
by measuring serum ferritin concentrations. Weekly or fortnightly
Fig. 12.5.4 Porphyria cutanea tarda in a 60-​year-​old heterozygote removal of 500 ml of blood will usually correct the abnormal urine
for the HFE p.C282Y mutation. This man, a taxi driver, had noticed and plasma porphyrin profile within a few months, but maintenance
irritation after exposure of his hands to light transmitted through the
windscreen. He had noticed fragility and blistering combined with
phlebotomy will be required, usually amounting to the removal of
pigmentary changes typical of this disorder. After treatment by controlled 2 to 4 units of blood at intervals each year. Successful therapy re-
phlebotomy his skin complaint has regressed. duces the urinary excretion of porphyrins to normal. Patients with
2048 section 12 Metabolic disorders

porphyria complicating renal failure should be treated with recom- macrocycle, partial deficiency of this enzyme will give rise to the
binant human erythropoietin and depleted of iron by gentle phle- compensatory increase in protoporphyrin abundance and hence the
botomy or parenteral desferrioxamine if necessary. consequential photodynamic effects of protoporphyria.
The cutaneous manifestations of porphyria cutanea tarda respond These findings are reflected in a large series of 226 patients with
rapidly to low-​dose chloroquine treatment, which should be con- a clinical and biochemical diagnosis of protoporphyria from the
sidered in patients with persistent symptoms or at the outset before United States of America. This demonstrated an equal sex distri-
iron storage has been fully corrected. This action of chloroquine bution and mean age of 37 years. A ferrochelatase mutation and
was discovered empirically, but the agent forms complexes with the common low-​expression mutation was detected (presumed in
uroporphyrin deposits and promotes their external cellular disposal, trans) in 186 (82.3%) and only one patient had two FECH mutations.
promoting excretion of uroporphyrin from the liver and inducing Twenty-​two patients had X-​linked protoporphyria (9.7%; 10 male
marked but transient porphyrinuria. Although chloroquine usually and 12 female). Of note, nine patients (4.0%) had symptomatic and
provides rapid relief from the cutaneous disease and photosensi- biochemical evidence of protoporphyria but no detectable mutation
tivity, it does not correct the underlying metabolic defect in the liver in the FECH or ALAS2 genes (see following subsections).
and its long-​term use is not recommended unless the other pro-
vocative factors in porphyria cutanea tarda have been removed. The CLPX gene-​related protoporphyria
usual effective dose of chloroquine is 100 to 200 mg given once or Several patients with clinical and biochemical protoporphyria but
twice weekly; larger doses are associated with marked hepatic tox- lacking FECH or ALAS2 mutations have been shown to harbour
icity in porphyria cutanea tarda. The drug is reported to have no heterozygous mutations in an unusual AAA+ (ATPases associated
therapeutic effect on other photosensitive porphyrias. with diverse cellular activities) protease, caseinolytic mitochondrial
matrix peptidase chaperone subunit (ClpXP), of the Clp protease
(Erythropoietic) protoporphyria and X-​linked complex that regulates ALAS2 activity among other mitochondrial
protoporphyria proteins. The gene CLPX encodes a chaperone subunit that confers
Protoporphyria is caused by the overproduction of the immediate ATP-​dependent specificity of the Clp protease complex, which acts
precursor of haem, protoporphyrin IX, principally in the bone as an unfolding enzyme that regulates ALAS1 and ALAS2 proteins.
marrow. It causes an unusual cutaneous photosensitivity syndrome Another action of the protein is to facilitate incorporation of the
that presents in infancy and is a neglected cause of fatal hepatobiliary essential pyridoxal 5´-​phosphate cofactor into 5-​aminolaevulinate
disease in about 5% of those affected. synthase.
Detailed studies in several experimental systems of the first mu-
Genetics tant ClpXP protein in a family with protoporphyria but no muta-
Protoporphyria is inherited as a recessive condition but often tions in either FECH or ALAS2 genes convincingly showed that the
generation-​to-​generation transmission of the disease has been ob- mutation would disrupt the ATP binding domain of the protein
served. An original ingenious postulate of an autosomal three-​allele but leave the activating and stabilizing chaperone function towards
mode of transmission has been further refined by the remarkable the ALAS pyridoxal cofactor intact. The predicted net effect would
identification of causal mutations at three distinct chromosomal be activation of the ALAS2 enzyme in erythroid cells and in effect
loci—​the ferrochelatase gene (FECH on chromosome 18q21.31), protoporphyrin substrate overdrive at the next rate-​limiting step in
the erythroid 5-​ aminolaevuliate synthase gene (ALAS2, which the pathway, ferrochelatase. These are early findings and more com-
maps to Xp11.21), and the caseinolytic mitochondrial matrix prehensive genetic studies are needed fully to explore the role of
peptidase chaperone subunit gene (CLPX, localized on chromo- ClpX mutations in erythropoietic protoporphyria.
some 15q21.32). Inheritance of mutations in the coding region
of the ferrochelatase gene that partially inactivate the enzyme are X-​linked protoporphyria
coinherited in the trans isomer with a low-​expression allele (FECH X-​linked protoporphyria is due to inheritance of gain-​of-​function
IVS3–​48T>C) that occurs at polymorphic frequency (c.10%) in the variants of ALAS2 enzyme in which erythroid precursor cells over-
population, which gives rise to apparent dominant transmission in produce 5-​aminolaevulinate and accounts for 5 to 10% of patients
some families. Parent-​to-​offspring transmission of protoporphyria with a diagnosis of protoporphyria. While this disorder also demon-
occurs in less than 10% of cases, but in all instances of the disease strates generation-​to-​generation transmission and may erroneously
there is a marked deficiency of the enzyme ferrochelatase (substan- be considered as a dominant trait of variable penetrance, the ALAS2
tially <50% of control values). The asymptomatic carrier parent only gene on the short arm of the X chromosome undergoes gene-​dosage
shows mild ferrochelatase deficiency with occasional fluorescent red compensation by lyonization. Females with the trait may be asymp-
cells that are even visible on examining the unstained blood film by tomatic and—​as somatic mosaics—​show greater variability of clin-
conventional ultraviolet light transmission microscopy. ical expression than affected males within their pedigree.
A few patients, usually with clinically severe protoporphyria,
have biallelic mutations in ferrochelatase—​ true recessive Diagnosis
protoporphyria—​ and these may be predisposed to the severe The detection of markedly increased free erythrocyte protoporphyrin
cholestatic liver disease described in several pedigrees. Since and zinc-​chelated erythrocyte protoporphyrin is the most sen-
ferrochelatase, an iron-​ sulphur cluster protein located on the sitive biochemical diagnostic test for this disease. Identification
inner mitochondrial membrane, is responsible for the final step of of pathogenic gain-​of-​function variants affecting the last exon of
haem biosynthesis in the inner mitochondrial membrane, where it ALAS2, the gene encoding erythroid-​specific 5-​aminolaevulinate
catalyses the insertion of ferrous iron into the protoporphyrin IX synthase 2, confirms the diagnosis. These mutations have proved
 12.5 The porphyrias 2049

to be sequence variants in exon 11 and in other coding and spli-

cing regions. Thorough expression studies of the cognate isozyme
show consistently enhanced catalytic activity for the formation of
aminolaevulinate, which in the pathological milieu of erythroid
precursor cells in protoporphyria presumably leads to a relative,
secondary bottleneck at the level of ferrochelatase with the conse-
quential constitutive overproduction of protoporphyrin IX.

Clinical features and pathology

Skin disease
Protoporphyria characteristically presents with severe burning pain
and cutaneous irritation on exposure to visible light and is usually
obvious in infancy or early childhood. Erythema and diffuse oe-
dema may follow marked light exposure, but vesicles, blistering, and
altered skin fragility are most unusual. After several years, increased
pigmentation and thickening of the skin (lichenification) occur, es-
pecially over the knuckles. A typical feature is of shallow scarring in
the malar regions of the cheeks and at the angle of the lips, where Fig. 12.5.6 Examination of human plasma under long-​wave ultraviolet
scarring is termed ragades. Overt scarring is unusual. There are no light. Plasma on the left was obtained from a patient with protoporphyrin
changes in urine colour. Protoporphyria is often the subject of de- hepatopathy and greatly increased photosensitivity. On the right is
layed diagnosis because of the marked disparity between the severity plasma obtained from a healthy subject. Maximum fluorescence
was obtained by exposure to visible light in the violet and green–​
of the symptoms and the development of physical signs in the skin. yellow spectral regions, corresponding to the absorbance bands of
The cutaneous pathology results from photoactivation of red protoporphyrin. Note the bright red fluorescence due to the presence of
cell-​and plasma-​ derived protoporphyrin IX in skin capillaries high concentrations of free protoporphyrin.
(Figs. 12.5.4 and 12.5.5). Protoporphyrin IX is a hydrophobic mol-
ecule that dissolves in cell membranes; it has a photoactivation spec-
trum in the Soret region with subsidiary activation by green and insignificant until severe cholestatic hepatic disease occurs, when
yellow light. Photoinjury is associated with complement activation splenomegaly and hypersplenism aggravate haemolysis. The
and release of vasoactive factors; there is intracellular epidermal photosensitivity worsens under these circumstances and there is
oedema accompanied by acute inflammatory changes and extrava- upper abdominal pain with splenic enlargement, jaundice, and ex-
sated red cells. Deposits of hyaline material are found in superficial treme photosensitivity as concentrations of free protoporphyrin in
capillaries with thickening of the basement membranes. the plasma rise (Fig. 12.5.6). A vicious cycle of decompensation is
established with either fulminant hepatic failure associated with
Haematological and liver disease cholestasis due to protoporphyrin deposits within biliary radicals,
Mild hypochromic microcytic changes with mild anaemia are or the development of cirrhosis. Without treatment (hepatic trans-
usually the only manifestations of disturbed haem biosynthesis plantation) the prognosis is dismal.
and iron metabolism in the bone marrow, although examin- Protoporphyria is normally associated with trivial abnormalities of
ation of the marrow may reveal occasional sideroblasts with serum liver-​related tests but in a few patients micronodular cirrhosis
intramitochondrial iron deposits. Haemolysis is usually clinically with pigment deposition occurs. Examination of the liver under po-
larized light shows birefringent crystals with a characteristic Maltese-​
cross appearance, and examination under long-​ wave ultraviolet
light reveals bright fluorescence. Gallstones containing precipitated
protoporphyrin occur frequently, but cholestasis results principally
from intracellular and canalicular precipitation of protoporphyrin.
Deteriorating hepatic disease is heralded by generalized abdominal
pain, splenic enlargement, worsening jaundice, and haemolysis.

Treatment
Interruption of the enterohepatic circulation of protoporphyrin
with charcoal or polymeric cationic resins, such as cholestyramine,
may arrest the early downhill course by binding protoporphyrin or
promoting hepatic bile acid secretion. However, once established,
hepatic decompensation and accelerating photosensitivity is rapid.

Haematopoietic stem cell transplantation or bone

Fig. 12.5.5 Fluorescence microscopy of an unstained blood film from marrow transplantation
a patient with erythropoietic protoporphyria. Note the fluorescence of
increased free protoporphyrin within individual young erythrocytes and Studies in mice and in a few human patients with protoporphyria
reticulocytes. confirm that the disease can be arrested, and in practical terms
2050 section 12 Metabolic disorders

completely corrected by HSCT or bone marrow transplantation. β-​carotene had only small or marginal objective benefit for the light-​
Carried out sufficiently early, HSCT allows at least partial recovery induced symptoms of protoporphyria.
of the damaged or failing protoporphyric liver and is the ideal pro- Melanin, in the form of eumelanin, quenches ultraviolet light and
cedure in patients who are at high risk of fatal liver disease: por- scavenges free radicals; it also acts as a neutral density filter that re-
phyrin biochemistry is corrected and photosensitivity is no longer duces all wavelengths of light. Moreover, melanogenesis may pro-
present, liver-​related tests and imaging can be restored to healthy vide a major antioxidant drive. Increasing melanin formation in the
values. epidermis by narrow-​band phototherapy has been shown to im-
Theoretically, the definitive therapy of protoporphyria will re- prove phototoxic symptoms in five patients with protoporphyria,
quire restoration of erythroid cell ferrochelatase activity in bone whose tolerance of a standardized source of high-​radiance xenon
marrow. There is a single report of successful marrow transplant- light improved progressively over 120 days. While the narrow-​band
ation in protoporphyria with coincidental myeloid leukaemia. This phototherapy requires careful exposure protocols and is reserved for
procedure cured the symptomatic protoporphyria. In future, either specialist centres, the benefit gained provides proof of concept for
bone marrow transplantation or erythroid progenitor gene therapy the exploration of other means to stimulate melanin synthesis.
will be used to correct this disease in patients with life-​threatening Administration of a depot preparation of afamelanotide, an α-​
liver sequelae. Ancillary treatment by blood transfusion or red cell melanocyte-​stimulating hormone analogue, has been explored in
exchange transfusion will reduce the immediate source of plasma clinical trials in patients with protoporphyria in Europe and the
and red cell protoporphyrin, and in the immediate preoperative United States of America. Compared to placebo, subcutaneous
period plasmapheresis may also reduce phototoxicity. implants of the drug given every 60 days increased the patients’
hours of direct exposure to sunlight, greatly reduced the number
Liver transplantation of phototoxic reactions, and the patients’ quality of life improved.
Established severe protoporphyrin hepatotoxicity remains an in- Adverse events were mostly mild, serious adverse events were not
dication for liver transplantation, but even successful treatment is considered to be related to the afamelanotide, and it has received
likely to be complicated by recurrence of the disease in the engrafted marketing approval as Scenesse for this indication in the European
liver, with the pace at which the liver deteriorates being difficult Union since 2014.
to predict. For these reasons, some patients will be considered for
serial hepatic and marrow transplantation/​HSCT. There is evidence
that splenectomy may reduce the haemolytic component of end-​ Treatment of an acute porphyric attack
stage protoporphyria, hence consideration should be given to the
simultaneous removal of the enlarged spleen at the time of the liver It is essential to establish that the symptoms complained of are caused
transplantation. by an acute attack of porphyria. Of key importance is the careful la-
In some patients with end-​ stage liver disease due to proto­ boratory analysis of urine and blood early in the course of the illness.
porphyria, a bizarre neurological syndrome has been identified. This demonstrates elevated concentrations of porphyrins and haem
Axonal neuropathies requiring mechanical ventilation and cranial precursors typified by elevated urinary 5-​ aminolaevulinate and
nerve palsies have been reported in the perioperative period. Under porphobilinogen, which should be high in an attack of acute por-
these circumstances, coproporphyrin and uroporphyrins appear in phyria. The urine sample should be freshly taken from the patient
the urine and may account for a blistering photosensitivity in end-​ and protected from light before analysis to avoid nonenzymatic
stage protoporphyric liver disease. conversion of the porphyrin precursors to porphyrins and hence
Operative treatment in patients with protoporphyria can be very misdiagnosis.
dangerous as a result of phototoxic injury to visceral tissues and
mucous membranes exposed to brilliant vertical lighting in the Immediate management
operating theatre. Surgical lights are best attenuated by the use of An immediate and fastidious review of avoidable factors that would
filters that reduce spectral power output below 530 nm; such precau- precipitate or aggravate an attack is mandatory. The precipitating
tions should be used throughout the perioperative period to reduce factors are usually drugs, alcohol, exogenous or endogenous hor-
overall phototoxicity in the clinical environment. monal changes, fasting (including that due to dieting), or recent
surgical procedures. More than 100 drugs may induce attacks of
Management of photosensitivity porphyria (Boxes 12.5.1 and 12.5.2). Particular care should be
Photosensitivity is managed by avoiding excessive light exposure, taken to exclude agents that are obtained over the counter as tonics
remembering that visible light of exciting green and violet wave- or herbal remedies. Any agent that might be implicated should be
lengths traverses ordinary window glass. Effective sunscreen prepar- stopped immediately.
ations may assist management, especially in young children at risk. Abdominal pain and distress, together with anxiety, require
For many years, β-​carotene has been given to patients with prompt treatment; opiates which are safe in porphyria may be useful,
protoporphyria: it may absorb light energy at the appropriate wave- although they often exacerbate constipation. Opiates may be com-
lengths and also serve as a free-​radical quenching agent. The prep- bined with phenothiazine tranquillizers such as chlorpromazine,
aration Lumitene at a dosage of 120 to 180 mg/​day is normally used. which may usefully potentiate their action.
This causes orange staining of the skin due to carotenaemia, but Since starvation induces attacks of porphyria and haem biosyn-
is otherwise well tolerated and may improve tolerance to sunlight thesis may be suppressed by the ingestion of carbohydrate, it is
when plasma carotene concentrations between 10 and 15 µmol/​ advised that patients with minor attacks should eat regular meals
litre are achieved. A recent review of 20 studies of concluded that containing carbohydrate in a complex form such as starch for its
 12.5 The porphyrias 2051

slow release. One-​half to two-​thirds of the energy intake should be of exaggerated oscillation of haem catabolism by the induction of
derived from ingested carbohydrate. haem oxygenase in the liver. Tin protoporphyrin, an inhibitor of
The management of an acute attack should involve repeated moni- haem oxygenase, has been considered in this circumstance. This
toring for the development of hyponatraemia, which may be very se- agent is only available in specialist centres and, because it contains
vere as a result of inappropriate secretion of antidiuretic hormone. toxic heavy metal and itself may induce photosensitivity, is currently
In the past, intravenous glucose or fructose solutions have been ad- not recommended for routine use.
vocated as a means to suppress haem biosynthesis in the liver. Great Hypersensitivity reactions to haem arginate are rare and the drug
caution is needed in the use of these agents, either as 5 or 20% solu- has been used during attacks in pregnant women without injury to
tions, since they exacerbate hyponatraemia and may cause fatal cere- either the mother or the child.
bral oedema. In the author’s view, if the patient is sufficiently unwell Haem contains 10% by weight of iron and the maximum daily
not to be able to control the attack with oral carbohydrate-​rich food, dose of haem arginate would contain only 23 mg of elemental iron;
parenteral preparations of haem such as haem arginate, rather than the development of iron storage disease is unlikely, except in very
glucose or other sugar solutions, should be administered. rare instances where an acutely ill patient receives numerous infu-
sions of haematin over prolonged periods. However, patients who
Haem therapy have received regular haem arginate infusions over more than
Haem arginate is administered by a short intravenous infusion in 10 years have developed iron accumulation, with increased serum
porphyric crises of sufficient severity to merit hospital admission or ferritin concentrations and magnetic resonance signals indicating
those associated with limiting pain or metabolic disturbance. Haem iron accumulation in the liver, spleen, and bone marrow. Such iron
arginate supplied by Orphan Europe (see ‘Sources of information) is accumulation has been associated with histological evidence of hep-
provided as a stable 25 mg/​ml concentrate and should be adminis- atic fibrosis and emphasizes the need for careful evaluation of the
tered at a dosage of 3 mg/​kg body weight (to a maximum dose of 250 relative harm and benefits of treating refractory disease by haem
mg) once daily for up to 4 days. It should be given in 100 ml physio- arginate or liver transplantation.
logical saline infused into a large vein over at least 30 min. Haem
arginate, like all preparations of haem, tends to polymerize and is Carbohydrate loading
unstable, hence the administration should be completed within 1 h Where haem therapy is not available, parenteral carbohydrate
after diluting the concentrate, the shelf-​life of which is about 2 years. loading is the only alternative treatment for an acute attack; 2 litres
In the United States of America, haemin appears to be a compar- of a 20% weight per volume glucose solution is recommended over a
able preparation for suppressing hepatic haem synthesis and cor- 24-​h period, administered through a central venous catheter. There
recting the metabolic disturbance of the acute attack. Haem arginate are risks from giving such therapy as outlined previously and in the
and a preparation of haem albumin are apparently somewhat more author’s opinion the treatment has been superseded by the introduc-
stable than haemin, which tends to produce phlebitis or interfere tion of stable preparations of haem.
with the action of coagulant proteins. Recovery from an acute attack
depends on the degree of damage to the nervous system and may Management of complications of acute
occur within 1 or 2 days if haem therapy is introduced at the outset. porphyric attacks
Certain proof of clinical benefit of haem treatment is lacking, but
Hypertension
there is sufficient evidence of its benefit for it to be approved in 19
countries, including the United Kingdom. Haem arginate has a rapid Hypertension is frequent in porphyric attacks and may be very se-
effect on the excretion of aminolaevulinate and porphobilinogen in vere as a result of sympathetic overactivity; during the attack, sinus
acute porphyria, and retrospective studies suggest that outcomes tachycardia is frequent. β-​Blockers are effective in the control of the
are better than that in patients previously documented before the hypertension and labetalol and propranolol are safe; they also relieve
use of the agent. Moreover, the results of a double-​blind study com- the sinus tachycardia.
paring placebo and haem therapy showed a trend in favour of haem
arginate in terms of duration of hospital stay and the requirement Hyponatraemia and seizures
for pain relief, although the differences did not quite reach statistical Hyponatraemia may be very severe and in acute porphyria pro-
significance in the limited study of 12 patients. On the balance of gresses on a daily basis during the course of the acute attack in most
probabilities, however, the evidence for a beneficial effect of haem patients. The rapid onset of severe hyponatraemia clearly contributes
arginate therapy, particularly at the onset of a porphyric attack, is to confusion and other mental symptoms associated with a porphyric
compelling. attack. Prompt treatment by fluid restriction and appropriate careful
Haem therapy should be used in any patient with significant use of hypertonic saline is needed (see Chapter 22.2.1). The place-
hyponatraemia, incipient neuropathy, seizures, or bulbar paralysis, ment of a patient with porphyric abdominal pain on a surgical ward,
and in any patient with severe symptoms, particularly of abdominal with the almost inevitable administration of an intravenous infusion
pain. It must be recognized that patients with established neuropathy of 5% dextrose, may contribute to death as a result of cerebral oe-
may take many months or even years to recover from an attack and, dema or the complications of rapid-​onset hyponatraemia.
if it is to be effective, haem therapy should be introduced early. Grand mal seizures in acute porphyric attacks pose a par-
Occasional patients, usually women, are seen in whom repeated ticular problem for management; they are often precipitated by the
acute attacks occur irrespective of the use of one or two courses hyponatraemia that frequently complicates an acute attack. Clearly,
of haem arginate. The reason for this is unknown, but it is pos- from every aspect, prevention is the optimal course of action and
sible that haem arginate therapy induces tachyphylaxis as a result appropriate management of the electrolytic abnormality is an
2052 section 12 Metabolic disorders

essential element of treatment. Even in an era of greater awareness, Acute perimenstrual attacks can be controlled by the prompt ad-
fits and status epilepticus occur and pose special difficulties. Seizures ministration of haem arginate for 1 to 2 days at the predicted time
have been treated successfully with parenteral diazepam or the re- of susceptibility.
lated benzodiazepine, temazepam. Carbamazepine, lorazepam,
and midazolam are probably (but not definitely) safe in acute por- Liver transplantation
phyria. Clonazepam and valproate have each been used for seizure The combination of recurrent life-​threatening porphyric attacks and
prevention; the generally outmoded therapy of bromide may also poor venous access for administration of therapeutic haem prepar-
have a role. Acetazolamide, which has been used as a minor agent ations, or unresponsiveness to haem treatment, has led to the use of
in seizure prophylaxis, has been used safely in acute porphyria, but liver transplantation in a few young women with this disease. This
many first-​line drugs such as carbamazepine, sodium valproate, approach can be successful, although it should be reserved for those
phenytoin, and chloral hydrate have been classified as unsafe or are who are able to cooperate with the peri-​and postoperative surgical
frankly porphyrinogenic. Primidone and phenobarbitone are abso- regimens. Scrupulous attention to removing all definable risk fac-
lutely forbidden. tors, including smoking, is clearly necessary before such measures
Further problems arise in the management of acutely disturbed are considered.
patients who are not responsive to the safe but outdated phenothia- The first successful transplant was carried out in 2002 in a young
zine, chlorpromazine. Thioridazine is classed as unsafe, but paren- woman with severe frequent neurovisceral attacks which were cured
teral haloperidol was used with good effect in a few patients with by the procedure. A subsequent retrospective review of 10 patients
uncontrollable or life-​threatening manic aggression and paranoid (9 women) aged 18 to 50 years reported that clinical and biochem-
disturbance during their acute attack. In all instances, prescription ical remission occurred in all patients, with urinary porphyrin
of any agent to a patient who has had or is having an acute porphyric precursors returning to the healthy reference range within 72 h of
crisis must involve consultation with a reliable pharmacopoeia with surgery. In a few cases, patients with renal failure requiring haemo-
individual drugs categorized for safety (see Boxes 12.5.1–12.5.3). dialysis and associated hypertension have undergone simultaneous
liver and kidney transplantation.
Cimetidine
The ability of most drugs to initiate attacks of porphyria appears Gene therapies
in many instances to be related to their effects on the induction of Complementing, liver-​directed gene therapy
haem biosynthesis in the liver and specifically for the formation Gene delivery of porphobilinogen deaminase (hydroxymethylbilane
of the relevant P450 xenobiotic-​metabolizing isoforms. One key synthase) to hepatocytes using a recombinant adeno-​associated
isoform involved in the induction of porphyria is inhibited, at least virus vector serotype 5 (rAAV2/​5-​PBG) in a murine model of acute
in vitro, by the H2 antagonist cimetidine. It has been reported that intermittent porphyria prevented acute porphyric attacks after chal-
cimetidine at 400 to 800 mg daily is sufficient to inhibit induction lenge of the animals with barbiturate. In a subsequent human phase
of this P450 isozyme in adult humans. Cimetidine has been ad- I, open label, dose-​escalation, multicentre clinical trial, administra-
ministered with occasional success as a means to inhibit or control tion of rAAV2/​5-​PBGD to patients with severe acute intermittent
spontaneous porphyric crises and as a last resort it might be con- porphyria was safe, but metabolic correction was not achieved at
sidered in patients with life-​threatening and otherwise uncontrol- the doses tested although two out of eight patients were able to stop
lable disease. haemin infusions. However, securing long-​term correction of the
Prevention and management of recurrent acute liver would require permanent transduction of the entire organ and
porphyric attacks this challenge has yet to be overcome with the recombinant adeno-​
associated viral system.
Hormonal interventions
Young women with cyclical porphyric attacks may benefit tem- RNA interference
porarily from hormonal intervention by the use of gonadotropin-​ Short-​interfering RNA molecules (siRNAs) are able to modulate gene
releasing hormone analogues such as goserelin or buserelin. These expression. Experiments conducted in mice that model acute inter-
agents inhibit androgen, oestrogen, and progestogen production mittent porphyria have explored an investigational RNA interference
and as a result they induce menopausal-​like symptoms and depres- agent (givosiran) that specifically targets hepatic ALAS1 gene expres-
sion, as well as rapid decreases in trabecular bone density. Doses sion: it was able to prevent and curtail the biochemical abnormalities
sufficient to suppress luteinizing and follicle-​stimulating hormone and paralysis associated with barbiturate challenge in affected animals.
concentrations in serum are required. Prolonged use for more Givosiran is currently undergoing late-​phase clinical development for
than a few months is not recommended, but buserelin may be used the treatment of acute hepatic porphyria: monthly subcutaneous ad-
intranasally and may be more convenient. To avoid the worst aspects ministration suppresses pathologically induced liver ALAS1 activity
of hypogonadism in women, low-​dose oestrogen therapy under ap- in a sustained manner, thereby decreasing aminolaevulinate and
propriate gynaecological supervision may be coadministered once porphobilinogen to near normal concentrations in plasma and urine.
cyclical porphyric attacks have come under control. Given the risk of At the time of writing, givosiran has been granted ‘Breakthrough
accelerated skeletal demineralization and osteoporosis, it is prudent, Therapy’ designation by the Food and Drug Administration in the
especially in women, to monitor bone mineralization density in pa- United States of America and PRIME designation by the European
tients receiving gonadotrophin-​releasing hormone analogues and to Medicines Agency; it has also been granted orphan drug designations
use appropriate bone conserving therapy as advised. in both the United States of America and the European Union for the
 12.5 The porphyrias 2053

treatment of acute porphyria. Its safety and efficacy are under investi- The American Porphyria and Canadian Porphyria Foundations
gation in the ENVISION phase III clinical trial and an ongoing phase may be accessed via the Internet websites.
I/​II study. The outcomes of these studies have yet to be formally evalu- Warning jewellery: it is often valuable in patients with acute
ated by the regulatory authorities, but interim updates indicate that porphyrias for them to have a wrist bracelet or neck pendant that
annualized rates of acute porphyric attacks and of haemin use are both provides information about diagnosis in medical emergencies.
reduced by over 90%, with no significant safety concerns excepting an Details in the United Kingdom can be obtained from The MedicAlert
anaphylactic reaction in a single patient. Foundation, 12 Bridge Wharf, 156 Caledonian Road, London N1
Given the striking efficacy and relatively sustained and salutary effects 9UU. Telephone: +44 (0)207 833 3034.
of givosiran in patients with severe recurrent acute porphyria under-
going clinical trials, it seems likely that those who are able to gain access
to this innovative RNA interference therapy will no longer be looking to FURTHER READING
liver transplantation or repeated use of haem infusions to control their
Anderson KE, et al. (2004). Disorders of heme biosynthesis: X-​linked
disease. At the time of writing (2019), long-term safety data and reim- sideroblastic anemia and the porphyrias. In: Scriver CR, et al. (eds)
bursement stratagems for this are incompletely worked out; however, The metabolic and molecular bases of inherited disease, 8th edi-
it seems very likely that the recommended management of all but the tion, vol. 2, pp. 2991–​3062. McGraw-​Hill, New York. http://​www.
most mild or occasional disease will include siRNA therapy. ommbid.com.
Balwani M, et al. (2017). Clinical, biochemical, and genetic characteriza-
tion of North American patients with erythropoietic protoporphyria
Sources of information and X-​linked protoporphyria. JAMA Dermatol, 153, 789–​96.
Balwani M, et al. (2017). Acute hepatic porphyrias: recommenda-
Drugs, drug interactions, and safe prescribing tions for evaluation and long-​term management. Hepatology, 66,
1314–​22.
British National Formulary, British Medical Association, Bylesjö I, Wikberg A, Andersson C (2009). Clinical aspects of acute
Tavistock Square, London WC1H 9JP. intermittent porphyria in northern Sweden: a population-​based
United Kingdom and Royal Pharmaceutical Society of Great study. Scand J Clin Lab Invest, 69, 612–​18.
Britain, 1 Lambeth High Street, London SE1 7JN. Chiabrando D, Mercurio S, Tolosano E (2014). Heme and erythropoi-
The Drug Database for Acute Porphyria: http://​ www.drugs-​ esis: more than a structural role. Haematologica, 99, 973–​83.
porphyria.org/​. Collins P, Ferguson J (1995). Narrow-​band UVB (TL-​01) photo-
The United Kingdom Drug Information Pharmacists Group: therapy: an effective preventative treatment for the photdermatoses.
http://​www.ukdipg.org.uk. Br J Dermatol, 132, 956–​63.
The Welsh Medicines Information Centre (WMIC) provides ad- Cox TM (2007). The porphyrias. In: Lomas D (ed) Horizons in medi-
vice on drug safety in acute porphyria. The Cardiff safe drug list is cine, vol. 19, pp. 67–​83. Royal College of Physicians, London.
Elder G, et al. (2013). The incidence of inherited porphyrias in Europe.
available via their website. Contact is by telephone: +44 (0)29 2074
J Inherit Metab Disease, 36, 849–​57.
3877 or fax: +44 (0)29 2074 3879.
Elder GH, Smith SG, Smyth SJ (1990). Laboratory investigation of the
Haem arginate (Normosang) is supplied in the United Kingdom porphyrias. Ann Clin Biochem, 27, 395–​412.
by Orphan Europe (UK) Limited: 200 Brook Drive, Green Park, Fontanellas A, Ávila MA, Berraondo P (2016). Emerging therapies for
Reading, Berkshire, RG2 6UB, UK. http://​ www.orphan-​ europe. acute intermittent porphyria. Expert Rev Mol Med, 18, e17.
com. Telephone: +44 (0)1491 414 333. Medical Information e-​mail: Gorchein A (1997). Drug treatment in acute porphyrias. Br J Clin
infoUK@orphan-​ europe.com; stock availability: krobinson@ Pharmacol, 44, 427–​34.
orphan-​europe.com Handshin C, et al. (2005). Nutritional regulation of hepatic heme syn-
thesis and porphyria through PGC-​1α. Cell, 122, 505–​15.
Advice about management of acute porphyria Holme SA, et al. (2006). Erythropoietic protoporphyria in the
National Acute Porphyria Service—​Cardiff & Vale University U.K.: clinical features and effect on quality of life. Br J Dermatol, 155,
Health Board and Kings College Hospital London are designated 574–​81.
by the Advisory Group for National Specialised Services, NHS Innala E, et al. (2010). Evaluation of gonadotropin-​releasing hormone
England, to provide a national service for patients with active acute agonist treatment for prevention of menstrual-​related attacks in
acute porphyria. Acta Obstetrica Gynecol Scandanvica, 89, 95–​100.
porphyria (acute intermittent porphyria, variegate porphyria, her-
Kauppinen R, Mustajoki P (1992). Prognosis of acute porphyrias: oc-
editary coproporphyria).
currence of acute attacks, precipitating factors, and associated dis-
Two further Regional Porphyria Centres provide services (in eases. Medicine (Baltimore), 71, 1–​13.
Salford and Leeds) for patients who have recently had a new acute Kauppinen R (2005). Porphyrias. Lancet, 365, 241–​52.
attack or with recurrent acute attacks. They provide clinical advice Langendonk JG, et al. (2015). Afamelanotide for erythropoietic
and support to healthcare professionals within the patient’s own protoporphyria. N Engl J Med, 373, 48–​59.
hospital. 24-​h emergency telephone: 029 2074 7747. Lenglet H, et al. (2018). From a dominant to an oligogenic model of
inheritance with environmental modifiers in acute intermittent por-
Patient associations phyria. Hum Mol Genet, 27, 1164–​73.
The British Porphyria Association, 136, Devonshire Road, Durham Marsden JT, et al. (2015). Audit of the use of regular haem arginate in-
City, DH1 2BL, UK. http://​www.porphyria.org.uk; email: helpline@ fusions in patients with acute porphyria to prevent recurrent symp-
porphyria.org.uk toms. JIMD Rep, 22, 57–​65.
2054 section 12 Metabolic disorders

Millward LM, et al. (2001). Self-​rated psychosocial consequences Shaw PH, et al. (2001). Treatment of congenital erythropoietic por-
and quality of life in the acute porphyrias. J Inherit Metab Dis, 24, phyria in children by allogeneic stem cell transplantation: a case re-
733–​47. port and review of the literature. Bone Marrow Transplant, 27, 101–​5.
Mustajoki P, Nordmann Y (1993). Early administration of heme Singal AK, et al. (2014). Liver transplantation in the management of
arginate for acute porphyric attacks. Arch Int Med, 153, 2004–​8. porphyria. Hepatology, 60, 1082–​9.
Neeleman RA, et al. (2018). Medical and financial burden of acute Stein PE, Badminton MN, Rees DC (2017). Update review of the acute
intermittent porphyria. J Inherit Metab Dis, 41, 809–​17. porphyrias. Br J Haematol, 176, 527–​38
Peoc’h K, et al. (2018). Hepatocellular carcinoma in acute hepatic Sylantiev C, et al. (2005). Acute neuropathy mimicking porphyria in-
porphyrias: a Damocles sword. Mol Genet Metab, Oct 9. doi: 10.1016/​ duced by aminolevulinic acid during photodynamic therapy. Muscle
j.ymgme.2018.10.001. Nerve, 31, 390–​3.
Pischik E, Kauppinen R (2015). An update of clinical management of Urquiza P, et al. (2018). Repurposing ciclopirox as a pharmacological
acute intermittent porphyria. Appl Clin Genet, 8, 201–​14. chaperone in a model of congenital erythropoietic porphyria. Sci
Poh-​Fitzpatrick MB (1985). Porphyrin-​sensitized cutaneous photo- Transl Med, 10, eaat7467.
sensitivity: pathogenesis and treatment. Clin Dermatol, 3, 41–​82. Whitman JC, Paw BH, Chung J (2018). The role of ClpX in erythropoi-
Puy H, Gouya L, Deybach JC (2010). Porphyrias. Lancet, 375, etic protoporphyria. Hematol Transfus Cell Ther, 40, 182–​8.
924–​37. Windon AL, et al. (2018). Erythropoietic protoporphyria in an adult
Sardh E, Harper P, Balwani M, et al. (2019). Phase 1 trial of an RNA with sequential liver and hematopoietic stem cell transplantation
interference therapy for acute intermittent porphyria. New Engl J Am J Transplant, 18, 745–​9.
Med, 380, 549–58. Yin L, et al. (2007). Rev-​erbα, a heme sensor that coordinates meta-
Schmid R (1998). The porphyrias. Semin Liver Dis, 18, 1–​101. bolic and circadian pathways. Science, 318, 1786–​9.
12.6
Lipid disorders
Jaimini Cegla and James Scott

ESSENTIALS (also called type 3 hyperlipoproteinaemia)—​ a Mendelian reces-

sive disorder, which becomes manifest when an acquired cause of
High blood cholesterol and high blood triglycerides are causal risk dyslipidaemia also occurs. (6) Severe hypertriglyceridaemia—​can be
factors for atherosclerotic cardiovascular disease, which remains the due to overproduction of very LDL, defective peripheral lipolysis,
leading cause of death in the developed world. and/​or reduced triglyceride uptake. Can be associated with recurrent
Lipid and lipoprotein metabolism pancreatitis.
Secondary or aggravating factors—​these include excess alcohol,
Cholesterol, triglycerides, and fat-​soluble vitamins are transported
diabetes mellitus, obesity and insulin resistance, hypothyroidism,
with specific proteins in the blood as multimeric complexes called
chronic kidney disease, nephrotic syndrome, Cushing’s syndrome,
lipoproteins. Lipid and lipoprotein metabolism are effected by three
certain drugs (such as β-​adrenergic blocking agents or thiazide diur-
principal physiological processes: (1) intestinal absorption of dietary
etics), and liver disease.
lipid and transport in the blood of dietary lipid and lipids, principally
derived from the liver (as triglyceride-​rich lipoproteins) to peripheral Management of dyslipidaemia
tissues for catabolism by skeletal and cardiac muscle or storage in The key questions are: (1) what classes of lipoproteins and lipids are
adipose tissue; (2) return of triglyceride-​rich lipoprotein remnants to increased or decreased in the patient’s plasma? (2) Does the pa-
the liver, hepatic synthesis of low-​density lipoprotein (LDL), and the tient has a primary (genetic) or secondary (acquired) dyslipidaemia
transport of cholesterol between peripheral tissues and the liver; and (often contributions from both influences)? (3) Is the patient at
(3) reverse cholesterol transport by high-​density lipoprotein (HDL) risk of atherosclerotic cardiovascular disease or acute pancrea-
between peripheral tissues and the liver. titis? (4) What other risk factors (e.g. hypertension or diabetes)
Dyslipidaemias are disorders of lipoprotein metabolism in which are present? (5) What treatments might be used to address these
there is elevation of total cholesterol and/​or triglycerides, often ac- abnormalities?
companied by reduced levels of HDL cholesterol. They are caused by
Hypercholesterolaemia
a combination of genetic (primary) and acquired (secondary) factors
(lifestyle, metabolic conditions, and drugs). In those with a 10% or greater risk of a cardiovascular event in
the next 10 years, according to United Kingdom guidelines, it is
Causes of dyslipidaemia usually recommended that cholesterol should be reduced. In
Particular lipid disorders—​(1) polygenic hypercholesterolaemia—​in the United States of America, a threshold of 7.5% for treatment
people with predominantly hypercholesterolaemia who do not is used, with the option for treatment at 5% risk. The National
show Mendelian inheritance, and do not have the clinical features Institute for Health and Care Excellence in the United Kingdom
of primary hypercholesterolaemia syndromes, polygenic hyperchol- currently recommends target reductions greater than 40% of non-​
esterolaemia is likely. (2) Familial hypercholesterolaemia (FH)—​an HDL cholesterol (an accurate predictor of cardiovascular risk), but
autosomal codominant disorder most commonly caused by dele- such targets are no longer recommended in the United States of
terious mutation of the LDLR gene which encodes the LDL receptor. America. The principal objectives of treatment are primary and
Premature atherosclerotic cardiovascular disease is very common. secondary prevention of atherosclerotic cardiovascular disease
(3) Combined hypercholesterolaemia and hypertriglyceridaemia—​ and its complications.
mixed (combined) dyslipidaemia is common and caused by a Lifestyle—​an atheroprotective lifestyle should be instituted, with
combination of genetic (primary) and acquired (secondary) fac- encouragement of weight loss in overweight and obese individuals.
tors. Elevated fasting triglycerides, increased total cholesterol and Statins—​HMG-​CoA reductase inhibitors are the first-​line drugs for
low HDL concentration are commonly associated with athero- the treatment of hypercholesterolaemia, with much evidence sup-
sclerotic vascular disease. (4) Familial combined hyperlipidaemia—​ porting their use in reducing the risk of atherosclerotic cardiovascular
polygenic and non-​Mendelian. (5) Familial dysbetalipoproteinaemia disease.
2056 section 12 Metabolic disorders

feature of atherosclerosis (Fig. 12.6.2) (see Chapter 16.13.1). High

Other drugs—​these include ezetimibe (blocks the action of the
blood triglycerides (TGs) are also causally linked to atherosclerotic
NPC1L1 protein and intestinal cholesterol absorption, bile acid
cardiovascular disease. Unhealthy diet, lack of exercise, hyperten-
sequestrants (resins), nicotinic acid, and PCSK9 inhibitors (fully
sion, diabetes, and smoking are other major risk factors associated
humananized monoclonal antibodies that block the protease,
with atherosclerotic cardiovascular disease.
PCSK9, at the surface of hepatocytes thereby reducing the physio-
Improvements in lifestyle and pharmaceutical treatment to re-
logical degradation of the LDL receptor).
duce blood cholesterol and other risk factors for atherosclerotic car-
LDL apheresis—​generally restricted to homozygous FH patients
diovascular disease in part account (Fig. 12.6.1) for the decrease in
and heterozygotes with rapidly progressive cardiovascular disease.
disease prevalence in the developed world. In the countries of the
Raised lipoprotein(a)—​associated with seriously increased risk of
developing world, the risk factors for atherosclerotic cardiovascular
atherosclerotic cardiovascular disease. Specific treatment is chal-
disease are becoming more prevalent as their populations espouse
lenging as treatment of acquired factors does not affect concentra-
a Western lifestyle, and this is likely to be the cause for the increase
tions of lipoprotein(a). Nicotinic acid (no longer readily available in
in disease.
Europe and the United Kingdom) and PCSK9 inhibitors have some
Cholesterol, TGs, and fat-​soluble vitamins are transported with
effect. An antisense lipoprotein(a) mRNA inhibitor has proved re-
specific proteins in the blood as multimeric complexes called
markably efficacious in early clinical trials and is in late-​phase clinical
lipoproteins. Here the normal physiology of lipoproteins will be
development.
described, together with their pathophysiology in relation to ath-
Hypertriglyceridaemia erosclerotic cardiovascular disease and other diseases, particularly
Triglyceride concentrations greater than 10 mmol/​litre (900 mg/​dl) acute pancreatitis. The importance of genetic, dietary, and acquired
cause an increased risk of acute pancreatitis and require prompt factors which influence lipoprotein metabolism, together with
treatment. A secondary treatment goal is to reduce the risk of ath- diagnostic and treatment approaches to disease prevention will be
erosclerotic cardiovascular disease. discussed.
In addition to diabetes mellitus, other causes including dietary in-
discretion with high fructose intake, obesity, insulin resistance, excess
alcohol consumption, reproductive hormone deficiency, or medical Lipoproteins, lipids, and apolipoproteins
use of steroid hormones should be considered.
Lifestyle changes—​these often reduce plasma triglyceride concen- Lipoproteins
trations markedly. A reasonable dietary goal is to restrict total fat in-
Lipoproteins are large, multimeric complexes of lipid and specific
take to around 20–​30 g daily and avoid refined carbohydrate.
proteins called apolipoproteins (see ‘Apolipoproteins’). They trans-
Drug treatment—​includes fibrates (the drugs of first choice), omega-​
port lipid in plasma and other bodily fluids (lymph, interstitial fluid)
3 fatty acids, and statins (can reduce modest hypertriglyceridaemia
between metabolically active tissues (Table 12.6.1, Fig. 12.6.3) (see
but have no value in severe hypertriglyceridaemia).
‘Lipid and lipoprotein metabolism’).
The outer shell of lipoproteins consists of amphipathic (having
hydrophilic and hydrophobic parts) lipids (phospholipid and free
Introduction cholesterol) and apolipoproteins surrounding a core of water-​
insoluble, hydrophobic lipids (TG and cholesteryl ester).
Despite a more than 50% reduced prevalence over the past 50 years Lipoproteins are grouped into five classes (Table 12.6.1, Fig. 12.6.3)
(Fig. 12.6.1), atherosclerotic cardiovascular disease remains the according to their density (assessed by ultracentrifugation), which
leading cause of death in the developed world. Atherosclerotic car- determines their size (assessed by MRI and nondenaturing electro-
diovascular disease accounts for about a third of all deaths, and 60% phoresis). The amount of lipid in a lipoprotein determines its density,
of people will suffer major life-​threatening cardiovascular events. By because lipids are not as dense as water.
contrast with the developed world, the occurrence of atherosclerotic The lipid and apolipoprotein composition of lipoproteins differs
cardiovascular disease is increasing in the developing world where it (Table 12.6.1, Fig. 12.6.4). Chylomicrons contain the most lipid
is becoming a leading course of mortality. and are the least dense; they are amongst the largest entities se-
Atherosclerotic cardiovascular disease is a disease of large-​and creted from eukaryotic cells. Chylomicron remnants, the product
medium-​sized arteries. It develops slowly over many years as a of peripheral lipolysis of chylomicron TG, remain very large. Very
direct consequence of several major risks factors. Evidence from low-​density lipoproteins (VLDLs), VLDL remnant intermediate-​
epidemiology, meta-​ analyses of cholesterol-​ lowering end-​ point density lipoproteins (IDLs), LDLs, and high-​density lipoproteins
clinical trials, human and animal genetics, and pathology over- (HDLs) are increasingly dense and less buoyant and have lower
whelmingly demonstrate the prominence of elevated levels of high lipid content. LDL and HDL also vary in size and lipid compos-
blood cholesterol as a causal risk factor for atherosclerotic cardio- itions and this affects their atherogenicity (see ‘Lipid and lipopro-
vascular disease. tein metabolism’).
Cholesterol is termed the ‘agent provocateur’ of atherosclerosis,
because its accumulation as oxidized low-​density lipoprotein (LDL) Lipoprotein(a)
cholesterol within macrophages in the artery wall has a direct patho- Lipoprotein(a) (Lp(a)) is a LDL particle with a single molecule of
genetic role in atherosclerosis. Cholesterol-​ laden macrophages apolipoprotein(a) (apo(a)) linked to apoB100 by a disulphide bridge
have a characteristic foamy appearance. ‘Foam cells’ are a hallmark (Fig. 12.6.5). Its physiological function is uncertain. Lp(a) is not
 12.6 Lipid disorders 2057

(a) 1600 Men Women

1200

death rate per 100,000

cardiovascular disease
Age-standardized

800

400

1950 1960 1970 1980 1990 2000 2010 1950 1960 1970 1980 1990 2000 2010
Year

Hungary USA Greece Finland

Japan France Australia Norway

(b) Coronary heart

disease
25000 17,894 males
21,405 females
Coronary heart
20000 disease
15,466 males
Number of deaths

Coronary heart 7,394 females

disease
15000
7,987 males

Breast cancer
1000
3,665 females

Suicide
5000 Congenital 952 males
abnormalities 249 females
73 deaths
0
1–4 5–34 35–64 65–79 80+
Age (years)

Men Women

Fig. 12.6.1 Cardiovascular death rates in the developed world. (a) Trends in death rates from cardiovascular diseases in
adults over 30 years of age in selected countries with vital registration and medical certification of the underlying cause of
death. Death rates are age-​standardized to the World Health Organization standard population and smoothed using a
5-​year moving average. (b) Death rates in the United Kingdom by age.
Source data from (Panel (a)) Ezzati M and Riboli E. (2012). Can noncommunicable diseases be prevented? Lessons from studies of populations
and individuals. Science, 21, 337(6101), 1482–​7. Copyright © 2012, American Association for the Advancement of Science. (Panel (b)) Government
data, Office for National Statistics, UK 20 October 2011.

fully formed until the apo(a) protein is for the main part conju- This results in apo(a) proteins with 10 to 50 or more kringle IV re-
gated with LDL in the extrahepatic space, though some assembly peats. There is an inverse correlation between the size of the apo(a)
may occur with intracellular LDL-​sized particles. Apo(a) is similar isoform and the Lp(a) plasma concentration. The larger the isoform,
to plasminogen; the genes reside together in the genome, but apo(a) the slower the rate of production, which limits the plasma concen-
has no catalytic activity. In addition to the plasminogen domain, tration. Particle number is the now favoured measure as this reflects
it contains repeated domains called kringles, after a Belgian cake, atherogenicity (Fig. 12.6.6).
which is similar in shape to apo(a). Lp(a) is cleared mainly by the liver but the receptor has not been
Apo(a) proteins vary due to a size polymorphism, and a variable determined. Some may be cleared by the kidney because Lp(a)
number of kringle IV repeats (each of 114 amino acids) in the gene. plasma levels increase in chronic renal failure.
2058 section 12 Metabolic disorders

the liver signals the activation of a carbohydrate responsive tran-

scription factor MLXIPL/​CHREBP, and of LXR alpha and sterol
regulatory element-​binding protein (SREBP), which together acti-
vate the genes encoding the enzymes required for the biosynthesis
of fatty acids and, in turn, TGs (Fig. 12.6.8).
Hepatic TG is normally secreted as VLDL (see ‘Hepatic lipid
transport’). Excess bodily TG is stored as fat depots in adipose tissue,
and in liver and other tissues in times of gross nutritional excess—​
overweight and obesity; or burned as a source of energy by skeletal
and cardiac muscle.

Phospholipids
Phospholipids are a major structural component of most bio-
logical membranes. They also have an important role in cell sig-
nalling through acetyl choline and prostaglandin synthesis, and
phosphatidylinositol signalling pathways. They are amphipathic: the
head is hydrophilic and the tail hydrophobic. This property enables
Fig. 12.6.2 Foam cells, a hallmark feature of atherosclerotic plaque.
Atherosclerotic plaque (AHA stage 4, i.e. with lipid necrotic core and them to form the lipid bilayer of biological membranes, and the
fibrous cap). Brown, immunoperoxidase/​di-​aminobenzidine for CD68 monolayer outer shell of lipoproteins.
(a macrophage lysosome protein). Blue, haematoxylin counterstain. Like TGs, they comprise a hydrophobic glycerol backbone, but
A series of macrophages are shown, including foam cells in increasing with only two fatty acids bonded to the glycerol (usually one satur-
stages of lipid accumulation and foam cell formation. The brown-​ ated and one unsaturated). The third side-​group of glycerol is occu-
staining extracellular matrix is not background or nonspecific staining
pied by a hydrophilic phosphate group.
but represents residual epitopes on cellular debris derived from dead
macrophages. For reference, typically, a leucocyte would be expected to
be approximately 10 mm in diameter. The foam cell shown is therefore in
the region of 10-​fold the diameter of a typical leucocyte. Chylomicron
Photo courtesy of Joseph Boyle, Imperial College London. 0.95 VLDL
VLDL
remnants
Lipids 1.006
Particle density (g/mL)

IDL
Chylomicron
The major lipoprotein lipids are TG, phospholipid, free cholesterol, remnants
1.02
cholesteryl ester, and fat-​soluble vitamins (Fig. 12.6.7). Buoyant LDL
sdLDL
Triglycerides 1.06
HDL2
TGs are the essential energy transfer and storage lipids. They com- 1.10 Lp(a)
prise three fatty acids, which can be either saturated or unsaturated 1.2 HDL3
fatty acids, esterified to a glycerol backbone, and are water-​insoluble. 18–25
The main dietary sources of TGs are fatty red meat, poultry skin,
5 10 20 40 60 80 1000
lard, high-​fat dairy products, shellfish, and shrimps. Vegetable oils
Particle size, diameter (nm)
contain TGs. TGs are also the product of endogenous synthesis in
the liver from excess dietary carbohydrate. Excess carbohydrate in Fig. 12.6.3 Lipoprotein subclasses classed by particle size and density.

Table 12.6.1 Major types of lipoproteins in circulating blood

HDL LDL VLDL Chylomicrons

Physical property
Particle size (nm) 4.5–​12 18–​25 30–​75 >75
Density (g/​litre) 1064–​1210 1019–​1063 1006 <950
Components
Triglycerides 3% 10% 59% 80–​95%
Cholesterol (free and esters) 2% 45% 15% 3–​7%
Phospholipids 27% 22% 5% 3–​6%
Proteins 48% 20–​25% 10% 1–​2%
Apolipoproteins A1/​2, C1/​2/​3, E B100,C2/​3, E, (a) B100, C2/​3, E B48, C2/​3, E
Other components LCAT, CETP paroxonase Vitamin E Vitamin E Retinyl ester Vitamin E
 12.6 Lipid disorders 2059

LDL
Triglyceride rich lipoprotein

NH2 Lipoprotein assembly

ApoB100, B48
Cysteine rich NH2
ApoB100

Triglyceride Phospholipid Phospholipid

Free cholesterol COOH Free cholesterol
cholesteryl-ester Cysteine
Fat-soluble rich
vitamins LDL receptor binding

Other COOH LDL receptor binding

apolipoproteins ApoB100
ApoC5, ApoE 75–1000 nM 20–30 nM
Fig. 12.6.4 Comparison of a triglyceride rich lipoprotein (e.g. VLDL and chylomicron) and low-​density lipoprotein.

The phosphate groups can be modified with simple organic mol- Cholesterol
ecules such as choline to form lecithin or phosphatidylcholine, Free cholesterol is an essential structural component of all animal
or serine, ethanolamine, or inositol to form phosphatidylserine, plasma membranes. It is required to maintain membrane structural
phosphatidylethanolamine, or phosphatidylinositol respectively. integrity and fluidity by reason of its packing with phospholipids.
Plasmalogens and sphingomyelin are also phospholipids, and The properties of cholesterol are conferred by a single hydroxyl
constitute more than 20% of total phospholipids in cell membranes. (OH) group, which renders cholesterol polar, but only slightly sol-
Eggs, organ and lean meats, fish, shellfish, cereal grains, and oil- uble in water.
seeds are the main sources of phospholipids. Their synthesis in ani- These properties enable cholesterol to function in intracellular
mals occurs in the cytosol through endoplasmic reticulum (ER) transport by caveolae and clathrin-​coated pits and cell signalling
membrane-​located enzymes. through receptor clustering in lipid rafts. Cholesterol serves as a
precursor for the biosynthesis of steroid hormones, bile acids, and
vitamin D.

Kringle IV type 2 repeats

(variable number) 900
(KIV-2)
800

700

600
Lp(a)-P(nmol/L)

NH 2 ApoB100
500

400
S–S
Cysteine 300
(ApoB100–Lp(a))
rich COOH 200
Phospholipid
Free cholesterol 100
KV
Protease (plasminogen 0
LDL homology) 0 50 100 150 200 250
receptor
Lp(a)-Mass(mg/dL)
binding
MW = 700–800 MW = 600–700 MW = 300–600
KIV-3 to 10 200–300A
Fig. 12.6.6 Discordance between Lp(a) mass and particle number
Fig. 12.6.5 The structure of Lp(a). Lp(a) is an LDL particle with a single assays. Comparison of Lp(a) particle number in nmol/​litre (Lp(a)-​P) with
molecule of apo(a) linked to apoB100 by a disulfide bridge. Apo(a) Lp(a) mass in mg/​dl for samples of large (blue, n = 51), intermediate
contains an inactive protease domain, one kringle V, and kringle IV which (green, n = 25), and small (red, n = 38) Lp(a) isoform sizes. Isoform sizes
is composed of 10 different types based on their amino acid sequences, determined by Western blot analysis. The difference in slopes observed
referred to as KIV types 1 to 10. KIV types 1 and 3 to 10 are present as here indicates that the mass assay is influenced by apo(a) isoform size.
single copies, whereas KIV type 2 (KIV-​2) is present as multiple copies, Source data from Guadagno PA, et al. (2015). Validation of a lipoprotein(a) particle
varying in number from 3 to more than 40 copies, explaining the isoform concentration assay by quantitative lipoprotein immunofixation electrophoresis.
size heterogeneity between patients. Clinica Chimica Acta, 439, 219–​24.
2060 section 12 Metabolic disorders

Fig. 12.6.7 The chemical structure of key lipids molecules.

Glycolysis
Pyruvate
L-PK
Citrate
Krebs
Glucose ACL
cycle
Acetyl-CoA
ACC Mitochondria
MLXIPL
Malonyl-CoA
Lipogenesis
FAS
LCE
SCD
FFA

Triglycerides

FFA
LPL

ApoB100
ApoC2/3/A5

VLDL Adipose tissue

Fig. 12.6.8 De novo biosynthesis of fatty acids from carbohydrate. Excess carbohydrate in the liver signals
the activation of a carbohydrate responsive transcription factor, MLX-​interacting protein-​like (MLXIPL)
(also known as carbohydrate-​responsive element-​binding protein (CHREBP)), which activates the genes
encoding the enzymes required for the biosynthesis of fatty acids and in turn triglycerides. ACC, acetyl-​
CoA carboxylase; ACL, ATP-​citrate lyase; FAS, fatty acid synthase; FFA, free fatty acids; LCE, long-​chain fatty
acyl elongase; L-​PK, liver pyruvate kinase; LPL, lipoprotein lipase; SCD, stearoyl-​CoA desaturase.
 12.6 Lipid disorders 2061

The main dietary sources of cholesterol are the same as TGs. Egg The gallbladder empties in response to food in the intestine.
yolks are also rich in cholesterol. Plants make cholesterol in very In the intestine, bile salts form miscelles, which solubilize lipids
small amounts. Rather, plants make phytosterols, which are chem- and facilitate their absorption. Approximately 95% of the bile acids
ically similar to cholesterol and can compete with cholesterol for ab- are reabsorbed from the ileum and the remainder are lost in the
sorption in the intestinal tract, thus potentially reducing cholesterol faeces.
absorption (see ‘Plant sterols’). The excretion and reabsorption of bile acids forms the basis of the
Cholesterol is essential for animal life therefore most cells synthe- enterohepatic circulation, which is essential for the digestion and
size cholesterol from acetyl-​coenzyme A (CoA) through a complex absorption of dietary lipids. The liver also excretes free cholesterol in
multistep pathway. Humans synthesize about 1 g of cholesterol daily, bile into the duodenum. Typically, about 50% of the excreted choles-
and compensate for any excess absorption by reducing cholesterol terol along with dietary cholesterol is reabsorbed by the small bowel,
synthesis. Thus 12 h after ingestion, cholesterol will show little effect but this varies between people.
on total body cholesterol content or concentrations of cholesterol The biosynthesis of cholesterol is directly regulated by the choles-
in the blood. In the 7 h after ingestion of cholesterol, however, the terol levels in the cell (Fig. 12.6.10). Thus high dietary intake reduces
levels in plasma increase, and this is moderated by genetic factors endogenous production, whereas lower intake does the reverse. The
(see ‘Lipid and lipoprotein metabolism’). principal regulatory mechanism is the sensing of intracellular chol-
Cholesterol is susceptible to oxidation and easily forms oxygen- esterol in the ER by the proteins SREBP1 and SREBP2. In the pres-
ated derivatives known as oxysterols. Oxysterols exert inhibitory ence of cholesterol, SREBP is bound to two other proteins: SREBP
actions on cholesterol biosynthesis. Oxidized LDL is associated cleavage-​activating protein (SCAP) and insulin-​induced gene 1
with the pathogenesis of atherosclerotic cardiovascular disease (see (INSIG1).
‘Introduction’). At low cholesterol levels, INSIG1 dissociates from the SREBP–​
Cholesterol is also oxidized by the liver into bile acids, which may SCAP complex, which then moves to the Golgi apparatus. In the
be conjugated with glycine, taurine, glucuronic acid, or sulphate Golgi apparatus, SREBP is cleaved by site-​1 protease and site-​2
(Fig. 12.6.9). A mixture of conjugated and nonconjugated bile acids protease (S1P and S2P), two enzymes that are activated by SCAP
(c.80% of biliary constituents), with free cholesterol and phospho- at low cholesterol levels. After cleavage SREBP migrates to the nu-
lipids (c.20% of bile constituents), is excreted from the liver into the cleus, where it binds to the sterol regulatory element (SRE), and pro-
bile, and stored in the gallbladder. motes transcription of multiple genes that control lipid formation,

7α-hydroxylase (CYP7A1)
‘Classic pathway’
7 7
HO HO OH
Cholesterol 7-hydroxycholesterol

HSDB37 HSDB37
Sterol
12α-hydroxylase
Several steps (CYP8B1)

OH

HO OH HO OH
H H
Chenodeoxycholic acid Cholic acid
Fig. 12.6.9 Bile acid synthesis. Cholesterol is oxidized by the liver into bile acids. A hydroxyl
optionally added in the liver determines the formation of chenodeoxycholic acid versus cholic
acid. In the liver, bile acids may be conjugated with glycine, taurine, glucuronic acid, or sulphate.
A mixture of conjugated and nonconjugated bile acids, with free cholesterol and phospholipids,
is excreted from the liver into the bile, and stored in the gallbladder. In the gut, a hydroxyl group
may be removed by gut bacteria to create deoxycholic acid and lithocholic acids from cholic acid
and chenodeoxycholic acid respectively.
2062 section 12 Metabolic disorders

ER membrane
SREBP
SCAP WD HLH
INSIG
Cytoplasm
High
cholesterol
Lumen

Golgi apparatus

SREBP
SCAP WD
HLH
Cytoplasm
Low
S2P SREBP cholesterol
HLH
Lumen
S1P
Nucleus
– ACS
– FAS
– GPAT
SREBP
– Squalene
HLH
synthase
– HMGCoAR
SRE – LDLR
– etc.

Fig. 12.6.10 Regulation of cholesterol biosynthesis. The principal regulatory mechanism is the sensing of intracellular cholesterol
in the ER by the proteins, sterol regulatory element-​binding protein (SREBP) 1 and 2. Starting out wrapped in the ER membrane, their
activation as transcription factors requires a maturation process tightly controlled by the levels of cholesterol present in the membrane.
In the presence of cholesterol, SREBP is bound to two other proteins: SREBP cleavage-​activating protein (SCAP) and insulin-​induced
gene 1 (INSIG1). SCAP acts as a sensor of the content of cholesterol in the ER membrane. In the presence of high levels of cholesterol,
SCAP remains anchored in the ER membrane due to its interaction with the INSIG proteins. At low cholesterol levels, INSIG1 dissociates
from the SREBP–​SCAP complex, which then moves to the Golgi apparatus. SREBP is then cleaved by site-​1 protease and site-​2 protease
(S1P and S2P), two enzymes that are activated by SCAP at low cholesterol levels. This fragment contains a basic helix–​loop–​helix (HLH)
leucine zipper domain, which functions as a transcription factor. After cleavage, SREBP migrates to the nucleus, where it binds to the
sterol regulatory element (SRE), and promotes transcription of multiple genes that control lipid formation, metabolism, and energy
supply, including the LDL receptor (LDLR) and 3-​hydroxy-​3-​methyl-​glutaryl-​CoA reductase (HMGCoAR). WD, WD40 domain.
Source data from Desvergne B, et al. (2006). Transcriptional regulation of metabolism. Physiological Reviews, 86(2), 465–​514.

metabolism and energy supply, including the LDL receptor (LDLR) They are the intracellular storage form and intravascular transport
and 3-​hydroxy-​3-​methyl-​glutaryl-​CoA reductase (HMGCoAR). form of cholesterol.
The LDLR removes LDL from plasma. HMGCoAR is the rate-​
limiting enzyme of cholesterol biosynthesis. The turnover of Plant sterols
HMGCoAR by protein degradation is sensitive to cholesterol levels Phytosterols derived from plants account for 25% of dietary sterols.
in the cell (Fig. 12.6.11). The most commonly occurring phytosterols in the human diet
The activity of the LDLR is also regulated by protein convertase are β-​sitosterol, campesterol and stigmasterol, which account for
subtilisin/​kexin type 9 (PCSK9), an extracellular protein which binds about 65%, 30%, and 3% of diet contents, respectively, but are not
to the epidermal growth factor-​like repeat A (EGF-​A) domain of the normally well absorbed by humans. Stanols are saturated sterols,
LDLR, inducing its degradation. After internalization, the LDLR having no double bonds in the sterol ring structure, and normally
usually disassociates in the acid environment of the endosome and form only a tiny component of the diet, but are synthesized as a
recycles to the cell surface. With PCSK9 bound, the LDLR is targeted gut microbial byproduct of cholesterol metabolism. Absorbed plant
to the lysosome and degraded rather than recycled. sterols are re-​excreted in bile or by the enterocyte. Plant sources are
Cholesteryl esters are formed between the carboxylate group of a vegetable oils, nuts, peanuts, and avocados. Plant sterols compete
fatty acid and the hydroxyl group of cholesterol. Cholesteryl esters with cholesterol for absorption, with potential beneficial effect on
have a lower solubility in water due to their increased hydrophobicity. plasma cholesterol levels.
 12.6 Lipid disorders 2063

1. HMG CoA
ER reductase

LDL receptors
2. ACAT
LDL
Protein Cholesterol Cholesteryl
oleate
3. LDL receptors
Cholesteryl
linoleate Lysosome
Amino
acids

LDL binding Internalization Lysosomal Regulatory

hydrolysis actions
Fig. 12.6.11 Intracellular uptake of LDL by the LDL receptor. LDL is internalized through
receptor-​mediated endocytosis. The cholesterol derived from lysosomal hydrolysis exerts
feedback to protect the cell from overaccumulation of cholesterol by (1) suppressing activity of
3-​hydroxy-​3-​methylglutaryl-​coenzyme A reductase (HMG-​CoA reductase), the rate-​controlling
enzyme of cholesterol biosynthesis; (2) activating acyl-​CoA:cholesterol acyltransferase (ACAT),
a cholesterol-​esterifying enzyme so that excess cholesterol can be stored as cholesteryl ester
droplets; and (3) suppressing synthesis of new LDL receptors thus preventing further cholesterol
intake into the cell.
Source data from Goldstein J and Brown M (2009). The LDL receptor. Arterioscler Thromb Vasc Biol, 29, 431–​8.

Trans fatty acids Fat-​soluble vitamins

Artificial trans fats are created in an industrial process that adds Vitamin E is one of the most abundant lipid-​soluble antioxidants
hydrogen to liquid vegetable oils to make them more solid. The found in the plasma and somatic cells of higher mammals. It comes
primary dietary source for trans fats in processed food is ‘partially mainly from plant rather than animal sources. The main dietary
hydrogenated oils’. They are used by food manufacturers because forms of preformed vitamin A are carotenoids in fruits and veget-
they have a long shelf life and are able to withstand repeated heating ables and long-​chain fatty acids esters of retinol in foods of animal
without breaking down. Doughnuts, biscuits, crackers, muffins, pies, origin.
and cakes are examples of foods that may contain trans fat. Trans fats
may also be produced when ordinary vegetable oils are heated to Apolipoproteins
fry foods at very high temperatures and this is one reason why take- Apolipoproteins function as structural components of lipopro-
away foods can sometimes be high in trans fats. While many old-​ tein particles (Table 12.6.2). They also act as cofactors for en-
fashioned margarines contain a high proportion of trans fats, newer zymes of lipid metabolism and as ligands for cell surface receptors.
brands should contain low amounts. There are two types of apolipoproteins. The first are the huge

Table 12.6.2 Major apolipoproteins and their function

Apolipoprotein Primary source Lipoprotein association Function

ApoA1 Intestine, liver HDL, chylomicrons Structural protein HDL Activates LCAT
ApoA2 Liver HDL, chylomicrons Structural protein HDL
ApoA4 Intestine, liver HDL, chylomicrons Unknown
ApoA5 Liver VLDL, chylomicrons Promotes LPL-​mediated TG lipolysis
Apo(a) Liver Lp(a) Unknown
ApoB48 Intestine Chylomicrons, chylomicron remnants Structural protein for chylomicrons
ApoB100 Liver VLDL, IDL, LDL, Lp(a) Structural protein for
VLDL, LDL, IDL, Lp(a)
Ligand for binding LDL receptor
ApoC1 Liver Chylomicrons, VLDL, HDL Unknown
ApoC2 Liver Chylomicrons, VLDL, HDL Cofactor for LPL
ApoC3 Liver, intestine Chylomicrons, VLDL, HDL Inhibits LPL activity and lipoprotein binding to receptors
ApoE Liver Chylomicron remnants, IDL, HDL Ligand for binding to LDL receptor and other receptors
2064 section 12 Metabolic disorders

apoB-​containing lipoproteins, which associate with lipid droplets Intestinal lipid absorption and transport
irreversibly (they do not exchange between lipoprotein particles) as chylomicrons
from the time of assembly of lipoproteins within the ER and se-
Intestinal lipid sources
cretion from the cell, until they are cleared from the circulation by
the LDLR. Lipid binding through apoB is mainly by amphipathic TG is the main lipid in the diet, contributing 90 to 95% of the lipid-​
β strands, with less of the amphipathic α helices that characterize derived energy. Dietary lipids also include phospholipids, cholesterol
other apolipoproteins. and plant sterols, and fat-​soluble vitamins. The main phospholipid
The two forms of apoB, apoB100 (514 kDa) and apoB48 (247 kDa), in the small intestinal lumen is phosphatidylcholine, mostly derived
are the products of the same gene, and in humans are synthesized in endogenously from bile, 10 to 20 g per day in humans, with 1 to 2 g
the liver and intestine respectively. ApoB48 is generated by editing contributed by the diet. The predominant dietary sterols are choles-
of the APOB100 mRNA by a site-​specific RNA editing cytosine terol, of animal origin, and sitosterol, the major plant sterol.
deaminase designated apolipoprotein B mRNA editing enzyme, The Western diet provides 300 to 500 mg of cholesterol daily. Bile
catalytic polypeptide 1 (apoBEC1), which terminates the transla- contributes 800 to 1200 mg daily and intestinal mucosal turnover
tional reading frame, to create the smaller apoB48. provides around 300 mg. Approximately 50% of the cholesterol in
ApoB48 is required for TG-​rich chylomicron assembly and se- the intestine is absorbed, but this varies between individuals; the re-
cretion from the intestine, and for the delivery of TG to peripheral mainder is excreted in faeces. In high absorbers, there is more likely
tissues. ApoB48 lacks the C-​terminal LDLR binding domain found to be an increase in plasma cholesterol levels, and better response to
in apoB100. The clearance from the circulation of chylomicron a low-​cholesterol diet.
remnants after depletion of TGs is mediated by apoE through The essential fat-​soluble vitamins, vitamins E and A, are derived
the LDLR. mainly from plants, or secondary animal sources.
ApoB100 is required for TG-​rich VLDL assembly and secretion
from the liver. After secretion, VLDL goes on to form remnants or Emulsification, digestion, and micelle formation
IDL and subsequently LDL, which is cleared from the circulation by Lipid digestion begins in the mouth and stomach through the action
direct interaction of apoB100 with the LDLR. of lingual lipase and gastric enzymes. Gastric peristalsis breaks up
All other apolipoproteins are very much smaller and make im- dietary fat globules into much smaller emulsion droplets (emulsifi-
portant exchanges between lipoprotein particles in the course of cation). Fine emulsion droplets enter the duodenum and mix with
lipoprotein metabolism and remodelling in the circulation. The amphipathic biliary phospholipid, free cholesterol, bile acids, pan-
smaller exchangeable apolipoproteins, the apoAs, apoCs, and apoE creatic enzymes, and colipase (an amphipathic protein that anchors
form a multigene family, and have similar intron/​exon organiza- lipase at the surface of the emulsion droplet). Emulsification greatly
tion in their genes. They bind lipid through repeated amphipathic increases the surface area where water-​soluble enzymes act to digest
α helices in their structure. They are the products of duplication of water-​insoluble lipids.
an ancestral gene. In the jejunum, TG is digested primarily by pancreatic lipase to
ApoA1 and apoA2 are the core structural proteins of HDL. ApoA4 yield free fatty acids and glycerol; phospholipid digestion is car-
is thought to act primarily in intestinal lipid absorption. ApoA5 pos- ried out by pancreatic phospholipase A2 and lysophospholipase;
sibly acts by increasing VLDL production in the liver, stimulation of and cholesteryl ester. About 10 to 15% of dietary cholesterol is
proteoglycan-​bound lipoprotein lipase (LPL) at the endothelium of hydrolysed by cholesterol esterase to release free cholesterol. After
capillaries in peripheral organs, or enhancing the clearance of TG-​ digestion, monoglycerides, free fatty acids, free cholesterol, and fat-​
rich lipoproteins via lipoprotein receptors in the liver. The function soluble vitamins associate with bile salts and phospholipids to form
of apoC1 and apoC4 is uncertain. micelles. Micelles are about 200 times smaller than emulsion drop-
ApoA1 and apoC2 are cofactors for lecithin–​ cholesterol lets, and are small enough to enter between the microvilli and be
acyltransferase (LCAT) and LPL respectively. ApoC3 is an inhibitor absorbed (Fig. 12.6.12).
of LPL. ApoE is a ligand for the LDLR and mediates the clearance of
chylomicron and VLDL remnants or IDLs by the liver LDLRs. Absorption
Free fatty acids are taken up from the intestinal lumen into the entero-
cytes and used for the biosynthesis of neutral fats (TG, cholesteryl
Lipid and lipoprotein metabolism ester) (Fig. 12.6.12). Fatty acid transport proteins (FATPs) such
as FATP4 and FAT/​CD36 facilitate the uptake of fatty acids by the
Lipid and lipoprotein metabolism can be grouped into a variety enterocytes.
of physiological processes: (1) the intestinal absorption of dietary Cholesterol and plant sterol absorption is controlled by Niemann–​
lipid (long-​chain fatty acids, cholesterol, fat-​soluble vitamins) Pick C1-​like 1 (NPC1L1) and ATP-​binding cassette (ABC) proteins
and transport in the blood of dietary lipid and hepatically derived ABCG5 and ABCG8, which act as cholesterol uptake transporters
lipids, principally TGs as TG-​rich lipoproteins, to peripheral tis- and as plant sterol efflux transporters respectively. ABCA1 transfers
sues for catabolism by skeletal and cardiac muscle or storage in enterocyte cholesterol to apoA1 for intestinal HDL formation and
adipose tissue; (2) the transfer of the TG-​rich lipoproteins rem- secretion into lymph, and accounts for 30% of all HDL.
nants back to the liver, and the formation of LDL and the transport Vitamin E absorption requires micelle formation, and scav-
of cholesterol between peripheral tissues and the liver; and (3) re- enger receptor class B member 1 (SRB1) for absorption. Dietary
verse cholesterol transport by HDL between peripheral tissues and vitamin A is in the form of carotenoids and fatty acid esters of ret-
the liver. inol. Carotenoids are cleaved to generate retinol or absorbed intact.
 12.6 Lipid disorders 2065

Efflux
Micelles

ABCG5/8

NPC1L1

SR-B1
Retinol
CD36

MAG
C VitE
FA R
C CRBP
FA
FABP
FA
FATP DGAT
ACAT LRAT
RE
CE CM

B48 1 2
MTP
A4 HDL
ER
ApoB-independent

Golgi

4 3

ApoB48-dependent
ApoA1

5
ABCA1

Nascent
HDL
Blood 6 CM
Lymph

Fig. 12.6.12 Lipid absorption. Hydrolysed lipids are solubilized in micelles and presented to the apical membranes of
enterocytes. Here, transport proteins facilitate the uptake of various lipid entities: Niemann–​Pick C1-​like 1 (NPC1L1) is involved
in cholesterol uptake, CD36 and fatty acid (FA) transport protein (FATP) facilitates FA transport and scavenger receptor class
B type I (SR-​BI) is involved in vitamin E (Vit E) uptake. In the cytosol, FA-​binding protein (FABP) and cellular retinol-​binding
protein (CRBP) transport FAs and retinol (R) respectively. In the endoplasmic reticulum (ER) membrane, acyl-​CoA:cholesterol
acyltransferase (ACAT), diacylglycerol acyltransferase (DGAT), and lecithin:retinol acyltransferase (LRAT) facilitate the esterification
of cholesterol, monoacylglycerols (MAG), and retinol respectively. These esterified products are then incorporated into apoB48-​
containing chylomicrons; this process is mediated by microsomal triglyceride (TG) transport protein (MTP). The newly synthesized
prechylomicrons are transported in specialized vesicles to the Golgi apparatus for further processing and secretion. Enterocytes
also express ATP-​binding cassette (ABC) transporter A1 on the basolateral membrane to promote the efflux of cholesterol. A3,
apoA3A4, apoA4; C, free cholesterol; CE, cholesteryl ester; RE, retinyl ester.
Source data from Iqbal J, et al. (2009). Intestinal lipid absorption. Am J Physiol Endocrinol Metab, 296, 1183–​94.

Retinyl esters must be hydrolysed by lipase to release free retinol contains TGs (85% of chylomicron lipid), cholesteryl esters, and fat-​
before it can be taken up by enterocytes from micelles. soluble vitamins. The surface contains a monolayer of phospholipids
(mainly phosphatidylcholine) and free cholesterol. The surface is
Chylomicrons populated by apoA1, apoA4, and the apoCs.
Nascent chylomicrons are huge, spherical, TG-​rich lipoproteins. Free fatty acids (>12 carbons), monoglycerides, and vitamin E are
ApoB48 is the principal structural component of chylomicrons. It is transferred from the enterocyte microvillus membrane to the ER
very large, hydrophobic, and nonexchangeable. The lipoprotein core for re-​esterification and lipoprotein assembly by fatty acid binding
2066 section 12 Metabolic disorders

Gut ApoC
Adipose tissue,
muscle, heart
LPL, ApoA5,
ApoB48 VLDL
C2,C3
ApoC Liver
ApoB100
Chylomicron
LDLR IDL ApoE
ApoE
Remnant

Other LDL
Adipose tissue, sites
muscle, heart
Exogenous Endogenous
LPL, ApoA5,
C2,3
Fig. 12.6.13 The exogenous and endogenous lipid metabolism pathways. Chylomicrons from
the gut transport dietary triglycerides to tissue where they are removed by lipoprotein lipase (LPL).
The remnants are taken up by the liver via remnant and LDL receptors and catabolized. VLDL is
synthesized in the liver and transports endogenous triglycerides to tissue where they are removed
by LPL, resulting in IDL. Some IDL is taken up directly by hepatocytes but for the majority of
IDL, further triglyceride is removed by hepatic lipase and thereby IDL is converted to LDL. LDL is
removed by the liver via the LDL receptor (LDLR).

proteins (FABPs). Re-​esterification of free fatty acids and cholesterol Hepatic lipid transport as VLDL, IDL, and LDL
is mediated by diacylglycerol acyltransferase (DGAT1) and acetyl-​ VLDL
CoA acetyltransferase (ACAT2). Retinol is transferred to the ER by
cellular retinol-​binding proteins (CRBP). Chylomicrons nucleate in Lipids from the liver are transported to the periphery on VLDLs
the ER around a single molecule of apoB48. (Fig. 12.6.13). VLDLs, like chylomicrons, are TG-​rich lipoproteins.
TGs, phospholipids, free cholesterol, and cholesteryl esters along They also carry free cholesterol and cholesteryl ester, with a TG-​to-​
with fat-​soluble vitamins are loaded onto apoB48 during chylo- cholesterol ratio of approximately 5:1, and vitamin E. VLDLs, like
micron assembly in the ER by a microsomal triglyceride transfer chylomicrons, nucleate in the ER around a single molecule of apoB,
protein (MTTP). Chylomicrons are further lipidated in the secretary in this case apoB100 rather than apoB48. ApoB100 is twice the size
pathways, before secretion from the enterocyte basolateral mem- of the apoB48 on the centile system.
brane into the lymphatic system, and delivery by the thoracic duct to VLDL TGs are derived predominantly from the esterification of
the systemic circulation. the long-​chain fatty acids in the liver. These come from chylomicron
In the circulation, chylomicrons undergo extensive modification remnants and through de novo synthesis from excess dietary carbo-
(Fig. 12.6.13). They transfer phospholipid and cholesteryl ester to hydrate. As with chylomicrons, TG is loaded on to apoB100 in the
HDL, which in turn donates apoC2 and apoE to the nascent chylo- ER through the agency of MTTP.
micron, converting it to a mature chylomicron. After secretion into the blood, VLDL acquires several molecules
In the peripheral capillaries of adipose tissue, skeletal muscle of apoE and of the apoC apolipoproteins from HDL. As with chylo-
and heart chylomicrons associate with LPL, which is anchored to microns, the VLDL TGs are hydrolysed by LPL in peripheral adi-
glycosylphosphatidylinositol-​anchored protein (GPIHBP1). Lipase pose tissue, muscle, and heart blood capillaries.
maturation factor 1 (LMF1) resides in the ER, and is involved in the
maturation and transport of LPL, hepatic lipase (HL), and pancre- IDL and LDL
atic lipase through the secretory pathway. ApoC2 is the cofactor for The remnants of peripheral lipolysis, IDLs, disassociate from LPL.
LPL activity. Chylomicron TG is hydrolysed by LPL releasing free After TG hydrolysis, IDLs contain approximately the same amount
fatty acids, which are stored in fat as TG or burnt to create energy of cholesterol and TG. About half of IDLs are removed by liver LDL
in muscle. receptors through interaction with its ligand apoE. The remaining
Some free fatty acids associate with albumin and are transported IDL is refashioned by HL with removal of further TG and phospho-
to other tissues, mainly the liver. The chylomicron progressively de- lipid to form the cholesterol-​rich LDL.
creases in size as TG is hydrolysed. In the process of LDL formation, apoE and the apoCs are trans-
Once TG is depleted, the chylomicron remnant returns apoC2 to ferred to other lipoprotein particles. LDL comprises one molecule
the HDL but retains apoE. The remnant of this metabolism is rapidly of apoB100, a shell of phospholipid and free cholesterol, and a core
cleared from the circulation by the interaction of apoE with hepatic of cholesteryl ester. LDL can vary in size according to its neural
LDLRs. In the normal postprandial state, few or no chylomicrons or lipid content; particles with more TG and less cholesteryl ester are
chylomicron remnants are present in blood after a prolonged fast, smaller and denser (sdLDL). The size of LDL has implications for
except in those with dyslipidaemia, in whom they may persist. its atherogenicity (Table 12.6.1, Fig. 12.6.4). Most LDL is removed
 12.6 Lipid disorders 2067

Nascent
discoid Intestine
Tissue Circulation
HDL
ApoA1
Macrophage Excretion

ABCA1
ABCG1
Bile

Peripheral ABCA1
cell Mature
ABCG1 Cholesteryl
HDL HDL
ester

Cholesterol
SR-B1
Liver
CETP and PLTP,
transfer of cholesteryl
ester and phospholipids

CM VLDL
Fig. 12.6.14 Reverse cholesterol transport. Nascent HDL acquires free cholesterol from extrahepatic cells.
The free cholesterol in HDL is esterified by lecithin cholesterol acyltransferase (LCAT). ApoA1 is a necessary
co-​factor for LCAT. Further cholesteryl esters (CE), phospholipids, and apoC and apoE are transferred during
lipolysis from chylomicrons and VLDL to create mature HDL particle. Cholesteryl ester and phospholipid
are transferred by cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP)
respectively. CETP and PLTP generate a TG-​rich HDL, which is then hydrolysed by hepatic lipase to generate
small HDL particles. HDL-​C is cleared by the liver. Additionally, cholesterol from HDL can be taken up by
hepatic SRB1 cell surface receptors.

from the blood by the liver through the binding to the LDLR by a TG-​rich HDL, which is substrate for HL. HL hydrolyses TG and
C-​terminal LDL receptor binding domain in apoB100. phospholipid to generate small HDL particles. Another lipase, endo-
thelial lipase, hydrolyses HDL phospholipid and generates even
Reverse cholesterol transport by HDL smaller HDL, which is rapidly catabolized.
While most cells make cholesterol, it cannot be degraded and only HDL cholesterol (HDL-​C) is cleared by the liver. Cholesterol from
the liver and intestine excrete it, either by secretion into bile or into the HDL can also be taken up by hepatic SRB1 cell surface receptors
intestinal lumen by the enterocyte. Biliary cholesterol is either in the that mediate the selective uptake of lipids into cells. Cholesteryl
form of free cholesterol or bile acids, after the conversion of liver ester from HDL is also transferred to apoB-​containing IDL and LDL
cholesterol to bile acids. HDL mediates the ‘reverse cholesterol trans- lipoproteins in exchange for TGs by CETP. These apoB-​containing
port’ of cholesterol derived from peripheral cell plasma membranes particles are then removed by LDLR-​mediated endocytosis. Some
back to the liver and gut for recycling or excretion (Fig. 12.6.14). apoA1 is catabolized by the kidneys.
Freshly secreted apoA1 acquires phospholipids and free choles-
terol from liver and intestinal cell plasma membranes, where their
efflux is mediated by ABCA1. The nascent HDL gains additional free Dyslipidaemia affecting cholesterol and
cholesterol from peripheral cells or circulating lipoproteins. The free triglyceride plasma levels
cholesterol in HDL is esterified by the enzyme LCAT, which is as-
sociated with HDL, and the cholesteryl ester transferred to the core The term dyslipidaemia is used to describe disorders of lipoprotein
of the lipoprotein particle. ApoA1 is a necessary cofactor for LCAT. metabolism in which there is elevation of TC and/​or TGs, often ac-
The acquisition of further cholesteryl ester, phospholipid, and add- companied by reduced levels of HDL-​C. It is very common.
itional apoCs and apoE transferred from chylomicrons and VLDL Dyslipidaemia is also used here to encompass high levels of
during lipolysis creates the mature HDL particle. apoB and LDL particle number without elevation of LDL chol-
HDL particles are extensively modified in the blood. Cholesteryl esterol (LDL-​C), which indicates the presence of sdLDL; high
ester and phospholipid are transferred by cholesteryl ester transfer levels of Lp(a); low levels of apoB-​containing lipoproteins; low
protein (CETP) and phospholipid transfer protein (PLTP) to HDL HDL-​C; and high levels of HDL-​C. The terms hyperlipidaemia or
from other lipoproteins or between various ‘classes’ of HDL lipo- hyperlipoproteinaemia refer to raised lipids, and do not encompass
proteins (Table 12.6.1, Fig. 12.6.14). CETP and PLTP generate a HDL. The term dyslipidaemia is used preferentially in this chapter.
2068 section 12 Metabolic disorders

The units used here are in mmol/​litre with mg/​dl in brackets. The value in severe hypertriglyceridaemia (see the ‘fridge test’, described
conversion factor for cholesterol from mmol/​litre to mg/​dl is times in ‘Familial chylomicronaemia (syndrome)).
38.7, and for TGs is times 88.6.
In clinical practice, the lipid profile of total cholesterol (TC), TG, The evidence base
and HDL levels is routinely measured, and LDL-​C and/​or non-​HDL The evidence concerning the relationship the between plasma lipid
cholesterol (NHDL-​C) usually calculated. The use of calculated and lipoprotein levels and atherosclerotic cardiovascular disease
LDL-​C versus NHDL-​C is discussed later in this chapter. comes from epidemiology, genetics, and the meta-​analysis of clin-
The measurement of lipid and lipoprotein levels in clinical prac- ical trials to treat dyslipidaemia. This data is supported by experi-
tice is important because the presence of raised plasma levels of mental medicine and pathology.
cholesterol is causally associated with atherosclerotic cardiovascular Epidemiology demonstrates a very strong relationship between
disease, and intervention to lower cholesterol levels will decrease the blood cholesterol at all blood cholesterol levels and atherosclerotic
risk of atherosclerotic cardiovascular disease events. Raised plasma cardiovascular disease events; TG levels throughout the normal
TG is also causally associated with increased atherosclerotic cardio- range and with mild to moderate elevations are similarly associated
vascular disease risk, and lowering TGs decreases atherosclerotic (Figs. 12.6.15 and 12.6.16).
cardiovascular disease events. By contrast, low plasma HDL levels Genome-​wide association studies and Mendelian randomization
are a marker of increased atherosclerotic cardiovascular disease risk, (Fig. 12.6.17) studies show that this relationship between LDL-​C
but this relationship is not causal. and TG levels and atherosclerotic cardiovascular disease is causal.
Less commonly there can be severe hypertriglyceridaemia, Mendelian causes of severe hypercholesterolaemia are strongly
which should be recognized as it can cause potentially fatal, acute linked to premature atherosclerotic cardiovascular disease. Severe
pancreatitis, the risk of which can be reduced by treatment of hypertriglyceridaemia also possibly increases the risk of atheroscler-
hypertriglyceridaemia. otic cardiovascular disease.
Dyslipidaemia is caused by a combination of genetic (primary) An important distinction between TGs and cholesterol is that
and acquired (secondary) factors (lifestyle, medical or metabolic TGs can be broken down by most cells, but cholesterol can be de-
conditions, and drugs). The genetic architecture of dyslipidaemia is graded by none. This property of cholesterol and the small size of
made up of both common and low-​frequency polymorphic variants, LDL, which enables it to enter the vascular intima, account for the
which affect lipid and lipoprotein metabolism and other metabolic direct atherogenicity of LDL. In the intima it is oxidized to form
traits such as obesity, insulin resistance, and hypertension. Rare al- oxidized LDL, which along with native LDL, is taken up by activated
leles make a small population, but large individual contribution to macrophages leading to a cascade of events that cause atheroscler-
genetic risk. Genetic variation confers around 50% to the total vari- otic cardiovascular disease.
ation in LDL-​C, TG, and HDL-​C levels. The role of TGs in atherogenesis is less clear. TG-​rich lipoproteins
Traditionally, familial hyperlipidaemias have been typed ac- and remnants both appear to be involved. TG-​rich chylomicron and
cording to the Fredrickson (World Health Organization) classifica- VLDL are, however, too large to enter the vascular intima, where
tion (Table 12.6.3), which is based on the pattern of lipoproteins on they could have a direct pathogenetic role in atherosclerotic car-
electrophoresis or ultracentrifugation. This is a descriptive typing of diovascular disease. Rather, free fatty acids and monoacylglycerol
apoB-​containing lipoproteins, and does not include HDL. released by TG lipolysis from TG-​rich lipoproteins can produce
The Fredrickson classification does not distinguish among low-​grade intimal inflammation. Remnants are small enough to
the gene defects that are wholly or partially responsible for the pass into the vascular intima, where remnant cholesterol is the likely
dyslipidaemia. Here, reflecting advances in mechanistic cell biology agent provocateur of atherosclerotic cardiovascular disease. Foam
and molecular genetics, a classification-​based mechanism is pre- cells accumulate cholesterol not TGs.
ferred, and where the genetic basis is known this is used, rather than The meta-​analyses of large clinical trials with statins overwhelm-
the Fredrickson classification. The Fredrickson classification is of ingly and conclusively demonstrate that LDL-​C lowering at all

Table 12.6.3 Fredrickson/​World Health Organization classification of primary hyperlipidaemias

Type Overnight serum High lipoprotein Clinical disorders Serum TC Serum TG

particles
1 Creamy top layer Chylomicrons Lipoprotein lipase deficiency, apoC2, apoA5, GPIHBPI, LMF1, GDP1 N ++
deficiency
2a Clear LDL Familial hypercholesterolaemia, polygenic hypercholesterolaemia, ++ N
nephrotic syndrome, hypothyroidism, familial combined hyperlipidaemia
2b Clear LDL, VLDL Familial combined hyperlipidaemia ++ +
3 Turbid IDL Dysbetalipoproteinaemia +/​++ +/​++
4 Turbid VLDL Familial hypertriglyceridaemia, familial combined hyperlipidaemia, N+ ++
sporadic hypertriglyceridemia, diabetes
5 Creamy top, Chylomicrons, Diabetes, lipoprotein lipase deficiency, apoC2, apoA5, GPIHBP1, LMF1, + ++
turbid bottom VLDL GPD1 deficiency

+, increased; ++, greatly increased; N, normal; N+, normal or increased; TC, total cholesterol.
 12.6 Lipid disorders 2069

40 plasma concentrations reduces atherosclerotic cardiovascular dis-

ease events. This is the case for LDL-​C levels to as low as 1.3 mmol/​
litre (50 mg/​dl). The remarkable success of statins is without harm,
Age-adjusted 6-year death rate

30 apart from a modest increase in the risk of diabetes.

per 1,000 men (n=361,662)

Total mortality (MRFIT)

Even this low level of LDL-​C is double the true physiological con-
centration seen in animals in the wild and human neonates, so that
20 the level to which LDL-​C can be reduced to prevent atherosclerosis
remains to ascertained. No increase in the risk of haemorrhagic
stroke has been observed at very low cholesterol levels.
CVD mortality (MRFIT)
10 Bulk of CVD While large clinical trials have not formally evaluated the effect of
5 TG reduction on atherosclerotic cardiovascular disease events, sec-
4
3 ondary analysis of trials of fibrates and nicotinic acid on TG reduc-
2
1 Shanghai study tion indicate a comparable effect to that achieved with statins. This
0
needs to be validated in appropriately designed clinical trials.
4.0 5.0 6.0 7.0 8.0 Contrary to previously held views, low HDL levels are not as-
Total cholesterol (mmol/L)
sociated with increased atherosclerotic cardiovascular disease risk
Fig. 12.6.15 Population cholesterol levels and cardiovascular risk. in genome-​wide association studies and Mendelian randomiza-
MRFIT study: this prospective study of 356 222 American men, aged tion studies, and the meta-​analysis of large clinical trials show no
35 to 57 years in 1973 to 1975, demonstrated that the relationship benefit from increasing HDL levels. Rather, HDL levels appear to be
between serum cholesterol and risk of cardiovascular disease death was
continuous, graded (dose related), and strong over the entire range of a biomarker of risk conferred by associated factors such as obesity,
the distribution of cholesterol levels. The Shanghai Study: Chen et al. insulin resistance, and diabetes. Whether improvement in the
followed 9021 men and women aged 35 to 64 from urban Shanghai, functionality of HDL, as, for example, in reverse cholesterol trans-
China, for 8–​13 years and found that even for cholesterol levels port improves atherosclerotic cardiovascular disease risk is not at
significantly lower than those in the MRFIT study, there was a significant present known.
correlation between cholesterol levels and atherosclerotic cardiovascular
disease death, with the risk increasing 4.5 times from the lower values to Intestinal lipid absorption and dyslipidaemia
the higher and no apparent threshold.
MRFIT study figure source data from: Stamler J, et al. (1986). Is relationship between
Intestinal cholesterol absorption varies between 30 and 80% in indi-
serum cholesterol and risk of premature death from coronary heart disease continuous viduals, and on average is around 50%. These differences are partly
and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor genetic and likely to be conferred by common and low-​frequency
Intervention Trial (MRFIT). JAMA, 256(20), 2823–​8. Shanghai Study figure source
data from: Chen Z, et al. (1991). Serum cholesterol concentration and coronary heart variants for the main part, but strongly influenced by secondary
disease in population with low cholesterol concentrations. BMJ, 303(6797), 276–​82. (acquired) factors.

5 5

4 4
Hazard ratio (95% CIs)

Hazard ratio (95% CIs)

3 3
for ASCVH

for ASCVD

2 2

1 1

0 0
1 2 3 4 5 6 7 1 2 3 4
Non-fasting triglycerides (mmol/L) Mainly fasting
triglycerides (mmol/L)
N = 93410 (cardiac events = 7183)
Median follow-up 6 years N = 302430 (cardiac events = 12785)
Median follow-up 8 years
Copenhagen City Heart Study and
Copenhagen General Population Study Emerging Risk Factors Collaboration

Fig. 12.6.16 Population triglyceride levels and cardiovascular disease risk. Observational
associations between raised concentrations of triglycerides and cardiovascular disease in the
Copenhagen City Heart Study and Copenhagen General Population Study combined (left) and in
the Emerging Risk Factors Collaboration (right). Hazard ratios were estimated by Cox proportional
hazard regression models, and were adjusted for age, sex, and trial group.
From Nordestgaard BG and Varbo A (2014) Triglycerides and cardiovascular disease. Lancet, 384 (9943):626–​35.
2070 section 12 Metabolic disorders

Odds ratio
Allele Studies per 1 unit increase
score (cases, total) in lipid (95% Cl) P-value

HDL-C allele score

Restricted (19 SNPs) 16 (11826,53514) 0.91 (0.42, 1.98) 0.817

LogTG allele score

Restricted (27 SNPs) .. .. .. 1.61 (1.00, 2.59) 0.05

LDL-C allele score

Restricted (19 SNPs) .. .. .. 1.92 (1.68, 2.19) 4.6x10–22

0.5 1 2 3
Odds ratio
Fig. 12.6.17 Mendelian randomization of HDL, TG, and LDL for atherosclerotic cardiovascular disease risk. This
meta-​analysis demonstrates the effect of a 1-​unit increase in blood lipid traits on atherosclerotic cardiovascular
disease risk. The genetic findings support a causal effect of triglycerides and LDL on atherosclerotic cardiovascular
disease risk, but a causal role for HDL-​C is not clear. Estimates were derived incorporating data on the association
between the allele scores and blood lipid traits from prospective cohorts (in which most individuals were free from
disease when lipid traits were measured) and applying this estimate to all studies with data on the association
between the scores and coronary heart disease.
Adapted from: Holmes MV, et al. (2015) Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J.
36(9):539–​50.

Primary factors affecting intestinal lipid absorption Patients can have prominent tendon xanthomas, and these may be
Polymorphic genetic variation at the APOE locus accounts for about disproportionate to the cholesterol levels, and occurrence of prema-
a quarter of variability in the absorption of cholesterol. APOE2 car- ture atherosclerotic cardiovascular disease. They also have abnormal
riers have the lowest absorption and APOE4 carriers the highest haematological and liver function test results due to the presence of
absorption. Those with an APOE4 allele also show a greater eleva- plant sterols in cell membranes. They can get attacks of haemolysis,
tion in plasma cholesterol levels in response to dietary cholesterol. and may have splenomegaly.
Common variants of the cholesterol 7 α-​hydroxylase gene (CYP7A1) These distinct clinical characteristics suggest the diagnosis: tendon
also affect intestinal bile acids and cholesterol absorption. Rare mu- xanthomas, perhaps in disproportion to the cholesterol levels, and
tations of the NPC1L1 gene decrease cholesterol absorption and are high cholesterol in the absence of a family history of atherosclerotic
associated with a decreased risk of atherosclerotic cardiovascular cardiovascular disease. A further clue to the clinical diagnosis is a
disease. poor response to statins. The diagnosis is made by the laboratory
finding of high blood levels of sitosterol and campesterol, and gene
Sitosterolaemia sequencing. The diagnosis is important because a low plant sterol
Sitosterolaemia also known as ‘phytosterolaemia’ is a rare autosomal diet, cholesterol absorption inhibitors, and bile acid sequestrants
recessive disease. LDL-​C levels can be normal to severely elevated in are highly effective treatments, while statins are less so. LDL and
the familial hypercholesterolaemia (FH) range (see ‘Familial hyper- sitosterol blood levels require monitoring as elevated plant sterols
cholesterolaemia’). It results from a deleterious mutation in either of are themselves atherogenic.
two related ABC half-​transporter genes, ABCG5 and ABCG8, which
Acquired (secondary) factors affecting intestinal
are expressed in enterocytes and liver cells. ABCG5 and ABCG8
lipid absorption
proteins heterodimerize to form a transporter for plant sterols such
as sitosterol and campesterol, and cholesterol from the liver into bile Secondary factors such as dietary fibre and plant sterol consump-
and from the enterocytes into the gut. tion affect cholesterol absorption. The microbiome is increasingly
Normally approximately 5% of plant sterols are absorbed by recognized as important. Intestinal bacteria dehydroxylate and
the jejunum, and these are disposed of by secretion into bile after deconjugate bile acids, and this affects cholesterol absorption. They
cycling through the liver. Consequently, systemic levels of plant also break down nonabsorbable dietary constituents rendering them
sterols remain very low. Patients with sitosterolaemia have high absorbable and a source of nutrients. Stanols are synthesized as a gut
jejunal absorption of plant sterols and cholesterol, but biliary and microbial byproduct of cholesterol metabolism.
faecal excretion is decreased causing high blood and tissue con- Despite the primary and secondary factors affecting cholesterol
centrations of plant sterols and cholesterols. In the liver, the high absorption, a 1-​g per day difference in dietary intake of cholesterol
level of sterols suppresses the expression of the LDLR gene, with on average only results in a 5% change in plasma cholesterol. This
low LDL-​C clearance and high plasma cholesterol levels. In con- is the main reason why restriction in dietary cholesterol intake
sequence, there is a failure to respond well to statins as the LDLR is no longer recommended in the United States of America (see
is not induced. ‘Treatment of dyslipidaemia’ and ‘Lifestyle’).
 12.6 Lipid disorders 2071

Interindividual variation in cholesterol absorption and response neurological complications, which can still develop even with ap-
in plasma cholesterol levels does, however, have therapeutic impli- propriate parenteral vitamin supplements. Medium-​chain TGs can
cations. High absorbers respond well to dietary restriction of choles- be helpful, with the caveat that their long-​term use may be hepato-
terol and in turn to ezetimibe treatment, and low absorbers respond toxic. Without treatment death is usually by the third decade.
poorly. In later life, due to failure to export lipid there is chronic fatty liver,
The measurement of noncholesterol sterols and stanol concen- often with raised transaminases, and there is increased fibrosis, pro-
trations provides a measure of cholesterol absorption status—​high gressing sometimes to cirrhosis.
absorbers have high plant sterol plasma levels—​but these tests are
not generally available, nor are they fully validated. ApoE4 carriers Hypobetalipoproteinaemia
also have higher levels of cholesterol absorption, and tend to show a Hypobetalipoproteinaemia is an autosomal codominant disorder
poor response to statins, perhaps partly due to the effect of apoE4 on caused by mutation of the APOB gene, with low TC, LDL-​C, and
cholesterol absorption. apoB levels. Often mutations lead to the formation of truncated
Empirical use of a low-​cholesterol diet in those with hyperchol- apoB, with defective chylomicron and VLDL and the formation of
esterolaemia is well worthwhile as high absorbers may show a dra- small lipoproteins that are rapidly removed from the blood.
matic effect. Patients with a poor response to ezetimibe are likely to The diagnosis is based on the lipid levels and inheritance pattern.
be low absorbers. DNA sequencing will confirm the diagnosis, but is not usually done
Chronic kidney disease (CKD) patients respond well to ezetimibe as the gene is large. Heterozygotes often have TCs of approximately
with reduction in atherosclerotic cardiovascular disease events, 2.5 mmol/​litre (100 mg/​dl), TGs of approximately 0.5 mmol/​litre
when used with statins, potentially implicating increased cholesterol (45 mg/​dl), and LDL-​C levels below 1.25 mmol/​litre (50 mg/​dl).
absorption in chronic renal disease. ApoB levels are approximately 20 mmol/​litre (60–​140 mg/​dl, 5th to
95th percentile). Vitamin E levels tend to be mildly reduced or low
Reduced production of chylomicrons and VLDL by normal. Fatty liver with raised transaminases is common, though
the intestine and liver not as marked as in abetalipoproteinaemia. Inflammation with pro-
Primary factors affecting production gression to fibrosis and cirrhosis is not frequent.
of chylomicrons and VLDL Hypobetalipoproteinaemia patients tend to be long-​lived, pre-
sumably due to the low levels of LDL-​C and reduced atherosclerotic
Abetalipoproteinaemia cardiovascular disease.
The production of apoB48-​containing chylomicrons and apoB100-​ Hypobetalipoproteinaemia homozygotes are very rare. They
containing VLDL in the gut and liver respectively requires MTTP resemble abetalipoproteinaemia, but the parents are typical
to load the nascent lipoproteins with TGs, phospholipids, and fat-​ hypobetalipoproteinaemia heterozygotes, and the fat-​ soluble
soluble vitamins (as discussed previously). vitamin deficiency and neurological sequelae less problematic,
Abetalipoproteinaemia is a rare Mendelian recessive disorder because of the ability to transport some fat. Again, diagnosis can
caused by deleterious mutations of the MTTP gene. Blood levels of be made by intestinal biopsy showing fat accumulation in the
cholesterol and TG are exceptionally low, and chylomicrons, VLDL, enterocytes.
LDLs, and apoB are absent from blood. Parents display normal lipid
and apoB-​containing lipoprotein levels. Affected infants may ap- PCSK9 deficiency
pear normal at birth, but by the first month of life fail to thrive; they PCSK9 deficiency also causes very low remnant and LDL plasma
develop steatorrhea, abdominal distention, and growth retardation levels, and is discussed further later in this chapter.
due to fat and fat-​soluble vitamin malabsorption.
Neurological and retinal abnormalities occur due to fat-​soluble Acquired (secondary) factors affecting production
vitamin deficiency, particularly of vitamins E and A, which are nor- of chylomicrons and VLDL
mally carried to the liver by chylomicrons and chylomicron rem- Very low levels of apoB-​containing lipoproteins with LDL-​C below
nants. Vitamin E is then transported on VLDL out of the liver to 1.5 mmol/​litre (60 mg/​dl) can be a feature of serious chronic illness
other tissues. such as cirrhosis, cancer cachexia, malnutrition, or malabsorption.
Infants develop neurological abnormalities with loss of reflexes and In the generally well person, however, it may reflect genetic defi-
decreased vibration and joint position sense. Later in life, in the third ciency of apoB-​containing lipoproteins (see ‘Abetalipoproteinaemia’
and fourth decade, ataxia and a spastic gait develop. A pigmented ret- and ‘Hypobetalipoproteinaemia’).
inopathy is also characteristic, with reduced night-​time and colour
vision and later eventually blindness. This constellation of clinical fea- Overproduction of VLDL by the liver and dyslipidaemia
tures is similar to Friedreich’s ataxia, and can lead to incorrect diag- Mixed (combined) dyslipidaemia with elevated fasting levels of TGs,
nosis. In addition, patients have acanthocytosis of red blood cells. increased TC, and low levels of HDL is often seen in clinical practice.
The diagnosis is made by intestinal biopsy and special fat staining Excess production of the VLDL by the liver is a common cause of
as with oil red O, which shows fat accumulation in enterocytes, and mixed dyslipidaemia. It is usually caused by a combination of gen-
confirmed by DNA sequencing of the MTTP gene. Diagnosis and etic (primary) and acquired (secondary) factors.
management is best achieved in specialized centres. Mixed dyslipidaemia is often associated with the metabolic syn-
Abetalipoproteinaemia patients are treated with a low-​fat, high-​ drome, which includes obesity, insulin resistance, hypertension,
calorie diet, and large parenteral fat-​soluble vitamin supplements diabetes, renal disease, and pre-​eclampsia (Table 12.6.4). Often
especially of vitamin E. Early treatment is essential to prevent there is sdLDL. Hypertriglyceridaemia and excess sdLDL with low
2072 section 12 Metabolic disorders

Table 12.6.4 Secondary causes of dyslipidaemia

VLDL LDL elevated LDL reduced

elevated
Obesity Hypothyroidism Severe liver disease
Type 2 diabetes Nephrotic syndrome Malabsorption
Glycogen storage disease Cholestasis Malnutrition
Nephrotic syndrome Acute intermittent porphyria Gaucher’s disease
Hepatitis Anorexia nervosa Chronic infectious disease
Alcohol Hepatoma Hyperthyroidism
Renal failure Drugs: thiazides, ciclosporin, carbamazepine Drugs: nicotinic acid
Sepsis
Cushing’s syndrome
Pregnancy
Acromegaly
Lipodystrophy
Drugs: oestrogen, β-​blockers, glucocorticoids, bile acid
binding resins, retinoic acid
IDL elevated Chylomicrons elevated HDL elevated HDL reduced Lp(a)
elevated
Multiple myeloma Autoimmune disease Alcohol Obesity Chronic kidney disease
Monoclonal gammopathy Type 2 diabetes Exercise Type 2 diabetes Nephrotic syndrome
Autoimmune disease Exposure to chlorinated Smoking Inflammation
Hypothyroidism hydrocarbons Gaucher’s disease Menopause
Drugs: oestrogen Acute glomerular nephritis Orchidectomy
Hypothyroidism
Acromegaly
Drugs: growth hormone, isotretinoin

levels of HDL is called ‘atherogenic dyslipidaemia’, because of its as- and apoB levels are increased, indicative of sdLDL. This condition
sociation with atherosclerotic cardiovascular disease (Table 12.6.1, has been called hyperapoB.
Fig. 12.6.17). FCHL affects about 1% of people. About a quarter of patients
SdLDL is produced by vascular remodelling of lipoproteins as with FCHL develop premature atherosclerotic cardiovascular dis-
a result of metabolic disturbance. The key predisposing factor is ease (men <55 years and women <65 years). The lipid phenotype
hypertriglyceridaemia with large VLDL, which leads to the forma- (high TC or TG or both) in an individual can vary from time to time
tion of slowly metabolized LDL particles that are subject to exchange depending on metabolic factors such as diet, exercise, overweight,
processes with removal of cholesteryl ester from the particle core insulin resistance, and diabetes.
and replacement with TG. This altered LDL is a substrate for HL, FCHL often does not emerge until early or even middle adult life
and lipolysis generates sdLDL. SdLDL shows defective clearance by probably due to the accumulation of the metabolic factors, which
the LDLR, increased vascular proteoglycan binding, and suscepti- contribute to the phenotype. It is rarely seen in children. Although
bility to oxidation, rendering it more atherogenic. The metabolic the FCHL clusters in families, the lipid phenotype varies between
factors associated with the formation of sdLDL also probably con- individuals.
tribute to atherosclerotic cardiovascular disease. While inheritance studies have suggested major gene effects, the
Mixed dyslipidaemia is also associated with a carbohydrate-​rich mode of inheritance is non-​Mendelian, and no single gene defect
diet, excessive alcohol consumption, and drugs such as oestrogen has been identified to cause this disorder. Rather, it is likely to be
(Table 12.6.4). polygenic due to the clustering of several genes with significant gen-
etic variation.
Primary causes of VLDL overproduction The diagnosis is indicated by family history, and the finding of
Common and low-​frequency variants of a number of genes that mixed dyslipidaemia, or isolated raised TC or TGs in family mem-
increase the risk of atherosclerotic cardiovascular disease are asso- bers, in whom the lipid phenotype varies, and low HDL. ApoB levels
ciated with VLDL overproduction. Mendelian causes are listed in are always high.
Table 12.6.5. Early treatment should be vigorous because of the high risk of
premature atherosclerotic cardiovascular disease. Dietary interven-
Familial combined hyperlipidaemia (FCHL) tion should include decreased intake of sugar and starch, which are
FCHL features increased levels of apoB-​containing lipoprotein pro- turned into TG by the liver and secreted as VLDL (Table 12.6.6),
duction from the liver giving rise to elevated levels of fasting VLDL in conjunction with weight reduction and physical exercise. Insulin
TG, LDL-​C, and often low levels of HDL. TG levels vary between resistance should be recognized and treated. Diabetes should be
3 and 7 mmol/​litre (265 and 620 mg/​dl), TC levels between 5 and aggressively managed.
10 mmol/​litre (200 and 400 mg/​dl), and HDL-​C below 1 mmol/​ High-​intensity lipid lowering with statins is indicated, often
litre (40 mg/​dl) in males and 1.25 mmol/​litre (50 mg/​dl) in females. with omega-​3 fatty acids derived from fish. Fibrates are indicated
Patients tend to have sdLDL and plasma apoB levels are increased. if the TGs are not reduced by statin and omega-​3 fatty acid treat-
Sometimes LDL-​C levels can be normal, but LDL particle number ment (Tables 12.6.7 and 12.6.8), and the benefits outweigh the risk
 12.6 Lipid disorders 2073

Table 12.6.5 Genetic defects affecting apoB-​containing lipoprotein metabolism

Genetic disorder Gene defect Lipoproteins elevated Clinical findings

Hypercholesterolaemia
Familial hypercholesterolaemia (AD) LDL receptor (LDLR) LDL Tendon xanthomas, CHD
Familial defective apoB100 (AD) ApoB100 (APOB) LDL Tendon xanthomas, CHD
Autosomal dominant hypercholesterolaemia, type 3 (AD) PCSK9 (PCSK9) LDL Tendon xanthomas, CHD
Autosomal recessive hypercholesterolaemia (AR) ARH (LDLRAP) LDL Tendon xanthomas, CHD
Sitosterolaemia (AR) ABCG5 or ABCG8 LDL Tendon xanthomas, CHD
Hypertriglyceridaemia
Lipoprotein lipase deficiency (AR) LPL (LPL) CM, VLDL Eruptive xanthomas, hepatosplenomegaly,
pancreatitis
Familial apoC2 deficiency (AR) ApoC2 (APOC2) CM, VLDL Eruptive xanthomas, hepatosplenomegaly,
pancreatitis
ApoA5 deficiency (AR) ApoA5 (APOA5) CM, VLDL Eruptive xanthomas, hepatosplenomegaly,
pancreatitis
GPIHBPI deficiency (AR) GPIHBP1 CM Eruptive xanthomas, pancreatitis
LMFI deficiency Eruptive xanthomas, pancreatitis
Combined hyperlipidaemia
Familial hepatic lipase deficiency (AR) Hepatic lipase (LIPC) VLDL remnants, HDL Pancreatitis, CHD
Familial dysbetalipoproteinaemia (AR) ApoE (APOE) CM remnants Palmer and tuberoeruptive xanthomas
VLDL remnants

AD, autosomal dominant; AR, autosomal recessive; CHD, coronary heart disease; CM, chylomicron.

of rhabdomyolysis with combined statin and fibrate use (see ‘Drug lipodystrophy). There is dyslipidaemia with raised TGs, TC,
treatment of hypertriglyceridaemia’). and low HDL. VLDL is overproduced and there is decreased lip-
olysis of TG-​rich chylomicrons and VLDL. Complete absence
Lipodystrophy of fat is sometimes congenital. It is associated with absence of
In lipodystrophy, there is a marked reduction in adipose tissue, leptin. A variety of causal gene defects have been described. It is
which may affect all or just some adipose depots (partial very rare.

Table 12.6.6 Cardioprotective lifestyle measures

Diet Exercise
• Total fat intake 30% or less of total energy intake, with saturated fat 7% or less of • 3000–​4000 metabolic equivalent of tasks (MET) minutes a week.a
energy, and minimal trans fat. Saturated fat should be replaced by mono-​unsaturated This can be a combination of many different activities
and poly-​unsaturated fats (in moderation). Cholesterol intake should be limited to • For example, to reach the total number, one could do all of these
300 mg daily every day:
• Replace fat from animal sources with mono-​unsaturated fat from olive oil or rape • Climbing stairs for 10 min
seed oil, or spreads made from these oils • Vacuuming for 15 min
• Try to eat red meat no more than 3–​4 times weekly • Gardening for 20 min
• Instead of frying foods—​which adds unnecessary fats and calories—​use cooking • Running for 20 min
methods that add little or no fat, like stir-​frying, grilling, baking, poaching, and • Walking or cycling for 25 min
steaming • Or do all of these every day:
• Avoid overheating cooking oils to their smoke-​point as this causes oils to lose their • Biking for an hour
beneficial nutrients and forms trans fats • Walking the dog for 30 min at a leisurely stroll
• Avoid prolonged storage of oils, especially in the light, as this causes oils to become • Cooking and washing dishes for 30 min
rancid through the formation of compounds like butyrate which, though not harmful, • Or do this every day:
taste unpleasant • Running at a vigorous pace for an hour
• Choose wholegrain varieties of starchy food • Weight loss, avoidance of excessive alcohol consumption, and
• Reduce sugar intake from food and drink, and this will reduce both glucose and smoking cessation are to be strongly encouraged
fructose
• Eat at least five portions of fruit and vegetable daily, but beware starchy vegetables,
and very sweet fruit in excess, raw is better than cooked
• Eat two portions of fish per week, including one of oily fish
• Eat at least four to five portions of unsalted nuts, seeds, and legumes per week
Notes: recent guidelines from the United States of America no longer restrict cholesterol consumption as, on average, this does not greatly impact plasma cholesterol levels. Cholesterol
consumption is best limited in those with hypercholesterolaemia, as individuals vary greatly in the amount they absorb and the effect of this on plasma levels of cholesterol.
Two large meta-​analyses have suggested that reduction in saturated fat consumption and increased unsaturated fat consumption does not decrease atherosclerotic cardiovascular
disease risk. The interpretation of these conclusions is unclear as other studies indicate benefit from reduced saturated fat consumption.
a
Kyu H, Bachman V, Alexander L, et al. (2016) Physical activity and risks of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review
and dose-​response meta-​analysis for the Global Burden of Disease Study 2013. BMJ, 354, i3857.
2074 section 12 Metabolic disorders

Table 12.6.7 Statin characteristics

Drug Reduction in Reduction in Reduction in Increase in Metabolism Half-​life (h) Hydrophilic

TC (%) LDL-​C (%) TG (%) HDL-​C (%)
Pravastatin 16–​25 22–​34 15–​24 2–​12 Sulphation 2–​3 Hydrophilic
Fluvastatin 16–​27 22–​36 12–​25 3–​11 CYP2C9 0.5–​3.0 Lipophilic
Simvastatin 19-​36 26–​47 12–​34 8–​16 CYP3A4 1–​3 Lipophilic
Atorvastatin 25–​45 26–​60 17–​53 5–​13 CYP3A4 13–​30 Lipophilic
Rosuvastatin 33–​46 45–​63 10–​35 8–​14 CYP2C9 19 Hydrophilic
Pitavastatin 20–​45 20–​48 6–​24 14–​25 CYP2C9 11 Lipophilic

Primary partial lipodystrophy is a codominant disorder as- GPD1 deficiency

sociated with defects of lamin A and other genes. Acquired This is a very rare autosomal disorder caused by mutations in the
partial lipodystrophy is described in membranoproliferative glom- GPD1 (glycerol-​3-​phosphate dehydrogenase) protein, which cata-
erulonephritis and autoimmune diseases such as systemic lupus lyses the reversible redox reaction of dihydroxyacetone phosphate
erythematosus, often with complement C3 consumption and the and NADH to glycerol-​ 3-​phosphate and NAD. Presentation is
presence of C3 nephritic factor. with massive hepatomegaly, steatosis, and marked, albeit transient,
Partial lipodystrophy is associated with decreased fat on the torso hypertriglyceridemia in infancy. VLDL production is increased. The
and limbs, though there may also be increased fat in other areas such hypertriglyceridaemia corrects with age.
as the face.
Insulin resistance is very common, and this may be profound. Acquired (secondary) causes of increased VLDL production.
There is usually hepatic steatosis, and this can be exacerbated by cer- Acquired causes of VLDL overproduction often accompany primary
tain drugs that block VLDL secretion such as nicotinic acid. Diabetes causes, particularly as this condition is polygenic in origin. The sec-
may develop. Acute pancreatitis can be precipitated by various drugs ondary causes of dyslipidaemia are listed in Table 12.6.4.
(Table 12.6.4).
Patients with partial lipodystrophy are at increased risk of athero- Diet and alcohol
sclerotic cardiovascular disease. Treatment can be difficult, especially in Excess dietary sugar and starch are rapidly turned into fatty acids
complete lipodystrophy. The treatment of the dyslipidaemia is similar and then TGs by the liver leading to increased VLDL production.
to that in FCHL, focusing on the insulin resistance and diabetes. Dietary carbohydrate excess is very common in Western society.

Table 12.6.8 Nonstatin lipid-​lowering drugs

Major Starting Maximal Mechanism Common side effects

indications dose dose of action
Cholesterol absorption blockers
Ezetimibe Elevated LDL-​C 10 mg daily 10 mg daily ↓Cholesterol absorption, Headache, dyspepsia
↑LDL receptors
Bile acid sequestrants
Colesevelam Elevated LDL-​C 3.75 g daily 4.375 g daily ↑Bile acid excretion and Constipation, worsening
Cholestyramine 4 g daily 32 g daily ↑LDL receptors hypertriglyceridaemia
Colestipol 5 g daily 40 g daily
MTP inhibitor
Lomitapide HoFH 5 mg daily 60 mg daily ↓VLDL production Nausea, steatorrhoea, increased
hepatic fat
ApoB inhibitor
Mipomersen HoFH 200 mg SC weekly 200 mg SC weekly ↓VLDL production Injection site reactions, flu-​like
symptoms, increased hepatic fat
Fibric acid derivativesa
Gemfibrozil Elevated TG 300 mg twice daily 600 mg twice daily ↑LPL Dyspepsia, myalgia, gallstones,
Fenofibrate 67 mg once daily 267 mg once daily ↓VLDL production elevated transaminases
Bezofibrate 400 mg once daily 400 mg once daily
Omega-​3 fatty acids
Omega-​3 fatty acid Elevated TG 2 g daily 4 g daily ↓VLDL synthesis Dyspepsia
ethyl esters ↑TG catabolism

HoFH, homozygous FH.

a
With concomitant statin, there is an increased risk of myopathy and rhabdomyolysis; use reduced dose. Risk highest with gemfibrozil.
 12.6 Lipid disorders 2075

Too much, frequent alcohol consumption impairs fatty acid β-​ which impairs biliary cholesterol excretion. Free cholesterol and
oxidation leading to increased TGs and VLDL production, often in phospholipids are secreted into the blood as a lamellar particle des-
the presence of raised HDL-​C caused by an increased transport rate ignated lipoprotein-​X (LP-​X). LP-​X can form xanthomas in skin
of apoA1 and apoA2. Elevated TGs and HDL-​C found together sug- folds similar to those found in FDBL (xanthomata striata palmaris),
gests excessive alcohol consumption. as well as planar and eruptive xanthomas. Statins appear to be safe
and effective in severe chronic cholestasis such as in primary biliary
Obesity, insulin resistance, and type 2 diabetes cirrhosis. Increased liver transaminases and statin treatment are dis-
(See Chapters 11.5, 11.6, and 13.9.1.) Dyslipidaemia is a common cussed later in this chapter (see ‘Drug treatment of hypercholester-
finding in obesity, insulin resistance with hyperinsulinaemia, and olaemia’ and ‘Statins’).
diabetes. The dyslipidaemia features raised TGs and low HDL-​C;
often with raised LDL-​C and sdLDL—​atherogenic dyslipidaemia. Defective peripheral lipolysis and dyslipidaemia
Overweight and obesity are associated with inflammation in fat The main goal in severe hypertriglyceridaemia is to prevent acute
tissue leading to insulin resistance, hyperinsulinaemia, and per- pancreatitis (see ‘Drug treatment of hypertriglyceridaemia’). Raised
turbed lipid metabolism—​the metabolic syndrome. plasma TGs are also associated with an increased risk of atheroscler-
A prominent characteristic is VLDL overproduction from the otic cardiovascular disease.
liver, which is driven by free fatty acids released from fat tissue Decreased lipolysis of TG-​rich lipoproteins is commonly associ-
and transported to the liver principally on albumin. In the liver, ated with dyslipidaemia. LPL is the principal enzyme responsible for
free fatty acid is converted to TG and phospholipid and assembled the peripheral lipolysis of chylomicron and VLDL TGs. Decreased
into VLDL for discharge into the blood, and this is favoured by LPL activity gives rise to fasting hypertriglyceridaemia with low
hyperinsulinaemia. Accompanying reduction in LPL function, with levels of HDL-​C, mostly in the absence of raised LDL-​C or apoB.
impaired lipolysis of chylomicrons and VLDL TG, worsens the ele- LPL is synthesized by and secreted from adipocytes, and skeletal and
vation of TGs. The metabolic syndrome is associated with a serious heart muscle cells, where it becomes bound to vascular endothelial
excess risk of atherosclerotic cardiovascular disease. cells through GPIHBP1. ApoC2 is a necessary cofactor for activation
The treatment is weight loss and good diabetes control. Lipid of LPL. ApoA5 and LMF1 activate and mature LPL respectively. LPL
lowering medication may be required, and should be considered in may be reduced for genetic or acquired reasons.
diabetes.
Primary causes of defective lipolysis
Cushing’s syndrome of triglyceride-​rich lipoproteins
(See Chapter 13.5.1.) Glucocorticosteroid excess due to Cushing’s Fifty per cent of the variance of TG levels has a genetic basis, and is
syndrome or glucocorticoid treatment causes increased fatty acid likely to be caused by a combination of common and low-​frequency
and TG biosynthesis, VLDL overproduction, and elevated blood genetic variants, and rare alleles. Variants are described in multiple
TGs. Cushing’s syndrome sufferers often have raised TGs and low genes that cause increased plasma TG levels, and several of these
HDL-​C, and sometimes high LDL-​C. Glucocorticoid-​induced in- affect lipolysis. Numerous variants are also described in LPL and
sulin resistance may contribute to VLDL overproduction. The genes directly associated with LPL activity, and some of these are
management is that of Cushing’s syndrome, or modulation of the associated with Mendelian recessive forms of hypertriglyceridaemia
therapeutic doses of glucocorticoids. (Table 12.6.5).

Nephrotic syndrome Familial chylomicronaemia (syndrome)

(See Chapters 21.3 and 21.6.) Increased VLDL secretion is common Primary deficiency of LPL or of its cofactor apoC2 causes marked
in the nephrotic syndrome. This is considered to be caused by the hypertriglyceridaemia (type 1 and 5 hyperlipoproteinaemia)
low oncotic pressure in blood due to hypoalbuminaemia leading (Table 12.6.3). Fasting TG levels are invariably greater than
to increased biosynthesis of liver protein, but the mechanism 10 mmol/​litre (900 mg/​dl), and can be 20 to 40 times normal with
for this is not understood. Treatment of the kidney disease is im- levels of 30 to 65 mmol/​litre (2500–​5700 mg/​dl). In the nonfasting
portant to decrease the loss of albumin in the urine and correct the state, particularly when there are intercurrent factors such as poorly
hypoalbuminaemia. Unrelieved nephrotic syndrome is likely to controlled diabetes, plasma TG levels can reach 100 times the
need lipid-​lowering drug treatment. normal value with levels of 170 mmol/​litre (15 000 mg/​dl). In type 5
hyperlipidaemia, where increased VLDL production is prominent,
Liver disease fasting cholesterol levels can be five times normal.
The liver affects lipoprotein metabolism through several pro- Primary LPL deficiency is an autosomal recessive disorder with
cesses because it is both a major organ of lipoprotein synthesis a frequency of around 1 per million people. It is best characterized
and of clearance. VLDL production is increased with modest for mutations of the LPL and APOC2 genes, but mutants of APOA5,
hypertriglyceridaemia in hepatitis caused by viruses, alcohol, and GPIHBP1, and LMF1 (see ‘Chylomicronaemia due to other gene de-
medications. fects’) can all cause chylomicronaemia with a type 1 or 5 ‘hyperlipid-
Failure of VLDL synthesis with marked reduction in plasma chol- aemia pattern’. Many causal mutations of LPL and APOC2 have been
esterol and TGs occurs in severe hepatitis and hepatic failure. described. LPL heterozygotes often have mild to moderate eleva-
Bile is an important channel for excretion of cholesterol, either tions of TG. APOC2 defective heterozygotes do not. Type 1 ‘hyper-
after conversion to bile acids or directly as cholesterol. Markedly lipidaemia’ is more likely to be caused by null alleles, and type 5 by
raised plasma cholesterol levels can occur in cholestatic disease, less deleterious alleles.
2076 section 12 Metabolic disorders

Nearly all patients have recurrent episodes of severe abdom- antisense oligonucleotide) has also proved remarkably efficacious
inal pain, with or without overt acute pancreatitis, that interfere as a treatment, confirming the role of apoC3 in the LPL-​mediated
with normal life and result in frequent hospitalizations. These metabolism of TG-​rich lipoproteins. Small-​molecule inhibitors or
episodes can result in chronic pancreatitis and symptoms of exo- DGAT1 and MTTP are efficacious in reducing TG absorption, but
crine or endocrine pancreatic insufficiency, including diabetes and are not licensed for this use.
even fatal events. Other symptoms include arthralgia and neuro- The management of primary hypertriglyceridaemia is particu-
logical symptoms such as loss of feeling in the feet or legs, and larly troublesome in acute hypertriglyceridaemic pancreatitis
memory loss. and during pregnancy, which are discussed in ‘Drug treatment of
On physical examination, patients may display small yellowish hypertriglyceridaemia’.
papules (eruptive xanthomas), which are often grouped on the ex-
tensor surfaces of the arms and legs, back, and buttocks. They are Chylomicronaemia due to other gene defects
painless, but may itch. Visualization of the fundus reveals milky-​
Deleterious mutations of APOA5, GPIHBP1, and LMF1 can all cause
white discoloration of retinal blood vessels—​ lipaemia retinalis.
chylomicronaemia syndrome with a type 1 or 5 ‘hyperlipidaemia
Hepatosplenomegaly may be caused by chylomicron uptake by the
pattern’. Affected patients can be homozygotes or even be heterozy-
mononuclear phagocyte system. Not all patients develop acute pan-
gous for defects of two of these genes acting together to reduce LPL
creatitis or the cutaneous features. There is an increased risk of ath-
activity, and produce the type 1 or 5 ‘hyperlipidaemia pattern’, par-
erosclerotic cardiovascular disease, but premature atherosclerotic
ticularly type 5. LMF1 mutations cause combined lipase deficiency.
cardiovascular disease is not a major manifestation.
DNA sequencing of these genes will disclose mutations in more than
A simple diagnostic test is to place a fasting plasma sample in the
80% of cases of type 1 and 60% of type 5 ‘hyperlipidaemia’. Others
refrigerator at 4°C overnight. Colloquially this is called the ‘fridge
genes, which have yet to be characterized and secondary factors con-
test’ or refrigerator test. Chylomicrons are of low density and float
tribute to this phenotype. The treatment is as previously described.
to the top, where they form a narrow, creamy band with a clear or
mildly cloudy infranatant (type 1), or the infranatant may be more Familial hypertriglyceridaemia (FHTG)
markedly turbid (type 5); this infranatant is VLDL and remnants.
The diagnosis is best confirmed by showing absence of lipase ac- FHTG features raised fasting TGs, in the range 2.3 to 10 mmol/​litre
tivity for TGs in postheparin plasma, which releases endothelium-​ (200 to 900 mg/​dl) without another primary or secondary reason,
bound LPL. LPL activity is very low in LPL and apoC2 defective often low levels of HDL-​C, and familial clustering. LDL-​C levels
patients. In apoC2-​or apoA5-​deficient patients, however, it is cor- may be normal or low due to reduced formation from TG-​rich lipo-
rected by supplementing apoC2 or apoA5 from normal plasma. proteins in the blood. ApoB levels unlike in FCHL are normal, and
DNA sequencing of the LPL, APOC2, APOA5, GPIHBP1, and the risk of atherosclerotic cardiovascular disease is not usually very
LMF1, and possibly other hypertriglyceridaemic genes, will help es- high. There is generally reduced lipolysis of TG-​rich lipoproteins,
tablish the diagnosis. often with overproduction of VLDL by the liver.
In the short term, the management of very severe hyper­ The blood is likely to display a type 4 ‘hyperlipoproteinaemia
triglyceridaemia to prevent acute pancreatitis is as described in picture’ without chylomicrons rather than type 1 or 5. Acquired
‘Drug treatment of hypertriglyceridaemia’. For the long-​term treat- factors can worsen the hypertriglyceridaemia and give risk to
ment of chylomicronaemia, dietary fat restriction to less than 20 chylomicronaemia and acute pancreatitis (see ‘Secondary causes of
to 30 g daily with fat-​soluble vitamin supplementation is neces- impaired lipolysis’).
sary. Calories can be supplemented with medium-​chain TGs which No single gene has been identified, rather the condition appears
provide energy, as they are absorbed directly into the portal vein, to be caused by a combination of gene variants leading to polygenic
though there is a possibility of liver damage with long-​term treat- hypertriglyceridaemia. It is important to identify and treat associ-
ment. Exercise can reduce TG levels. ated acquired causes. Diet and exercise are valuable. Lipid-​lowering
Secondary factors, commonly diabetes, should be vigorously medication, with statins (if plasma TGs are <5 mmol/​litre (450 mg/​
treated, and those drugs that increase TGs avoided or substituted. dl)), fibrates, and fish oils may be required to treat higher TG levels.
Factors that increase VLDL production will overwhelm residual The risks of the combined use of statins and fibrates are shown in
LPL function and greatly worsen hypertriglyceridaemia. Table 12.6.8.
Fibrates are the drugs of first choice in the management of severe
Acquired (secondary) causes of impaired lipolysis
hypertriglyceridaemia (Table 12.6.8). Omega-​3 fatty acids (fish oils)
of triglyceride-​rich lipoproteins
act by decreasing VLDL secretion so that they are not useful in pure
LPL deficiency, where they can increase hypertriglyceridaemia (see The secondary causes of dyslipidaemia are listed in Table 12.6.4.
‘Omega-​3 fatty acids’). In type 5 ‘hyperlipoproteinaemia’, they are an
important treatment and can be used at doses well in excess of doses Obesity, insulin resistance, and type 2 diabetes
normally used in patients with mild forms of hypertriglyceridaemia, (See Chapters 11.5, 11.6, and 13.9.1.) Obesity, insulin resistance,
particularly for short periods. and type 2 diabetes are associated with increased VLDL secretion,
Gene therapy with LPL has also been trialled using an adeno-​ but can also decrease LPL activity. There may be decreased expres-
associated viral vector containing the LPL gain-​of-​function variant sion of the LPL gene in peripheral tissues, and increased expres-
(Alipogene Tiparvovec) given by intramuscular injection leading sion of the gene for the LPL inhibitor apoC3 in the liver leading to
to myocyte expression of LPL. A second-​generation modified anti- hypertriglyceridaemia. Clinical management is by weight loss and
sense APOC3 mRNA inhibitor (2ʹ-​O-​(2-​methoxyethyl)-​modified good diabetes control. Lipid-​lowering medication may be required.
 12.6 Lipid disorders 2077

Alcohol the very rare primary hypercholesterolaemia syndromes de-

As well as increasing VLDL secretion, excessive alcohol significantly scribed in the following subsections, in whom a DNA diagnosis
decreases LPL activity. is not made, polygenic hypercholesterolaemia is likely. Plasma
cholesterol levels often overlap with those found in FH, but the
Defective hepatic clearance of remnants and LDL as a inheritance is not dominant, perhaps affecting around 10% of
cause of dyslipidaemia first-​degree relatives. Inheritance of the number of variants to-
Defective clearance of LDL and chylomicron and VLDL lipoprotein gether with elevated cholesterol coupled with diet is generally the
remnants by the hepatic LDLR is a frequent cause of dyslipidaemia. cause of this condition.
It is caused by genetic and acquired factors. Variation in a number In the evaluation of hypercholesterolaemia, however, single-​gene
of genes interferes with lipoprotein clearance by the LDLR and Mendelian disorders are relatively common and should be con-
these may give rise to polygenic disorders with elevated cholesterol. sidered in the differential diagnosis (Table 12.6.5). Common genetic
Mendelian disorders, which give rise to defective hepatic clear- variants also exacerbate FH.
ance of apoB-​containing lipoproteins, can cause marked elevation
of LDL-​C with premature atherosclerotic cardiovascular disease Familial hypercholesterolaemia
(Table 12.6.5). The clinical features of polygenic and Mendelian FH is an autosomal codominant disorder caused by deleterious mu-
hypercholesterolaemia overlap. tation of the LDLR gene. Patients have asymptomatic high TC, due
A diet high in saturated and trans fats decreases LDLR activity to elevation of remnants and LDL-​C, without raised TGs, usually in
and increases plasma cholesterol levels, which can worsen genetic the range of 7.5 to 10 mmol/​litre (290–​390 mg/​dl). Premature ath-
causes of hypercholesterolaemia. Hypothyroidism, CKD, and oes- erosclerotic cardiovascular disease is very common.
trogen deficiency after the menopause are associated with reduced The frequency of heterozygous FH is as high as 1 in 200 of the
LDLR activity. population according to recent estimates. In certain populations, the
frequency can be even higher due to a founder effect. These include
Primary (genetic) causes of impaired liver uptake Afrikaners in South Africa, French Canadians, Christian Lebanese,
of lipoproteins and the Finns.
Multiple common gene variants have been identified that affect It is important to recognize and treat FH early so as to prevent ath-
clearance of LDL and remnant lipoproteins by the LDLR. Indeed, erosclerotic cardiovascular disease in middle life. Secondary causes
more than 50% of the variation in LDL-​C levels is determined by of marked hypercholesterolaemia, including hypothyroidism, neph-
genetic factors. rotic syndrome, and obstructive hepatic disease, must be excluded
In people with predominantly hypercholesterolaemia (type in the differential diagnosis.
2a and b ‘hyperlipidaemia’; Table 12.6.3) who do not show Numerous LDLR gene mutations have identified by DNA sequen-
Mendelian inheritance, and do not have the features of one of cing (Fig. 12.6.18). Some are recurrent due to small founder effects

45 kb

5’ 3’
Exon 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 mRNA = 5.3 kb
number

Signal Ligand EGF precursor O-linked Membrane- Cytoplasmic

sequence binding homology sugars spanning 50 a.a.
21 a.a. 292 a.a. 400 a.a. 58 a.a. 22 a.a.

mRNA Binding Recycling No Secreted Internalization

Transport Transport effect ARH binding
PCSK9 binding

Class I: LDLR is not synthesized at all

Class II: LDLR is not properly transported from the endoplasmic reticulum (receptor negative) to the
Golgi apparatus for expression on the cell surface.
Class III: LDLR does not properly bind LDL on the cell surface because of a defect in either apolipoprotein
B100 (R3500Q) or in LDL-R.
Class IV: LDLR bound to LDL does not properly cluster in clathrin-coated pits for receptor-mediated
endocytosis.
Class V: LDLR is not recycled back to the cell surface.
Extent of LDLR deficiency will depend on deleteriousness of amino acid change.
Fig. 12.6.18 LDL receptor gene (LDLR) structure and familial hypercholesterolaemia mutations.
2078 section 12 Metabolic disorders

or possibly recurrent mutation at susceptible sites such as CpG 30% because many of these patients have polygenic hypercholester-
dinucleotides. olaemia. DNA diagnosis facilitates family cascade screening.
Mutations causing complete loss of LDLR activity (receptor nega- No other laboratory test is available for diagnosis, though in re-
tive) compared to those with low activity (receptor defective) lead to search laboratories LDLR binding studies for LDL in cultured cells
higher levels of cholesterol. LDLR defects decrease hepatic clearance has been valuable in characterizing the function of different dele-
of LDL from the blood; removal of IDL is also decreased with in- terious mutations. Clinical criteria have therefore been established
creased production of LDL from IDL. Individuals with two mutated for diagnosis. In the United Kingdom, these are the Simon Broome
receptor alleles (FH homozygotes) with the same or different mu- criteria (Table 12.6.9), and in other parts of Europe such as the
tations (compound heterozygotes) have very much higher levels of Netherlands, similar criteria are used.
LDL-​C than those with one mutant allele (FH heterozygotes). FH heterozygotes should be very vigorously treated to reduce
Hypercholesterolaemia in FH patients is present from birth or be- LDL-​C levels, and other risk factors minimized, preferably starting
fore. The early lesions of atherosclerosis, fatty streaks, can be seen in in childhood.
the fetus. Hypercholesterolaemia can be detected in the neonate if In children, a low-​cholesterol diet with low saturated and trans
family history indicates the need for cholesterol measurement. fat is valuable. Bile acid sequestrants can be used before puberty,
Detection of FH is either due to finding hypercholesterolaemia on with other lipid-​lowering drugs being introduced after puberty. The
health assessment screening, suspicion due to adverse family history, rationale for this delay is the importance of cholesterol for growth
the appearance of tendon xanthomas (Achilles tendon, dorsum of and sex hormone biosynthesis, but this is not evidence based.
the hand or feet), cutaneous xanthelasmas, often with corneal arcus, Increasingly, some centres are commencing statin therapy in the first
or development of premature atherosclerotic cardiovascular disease. decade of life, depending on the child’s LDL levels and the family
Clinical stigmata are present in many but not all patients with het- history of premature atherosclerotic cardiovascular disease.
erozygous FH, and this may depend on the level of cholesterol. The powerful, long-​acting statins are the most efficacious drugs
Dominant inheritance causes an affected parent to transmit the and should be used at high intensity in adults (Tables 12.6.7 and
disease to half of all children, so that usually there is a strong family 12.6.10). It is reasonable to supplement statins with cholesterol
history of premature atherosclerotic cardiovascular disease from the absorption inhibitors or bile acid sequestrants, and often these
one half of the family harbouring the mutant LDLR gene. Polygenic drugs are used in conjunction to achieve greater than 50% LDL-​
factors from both sides of the family may confound this pattern. C lowering. Other newer drugs, known as PCSK9 inhibitors, have
Untreated FH heterozygotes have a very high risk of premature recently become available for treatment of conditions such as FH,
atherosclerotic cardiovascular disease. Males have an approximately but their use is currently highly restricted (see ‘Drug treatment of
50% likelihood of myocardial infarction before the age of 60 and hypercholesterolaemia’).
females have an approximately 30% chance. The manifestations of In those planning pregnancy, statins should be stopped, as animal
atherosclerotic cardiovascular disease vary greatly in their age of ap- data suggests that statins are teratogenic although there is no human
pearance. This may depend on the level of cholesterol determined data to support this. When stopping statins prior to conception, a
by whether the LDLR mutation causes deficient (10% of mutations) 3-​month washout period is often recommended, but this is not evi-
or defective LDLR protein function (Fig. 12.6.18), and the presence dence based, and shorter periods are probably acceptable.
of other atherosclerotic cardiovascular disease risk factors such as Targets for LDL-​C/​NHDL-​C lowering should be to greater than
hypertension, smoking, obesity, diabetes, and elevation of Lp(a). 50% of the starting highest level. Greater reduction to the levels ad-
DNA sequencing is the only definitive diagnostic test, and with vised for secondary prevention is reasonable, LDL-​C to less than
advances in this technology, this becomes increasingly available in 2 mmol/​litre (80 mg/​dl), to minimize the risk of atherosclerotic car-
routine practice through specialized medical centres. Four genes are diovascular disease, and this is mandatory in established disease.
routinely analysed: LDLR, PCSK9, and LDLRAP by exon sequen- The role of imaging by carotid ultrasonography of CT coronary cal-
cing, and APOB by typing the glutamine for arginine at amino acid cium scoring in detecting premature atherosclerotic cardiovascular
3500 mutation (see ‘Familial defective apoB100 (FDB)’). A DNA disease is discussed in ‘Diagnosis of dyslipidaemia’.
diagnosis will be found in about 70% of patients with ‘definite’ FH Some FH heterozygotes will not achieve greater than 50%
(see ‘Simon Broome criteria’, Table 12.6.9). In those with possible FH LDL-​ C lowering with available medication. These patients are
on Simon Broome criteria, a DNA diagnosis will be found in about candidates for use of PCSK9 inhibitors (see ‘Drug treatment of

Table 12.6.9 Simon Broome criteria for the diagnosis of familial hypercholesterolaemia

Definite familial • Total cholesterol >6.7 mmol/​litre or LDL cholesterol >4.0 mmol/​litre in a child <16 years
hypercholesterolaemia • Total cholesterol >7.5 mmol/​litre or LDL cholesterol >4.9 mmol/​litre in an adult. (Levels either pretreatment or highest on
treatment)
• Plus tendon xanthomas in patient, or in first-​degree relative (parent, sibling, child), or in second-​degree relative (grandparent,
uncle, aunt)
• Or DNA-​based evidence of an LDL receptor mutation or familial defective apoB100
Possible familial • Total cholesterol >6.7 mmol/​litre or LDL cholesterol >4.0 mmol/​litre in a child <16 years
hypercholesterolaemia • Total cholesterol >7.5 mmol/​litre or LDL cholesterol >4.9 mmol/​litre in an adult
• Plus a family history of myocardial infarction: below age of 50 in second-​degree relative or below age 60 in first-​degree relative
• Or a family history of raised total cholesterol >7.5 mmol/​litre in adult first-​or second-​degree relative or >6.7 mmol/​litre in child
or sibling <16 years
 12.6 Lipid disorders 2079

Table 12.6.10 High-​, moderate-​, and low-​intensity statin therapy

High intensity Moderate intensity Low intensity

Daily dose lowers LDL-​C on average by 50% Daily dose lowers LDL-​C on average by 30% to <50% Daily dose lowers LDL-​C on average by <30%
Atorvastatin 40–​80 mg Rosuvastatin 20 (40) mga Atorvastatin 10–​20 mg Rosuvastatin 10 mg Simvastatin 10 mg
Simvastatin 20 mgb Pravastatin 10–​20 mg
Pravastatin 40 mg Fluvastatin 20–​40 mg Pitavastatin 1 mg
Fluvastatin XL 80 mg
Fluvastatin 20 mg twice daily
Pitavastatin 2 mg

Mechanism of action is by lowering cholesterol synthesis and increasing liver LDLR activity. Common side effects are myalgia, myopathy, elevated transaminase, and dyspepsia.
Specific statins and doses are noted in bold that were evaluated in randomized clinical trials, which showed a reduction in major cardiovascular events. Statins and doses not tested in
clinical trials are in italics.
Individual responses to statin therapy vary and there might be a biological basis for a poor response.
a
Starting dose 5 mg if hypothyroid, >65 years, Asian. The 40-​mg dose is contraindicated in Asians.
b
Simvastatin 80 mg is not recommended due to the increased risk of myopathy, including rhabdomyolysis.

hypercholesterolaemia’ and ‘PCSK9 inhibitors’). FH patients whose limited by problems associated with immunosuppression and graft
LDL-​C remains markedly elevated, greater than 5 mmol/​litre (200 rejection.
mg/​dl) with cardiovascular disease or 7.5 mmol/​litre (300 mg/​dl) Three new drugs have potential value. PCSK9 inhibitors which
without cardiovascular disease, despite maximum tolerated drug increase LDLR activity apparently have value in receptor-​defective
treatment, especially those with high Lp(a) levels, can be probably patients and are now licensed for use. A MTTP inhibitor, which
be improved with LDL apheresis (see ‘Drug treatment of hyperchol- prevents chylomicron and VLDL synthesis and subsequent conver-
esterolaemia’ and ‘LDL apheresis’). sion into remnants and LDL is effective in lowering LDL. Antisense
Homozygous FH is caused by mutations of the LDLR gene oligonucleotide treatment to block apoB synthesis is used in the
passed on from each parent. The frequency is around 1 in a mil- United States of America, but not in Europe. These drugs are dis-
lion people. Those with complete absence of LDLR activity (re- cussed in later subsections.
ceptor negative) compared to those with low, but present activity
(receptor defective) have higher LDL-​C levels. LDL-​C levels in Familial defective apoB100 (FDB)
homozygous FH patients range from about 12 (480) to in excess FDB is an autosomal dominant hypercholesterolaemia, which is
of 25 mmol/​litre (1000 mg/​dl). Those with higher LDL-​C levels clinically like heterozygous FH. Mutations of the APOB gene cause
develop tendon xanthomas on the hands, wrists, elbows, knees, FDB, and these usually affect the region of apoB100 that contains
Achilles tendons, or buttocks. the LDLR-​binding domain, which is lacking in apoB48. It is mostly
Homozygotes develop atherosclerotic cardiovascular disease in usually caused by a predominant mutation of glutamine for arginine
childhood or adolescence. Lesions are common in the aortic root at amino acid 3500, which reduces the binding and clearance of LDL
and aortic valve with subvalvular stenosis, often reaching into the by the LDLR.
coronary ostia, which become narrowed. The carotids and periph- It is seen in patients of central European origin and in derived
eral blood vessels become narrowed and can be problematic. Sudden populations in the United States of America, where the frequency
cardiac death is relatively common. Symptoms reflect decreased car- is 1 in 500 to 1 in 1000, and this reflects a founder effect mutation.
diac output and cardiac ischaemia. Without treatment, death is in It is common in the Pennsylvania Amish but is found worldwide.
the second to third decade, reflecting disease severity. Apheresis is Recurrent mutation occurs as Arg3500 is encoded by a CpG di-
the mainstay for treating homozygous FH. With apheresis and lipid-​ nucleotide, which is a hotspot for mutation. Mutations elsewhere in
lowering drugs, this grim prognosis is much improved. the gene have also been described.
Homozygous FH is suggested by the very high TC (>12 mmol/​ FDB is less common than FH, likely because the target for muta-
L, 480 mg/​dl) and LDL-​C levels (>10 mmol/​L, 400 mg/​dl) in the tion is mainly restricted to the LDLR binding domain of apoB100.
absence of an acquired reason. Skin xanthomas are virtually pathog- Homozygotes are extremely rare. Individuals with both LDLR
nomonic. Atherosclerotic cardiovascular disease in a young patient and FDB mutations have been described, and they behave as
and TC greater than 7.5 mmol/​litre (300 mg/​dl) in both parents are homozygotes.
both highly suggestive of homozygous FH. DNA sequencing will In FDB there is elevated plasma LDL-​C, but not of remnants be-
generally identify LDLR mutations. Receptor-​negative homozygotes cause clearance through the interaction of apoE with the LDLR is
are most commonly due to consanguinity, but are fortunately rare. normal. Thus TC levels tend to be lower than in FH. TGs are normal.
Homozygous FH patients should be treated early and most vigor- Tendon xanthomas are less prominent than in FH. Premature ath-
ously to retard the relentless onset and progression of atheroscler- erosclerotic cardiovascular disease is common.
osis. While maximal drug treatment may be adequate to treat some FDB cannot be distinguished clinically from FH. Homozygotes
LDLR patients most will require apheresis as well. High-​intensity tend to be less severely afflicted than FH homozygotes due to the
statin treatment, ezetimibe, and sequestrants are reasonably given lower cholesterol levels, because remnants are cleared normally
together. Receptor-​negative patients do not respond to these drugs. through the interaction of apoE with the LDLR. The definitive diag-
Liver transplantation has been used to treat homozygous FH, nosis is by DNA genotyping, which is usually focused on the amino
because the liver is the main site of LDL clearance, but its use is acid 3500 mutation, or by DNA sequencing. The treatment is similar
2080 section 12 Metabolic disorders

to FH for heterozygotes. The very rare homozygotes may require the safety and efficacy in infants (<6 months of age), children, and
apheresis as well as drugs. adults. A total of 106 patients (including 14 infants) with LAL defi-
ciency received treatment with sebelipase alfa. Significant improve-
Autosomal dominant hypercholesterolaemia due ments were observed for a number of disease parameters, including
to gain-​of-​function mutations in PCSK9 improvement in survival of infants with LAL deficiency for which
PCSK9 gene gain-​of-​function mutations are a very rare autosomal no treatment was available up until now. The long-​term efficacy of
dominant form of FH. The function of PCSK9 was described earlier this treatment is continuing through an ongoing study in infants
in this chapter. These mutations are much more frequent in individ- with LAL deficiency.
uals of African descent. Loss-​of-​function mutations in PCSK9 can
cause low levels of LDL-​C (see ‘Enhanced hepatic clearance of rem- Sitosterolaemia
nants and LDL as a cause of low cholesterol levels’). This rare autosomal recessive cause of increased absorption of chol-
Gain-​of-​function missense mutations that increase the activity of esterol and suppressed LDLR expression has already been described
PCSK9 cause hypercholesterolaemia because the number of LDLRs in the Sitosterolaemia’ subsection in ‘Primary factors affecting intes-
is reduced. Clinically, patients are similar to those with FH, but they tinal lipid absorption’.
are highly responsive to PCSK9 inhibitors (see ‘Drug treatment in
hypercholesterolaemia’ and ‘PCSK9 inhibitors’). Familial dysbetalipoproteinaemia (FDBL)
FDBL is also called type 3 hyperlipoproteinaemia (Table 12.6.3). It
Autosomal recessive hypercholesterolaemia (ARH) is a Mendelian recessive disorder, which becomes manifest when an
ARH is a very rare Mendelian recessive disorder. Clinically, pa- acquired cause of dyslipidaemia also occurs. It features combined
tients have plasma LDL-​C levels between those of heterozygous and dyslipidaemia with similarly raised levels of both cholesterol and
homozygous FH, and the TC levels are more variable. TGs due to accumulation of remnant particles (chylomicron and
ARH results from mutation of the gene encoding the LDLR-​ VLDL remnants).
adapter protein, (LDLRAP), which is needed for LDLR-​mediated Remnant clearance by the LDLR is mediated by apoE on these
endocytosis particularly in the liver. LDLRAP binds to the in- lipoproteins. ApoE has three common alleles. ApoE3 is most fre-
ternal domain of the LDLR, linking it to the endocytic machinery quent; apoE2 and apoE4 each differ from apoE3 by one amino
(Fig. 12.6.11). With ARH, LDL binds the LDLR, but is not acid. Homozygosity for the apoE2 allele (frequency of about 1/​200)
endocytosed, and accumulates at the liver cell surface. Individuals underlies FDLB. Overall the APOE gene locus confers approximately
are mostly of Middle Eastern, Turkish, or Sardinian origin, but 1.5 to polygenic dyslipidaemia and to risk of atherosclerotic cardio-
cases of ARH occur worldwide. Tendon xanthomas are found. vascular disease. The apoE4 allele causes a modestly higher LDL-​C
Atherosclerotic cardiovascular disease develops by the third decade. level and increases cholesterol absorption (see ‘Primary factors af-
ARH is more responsive to lipid-​lowering therapy than homozygous fecting intestinal lipid absorption’), with increased atherosclerotic
FH and may not require apheresis. cardiovascular disease risk, but does not cause FDBL. The presence
of one or two APOE4 gene copies does, however, increase the risk of
Cholesteryl ester storage disease Alzheimer’s disease. ApoE2 has much reduced binding affinity to the
Cholesteryl ester storage disease is a rare Mendelian recessive dis- LDLR, so that it slows the rate of remnant clearance; homozygosity
order. It features raised TC and LDL-​C, often with increased TGs for apoE2 is present in most patients with FDBL; heterozygotes are at
and low HDL-​C. Its worst manifestation, Wolman’s disease, is fatal moderate increased risk of dyslipidaemia. Very rare dominant mu-
in infancy. Cholesteryl ester storage disease and Wolman’s disease tants of apoE can cause FDBL.
are caused by deleterious mutation of the gene encoding lysosomal The acquired (Table 12.6.4) precipitating factors for FDBL in-
acid lipase (LAL). Patients with no enzyme activity are likely to have clude high fat and carbohydrate diets, obesity, insulin resistance and
the childhood severe presentation and those with partial deficiency diabetes, hypothyroidism, kidney disease, HIV, alcohol, and some
the adult presentation. LAL hydrolyses TGs and cholesteryl esters drugs. In women, it is rare prior to the menopause, after which oes-
from remnants and LDL taken up by the liver by the LDLR. This trogen deficiency plays a role.
leads to the accumulation of large amounts of neutral lipid in liver FDBL patients present as adults with mixed dyslipidaemia, with
cells and hepatosplenomegaly, with steatosis, fibrosis, and ultimately similarly raised TC and TGs carried in IDL, and normal HDL-​C.
cirrhosis. The high LDL may be the result of both increased produc- Typically, the TC is 8 to 12 mmol/​litre (320–​480 mg/​dl) and TGs 5
tion of apoB-​containing lipoproteins and decreased clearance. to 20 mmol/​litre (420–​1800 mg/​dl). LDL-​C is low due to reduced
The diagnosis is suggested in patients with elevated LDL-​C, low formation from VLDL and normal clearance by the LDLR. There
HDL-​C, and fatty liver without the metabolic syndrome. Diagnosis may be premature atherosclerotic cardiovascular disease, affecting
is made by measuring LAL activity on a dried blood spot, and veri- the peripheral blood vessels as well as the coronaries. There are dis-
fied by DNA sequencing. It is important to establish the diagnosis tinctive, pathognomonic xanthomas; tuberoeruptive xanthomas
and evaluate the liver as cirrhosis may occur. Heterozygotes may form small groups of small papules on the elbows, knees, or but-
have mild to moderately disturbed lipids. tocks, but can expand to be thumb nail-​sized; palmar xanthomas
In 2015, the Food and Drug Administration in the United States of (called xanthoma striae palmaris) are orangey, yellow discolorations
America and European Medicines Agency recommended granting in the palmar and wrist creases.
a marketing authorization for Kanuma (sebelipase alfa), recom- The diagnosis is best made by demonstrating apoE2 homozygosity
binant acid lipase, for the treatment of LAL deficiency. The recom- in conjunction with high levels of remnant lipoproteins. Methods of
mendation was based on four studies which provided evidence on phenotyping apoE include ultracentrifugation (β-​quantification),
 12.6 Lipid disorders 2081

lipoprotein electrophoresis (broad β-​band), and MRI, but these are Because dietary cholesterol intake is not found to correlate well
not routinely available. Polymerase chain reaction can be used to with serum cholesterol levels, dietary restriction is not now recom-
type the common alleles, but will miss rare disease-​causing variants. mended in the United States of America, but reduction of saturated
As a rule, cases of FDBL have a TC/​apoB ratio greater than 6.0 and a fat intake will perforce decrease cholesterol consumption. Recent
TG/​apoB ratio of less than 10.0, which are highly predictive, whereas meta-​analyses have not found an association between saturated
in type 4 hyperlipidaemia, the TC/​apoB ratio is below 5.0 and in type fat consumption and atherosclerotic cardiovascular disease, while
5 hyperlipidaemia, the TG/​apoB ratio is much greater than 10.0. other meta-​analyses have suggested increased risk (Table 12.6.6).
FDBL needs to be vigorously treated because of the high risk of Saturated fat should be replaced by unsaturated fat to lower LDL-​
premature atherosclerotic cardiovascular disease. The acquired C levels (Table 12.6.6). Low-​fat diets which replace saturated fat
metabolic factors that have precipitated FDBL need to be managed. with carbohydrates lower LDL-​C, but also lower HDL levels.
FDBL patients improve with weight reduction, atheroprotective life-
Hypothyroidism
style (Table 12.6.6), and reduction of alcohol consumption.
Fibrates are the drug of first choice as they have a spectacular ef- Hypercholesterolaemia is common and often severe in hypothy-
fect in lowering TGs and cholesterol in FDBL through VLDL and roidism. It is due to reduction of liver LDLR levels and reduced
IDL reduction. Often both LDL-​C and HDL-​C increase. A statin LDL and remnant clearance. The expression of the LDLR gene is
may also be required, with the caveat concerning the safety of the decreased in hypothyroidism. Mild hypertriglyceridaemia may
combined use of these drugs. Fish oils can reasonably be used if TGs coexist. Screening of all patients with high LDL-​C for hypothy-
remain raised. roidism is mandatory as hypothyroidism is easy to overlook.
Hormone replacement corrects the hypercholesterolaemia, un-
Hepatic lipase deficiency less there is another underlying dyslipidaemia. Statin treatment
HL hydrolyses TGs and phospholipids in remnants and HDL, which in hypothyroidism can be dangerous because of the risk of severe
favours liver uptake by apoE, and conversion of remnants into LDL. muscle toxicity.
HL deficiency is a very rare autosomal recessive disease caused by Oestrogen and progesterone
mutations of the HL gene, a relative of LPL. Deficiency features
mixed dyslipidaemia due to remnant accumulation and raised Endogenous oestrogens are important regulators of lipid metab-
HDL-​C, and in this respect resembles alcohol overconsumption. To olism and inhibit atherosclerotic cardiovascular disease develop-
make the diagnosis, HL activity is measured in postheparin plasma ment in premenopausal women. Oestrogen reduces LDL-​C levels
or the DNA of the gene sequenced. Statin therapy is appropriate to and increases HDL levels by increasing LDLR activity and decreasing
reduce potential atherosclerotic cardiovascular disease risk from LDL production and apoA1 and ABCA1 protein expression. It also
remnant accumulation. potently reduces the oxidation of LDL.
Administration of oestrogen to postmenopausal women in clinical
Acquired (secondary) causes of impaired liver uptake trials using ‘conjugated’ (horse) oestrogens and synthetic progestins
of lipoproteins (medroxyprogesterone acetate) as hormone therapy have shown in-
The secondary causes of dyslipidaemia are listed in Table 12.6.4. creased atherosclerotic cardiovascular disease risk despite beneficial
effects on the lipid profile. More recent trials using natural oestrogen
Diet or the selective oestrogen receptor modulators such as lasofoxifene
Diet plays a major role in determining LDL-​C levels. Western na- suggest therapeutic potential for the prevention of atherosclerotic
tions such as the United States of America and European nations cardiovascular disease, warranting further clinical trials. But this is
have overall higher cholesterol levels than nations such as China mitigated by increase breast and ovarian cancer risk.
and Japan. Even subjects with FH in China have much lower chol- Oral contraceptives and oral oestrogens (as hormone re-
esterol levels than their Western counterparts. Animals in the wild placement therapy) are contraindicated in patients with severe
and human neonates have very low cholesterol levels (LDL-​Cs of hypertriglyceridaemia (type 1, 3, 4, and 5 hyperlipidaemias) as they
0.65 mmol/​litre (25 mg/​dl)), consistent with the view that the human are reported to precipitate acute pancreatitis. Oestrogen decreases
diet plays a major role in determining plasma cholesterol levels. activity of HL, the actions of which include hydrolysis of VLDL, pos-
Saturated fat raises LDL-​C more than most other dietary compo- sibly decreased LPL activity, and increased synthesis of TGs in the
nents. Saturated fat is found in red meats, dairy products, chocolate, liver and secretion of VLDL. Oestrogen patches do not affect TG
baked goods, deep-​fried food, and processed food—​all common levels. Progesterone-​only pills reduce HDL.
in the Western diet. Among saturated fatty acids, lauric, myristic, Enhanced hepatic clearance of remnants and LDL as a
and palmitic acids are considered to be more hypercholesterolaemic cause of low cholesterol levels
than stearic acids. Lauric and myristic acids are found in coconut.
Trans fatty acids (trans fats) also raise LDL-​C and lower HDL-​ PCSK9 deficiency
C. Trans fats are made when hydrogen is added to vegetable oil to Inherited deleterious alleles of PCSK9 cause increased LDLR ac-
harden it. They are used in processed food to prolong its shelf life. tivity and decreased plasma LDL-​C levels. Deleterious mutations of
Trans fats are also generated by high-​temperature frying. PCSK9 are best described in people of African origin, but are also
Saturated and trans fats increase plasma LDL-​C by increasing the described in Europeans. Heterozygotes have a 30 to 40% decrease
formation of LDL in the plasma compartment by decreasing LDL in plasma levels of LDL-​C with much reduced occurrence of ath-
turnover and by decreasing the activity of the LDLR through the erosclerotic cardiovascular disease most likely as a consequence of
activity of SREBP. the low LDL-​C. Homozygotes for such mutations have LDL-​C levels
2082 section 12 Metabolic disorders

below 0.5 mmol/​litre and are well, indicating that lifelong low chol- and catabolism and can result in dramatic reductions in plasma
esterol levels are not deleterious to human health. levels of HDL-​C (Table 12.6.11).
Quite unlike the genes that confer high levels of LDL-​C, which
HDL cholesterol and dyslipidaemia greatly increase the risk of atherosclerotic cardiovascular disease,
In clinical practice, TC, TGs, HDL-​C, LDL-​C, and/​or NHDL-​C these genetic forms of hypoalphalipoproteinaemia are not defini-
plasma levels (the standard lipid profile) are routinely determined tively linked to increased risk of atherosclerotic cardiovascular
and the ratio of TC to HDL-​C calculated. The TC-​to-​HDL-​C ratio disease.
is one of the best predictors of atherosclerotic cardiovascular disease
risk, and it is the plasma lipid metric used in standardized athero- APOA1 gene cluster deletions
sclerotic cardiovascular disease risk calculators (see ‘Screening of The genes encoding apoA1, apoA5, apoC3, and apoA4 are grouped
plasma lipid and lipoprotein levels’). together on chromosome 11. Patients with deletion of the entire
Low levels of blood HDL-​C are very common in atheroscler- APOA1 gene, or of the whole gene cluster, have almost no HDL. In
otic cardiovascular disease sufferers. Yet low HDL-​C is a not these patients, the absence of LCAT activation leads to increased
causal factor in atherosclerotic cardiovascular disease, rather free cholesterol levels in the blood and tissues such as the eyes and
than a marker of association with other risk factors. Low HDL-​ skin, which can form substantial deposits in the cornea and skin re-
C is not independent despite its important role in reverse chol- sulting in corneal opacities and palmar xanthomas. Despite having
esterol transport, and may reflect the clustering of primary and very low levels of apoA1, deficient patients are not at increased risk
secondary atherosclerotic cardiovascular disease risk factors, of atherosclerotic cardiovascular disease.
which lead to the strong inverse correlation of low HDL-​C with
atherosclerotic cardiovascular disease risk. HDL-​C levels are much APOA1 gene mutations
affected by other atherosclerotic cardiovascular disease risk fac- Deleterious mutations of the APOA1 gene are a rare cause of low
tors including Toll-​like receptors, obesity, insulin resistance, and HDL-​C (often <0.5 mmol/​litre (20 mg/​dl)). A number of variants
systemic inflammation. have been described and these are usually named after the place in
which they were identified, such as apoA1 Milano and Marburg.
Primary causes of low HDL-​C (hypoalphalipoproteinaemia). They do not apparently cause premature atherosclerotic cardiovas-
As with the other components of the standard lipid profile, HDL-​C cular disease. This lack of association with atherosclerotic cardio-
levels are determined by genetic and acquired factors. Genetic fac- vascular disease is despite the finding that many apoA1 variants
tors determine approximately 50% of the total phenotypic variance produce very low levels of plasma HDL-​C levels due to defective
of HDL-​C, and these are accounted for by the clustering of multiple LCAT activation by apoA1 and enhanced removal of the abnormal
common polymorphisms, low frequency, and rare variants (as pre- HDL lipoprotein.
viously described). Increased risk of atherosclerotic cardiovascular ApoA1 Milano, which leads to dimerization of apoA1 with itself
disease in people with low HDL may occur due to the presence of or apoA2, appears to decrease the risk of atherosclerotic cardiovas-
other genes affecting pathways of lipid metabolism that increase cular disease, and has been used as a potential therapeutic agent, and
risk. Common genetic variants that affect the components of meta- this has led to development of infusible HDL mimetics that rapidly
bolic syndrome also affect HDL levels. remove cholesterol from arteries and stabilize unstable plaque.
A number of the key genes involved in HDL metabolism have been In addition some coding sequence variants of APOA1 and APOA2
found to have deleterious mutations, which affect HDL biosynthesis can aggregate and cause systemic amyloidosis.

Table 12.6.11 Genetic defects affecting HDL metabolism

Variant Molecular defect Inheritance Metabolic Lipoprotein Clinical features Premature

defect abnormality atherosclerosis
Familial apoA1 deficiency ApoA1,3,4,5 gene Autosomal Absent apoA1 HDL <0.5 mmol/​L , TGs Planar xanthomas, No
cluster codominant biosynthesis increased when cluster is corneal opacities
deleted
Familial apoA1 structural Abnormal apoA1 Autosomal Rapid apoA1 HDL 0.4–​0.8 mmol/​L , Often none, sometimes No
mutations dominant catabolism and TGs normal corneal opacities
abnormal HDL
Familial LCAT LCAT deficiency Autosomal Rapid HDL HDL <0.5 mmol/​L , TGs Corneal opacities, No
(complete) recessive catabolism increased anaemia, proteinuria,
renal insufficiency
Fish-​eye disease LCAT deficiency Autosomal Rapid HDL HDL <0.5 mmol/​L , TGs Corneal opacities No
(partial) recessive catabolism increased
Tangier disease ABCA1 deficiency Autosomal Very rapid HDL HDL <0.5 mmol/​L , TGs Corneal opacities, No to yes
codominant catabolism usually increased enlarged orange tonsils,
hepatosplenomegaly,
peripheral neuropathy
Familial Unknown Autosomal Usually rapid HDL <1.0 mmol/​L , TGs Often none, sometimes No to yes
hypoalphalipoproteinaemia dominant HDL catabolism normal corneal opacities
 12.6 Lipid disorders 2083

Tangier disease (ABCA1 deficiency) Mendelian (possibly codominant) transmission, without secondary
Tangier disease is caused by rare Mendelian codominant defects of causes, is called familial or primary hypoalphalipoproteinaemia.
the ABCA1 gene. ABCA1 mediates the cellular efflux of unesterified Some patients can have heterozygous defects of ABCA1 and
cholesterol and phospholipids for capture by apoA1 from the strictly speaking have Tangier disease. LCAT deficiency can usu-
liver, small intestine, and peripheral tissues. Without ABCA1, the ally be excluded clinically, but some patients may have APOA1 gene
poorly lipidated apoA1 is rapidly removed from the blood. Tangier defects. Polygenic clustering of low HDL gene variants is the likely
disease patients have very low blood HDL-​C and apoA1 levels. cause as no major gene has been discovered.
Heterozygotes have low HDL-​C levels of approximately 0.5 mmol/​ The diagnosis is made in patients with no known genetic or sec-
litre (20 mg/​dl). ondary causation. Mechanistically, there is often rapid catabolism
Cholesterol collects in the mononuclear phagocyte system of HDL, and of apoA1 and apoA2. It can be associated with athero-
causing hepatosplenomegaly and pathognomonic enlarged greyish, sclerotic cardiovascular disease, but the extent to which this is the
yellow, or orange tonsils. Patchy peripheral neuropathy and rarely a case may depend on the underlying gene defects.
syringomyelia-​like condition can occur. Nearly all children affected Acquired (secondary) causes of low HDL-​C
by Tangier disease are identified on the basis of large, yellow-​orange
tonsils, but it can be undetectable or overlooked in adults because The secondary causes of dyslipidaemia are listed in Table 12.6.4.
tonsils have often been removed. Obesity, insulin resistance, and diabetes
Foam cell formation from lipid storage in cells can be detected
by endoscopic examination of the rectal mucosa. In many patients, By far the most significant among the acquired factors associated
proctoscopy reveals a pale mucosa studded with 1-​to 2-​mm dis- with low HDL-​C is the tide of obesity afflicting modern society,
crete orange-​ brown spots. Other signs of Tangier disease are which leads to the metabolic syndrome of insulin resistance and
thrombocytopenia, anaemia, gastrointestinal disorders, and cor- type 2 diabetes. This clustering of metabolic abnormalities markedly
neal opacities. The diagnosis can be confirmed by DNA sequencing. increases the risk of atherosclerotic cardiovascular disease.
There is no clear evidence whether Tangier disease patients have an HDL levels are decreased through complex effects on lipid and
increased risk of atherosclerotic cardiovascular disease. lipoprotein metabolism. There is increased lipolysis in adipose
tissue; particularly intra-​abdominal fat, which is metabolically very
LCAT deficiency active. Free fatty acids are released into the portal circulation. The
liver converts free fatty acids into TGs. This and an increased supply
Deleterious mutations of the LCAT gene cause a rare Mendelian of glucose, which leads to fatty acid and further TG biosynthesis and
recessive disease. LCAT secretion from the liver is decreased, and overproduction of VLDL, raises the concentration of circulating
LCAT is reduced or absent from circulating lipoproteins. LCAT es- TG-​rich lipoproteins.
terifies free cholesterol in lipoproteins to form cholesteryl esters. There is reciprocal exchange of lipids between lipoprotein par-
LCAT deficiency greatly increases the proportion of free cholesterol ticles. Cholesteryl esters are transferred to VLDL and chylomicron
in lipoproteins (from 25 to 70% of total plasma cholesterol). HDL remnants, while TGs are transferred to LDL and HDL particles
maturation is defective and there is rapid clearance of apoA1—​ to form highly atherogenic, cholesterol-​poor sdLDL, and HDL
LCAT’s activating cofactor. (Table 12.6.1, Fig. 12.6.13). There is also rapid catabolism of HDL-​C
Complete LCAT deficiency with complete absence of protein ac- and its core protein apoA1 with further reduction of HDL-​C.
tivity contrasts with partial deficiency of enzyme activity. In com- Atherogenic dyslipidaemia—​the simultaneous presence of raised
plete deficiency and partial deficiency (called fish-​eye disease), there TGs and apoB concentration, and an increased proportion of sdLDL
is progressive corneal opacification caused by accumulation of free with low HDL is associated with a considerable increase in the risk
cholesterol in the cornea. Very low circulating HDL-​C and often for atherosclerotic cardiovascular disease.
hypertriglyceridaemia are features of both disorders. The management of these lifestyle and metabolic factors and the
Complete LCAT deficiency is also associated with haemolytic an- treatment of raised cholesterol are the most efficacious approaches
aemia and progressive renal failure. In partial deficiency, there are to manage low HDL (Table 12.6.6). Lipid lowering is reasonable.
no such clinical features. Premature atherosclerotic cardiovascular
disease has been described, but is not a usual accompaniment to ei- Renal disease
ther form of the disease. Very rarely, patients with glomerulonephritis with massive protein-
The diagnosis is suggested by the corneal opacification and the uria can develop very low levels of HDL-​C, which is self-​limiting
combination of haematological abnormality, renal dysfunction with the resolution of the proteinuria. Urinary loss of apoA1 con-
with proteinuria, very low HDL-​C, and high TG levels. The LDL is tributes to the low HDL-​C.
cholesteryl ester poor and small and sometimes apoB is raised; these
later features may be atherogenic. Inherited causes of very high levels of HDL-​C
The diagnosis is made by measuring LCAT activity in plasma, and Very high levels of HDL-​C with large, fluffy HDL-​C, and reduced
confirmed by DNA sequencing. particle number appear to be atherogenic.
Lipid-​lowering treatment should be considered.
CETP deficiency
Familial hypoalphalipoproteinaemia (isolated low HDL) Deleterious mutation of both copies of the CETP gene lead to a
The familial clustering of low plasma HDL-​C, well below 1.0 mmol/​ marked increase in HDL-​C levels (>4 mmol/​litre (160 mg/​dl)) and
litre (40 mg/​dl), with normal TGs and LDL particle size, with produce large, fluffy HDL without increased particle number, due to
2084 section 12 Metabolic disorders

the high cholesteryl ester content. Heterozygotes have only modestly however, after LDL-​C lowering to 1 to 2 mmol/​litre (40 to 80 mg/​dl)
raised HDL-​C levels. Normally, CETP transfers cholesteryl esters with statins no further benefit was accrued from the addition of nico-
from HDL to apoB-​containing lipoproteins and TG in reciprocity tinic acid to lower the Lp(a), suggesting that dramatic lipid lowering
(Fig. 12.6.14). In its absence, there is increased cholesteryl ester in alone is a reasonable treatment. Aspirin or another antiplatelet drug
HDL; plasma levels of LDL-​C are reduced. The large cholesterol-​rich should be given to suppress the thrombogenicity of Lp(a).
HDL particles are cleared slowly. CETP deficiency is rare outside
Japan, where it was first diagnosed. It is uncertain whether CETP Other secondary causes of dyslipidaemia
deficiency causes or prevents atherosclerotic cardiovascular dis- Chronic kidney disease
ease, but low CETP activity is not associated with increased lon- Modest elevation of TGs is frequently seen in CKD due to impaired
gevity. Clinical trials do not yet support the use of CETP inhibitors lipolysis through alteration in the composition of circulating TGs,
to reduce the risk of atherosclerotic cardiovascular disease by raising which become enriched with the LPL inhibitor apoC3. There is
HDL. Importantly, the finding of unduly advanced disease on vas- reduced LPL and HL activity. Lp(a) is increased due to decreased
cular imaging should indicate the need for lipid lowering. clearance. Atherosclerotic cardiovascular disease is common in se-
Lipoprotein(a) production by the liver vere CKD so that dyslipidaemia needs vigorous treatment with the
combination of statins and cholesterol absorption inhibitors as this
Lipoprotein(a) will decrease cardiovascular events, and mitigates the need for high-​
Lp(a) is synthesized exclusively in the liver. Its plasma levels differ dose statins and potential toxicity. The reduction of LDL-​C/​NHDL-​
greatly among people, and 75% of this reflects genetic variation in C is reasonable at all levels to reduce cardiovascular events.
the LPA gene. Secondary factors such as renal disease, oestrogen de- Transplant patients, due to the immunosuppressive drugs they re-
pletion, and severe hypothyroidism can increase Lp(a) to a modest quire, often have dyslipidaemia, which again needs careful, but vig-
extent. orous treatment with statins and cholesterol absorption inhibitors
As described earlier and in Fig. 12.6.5, a common copy-​number and sequestrants to help avoid muscle side effects from statins and
variation within the LPA gene determines the number of kringle IV possible nephrotoxicity.
repeats and hence the isoform size of apo(a). An inverse relation-
ship exists between the number of repeats and Lp(a) plasma levels. Anorexia nervosa
A small number of common variant alleles account for much of the Anorexia affects mainly teenagers and young adults, and is the third
genetic variance conferred by the LPA gene locus. Variants particu- most common long-​term illness among teenagers. Fifty per cent of
larly associated with increased atherosclerotic cardiovascular dis- suffers develop dyslipidaemia, often with high total, LDL, and HDL
ease tend to be small and be associated with an increased particle cholesterol. TGs are not raised. The pathogenesis is not clear, and
number. As a consequence of genetic variation, Lp(a) plasma levels is certainly not simply due to malnutrition, which reduces plasma
can vary 100-​fold, where borderline risk is defined as greater than cholesterol levels. It is argued that lipid lowering is not necessary be-
30 mg/​dl (75 nmol/​litre), high risk is 50 mg/​dl (125 nmol/​litre), and cause HDL is raised as well as LDL. TC levels can, however, be over
very high risk is greater than 50 mg/​dl (>125 nmol/​litre), rarely up 9 mmol/​litre (360 mg/​dl), so that careful review on a case-​by-​case
to a massive 300 mg/​dl (750 nmol/​litre). basis is required. Alcohol and other substance abuse need to be con-
Lp(a) levels should be checked in any patient with premature car- sidered as exacerbating factors. Effective treatment of the primary
diovascular disease, FH, family history of premature cardiovascular disorder is the best way forward.
disease, family history of elevated Lp(a), recurrent cardiovascular
disease despite statin treatment, and at least a 3% 10-​year risk of fatal Drugs
cardiovascular disease according to the European guidelines. Numerous medicinal drugs affect lipid and lipoprotein metabolism
An increased level of Lp(a) is associated with a seriously increased through various mechanisms and cause dyslipidaemia. Many drugs
risk of atherosclerotic cardiovascular disease, including both cor- also interact with lipid-​lowering drugs, so that coadministration
onary disease and stroke. It also increases the risk of calcific aortic should be approached with caution (Tables 12.6.4 and 12.6.8).
stenosis. The risk of atherosclerotic cardiovascular disease is greater See also Table 12.6.4 for other secondary causes of dyslipidaemia.
with very high LDL-​C, particularly in FH.
The mechanism by which an increased level of Lp(a) lipoprotein
increases the risk of disease is not well understood. This may involve The patient with dyslipidaemia
LDL-​C and atherogenesis, inhibition of conversion of plasminogen
to plasmin, activation of tissue factor and thrombogenesis, or the Cholesterol reduction with statins is highly effective in decreasing
carriage of proinflammatory oxidized phospholipids. vascular events. TG reduction appears to be similarly effective, but
Treatment is problematical (see ‘Drug treatment of hypercholes- the data are less robust than for cholesterol. Increasing HDL-​C is not
terolaemia’ and ‘Lipoprotein(a)’). The treatment of acquired factors effective in reducing events—​rather, HDL is a biomarker for other
does not impact Lp(a) levels. Nicotinic acid and the new PCSK9 in- risk factors. The diagnosis of dyslipidaemia and its effective treat-
hibitors can each reduce Lp(a) by approximately 30%. Nicotinic acid ment is thus of major clinical importance.
is not available in the United Kingdom. CETP inhibitors also po- This section is based on the up-​to-​date evidence-​based guide-
tentially lower Lp(a). An antisense Lp(a) mRNA inhibitor has also lines on lipids from the United States of America and Europe, with
proved remarkably efficacious as a treatment in early clinical trials, key differences highlighted (Table 12.6.12). It is supported by the
and is in development. In one large clinical trial (AIM-​HIGH), latest thinking in the field. A particular focus of these guidelines is
 12.6 Lipid disorders 2085

Table 12.6.12 Comparison of international lipid guidelines: NICE (2014), ESC/​EAS (2011), and ACC/​AHA (2013)

NICE guidelines ESC/​EAS guidelines ACC/​AHA guidelines

Year of publication 2014 2011 2013
Use of evidence Comprehensive literature review Comprehensive literature review Randomized controlled trials
Risk assessment tool QRISK2 SCORE Pooled cohort equations
End points CHD death, CHD (MI or angina), CHD death or fatal stroke CHD death, nonfatal MI, fatal or
stroke and transient ischaemic attack nonfatal stroke
Derivation sample British population, updated annually 12 European countries (pooled data) 4 cohort studies (pooled data)
Risk factors selected in the Age, sex, total cholesterol, HDL-​C , Age, sex, total cholesterol, systolic blood Age, sex, total cholesterol, HDL-​C ,
multivariable model systolic blood pressure, hypertension pressure, and smoking status systolic blood pressure, antihypertensive
treatment status, diabetes mellitus, (NB: separate models for high-​and low-​ treatment status, diabetes mellitus, and
smoking status, ethnicity, family risk countries) smoking status (NB: separate models
history of CHD, body mass index, created for white patients and black
socioeconomic deprivation, patients)
rheumatoid arthritis, CKD, and atrial
fibrillation
Cholesterol treatment 40% reduction in non-​HDL from LDL-​C (see below) Consider apoB or non-​ No
targets endorsed pretreatment level HDL-​C as alternative target
Statin therapy for primary 10-​year risk ≥10% or CKD LDL-​C ≥4.9 mmol/​litre (190 mg/​dl) LDL-​C ≥4.9 mmol/​litre (190 mg/​dl)
prevention in those without LDL-​C <4.9 mmol/​litre (190 mg/​dl), and: LDL-​C 1.8–​4.8 mmol/​litre
diabetes mellitus • 10-​year risk ≥10% (70–​189 mg/​dl) and:
• Moderate to severe CKD LDL-​C • 10-​year risk ≥7.5%
≥2.5 mmol/​litre (100 mg/​dl) and • 10-​year risk <7.5% after consideration
• 10-​year risk 5–​9.9% of other factors
• Severe risk factors: LDL-​C ≥3.0 mmol/​
litre (115 mg/​dl) and
• 10-​year risk 1–​4.9%
Statin therapy for primary Type 2 diabetes mellitus and 10-​year Type 2 diabetes mellitus and LDL-​C LDL-​C ≥70 mg/​dl
prevention in those with risk ≥10% ≥2.5 mmol/​litre (100 mg/​dl)
diabetes mellitus Type 1 diabetes mellitus and age High-​risk type 2 diabetes mellitusa and
>40 years, duration of disease LDL-​C ≥1.8 mmol/​litre (70 mg/​dl)
>10 years, nephropathy, or CVD risk Type 1 diabetes mellitus and target organ
factors damage
CKD considered a high-​risk Yes Yes No
feature
Recommendations for the QRISK2 is validated to age ≤84 years SCORE validated for ages 40–​65 years Pooled cohort risk equations not
elderly Clinician judgement in elderly validated for age >79 years
Consider lower-​intensity statin
Additional considerations Non-​LDL-​C targets Non-​LDL-​C targets Lifetime risk
for risk assessment

ACC/​AHA American College of Cardiology/​American Heart Association; apoB, apolipoprotein B; CHD, coronary heart disease; CKD, chronic kidney disease; CVD, cardiovascular
disease; ESC/​EAS, European Society of Cardiology/​European Atherosclerosis Society; HDL-​C , high-​density lipoprotein cholesterol; LDL-​C , low-​density lipoprotein cholesterol; MI,
myocardial infarction. NICE, National Institute for Health and Care Excellence; SCORE, Systemic Coronary Risk Evaluation.
a
High-​risk type 2 diabetes mellitus is defined as diabetes mellitus plus one of the following risk factors: established atherosclerotic cardiovascular disease, CKD, age over 40 years,
and one or more cardiovascular risk factor or target organ damage.
Source data from with permission from Brown MS, Goldstein JL. Receptor-mediated endocytosis: Insights from the lipoprotein receptor system. Proc Natl Acad Sci U S A.
1979;76: 3330–3337.

a patient-​centred approach to treatment options and lifestyle with (secondary prevention) with a view to establishing or maintaining
emphasis on individual global risk factor assessment through the treatment goals. It is also strongly recommended in those with a
use of risk calculator tools. family history of atherosclerotic cardiovascular disease, particularly
if premature, those with other atherosclerotic cardiovascular disease
Screening of plasma lipid and lipoprotein levels risk factors, all those with acute pancreatitis, and to monitor those
The measurement of standard lipid and lipoprotein levels should be a on lipid-​lowering medication.
routine part of clinical practice. Screening is best done by the general Most clinical chemistry laboratories measure TC and TG
practitioner or as part of a health screen. According to guidelines enzymatically. The HDL-​C is usually measured after precipitation of
from the United States of America, all adults above 21 years of age apoB-​containing lipoproteins. The LDL-​C is then most commonly
should have TC, TGs, HDL-​C, LDL-​C, and/​or NHDL-​C screened, estimated using the Friedewald formula: [LDL-​C] = [TC] minus
and screening should be repeated approximately every 5 years. [TG divided by 2.2] minus [HDL-​C] (where all concentrations are
In the United Kingdom, screening is recommended in those over given in mmol/​litre). For this, the VLDL cholesterol is estimated by
40 years (Box 12.6.1). Screening is particularly strongly indicated dividing the plasma TG by 2.2, the usual TG to cholesterol in VLDL
in patients with established atherosclerotic cardiovascular disease particles.
2086 section 12 Metabolic disorders

Box 12.6.1 United Kingdom criteria for screening lipids Box 12.6.2 QRISK risk assessment tool for atherosclerotic
cardiovascular disease and its exclusion criteria
1 People with diagnosed coronary heart disease (CHD) or other oc-
clusive arterial disease (cerebrovascular accident, peripheral vas- • The QRISK2 risk assessment tool can be used to assess atherosclerotic
cular disease) not yet on cholesterol-​lowering therapy for secondary cardiovascular disease (ASCVD) risk for primary prevention in people
prevention. up to 84 years.
2 People with diagnosed CHD or other occlusive arterial disease taking • Do not use QRISK2 in people with an estimated GFR of less than 60
cholesterol-​lowering therapy for secondary prevention—​to check that ml/​min per 1.73 m2 and/​or albuminuria as these people are at in-
target lipid concentrations are being achieved. creased risk of ASCVD.
3 People without diagnosed CHD or other occlusive arterial disease not • Do not use QRISK2 in people with type 1 diabetes as these people are
on cholesterol-​lowering therapy—​when CHD risk is to be estimated at increased risk of ASCVD
(e.g. in people known to have CHD risk factors, especially those with a • Do not use QRISK2 for people with pre-​existing ASCVD
family history of premature CHD1). (Risk assessment tool: http://​www. • Do not use QRISK2 for people who are at high risk of developing CVD
qrisk.org/​.) because of familial hypercholesterolaemia or other inherited disorders
4 People without diagnosed cardiovascular or other occlusive arterial of lipid metabolism.
disease taking cholesterol-​lowering therapy for primary prevention—​ • Use QRISK2 to assess CVD risk in people with type 2 diabetes.
to check that target lipid concentrations are being achieved. • Note that standard ASCVD risk scores will underestimate risk in people
5 People with CVD risk equivalents—​patients with diabetes mellitus, who have additional risk because of underlying medical conditions or
hypertension, or familial hypercholesterolaemia. treatments including:
6 Patients admitted with acute pancreatitis. —​ people treated for HIV
—​ people with serious mental health problems
—​ people taking medicines that can cause dyslipidaemia (e.g. anti-
While the Friedewald equation is an adequate method, it has psychotic medication, corticosteroids, or immunosuppressant
drugs)
shortcomings. Calculated LDL-​C is not accurate in patients who
—​ people with autoimmune disorders, e.g. systemic lupus
are nonfasting, have TGs greater than 5.0 mmol/​litre (450 mg/​dl), erythematosus.
or have type 3 hyperlipoproteinaemia. The equation is particularly • Note that ASCVD risk will be underestimated in people who are al-
inaccurate when LDL-​C is below 1.8 mmol/​litre (70 mg/​dl). For ex- ready taking antihypertensive or lipid modification therapy, or who
ample, calculated LDL-​C underperforms in obese diabetics, and de- have recently stopped smoking. Use clinical judgement to decide on
viates significantly from LDL-​C directly measured at concentrations further treatment of risk factors in people who are below the ASCVD
risk threshold for treatment.
below 1.8 mmol/​litre (70 mg/​dl).
• Note that severe obesity (body mass index >40 kg/​m2) increases
LDL-​C can be measured directly by a variety of methods. As ASCVD risk.
with calculated LDL-​C, directly measured LDL-​C has shortcom- • Consider people aged 85 or older to be at increased risk of ASCVD
ings. Directly measured LDL-​C can be discordant with other LDL-​ because of age alone, particularly people who smoke or have raised
related measures and may not reflect atherosclerotic cardiovascular blood pressure.
disease risk.
Recent guidelines endorse the use of NHDL-​C (i.e. TC minus
HDL-​C). NHDL-​C accurately predicts atherosclerotic cardiovas- lupus erythematosus to the risk of atherosclerotic cardiovascular
cular disease risk. It does not suffer from the discrepancies with disease.
LDL-​C measurement. A fasting sample is not generally needed, Global risk, however, has never been used as a selection criterion
which is more convenient for patients. NHDL-​C is on average for statin trials. While risk is driven largely by older age, in the ab-
1.0 mmol/​litre (40 mg/​dl) higher than LDL-​C. Nonfasting TGs are sence of vascular risk factors, it merits treating by cholesterol reduc-
also better predictors than fasting TGs of atherosclerotic cardiovas- tion as evidence suggests this will reduce risk. There is little data on
cular disease events. HIV-​positive and solid organ transplant patients, but lipid lowering
The main disadvantage of moving to NHDL-​C is that national may be considered.
guidelines have previously used (and in the United States of America Risk assessment tools that aid clinical decisions about lifestyle
still do use) LDL-​C. Furthermore, clinical trials and other clinical modification, and whether to use lipid-​and blood pressure-​lowering
studies have often been performed using LDL-​C. It will take effort, medication are valuable, but should not replace clinical judgement.
but should improve patient care. Statin treatment is recommended in those with a 10-​year risk
The use of risk assessment tools such as QRISK2 (Box 12.6.2), above 7.5% in the United States of America and it is suggested that
Joint British Societies’ consensus recommendations for the pre- treatment be considered above 5% risk at 10 years. In the United
vention of cardiovascular disease (JBS2/​3), or the American heart Kingdom, the recommended threshold is 10%. Caveats to the use
risk calculator is recommended to assess absolute atherosclerotic of risk calculators are given in Box 12.6.2. Risk calculators should
cardiovascular disease risk for the primary prevention in people not be used in those people with suspected genetic dyslipidaemia.
up an age between 75 to 84 years. Risk assessment using calcu- Guides for the treatment of dyslipidaemia are given in Tables 12.6.7,
lators is based on large amounts of observational data from the 12.6.8, and 12.6.10 and Fig. 12.6.19.
general population in whom the risk predictions are valid. The In a nonfasting individual, a NHDL-​C concentration greater than
lipid metric most calculators use is the TC-​to-​HDL ratio, which 5.5 mmol/​litre (220 mg/​dl) may indicate genetic hypercholester-
is the best predictive lipid parameter that we have. In addition, olaemia that requires further investigation. If nonfasting TGs are
these tools evaluate the contribution of ethnicity, deprivation, dia- greater than 5.0 mmol/​litre (450 mg/​dl), a fasting lipid panel should
betes, kidney disease, and rheumatic conditions such as systemic be performed; persistent elevation will suggest a genetic cause.
 12.6 Lipid disorders 2087

Statin Benefit Groups

Cardioprotective life-style is the basis of ASCVD prevention.
In those not receiving statin, recalculate estimated 10-y ASCVD risk
every 4–6 y in individuals aged 40–84 y without clinical ASCVD or
diabetes and with LDL–C 1.8–4.74 mmol/L (70–189 mg/dL)

Age <84 y
Yes High-intensity statin
(Moderate-intensity statin if not
suitable for high-intensity statin)
Adults age >21 y and Yes Clinical
a candidate for statin therapy ASCVD
Age >84 y OR if not candidate for
Yes high-intensity statin
Moderate-intensity statin
No

LDL–C High-intensity statin

Definitions of high- and ≥4.75 mmol/L Yes
moderate-intensity statin therapy (Moderate-intensity statin if not
(190 mg/dL) candidate for high-intensity statin)
High Moderate
Daily dose lowers Daily dose lowers
LDL–C by appox. LDL–C by appox. No
≥50% 30% to <50%
Yes
Moderate-intensity statin
Diabetes*
Type 1 or 2
Age 40–84 y Yes Estimated 10-y ASCVD risk ≥10%*
High-intensity statin
No

Estimate 10-y ASCVD risk

with risk calculation tools

≥10% estimated
Yes
10-y ASCVD risk Moderate-to-high intensity statin
and age 40–84 y

No

Benefit of statin in ASCVD prevention

may be less clear in others
Consider additional factors influencing ASCVD risk and potential ASCVD risk
benefits and adverse effects, drug interactions,
and patient attitude to statin treatment

*In diabetes less than 40 years statins are

optional and depend on clinical judgement

Fig. 12.6.19 Statin therapy for atherosclerotic cardiovascular disease (ASCVD): primary and secondary prevention.
Incorporating aspects of both the 2013 American College of Cardiology/​American Heart Association Blood
Cholesterol Guideline for statin initiation and the National Institute for Health and Care Excellence guideline (CG181)
‘Cardiovascular disease: risk assessment and reduction, including lipid modification’. Note: the American guidance
considers statin initiation at a 10-​year atherosclerotic cardiovascular disease risk of 5%/​7.5% whereas the United
Kingdom threshold is 10%. The Americans also consider atherosclerotic cardiovascular disease risk at age 21 years in
comparison to the United Kingdom where atherosclerotic cardiovascular disease risk is assessed at age 40.
Reproduced from Stone NJ, et al. (2013). ACC/​AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic
cardiovascular risk in adults: a report of the American College of Cardiology/​American Heart Association Task Force on Practice
Guidelines. Circulation. 24; 129 (25 Suppl 2):S1–​45 with permission from Wolters Kluwer and Rabar S, et al. (2014). Lipid modification
and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE
guidance. BMJ, 349, g4356 with permission from BMJ Group.

Referral to a specialist lipid clinic is indicated in patients with In the lipid specialist clinic, estimate of lipids are still gener-
(1) possible familial dyslipidaemia, (2) those who fail to respond ally done on a fasting blood specimen, taken 12–​14 h after an
adequately to diet and first-​line drug therapy, (3) those with severe overnight fast with complete dietary restriction (with the excep-
hypertriglyceridaemia who are at risk of acute pancreatitis, (4) those tion of water and medication). This is of value because postpran-
in whom statin intolerance is severe, and (5) those for whom there is dial TGs remain elevated for several hours, particularly in those
any uncertainty about diagnosis. with certain forms of dyslipidaemia, and to make an accurate
2088 section 12 Metabolic disorders

diagnosis of the nature of the dyslipidaemia, fasting TGs are risk assessment tools alone, but require better validation, and may
preferable. not help in younger people aged less than 40 years.
More esoteric lipoprotein biomarkers are sometimes measured
Diagnosis of dyslipidaemia and these include LDL and HDL particle number, sdLDL measures,
Once screening has established that a patient has a dyslipidaemia and HDL fractions, as well as markers of general inflammation such
a full clinical, diagnostic evaluation is needed. The key questions as high-​sensitivity C-​reactive protein and fibrinogen, and markers
are: (1) what classes of lipoproteins and lipids are increased or de- of arterial inflammation such as MPO and LpPLA2.
creased in the patient’s plasma? (2) Does the patient has a primary Increased LDL particle number and the presence of sdLDL are
(genetic) or secondary (acquired) dyslipidaemia, or as is often the directly pro-​atherogenic; low HDL particle number is a predictor
case contributions from both? (3) Is the patient at risk of atheroscler- of risk. Inflammatory markers indicate active disease. The rela-
otic cardiovascular disease or acute pancreatitis? (4) What other tionship of inflammatory markers to the incidence of vascular
atherosclerotic cardiovascular disease or pancreatitis risk factors are events is uncertain. However, for monitoring treatment, per-
present? (5) What are the treatment options? sistent inflammation may indicate the need for more aggressive
The evaluation should include a full medical, family, social, and treatment.
lifestyle history, and physical examination. The physical exam-
ination should be thorough, but specifically focus on cutaneous, Hypercholesterolaemia
tendon and ocular manifestations of dyslipidaemia, and evaluation In the United Kingdom, the mean TC is approximately 5.2 mmol/​
of the cardiovascular system. litre (210 mg/​dl) for men and women. Recommended levels are
Blood tests should include standard lipids, urea and electrolytes TC 5 mmol/​litre (200 mg/​dl), NHDL-​C 4 mmol/​litre (160 mg/​
with estimated GFR, liver function tests, fasting blood glucose, dl), and LDL-​C 3 mmol/​litre (120 mg/​dl) or less in healthy adults.
thyroid function tests including thyroid-​stimulating hormone and Nonetheless, approximately 40% of myocardial infarctions occur in
Lp(a) measurement (Figs. 12.6.5 and 12.6.6), and apoB and apoA1 apparently healthy people with levels TC below these levels.
as measures of apoB-​containing lipoproteins and HDL particles. After measuring lipid levels global risk assessment is, therefore,
ApoE phenotyping is indicated if TC and TGs are both elevated. In recommended. In those with a 10% or greater risk of an event in
statin-​intolerant patients, SLCO1B1 genotyping may be indicated the next 10 years, cholesterol levels should be reduced according
(see ‘Muscle’). Urine analysis should assess the presence of protein- to United Kingdom guidelines. In the United States of America, a
uria. A resting ECG should be performed to alert to overt CVD. threshold of 7.5% for treatment is used, with the option for treat-
The clinical evaluation and tests described just described will de- ment at 5% risk. In younger people, in whom the likelihood of an
termine the presence of secondary causes of dyslipidaemia including event in the next 10 years is low, a lifetime assessment is reasonable,
CKD and nephrotic syndrome, hepatitis and cholestasis, the meta- though not well validated by population data.
bolic syndrome and diabetes, and hypothyroidism. TC levels in adults above 6 mmol/​litre (240 mg/​dl), that is, the
In the absence, or with only a minor contribution from a sec- 95th percentile, are high and abnormal and suggest the presence of
ondary cause of dyslipidaemia, then a primary (genetic) cause is genetic factors. In those with suspected primary hypercholesterol-
likely. However, patients will often display components of both. aemia, risk calculation should not be used as the tools grossly under-
In primary dyslipidaemia, a full family history often with lipid estimate risk. Secondary causes also need to be identified. Often
studies in the family and occasionally specific tests will indicate the primary and secondary causes coexist. The differential diagnosis
diagnosis. of primary from secondary factors is greatly helped by an accurate
Imaging of the arteries by carotid ultrasonography or CT cor- family history.
onary artery calcium can be of value, as risk factors do not accur- A TC level above 7.5 mmol/​litre (300 mg/​dl) and a dominant pat-
ately predict the extent of atherosclerotic cardiovascular disease. The tern of inheritance (50% of siblings and children) with premature
carotid ultrasonographic and coronary artery calcium scans are ap- atherosclerotic cardiovascular disease will suggest the diagnosis of
proximately 70% correlated, and both detect the presence of athero- FH, and is diagnostic if accompanied by xanthomas (see ‘Familial
sclerotic plaque. The age at which coronary calcium can be detected hypercholesterolaemia’; Table 12.6.9).
is 40 years in men and 50 in women. A coronary artery calcium score Severe hypercholesterolaemia without a family history is rare,
greater than the 75th percentile is indicative of an increased risk of but might suggest a recessive disorder and diagnosis of ARH,
myocardial infarction or stroke. sitosterolaemia, or cholesteryl ester storage disease (see ‘Cholesteryl
In younger patients with suspected FH, due to more ‘cholesterol-​ ester storage disease’).
exposure years’ the finding of carotid plaques or coronary artery cal- In suspected FH patients, DNA sequencing is likely to reveal a
cium will support the diagnosis as longstanding dyslipidaemia in causal mutation in the LDLR or one of the other three genes asso-
FH leads to plaques at an earlier age. ciated with FH in 70% of patients with ‘definite’ FH (Table 12.6.9,
In polygenic hypercholesterolaemia in which the dyslipidaemia Fig. 12.6.18).
is considered to develop later than in FH, due to less ‘cholesterol-​ In patients with TC levels below or approximately 7.5 mmol/​litre
exposure years’ the coronary artery calcium is likely to be less (300 mg/​dl), with ‘possible’ FH, or in whom there is a family history,
advanced, and imaging may help the differential diagnosis from but not clearly dominant, perhaps coming from both sides of the
FH, if clinical criteria or a DNA diagnosis have not already family, a clear DNA diagnosis is less likely. It is likely to be achieved
established this. in approximately 30% of individuals.
Risk assessment tools have recently been combined with coronary In patients, who do not receive a DNA diagnosis by sequencing,
artery calcium scores and appear to be better predictors of risk than the clustering of polymorphic hypercholesterolaemia alleles and a
 12.6 Lipid disorders 2089

polygenic mode of inheritance is likely, and may affect about 10% an autosomal recessive disorder. The secondary trigger factor should
of family members. There is often overlap between FH and poly- be discovered.
genic hypercholesterolaemia, and polygenic factors can worsen the An assay of plasma apoB levels also helps diagnose patients with
FH phenotype. FCHL. In FCHL, a family history is to be expected, but this is likely
to be polygenic (see ‘Primary causes of VLDL production’). Those
Hypertriglyceridaemia with increased apoB are at high risk of atherosclerotic cardiovas-
Clinically, hypertriglyceridaemia can be classified as mild to mod- cular disease. In FHTG, the apoB levels are not generally raised. HL
erate (fasting plasma levels >1.7–​2.3 mmol/​litre (150–​200 mg/​dl) deficiency is a very rare cause of mixed dyslipidaemia.
and <5.0 mmol/​litre (450 mg/​dl)), severe (fasting 5–​10 mmol/​L, Obesity, the metabolic syndrome of insulin resistance, and dia-
450–​900 mg/​dl)), and very severe (fasting >10 mmol/​litre (900 mg/​dl). betes are common secondary causes of mixed dyslipidaemia, often
A fasting TG level elevated above 5 mmol/​litre (450 mg/​dl) sug- with atherogenic dyslipidaemia. There is frequent exacerbation by
gests a primary cause, but secondary factors are often also present, of genetic factors.
which undiagnosed or poorly controlled diabetes is common (Table In mixed dyslipidaemia, ascertainment of the nature of the lipo-
12.6.4). If a nonfasting level is above 5 mmol/​litre (450 mg/​dl), a protein abnormality will greatly affect treatment options and efficacy.
fasting level should be obtained.
Critically, those patients with TG levels above 10 mmol/​litre Treatment of dyslipidaemia
(900 mg/​dl) have an increased risk of acute pancreatitis and this The major treatment objectives are primary and secondary preven-
becomes more likely with levels between 15 and 20 mmol/​litre tion of atherosclerotic cardiovascular disease and its complications,
(1350 and 1800 mg/​dl). These patients should be treated to lower and prevention of hypertriglyceridaemic, acute pancreatitis.
their TG levels and the risk of pancreatitis. The ‘fridge test’ may
help in making the initial diagnosis. If chylomicrons are observed Cholesterol reduction to prevent atherosclerotic
(type 1 and 5 hyperlipidaemia), then familial chylomicronaemia cardiovascular disease
or a related disorder must be considered. The measurement of LPL There is overwhelmingly robust data that the reduction in LDL-​C
activity or DNA sequencing can help in making the diagnosis. The with statins at all ages less than 75 years, at all cholesterol levels, with
finding of chylomicrons is an indicator of an increased risk of acute and without other risk factors such as diabetes and smoking, greatly
pancreatitis. decreases the risk of atherosclerotic cardiovascular disease, and its
Many people with chylomicronaemia also have raised plasma complications such as angina, heart attack, heart failure, stroke,
VLDL (type 5). These people may not have a Mendelian problem, and overall mortality. Even at older ages evidence is reasonable that
but a genetic predisposition plus acquired factors. Excessive VLDL treatment reduces risk. Patients with high cholesterol must, there-
secretion can swamp residual LPL function and grossly worsen fore, be assessed for atherosclerotic cardiovascular disease risk and
hypertriglyceridaemia. In addition to diabetes, other secondary appropriate treatment. This is particularly the case at the higher TC
causes such as dietary indiscretion, obesity, insulin resistance, ex- levels as seen in FH. All patients with atherosclerotic cardiovascular
cess alcohol consumption, and reproductive hormone deficiency or disease should be treated irrespective of initial cholesterol values.
treatment should be considered (Tables 12.6.4 and 12.6.6). The treatment pathway for the patient with hypercholesterolaemia
is illustrated in Fig. 12.6.19 and Table 12.6.12. In the United States
Mixed (combined) dyslipidaemia of America, particular emphasis is given to patients with (1) clinical
The diagnosis of patients with combined hyperlipidaemia may be atherosclerotic cardiovascular disease; (2) primary TC levels above
tricky as a variety of genetic and acquired factors can be involved. 4.75 mmol/​litre (190 mg/​dl); (3) diabetics above 40 years of age, with
High plasma levels of TC and TGs are seen in patients with in- LDL-​C levels between 1.8 and 4.75 mmol/​litre (70 to 190 mg/​dl);
creased plasma levels of VLDL, remnants lipoproteins, and LDL-​C. and (4) estimated 10-​year risk greater than 7.5%.
Measurement of plasma apoB levels should be performed. A careful The recommended target reduction to be achieved by the treat-
family history helps make the diagnosis. ment of dyslipidaemia is a greater than 40% reduction in NHDL-​
If the TC is greater than 7.0 mmol/​litre (280 mg/​dl), FH must be C by the National Institute for Health and Care Excellence in the
considered, as approximately 30% of people have FH particularly United Kingdom; targets are no longer recommended in the United
if there is a Mendelian autosomal dominant family history. A DNA States of America.
diagnosis can be ascertained by sequencing. In such patients, other Previously, LDL-​C targets were used, but these have not been
polygenic factors or a secondary cause is likely to be responsible for tested in clinical trials. Rather, now a high-​, moderate-​, and low-​
the high TGs. intensity statin treatment approach based on risk is adopted
If the TC and TGs are raised to around the same level, this sug- (Fig. 12.6.19). The ‘lower is better’ approach to achieve values of at
gests a defect of remnant clearance (remnants contain equimolar least less than 2.5 mmol/​litre for NHDL-​C (equivalent to <1.8 mmol/​
amounts to TG and cholesterol), and FDBL or type 3 hyperlipid- litre for LDL-​C) is adopted by the JBS3, but not by guidelines from
aemia must be considered (see ‘Familial dysbetalipoproteinaemia’) the United Kingdom or United States of America as it has not been
(Table 12.6.3). In cases of FDBL a TC/​ApoB ratio greater than 6.0 tested (Fig. 12.6.20).
and a TG/​ApoB ratio of less than 10.0 are highly predictive, whereas In patients with other serious risk factors such as diabetes, CKD,
in type 4 hyperlipidaemia, the TC/​apoB ratio is below 5.0 and in type and high Lp(a), it is reasonable to reduce LDL-​C levels to 1 mmol/​
5 the TG/​apoB ratio is much greater than 10.0. In all such patients, litre (40 mg/​dl).
apoE typing should be performed as the presence of apoE2 homo- The association between atherosclerotic cardiovascular disease
zygosity will confirm the diagnosis. The family history of FDBL is of and LDL-​C levels will probably bottom out at levels of 0.65 mmol/​
2090 section 12 Metabolic disorders

Drug treatment of hypercholesterolaemia

The decision to implement cholesterol-​lowering drug treatment is
determined by the level of LDL-​C/​NHDL-​C, the presence of other
atherosclerotic cardiovascular disease risk factors, and overall ath-
erosclerotic cardiovascular disease risk. A risk assessment tool
should be used to assess the 10-​year risk in patients more than
40 years of age. Exclusions to the use of risk assessment tools are
shown in Box 12.6.2.
This should aid clinical decisions about lifestyle and whether to
use lipid and blood pressure-​lowering medication, but should not
replace clinical judgement. National guidelines are of great help in
making this decision (https://​www.nice.org.uk/​guidance/​cg181 for
the United Kingdom and https://​www.guideline.gov/​summaries/​
summary/​48337 for the United States of America). Present guide-
Fig. 12.6.20 Results of clinical trials and effect of LDL lowering on lines suggest a 10-​year risk of atherosclerotic cardiovascular dis-
atheroma volume. The relationship between low-​density lipoprotein ease of more than 7.5% and more than 10% should be considered
cholesterol levels and change in per cent atheroma volume for several
for statin treatment in the United States of America and United
intravascular ultrasonography trials. There is a close correlation between
these two variables (r2 = 0.97). Note that in the Asteroid trial, treatment Kingdom respectively.
to LDL levels below currently accepted guidelines can actually regress FH or other genetic disorders of lipid metabolism are important
atherosclerosis in coronary disease patients. A-​Plus, Asteroid, A Study to exclusions to the use of risk assessment tools as they grossly under-
Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-​Derived estimate risk. In younger people, in whom the likelihood of an event
Coronary Atheroma Burden; Avasimibe and Progression of Lesions on in the next 10 years is low, a lifetime assessment is reasonable. The
Ultrasound; Camelot, Comparison of Amlodipine vs Enalapril to Limit
treatment of FH in children is discussed in previous sections.
Occurrences of Thrombosis; Reversal, Reversal of Atherosclerosis With
Aggressive Lipid-​Lowering. Statins
Source data from Nissen SE, et al. (2006). Effect of very high-​intensity statin therapy on
regression of coronary atherosclerosis: the ASTEROID trial. JAMA, 295(13), 1556–​65. Statins are the first-​line drug for the treatment of hypercholester-
olaemia. The evidence base for their use to prevent atherosclerotic
cardiovascular disease is very strong.
litre (25 mg/​dl), the ‘physiological level’ in animals and human neo- Statins are orally active inhibitors of the cholesterol biosynthesis
nates, so that potentially there is much scope for further risk reduc- enzyme HMG-​CoA reductase. HMG-​CoA reductase is rate limiting
tion, and no indication so far that we are overtreating to hazardously in the multistep cholesterol biosynthesis pathway. Inhibition of chol-
low LDL-​C levels. esterol biosynthesis reduces intrahepatic cholesterol levels, leading
In addition, the concept that more ‘cholesterol-​exposure years’ as to activation of the LDLR gene and increased hepatic LDLR activity
in FH, compared to polygenic and secondary hypercholesterolaemia (see ‘Lipids’ and ‘Cholesterol’). The resultant increased uptake of
patients and healthy people, is associated with increased risk sug- LDL by the liver reduces plasma according to statin dose. Apart from
gests that reduction of cholesterol in early life could result in long-​ lipid lowering, evidence does not support other mechanisms to re-
term benefit. Evidence to better support these important concepts is duce atherosclerotic cardiovascular disease.
still to be established. Statins vary considerably in their structure, hydrophobicity and
hydrophilicity, potency, and duration of action (Table 12.6.7).
Lifestyle
The efficacy of statins in reducing LDL-​C/​NHDL-​C is patient de-
Modification of lifestyle is important in the management of ath- pendent, but beyond the initial lowest dose, doubling the statin dose
erosclerotic cardiovascular disease risk. An atheroprotective life- incrementally reduces the LDL-​C by approximately 6%, that is, ap-
style should be instituted (Table 12.6.6). In overweight and obese proximately 20% overall. With high-​intensity treatment, reductions
individuals, weight loss should be encouraged in line with re- of LDL-​C/​NHDL-​C are routinely greater than 50%, and even with
cent guidelines (http://​www.nhs.uk/​livewell/​loseweight/​Pages/​ low-​intensity statin treatment, a 30% reduction can be anticipated.
Loseweighthome.aspx in the United Kingdom and http://​www. If TGs are raised, but to less than approximately 5.0 mmol/​litre
cdc.gov/​healthyweight/​ losing_​
weight in the United States of (450 mg/​dl), statins also reduce TGs in the same proportion as LDL-​
America). This is particularly the case in patients with the meta- C, and this is not statin-​type dependent.
bolic syndrome or diabetes, where the risk of atherosclerotic Statins are administered once daily orally and without adverse re-
cardiovascular disease is high. The patient should have expert nu- actions in most people. With the longer-​acting statins this can be at
tritional counselling. any time of day, but with the shorter-​acting statins, administration is
They should expect on average a 5 to 10% reduction in chol- best in the evening (Table 12.6.7).
esterol levels, and this is coloured by genetic factors so that this The guidelines for statin use are summarized in Fig. 12.6.19 and
can vary considerably. Aerobic exercise has only a small effect in Table 12.6.12.
lowering cholesterol levels, but it has general health and circula-
tory health benefits in addition to improving lipids. Exercise can Statin side effects
be dramatic in reducing TG levels. Other risk factors should be One in ten people will experience mild to moderate side effects,
minimized. which are fully reversible on drug withdrawal. The most common
 12.6 Lipid disorders 2091

side effect is muscle pain, due to interference with muscle mitochon- plasma CK should be measured to differentiate myalgia from my-
drial electron transport function. Indigestion, headache, fatigue, opathy. In the event of raised CK greater than five times the upper
and joint pain also occur. limit of the reference range, the statin should be stopped as there is
a risk of rhabdomyolysis. This is a serious condition likely to require
Muscle hospitalization, as it can cause acute tubular necrosis in the kidneys.
The risk of statin-​induced myopathy is increased by age, renal im- CK levels in patients on statins are not routinely measured as ele-
pairment, concomitant administration of drugs, and dietary com- vated CK without muscle pain is not a feature of myopathy, and does
ponents (grapefruit juice in large quantities increases statin side not mean the statin needs to be stopped. Low vitamin D levels can
effects by increasing blood levels) that interfere with the oxidation exacerbate symptoms, so that vitamin D should be measured, and
of statins, mainly through using the same cytochrome P450 (CYP) replenished if low. There are no arguments for the use of CoQ10 to
pathway (Table 12.6.7), and those with a previous history of statin-​ reduce statin muscle side effects.
associated muscle pain. Raised CK levels have other causes, the most common of which
The risk of statin myalgia and myopathy is statin and dose related. is physical training. Primary muscle disease is also potentially a
It depends in part on a pharmacogenetic variation of SLCO1B1 problem and may militate against statin use and needs specialist as-
(OATP2), which transports statins into the liver, and the CYPs that sessment. MacroCK, a CK-​IgG antibody complex often associated
metabolize statins. with an underlying autoimmune myositis, or oligomeric mitochon-
Polymorphic variants of the SLCO1B1 gene are present in 15% of drial CK often seen in patients with malignancy or hepatic disease
the population, with a homozygous frequency of 1 in 200. SLCO1B1 are not uncommon, and are diagnosed by simple laboratory tests.
variants increase blood statin levels, and are associated with myalgia, A benign inherited hyperCKaemia due to defective caveolae, can
and myopathy with raised creatine kinase (CK) levels, as well as the also confound interpretation.
other side effects. The management of statin muscle problems is to (1) reduce
A single copy of one of the SLCO1B1 variants increases the risk dose and increase incrementally until the threshold for side ef-
of muscle problems from high-​ dose simvastatin treatment ap- fects is reached or (2) change the statin or resort to nonstatin
proximately fivefold, and two copies by approximately 20-​fold. By lipid-​lowering medications. Atorvastatin or rosuvastatin given on
contrast, rosuvastatin treatment is less associated with muscle com- a weekly, biweekly, or alternate-​day basis are efficacious because of
plaints, and this is regardless of SLCO1B1 genotype, and despite the their long half-​life and potency (Table 12.6.7). Referral to a spe-
greater potency of rosuvastatin. Atorvastatin appears to be less likely cialist centre is advised for severe problems. CK levels should be
to cause muscle and other toxicities than simvastatin. monitored.
It is possible that the increased circulating levels of the more hydro-
philic statins (pravastatin and rosuvastatin) produced by SLCO1B1 Liver
variants are less toxic to muscle than the more hydrophobic statins Liver enzymes should be measured prior to starting statin therapy,
such as simvastatin, even though the more hydrophilic statins at 3 and 12 months according to United Kingdom guidelines.
such as rosuvastatin are more dependent on the SLCO1B1 protein Measurement is no longer recommended in the United States of
for transport into the liver. In consequence of its greater toxicity, America unless there are signs or symptoms of liver disease—​
simvastatin is less favoured for use. fatigue, weakness, loss of appetite, abdominal pain, or icterus.
The differences between statins are in part due to alternative Statins can be started with safely in patients with abnormal
pathways of statin metabolism, as well as genetic variation of the liver enzymes, even over three times normal, but if after starting
CYP450s. Myopathic complaints are apparently more likely with statins liver transaminases (alanine transaminase and aspartate
statins oxidized by CYP3A4, simvastatin, and atorvastatin rather aminotransferase) become further raised, the statin should be
than those not oxidized by CYP3A4, pravastatin, and rosuvastatin. stopped while the situation is assessed.
Although there are insufficient data to come to firm conclu- Although data are not available on the toxicity of hydrophilic
sions about the value of SLCO1B1 genotyping in predicting statin (Table 12.6.7; actively transported by SLCO1B1) versus hydro-
side effects, available data do suggest that those with the decreased phobic (passive diffusion and high first-​pass uptake) statins, a dif-
transport variants are at increased risk of statin side effects. These ferent statin or a lower dose can be introduced to determine the
genotyping assays are available and may be of value in those patients effect on liver function.
in whom high-​intensity statin therapy is indicated, particularly if Abnormal transaminases are also common in the fatty liver that
their history indicates previous side effects on statins. In patients in commonly accompanies obesity, insulin resistance and diabetes,
whom muscle problems or other side effects are serious, genotyping and excess alcohol consumption, and can be confused as being due
of SLCO1B1 variants is now common practice as this may inform to statins. The statin-​associated increase in transaminases resolves
the choice of statin and dose. SLCO1B1 homozygotes are at greater upon discontinuation of the medication, whereas that due to other
risk of serious myopathy and the fortunately rare rhabdomyolysis. causes does not. Serious statin-​induced hepatitis is very rare, so that
Serious myopathy is best avoided by starting statins, particularly there is a reduced tendency to monitor liver function as indicated by
in those at risk, at modest doses rather than straightaway at the top guidelines from the United States of America.
dose. The exception to this ‘slowly, slowly’ approach is in patients Too many physicians stop statin medication unnecessarily and
with acute coronary syndromes, when the top dose of the more forget the benefits of statins in reducing cardiovascular morbidity
powerful statins is given. and mortality by approximately 50% because they think a small rise
Patients who start statins should visit their doctor at once if they in the liver function tests means that there is ongoing damage to
get unexpected muscle pain. In patients who get muscle pain, the the liver.
2092 section 12 Metabolic disorders

Statins can be used safely in patients with chronic liver disease and with reduced atherosclerotic cardiovascular disease risk, again sup-
well-​treated cirrhosis, but the physician may need to follow the pa- porting its therapeutic role.
tient more closely than would occur in a normal healthy patient on Ezetimibe is safe and well tolerated. The main side effects are
a statin, and the same applies to approximately threefold increases headache and gastrointestinal in about 1% of people; infrequent side
in transaminases. effects are myalgia, abnormal liver function tests, and rarely hyper-
Increased transaminases must first be established to be due sensitivity reactions (rash, angio-​oedema) or myopathy may occur.
to statins. If so, the dose can be reduced or the statin changed. Cases of rhabdomyolysis have been reported, as has pancreatitis.
Persistently raised transaminases can be tolerated but requires Ezetimibe is used as an adjunct to maximum statin dosing and
careful monitoring for risk of fibrosis or cirrhosis. when statin side effects occur.

Brain Bile acid sequestrants (resins)

Hydrophobic statins enter the brain, whereas hydrophilic statins These time-​tested drugs bind bile acids (Table 12.6.8) in the intes-
do not (Table 12.6.7). Not infrequently hydrophobic statins cause tine, and promote their excretion instead of their normal reabsorp-
cerebral symptoms including sleep disturbance, vivid dreams, anx- tion by the ileum. In turn, the liver synthesizes more bile acids from
iety, and memory disturbance. These side effects are fully reversible cholesterol, which reduces the liver cholesterol pool and induces the
on stopping the hydrophobic statin and substituting a hydrophilic LDLR with increased LDL-​C clearance.
statin. There is no evidence that the statin memory disturbance con- Bile acid sequestrants are traditionally available in resin form as
tributes to dementia. Other causes of these symptoms such as other cholestyramine and colestipol, which must be suspended in water;
medications, neuropsychiatric conditions, or organic brain disease colesevelam is a tablet. Sequestrants need to be taken twice a day
must be excluded. with the higher dose in the morning with breakfast and some-
what less in the afternoon. Colesevelam is taken as up to four tab-
Diabetes and other side effects lets with breakfast and up to three tablets in the afternoon. Taking
A serious consequence of statin therapy is an increased risk of dia- sequestrants with breakfast is desirable as it coincides with emptying
betes with an estimated risk in excess of 10%, particularly with of the gallbladder, which fills overnight, and facilitates maximum
higher doses of the potent statins. In most people with high ath- bile acid binding. The effect of sequestrants is dose dependent. At
erosclerotic cardiovascular disease risk, the reduced risk outweighs maximum dosing with colesevelam, around a 30% reduction in
the risk of diabetes. Statins are also the main treatment to prevent LDL-​C levels can be achieved.
macrovascular disease in diabetics. If the glycated haemoglobin or Resins should be given with caution in patients with hyper­
fasting glucose levels increase or indeed diabetes develops, changing triglyceridaemia as they can worsen this. Interruption of the entero-
statin therapy is not recommended. Lifestyle modification may miti- hepatic recirculation of bile acids has important effects on hepatic
gate the risk or the diabetes. lipoprotein metabolism. Activation of phosphatidic acid phos-
Very rarely, neuropathy, autoimmune myopathy—​distinct from phatase promotes hepatic TG synthesis and induces VLDL secre-
toxic myopathy, an autoimmune lupus-​like syndrome, autoimmune tion, and consequently, increases plasma TG levels.
hepatitis, and pancreatitis are ascribed to statin use. Haemorrhagic Sequestrants are not systemically absorbed so that other side ef-
stroke has not been a problem even when the LDL-​C is very low. The fects are restricted to intestinal bloating and constipation. In conse-
value of statin in the treatment of those with advanced heart failure quence, they are very safe and can be used in pregnancy and during
or on haemodialysis is uncertain. lactation.
Otherwise, in very large meta-​analyses, statins have been shown They are efficacious when given with statins or ezetimibe, but
to be effective and safe at all cholesterol levels and at all adult ages. need to be taken several hours apart from other drugs and vitamins,
There is no propensity to develop cancer. They are the most used which they bind to and prevent their absorption. They can be taken
lipid-​lowering drug. with statins and ezetimibe for the management of severe hyperchol-
esterolaemia. In statin intolerance, they can be used alone or with
Ezetimibe ezetimibe.
Ezetimibe is a small-​molecule drug that specifically blocks NPC1L1 Resins have not been tested in clinical trials. Their use needs to
and intestinal cholesterol absorption (see ‘Intestinal lipid absorption be determined by clinical experience. Recalcitrant heterozygous FH,
and transport as chylomicrons’). Intestinal cholesterol is two-​thirds and homozygous FH, including those with high Lp(a), are indica-
derived from bile and about one-​third dietary. A single ezetimibe 10 tions, particularly with symptomatic atherosclerotic cardiovascular
mg dose reduces cholesterol absorption by more than 50% so that disease. They are also indicated in those with serious statin side ef-
that there is signification reduction of delivery of intestinal choles- fects, and in pregnancy and lactation.
terol to the liver and consequent induction of LDLR activity.
Plasma LDL-​C is reduced by about 20%, and this adds to the ef- Nicotinic acid
fect of statins when the two drugs are used together. Occasionally Nicotinic acid, also called niacin or vitamin B3, has been used to
a larger dose of 20 mg has been used safely, but this is not gener- lower lipids over many years, particularly in the United States of
ally efficacious. Ezetimibe has no effect on TGs or HDL. It is only America, but is no longer recommend for use in Europe (see next
used alone in those intolerant of statins. For sitosterolaemia, it paragraph). In adipocytes, it decreases lipolysis by activation of the
is the drug of choice. It has been shown to be efficacious in redu- nicotinic acid receptor (NIACR1, a high-​affinity G protein-​coupled
cing atherosclerotic cardiovascular disease events in clinical trials receptor) which reduces the levels of intracellular cAMP thereby
when used with statins. Deficiency of the NPC1L1 gene is associated inhibiting lipolysis. In the liver, nicotinic acid suppresses APOC3
 12.6 Lipid disorders 2093

gene expression, thereby enhancing LPL activity. It suppresses is effective in receptor-​negative patients, because its action is inde-
VLDL and LDL-​C by about 30% at optimum doses and raises HDL-​ pendent of LDLR activity. Its side effects are mechanism of action
C comparably. Clinical trial data do not support its use to raise HDL based, with intestinal upsets due to fat malabsorption and fatty liver.
for prevention of atherosclerotic cardiovascular disease. Progressive hepatic fibrosis has not been problematic thus far.
Clinical trials, however, have shown that combination use of Another drug is mipomersen a second-​ generation 2ʹ-​O-​
statins with drugs containing nicotinic acid did not lead to add- methoxyethyl chimeric antisense oligonucleotide, which inhibits
itional benefits in reducing the risk of major vascular events such as the synthesis of apoB. It is approved in the United States of America
heart attack and stroke, but did result in a higher frequency of non- for treatment of homozygous FH. It achieves a similar LDL-​C reduc-
fatal but serious gastrointestinal events and infection. As a result, tion to lomitapide. As with lomitapide, mipomersen causes intes-
nicotinic acid is not available for use in Europe. tinal upsets due to fat malabsorption and fatty liver. It has not been
It is also, with PCSK9 and possibly CETP inhibitors, one of the few approved in Europe due to a 50 to 70% rate of side effects, mainly
drugs that reduce Lp(a). A 30% reduction in Lp(a) can be anticipated injection site reactions, flu-​like symptoms, liver enzyme elevations,
at optimum doses of these drugs, but this is of uncertain value (see and proteinuria.
‘Lipoprotein(a)’). PCSK9 inhibitors also reduce LDL-​C by greater than 30% in
Cutaneous flushing is a troubling side effect of nicotinic acid. homozygous FH patients, who are receptor deficient, but have no
It is mediated through NIACR1 and prostaglandin in the skin. effect in receptor-​negative patients.
Nicotinic acid therapy is therefore usually started at a low dose and
slowly increased to higher doses, under the cover of aspirin to re- LDL apheresis
duce prostaglandin activity and flushing. Nicotinic acid can cause Apheresis (ἀφαίρεσις ‘a taking away’) is a physical approach to re-
dyspepsia, mild increases in transaminases, and plasma uric acid. It moving LDL from the blood, analogous to haemodialysis. The blood
can precipitate gout in susceptible people. Acanthosis nigricans and of the patient is passed through a separator, which removes LDL by
maculopathy are rare side effects. specific binding to columns and spares other lipoprotein fractions
There are no strong arguments for the use of nicotinic acid in lipid including HDL and returns the blood to the patient.
lowering. Most homozygous FH patients do not achieve satisfactory reduc-
tion of LDL-​C levels on maximum drug treatment alone and disease
PCSK9 inhibitors will progress. Those with atherosclerotic cardiovascular disease and
Inhibitors of PCSK9 are fully human monoclonal antibodies that LDL-​C levels above 5 mmol//​litre (200 mg/​dl), or without athero-
block PCSK9 at the liver surface and reduce LDLR degradation. This sclerotic cardiovascular disease and LDL-​C levels above 7 mmol/​
concept emerged from the discovery that loss-​of-​function muta- litre (280 mg/​dl) are candidates for apheresis.
tions in the PCSK9 gene reduce plasma LDL-​C, along with the risk Apheresis is performed weekly or twice-​monthly depending on
of atherosclerotic cardiovascular disease. They have proved highly the degree of lipid lowering achieved. It is well tolerated and achieves
efficacious in meta-​analysis of clinical trials in reducing LDL-​C and a good reduction in LDL-​C levels, though there is rebound at the
TGs by approximately 50% and increasing HDL, but end-​point trials end of the treatment cycle to high levels of LDL-​C, due to increased
have not been reported as yet. They also reduce Lp(a) by 30%. These synthesis and defective LDLR function. Atherosclerotic cardiovas-
new and exciting drugs have recently received regulatory approval cular disease still progresses, but at a reduced rate.
by the FDA and European Medicines Agency, but the criteria for The main disadvantage is long-​term access to the circulation,
general use are restricted to severe genetic hypercholesterolaemia which is best achieved by an arteriovenous fistula, but venous access
with progressive atherosclerotic cardiovascular disease and failure or a central line can be used.
of adequate response to other lipid-​lowering agents. Their initial The advent of effective apheresis and effective drug treatment with
target is genetic hypercholesterolaemia, where cholesterol lowering conventional drugs has greatly improved the prognosis for homozy-
is not adequate, or when there are severe statin side effects. With gous FH. Further improvement is hoped for and anticipated with the
very very low LDL-​C levels, the risk of haemorrhagic stroke has not drugs described previously described.
materialized.
Lipoprotein(a)
Dietary supplements The treatment of elevated Lp(a) is a problem. It is a serious ath-
Supplements to the diet with plant sterols or stanols (such as erosclerotic cardiovascular disease risk factor and a risk factor for
FloraProActive or Benecol respectively) which compete for chol- calcific aortic stenosis. There is no truly effective treatment. Both
esterol absorption thus reducing plasma cholesterol levels can be nicotinic acid and PCSK9 inhibitors reduce Lp(a) by approximately
used as an adjunct to lifestyle measures. A daily intake of 1.5 to 2.4 30%, but the efficacy of this is uncertain compared to dramatic lipid
g sterols or stanol ester can lower the plasma cholesterol by 7 to 10% lowering. Nicotinic acid is not available in the United Kingdom. The
in 2 to 3 weeks as part of a healthy diet and lifestyle. role of CETP inhibitors in lowering Lp(a) has still to be established.
A second-​generation antisense Lp(a) mRNA inhibitor has also
Drugs for homozygous FH proved remarkably efficacious as a treatment in early clinical trials,
Two orphan drugs are available to treat homozygous FH. Lomitapide and is in development.
is an inhibitor of MTTP, which mimics abetalipoproteinaemia in its In the large AIM-​HIGH clinical trial, after LDL-​C lowering to
mechanism of action, and suppresses VLDL secretion. It is approved 1 to 2 mmol/​litre (40 to 80 mg/​dl) with statins no further benefit
for use in homozygous FH. It can achieve a greater than 30% reduc- was accrued from the addition of nicotinic acid to lower the Lp(a).
tion of LDL-​C when used alone or in conjunction with apheresis. It Profound lipid lowering should be aimed at and this may be
2094 section 12 Metabolic disorders

sufficient. Whether this applies with very high Lp(a) levels (>100 reduction by diet and exercise should help decrease TG. In obese
mg/​dl (250 nmol/​litre) is not known. Aspirin or another antiplatelet and overweight individuals, weight loss should be encouraged.
drug should be given to suppress the thrombogenicity of Lp(a).
In patients with high Lp(a) and symptomatic atherosclerotic car- ‘The rescue diet’
diovascular disease, apheresis is effective in reducing Lp(a) levels In more severe hypertriglyceridaemia (>15 mmol/​litre (1300 mg/​
and has potential to reduce disease progression, but its use is un- dl)), especially with chylomicronaemia, and out-​of-​control diabetes,
likely to be commonplace. the patient is often best managed in the hospital setting to achieve
rapid control. An extremely low-​fat diet, less than 10 g of fat daily,
Triglyceride reduction to prevent acute pancreatitis and for about 3 days is necessary (Table 12.6.13). This diet is called the
atherosclerotic cardiovascular disease ‘rescue diet’ as it rapidly lowers TGs. This strict low-​fat diet is not
The primary treatment goal in severe hypertriglyceridaemia is to easy to maintain and not nutritionally adequate in the long term.
lower TGs rapidly to reduce the risk of acute pancreatitis. Elevated
plasma TGs are also a risk factor for atherosclerotic cardiovascular Secondary factors
disease, as previously discussed. A secondary goal is therefore to re- Other factors contributing to hypertriglyceridaemia need to be ac-
duce the risk of atherosclerotic cardiovascular disease. tively sought and treated. In clinical practice, the most common
TG levels in patients are best measured on fasting samples, be- problem is either undiagnosed or uncontrolled diabetes. In suscep-
cause in the nonfasting state diet can have a profound effect on TG tible individuals, certain drugs, such as oestrogen, steroids, retin-
levels. Nonfasting TGs are better predictors of atherosclerotic car- oids, and protease inhibitors, can also trigger hypertriglyceridaemia
diovascular disease risk than fasting TG, probably because they (Table 12.6.4). If drugs are contributing significantly to hyper­
better reflect our usual status. triglyceridaemia, treatment should be switched or discontinued if
Patients with fasting TGs levels above 10 mmol/​litre (900 mg/​dl) the patient’s clinical condition allows and there are effective alterna-
are at increased risk of acute pancreatitis. Although in practice acute tive treatment options. Further information on the secondary causes
pancreatitis is rare with levels below 15 mmol/​litre (1300 mg/​dl), of hypertriglyceridaemia is found in Table 12.6.4.
fat consumption can readily achieve this level in the predisposed.
Those patients that display chylomicronaemia (type 1 and 5 hyper- Drug treatment of hypertriglyceridaemia
lipidaemia) as ascertained by the ‘fridge test’ are at particular risk of Severe hypertriglyceridaemia with TGs above 5 mmol/​litre (450
acute pancreatitis. mg/​dl) despite adequate lifestyle management is likely to need drug
TGs can vary markedly and rapidly and a patient with only mod- treatment. Fibrates and omega-​3 fatty acids derived from fish are
erately elevated TGs may develop acute pancreatitis following a the only drugs available to treat hypertriglyceridaemia in the United
short period of dietary indiscretion, which leads to much higher TG Kingdom. Nicotinic acid is not used in Europe, but is in the United
levels. States of America (see ‘Nicotinic acid’).
There are also patients, however, with persistent marked Statins can reduce TG, when levels are below 5 mmol/​litre (450
hypertriglyceridaemia who never develop pancreatitis. Pancreatitis mg/​dl), but have no value in severe hypertriglyceridaemia. Statins
is therefore an unpredictable complication of hypertriglyceridaemia may be necessary with fibrates if LDL-​C/​NHDL-​C remains high
and usually strikes unexpectedly. It is thus generally accepted that after TGs have been controlled (Table 12.6.8, with caveats for the
patients with very high TG levels should be treated to reduce TGs combined use of statins and fibrates). Ezetimibe does not lower TGs
and the risk of acute pancreatitis. No clinical trial has been per- significantly but can be combined with fibrates if additional LDL-​C
formed to validate this view. lowering is required and statins are not tolerated. Cholestyramine
can raise TGs and should be avoided in moderate to severe
Lifestyle hypertriglyceridaemia.
Moderately severe hypertriglyceridaemia (<15 mmol/​litre (1300
mg/​dl)) in the absence of chylomicrons (type 4 hyperlipidaemia) Fibrates
can be managed in the outpatient setting. Fibrates are central to the management of severe hypertrigly­
Lifestyle changes will usually significantly reduce plasma TG ceridaemia (TGs >5 mmol/​litre (450 mg/​dl)) and are the drugs of
levels. A reasonable dietary goal is to restrict total fat intake to around first choice. They lower TGs, increase HDL-​C, and may either lower
20 to 30 g daily. This is not always easy to achieve, because normal or in some cases increase LDL-​C. Fibrates are particularly effica-
consumption is approximately 70 g daily, and requires dedication cious in FDBL. They do not very much decrease atherosclerotic
from the patient in understanding their dietary fat consumption. cardiovascular disease events due to hypercholesterolaemia, but are
Excessive intake of starch and sugar should be discouraged because efficacious in hypertriglyceridaemia.
they drive TG production in the liver. A formal dietary consultation Fibrates regulate lipid metabolism by their agonist effect on the
and regular review with a dietitian with specific experience in the nuclear receptor PPARα. PPARα stimulates LPL and apoA5 expres-
management of severe hypertriglyceridaemia is desirable. Dietary sion and inhibits apoC3 expression. The increase in plasma HDL-​
fat restriction needs constant reinforcement. Spiking TG values on C depends partly on an overexpression of apoA1 and apoA2. They
follow-​up are often related to dietary indiscretions. Alcohol con- also increase fatty acid β-​oxidation by mitochondria. An increase in
sumption should be limited or stopped. LDL-​C arises in hypertriglyceridaemic subjects when more efficient
Regular physical activity, particularly strenuous activity, is valu- lipolytic processing brought about by fibrates results in increased
able to reduce TG levels, and may have dramatic results. Weight LDL-​C production.
 12.6 Lipid disorders 2095

Table 12.6.13 Hypertriglyceridaemia rescue diet

Daily menu Grams of fat Grams of fat

Breakfast (1.7 g)
125 ml orange juice 0.3 1 banana 0.4
3/​4 cup Rice Krispies 0.0 250 ml skimmed milk 0.5
1 slice white bread 0.5 15 ml honey 0.0
Lunch (1.6 or 2.4 g)
2 medium potatoes (2 slices bread) 0.2 (1.0) 60 g fat-​free cottage
Salad (lettuce, cucumber, tomato ...) 0.5 cheese 0.9
Supper (2.4 or 3.4)
375 ml white rice 0.6 (1.6) 125 ml tomato/​onion mix 0.4
125 ml lentils 0.4 Vegetables (carrot, broccoli) 0.4
Fruit (3 slices of pineapple) 0.6
Snacks (1.3 g)
Apple, morning 0.6 Pear, afternoon, morning 0.7
Other supplements
No diabetes Diabetes
Beverages
Carbonated drinks including colas Dietetic cold drinks
Lucozade Low-​calorie Lecol, Oros
Fruit juice, including orange, apricot, apple, grape
Sweets
Boiled sweets Artificially sweetened
Jelly babies, wine gums, marshmallows
Peppermints, vitamin C sweets
Spreads
Sugar, syrup, honey, molasses Dietetic jams
Jam, marmalade
Desserts
Jelly, canned fruit, custard made with skimmed milk (0.4 g fat/​250 ml) Artificially sweetened jelly
Meringues without cream Low-​calorie canned fruit
Dried fruit

Source data from Blom DJ, et al. (2010). Hypertriglyceridaemia: Aetiology, Complications and Management. JEMDSA, 15(1), 11–​17.

They are safe and have few side effects, but can increase the likeli- Fish oils are given in capsules as 4 g daily in divided doses, and effect-
hood of gallstones. In the presence of existing gallstones they should ively reduce TG levels in moderately severe hypertriglyceridaemia,
be used with caution. Fibrates (particularly gemfibrozil) are associ- and may lower TGs by up to 40% in some patients. They work in part
ated with toxic myopathy especially when combined with statins or mechanistically by increasing the turnover of MLXIPL mRNA (see
nicotinic acid (Table 12.6.8). ‘Lipids’ and ‘Triglycerides’), which inhibits the de novo biosynthesis
Care and appropriate monitoring is needed in patients on anti- of fatty acids from carbohydrate.
coagulants and some diabetic blood glucose-​reducing drugs as Fish oils are effective for the treatment of moderate hyper­
fibrates interact with these classes of drug. triglyceridaemia with levels of approximately 5 mmol/​litre (450 mg/​
Fibrates are excreted renally and doses need to be adjusted to renal dl). With more severe hypertriglyceridaemia, they are good in com-
function. They raise creatinine by about 10%, but this is not due to a bination with fibrates. Higher doses of up to 12 g have been used with
lowered GFR and reverses on discontinuation. apparent safety and efficacy in very severe hypertriglyceridaemia,
In the light of recent reanalysis of clinical trials of fibrates, their use but should not be used in pure type 1 hyperlipidaemia, where they
in treating mild to moderate hypertriglyceridaemia and preventing may exacerbate the phenotype. High doses can also be used with ap-
atherosclerotic cardiovascular disease needs reconsideration. parent safety in hypertriglyceridaemia during pregnancy. They can
cause a modest increase in LDL-​C.
Omega-​3 fatty acids The main side effect is dyspepsia. They may increase the bleeding
Omega-​3 polyunsaturated fatty acids or fish oils are present in high time. It is important that the fish oil is purified to remove mercury,
concentration in oily fish. They come from a variety of plants sources, dioxins, polychlorinated biphenyls, and other toxins that contam-
but omega-​3 fatty acids of plant origin are less well studied, and are inate fish, particularly if prolonged use is anticipated or in pregnancy.
not a recommended substitute for fish oils. Eicosapentaenoic acid There are active clinical trials to see if they reduce atherosclerotic
and docosahexaenoic acid are the main active ingredients in fish oil. cardiovascular disease risk due to high TGs.
2096 section 12 Metabolic disorders

Acute pancreatitis and diabetes are present in a patient with hypertriglyceridaemia

Severe hypertriglyceridaemia is a well-​ established trigger for then it can be highly effective in reducing TG levels. In the decision
acute pancreatitis. The pathogenesis of hypertriglyceridaemic as to whether to offer a patient bariatric surgery, the presence of dia-
acute pancreatitis remains ill-​understood. A likely precipitating betes and hypertriglyceridaemia are important considerations.
factor is sludging of the very large chylomicron particles in the Treatment protocols and new drugs
microvasculature of the pancreas leading to leakage of pancre-
atic enzymes into the circulation. This may lead to intravascular Treatment protocols, existing drugs, and new drugs for the treat-
TG hydrolysis by lipase with subsequent bulk release of ‘toxic’ ment of dyslipidaemia are given in Tables 12.6.7, 12.6.8, 12.6.10,
proinflammatory free fatty acids into the circulation; and activation and 12.6.12 and Fig. 12.6.19.
of the proteolytic enzyme trypsin in the circulation may lead to pan-
creatic autodigestion. FURTHER READING
Accurate measurement of serum amylase is challenging in the
Abifadel M, et al. (2012). Identification and characterization of new
presence of lipidaemia and pancreatitis may be falsely ruled out
gain-​of-​
function mutations in the PCSK9 gene responsible for
when the amylase is not apparently elevated. In many patients,
autosomal dominant hypercholesterolemia. Atherosclerosis, 223,
TGs are only measured several days after the onset of pancrea- 394–​400.
titis and a prolonged period of nil per mouth. In such situations, Adhyaru BB, et al. (2015). New cholesterol guidelines for the manage-
hypertriglyceridaemia may have improved markedly and may then ment of atherosclerotic cardiovascular disease risk: a comparison
be erroneously excluded as a possible cause of pancreatitis. of the 2013 American College of Cardiology/​ American Heart
The treatment of hypertriglyceridaemic pancreatitis does not Association Cholesterol Guidelines with the 2014 National Lipid
differ greatly from that of pancreatitis of any other cause. Metabolic Association recommendations for patient-​centered management of
disturbances should be sought and controlled. Should total paren- dyslipidemia. Cardiol Clin, 33, 181–​96.
teral nutrition be necessary, it is important to avoid excess fat supply Alphonse PAS, et al. (2016). Revisiting human cholesterol synthesis
(e.g. Intralipid or Lipovenoes). Other therapeutic measures in order and absorption: the reciprocity paradigm and its key regulators.
to correct the hypertriglyceridemia include the use of low molecular Lipids, 51, 519–​36.
weight heparin and insulin. Blom DJ, et al. (2010). Hypertriglyceridaemia: aetiology, complica-
tions and management. JEMDSA, 15, 11–​17.
Apheresis or plasma exchange will rapidly, but transiently, lower
Brunham LR, et al. (2006). Intestinal ABCA1 directly contributes to
plasma TGs, and may have a role if the high TGs are intransigent to
HDL biogenesis in vivo. J Clin Invest, 116, 1052–​62.
other treatment approaches. In the early stages of recurrent acute Chowdhury R, et al. (2014). Association of dietary, circulating, and
pancreatitis and in pregnancy it may have value. There is, however, supplement fatty acids with coronary risk: a systematic review and
no evidence that patients treated with apheresis recover more rap- meta-​analysis. Ann Intern Med, 160, 398–​406.
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12.7
Trace metal disorders

CONTENTS hypogonadism), arthritis, and pigment cirrhosis. Typical symptoms

include fatigue, arthralgia, abdominal pain, and loss of libido.
12.7.1 Hereditary haemochromatosis 2098
William J.H. Griffiths and Timothy M. Cox Diagnosis—​usually established by demonstrating abnormalities of
iron metabolism, with fasting serum transferrin iron saturation above
12.7.2 Inherited diseases of copper metabolism: 55% in males and 45% in females along with elevated serum ferritin
Wilson’s disease and Menkes’ disease 2115 concentration. Molecular analysis of the HFE gene, in particular for
Michael L. Schilsky and Pramod K. Mistry
homozygosity for the C282Y allele, is confirmatory.
Management and prognosis—​this is directed to the removal of iron
by phlebotomy, typically 500 ml of blood each week, until the serum
ferritin concentration is reduced to within the low normal range, after
which the frequency of phlebotomy is reduced. The oral iron che-
lator deferasirox has shown promise as an alternative to venesection
12.7.1 Hereditary haemochromatosis in phase II trials. Specific treatment may be required for estab-
lished end-​organ failure. Patients with advanced fibrosis or cirrhosis
William J.H. Griffiths and Timothy M. Cox should undergo 6-​monthly surveillance by ultrasonography and
serum α-​fetoprotein estimation for early detection of hepatocellular
carcinoma. The main causes of death in untreated patients are
ESSENTIALS hepatocellular failure and carcinoma of the liver. Intervention prior
Hereditary haemochromatosis syndromes are inherited disorders to the onset of cirrhosis or diabetes avoids the deterioration in sur-
whereby inappropriate absorption of iron by the small intestine leads vival associated with late presentation.
to iron deposition in the viscera, endocrine organs, and other sites, Family members—​ first-​
degree relatives should be offered
causing structural injury and impaired function. The most common screening. Asymptomatic subjects in whom molecular analysis of the
form is classical adult (HFE-​related) haemochromatosis, but other HFE or non-​HFE iron overload genes indicates a genetic predispos-
forms are recognized. Extended genetic platforms are increasingly ition to the disease require re-​evaluation by clinical and biochemical
used for specific diagnosis and noninvasive methods are increas- testing at intervals of between 2 and 5 years. Symptomatic subjects
ingly used to evaluate hepatic damage. The mainstay of treatment or those with significant iron indices (i.e. ferritin >750 µg/​litre) should
is venesection although iron chelation therapy is an emerging oral be considered for immediate treatment.
alternative. Unravelling the molecular genetics of haemochroma-
tosis is underpinning promising new therapies for disorders of iron
homeostasis.
Classical adult (HFE-​related) haemochromatosis
Introduction
Aetiology and pathogenesis—​inherited as a recessive trait and due to Pathological storage of iron
mutations in the major histocompatibility complex class I-​related
HFE gene that appear to reduce liver production of hepcidin. The The body contains about 4 g of iron, 3 g of which is complexed with
principal mutant allele of HFE, designated C282Y, is carried by ap- haem to form haemoglobin, myoglobin, and the cytochromes. The
proximately 1 in 10 individuals of European ancestry, hence around nonhaem storage compartment, which consists of ferritin and its
1 in 200 are homozygotes, usually with biochemical abnormalities of proteolytic degradation product haemosiderin, represents up to
iron storage that may lead to full-​blown clinical haemochromatosis. 0.5 g of elemental iron in adult women and slightly more than 1 g
Clinical features—​expression of disease may range from slight in adult men. Excess storage of body iron (iron overload) is asso-
abnormalities of blood parameters that reflect iron metabolism to ciated with an increase in hepatic iron concentrations and of the
the established clinical syndrome of cutaneous pigmentation, car- surrogate biomarker, serum ferritin. Minimal iron storage occurs
diomyopathy, endocrine failure (especially diabetes mellitus and when more than 1.5 g of total body iron is present. This is reflected
in a hepatic iron concentration of approximately 30 µmol/​g of tissue
 12.7.1 Hereditary haemochromatosis 2099

with a serum ferritin level of usually less than 250 µg/​litre. Moderate been described mainly in southern Europeans and is termed type
iron storage disease is reflected by a serum ferritin of approximately 3 haemochromatosis using the Online Mendelian Inheritance in
500 µg/​litre. Under these circumstances, the hepatic iron concentra- Man (OMIM) classification (Table 12.7.1.1). The phenotype resem-
tion rises to 100 µmol/​g. Severe iron storage disease (>5 g of storage bles HFE-​related haemochromatosis (type 1) although it is gener-
iron) is shown by a hepatic iron concentration of over 200 µmol/​g ally more severe and presents at a younger age. The TFR2 protein is
liver tissue, with a serum ferritin level of at least 750 µg/​litre. Under mainly expressed in the liver and has a lower affinity for iron uptake
these circumstances, tissue injury with impaired function is almost than the ubiquitous transferrin receptor. Latterly, a role for TFR2
invariably present. in erythrocyte production has been suggested whereby it forms a
component of the erythropoietin receptor complex and may act as
an iron sensor.
Clinical subtypes of haemochromatosis Identification of the protein responsible for iron transport across
the basolateral surface of enterocytes provided a candidate for a re-
Adult haemochromatosis cently recognized atypical form of haemochromatosis. The iron ex-
The familiar form of haemochromatosis is the classical adult type, porter in question has been termed ferroportin and appears to also
which typically presents in middle age and is usually expressed in control iron release from hepatocytes and, importantly, macrophages.
men. The disorder is inherited as a recessive trait and is due to mu- Single missense mutations in the SLC40A1 mutations which en-
tations in a gene, HFE, that maps to the short arm of chromosome 6 code ferroportin are associated with a specific dominantly inherited
in close apposition to the HLA class I loci of the human major histo- phenotype. Haemochromatosis due to heterozygous SLC40A1 muta-
compatibility complex (MHC). Expression of iron storage disease in tions has been coined ferroportin disease and also referred to as type
individuals carrying mutations in the HFE gene is very variable and 4 haemochromatosis. The disorder is typified by a raised ferritin level
is influenced by several environmental and sexual factors, as well with normal or low transferrin saturation and a tendency for anaemia
as emerging genetic modifiers. Mutant alleles of the HFE gene that with poor venesection tolerance. Not restricted to white people, the
predispose to adult-​type haemochromatosis are widespread and fre- condition is recognized in Asians and a unique and common poly-
quent in populations of northern European origin. There is evidence morphism (p.Q248H) in Southern African populations may con-
from haplotype analysis that a single mutation arose on an ances- tribute to the indigenous iron overload observed.
tral chromosome 6 and spread throughout this population, prob- Iron loading in type 4 haemochromatosis occurs predominantly
ably as a result of the migration of the Vikings from Scandinavia. within the reticuloendothelial system with splenic uptake visible
The disease occurs throughout the world as a result of intermarriage on MRI (Fig. 12.7.1.1). On liver microscopy, Kupffer cells are iron-​
but is at its highest frequency in France, Germany, Great Britain, laden with relative sparing of hepatocytes. SLC40A1 mutations re-
Ireland, Northern Italy, Scandinavia, Spain, and Eastern Europe as sult in iron trapping within macrophages and it has been proposed
far as European Russia. Colonization has led to its appearance in all that the reduced availability of plasma iron either directly or via an
populations of the United States of America and in Australasia, and ensuing anaemia drives increased intestinal absorption. As well as
for the same reason hereditary adult-​type haemochromatosis also the phenotype described earlier, where spillover of iron into hepato-
occurs in South America. cytes is minimal and disease course benign, a second ‘nonclassical’
Classical adult-​ type haemochromatosis (HFE-​related haemo- phenotype, less commonly observed, is characterized by an elevated
chromatosis) is a slowly progressive disease affecting the liver, transferrin saturation, hepatic parenchymal iron deposition, and
endocrine system, heart, and joints; it is often only diagnosed when liver disease.
irreversible tissue injury has occurred. The condition predisposes to
the development of primary carcinomas of the liver. A rare genetic Juvenile haemochromatosis
form of adult haemochromatosis occurs in patients homozygous Since the identification of adult iron storage disease by several
for mutations in the transferrin receptor 2 (TFR2). This form has European physicians during the 19th century, a similar disease has

Table 12.7.1.1 Inherited disorders of iron storage

Disorder OMIM number Locus Gene/​protein

Atransferrinaemia 209300 3q21 Transferrin
Acaeruloplasminaemia 604290 3q23–​q25 Caeruloplasmin
Haemochromatosis (type 1) (adult) 235200 6p21.3 HFE
Haemochromatosis (type 2A) ( juvenile) 608374 1q HJV/​haemojuvelin
Haemochromatosis (type 2B) ( juvenile) 606464 19q13.12 HAMP/​hepcidin
Haemochromatosis (type 3) (adult) 604250 7q22 Transferrin receptor 2
Haemochromatosis (type 4) (adult, dominant) 606069 2q32 SLC40A1/ferroportin
Haemochromatosis (type 5) (adult, dominant) 615517 11q12.3 FTH1
Haemochromatosis (neonatal) 231100 Unknown Unknowna
a
Autosomal recessively inherited in only a few families.
2100 section 12 Metabolic disorders

Fig. 12.7.1.1 Magnetic resonance imaging (T2 weighted) demonstrating iron overload
in the liver and spleen of a patient with classical ferroportin (FPN) disease (top panel). This
48-​year-​old male presented with a serum ferritin of 3000 µg/​litre, transferrin saturation
of 21%, and was heterozygous for the W158C mutation of the SLC40A1 gene. For
comparison is a normal control film (bottom left panel) and a patient with HFE-​related
haemochromatosis (bottom right panel) demonstrating low signal in the liver only as iron
loading here is predominantly in hepatocytes rather than the reticuloendothelial system.

been recognized in children and young adults who may develop iron of cases (type 2B haemochromatosis) are explained by mutations
storage disease of a more severe character, now designated juvenile in the HAMP gene on chromosome 19 which codes directly for
haemochromatosis (Fig. 12.7.1.2). This is defined as iron storage hepcidin. In mice with disruption of murine HAMP, or its promoter
disease occurring before the age of 35 years. It evolves rapidly, typ- sequence, hepatic iron loading occurs. Conversely, overexpression
ically affects the heart and endocrine system, and causes infantilism of murine HAMP results in anaemia in keeping with hepcidin sup-
and hypogonadism, as well as life-​threatening cardiac arrhythmias. pressing intestinal iron absorption. Indeed, HAMP overexpression
Juvenile haemochromatosis is inherited as a very rare recessive trait overrides the effect of the C282Y mutation on dietary iron up-
in which there is an increased frequency of consanguinity among take and prevents haemochromatosis in HFE-​deficient mice. This
the parents of affected subjects. Juvenile haemochromatosis resem- finding supports the more severe phenotype observed in this form
bles the severe iron storage disease associated with the iron-​loading of juvenile disease compared with HFE-​related haemochromatosis.
anaemias, such as β-​thalassaemia. Juvenile haemochromatosis af- Hepcidin is thought to play a central role in iron homeostasis and
fects males and females equally—​an observation that reflects the current models are premised on hepcidin acting as a putative iron-​
overwhelming nature of the iron homeostatic defect. Iron overload regulatory hormone with effects on end organs, including the intes-
develops before the modifying effects of menstruation and dietary tine and the monocyte/​macrophage system.
factors supervene.
The genetic basis of juvenile haemochromatosis has been elu- Neonatal haemochromatosis
cidated and revealed key proteins involved in iron metabolism. Neonatal haemochromatosis is a newly identified syndrome of un-
Most cases have been associated with mutations in the HJV gene certain cause, characterized by congenital cirrhosis or fulminant
on chromosome 1q, encoding the protein haemojuvelin; the hepatitis associated with the widespread deposition of iron in hep-
homozygous mutation G320V accounts for approximately 50% of atic and extrahepatic tissues. Approximately 100 cases of neonatal
HJV-​associated or type 2A haemochromatosis. Haemojuvelin is ex- haemochromatosis have been reported. Neonatal haemochroma-
pressed predominantly by hepatocytes but also in cardiac and endo- tosis occurs in the context of maternal disease (including viral in-
crine tissues. The common mutations abrogate expression at the cell fection) and in the presence of maternal antinuclear factor, as a
surface of hepatocytes where haemojuvelin may act as a coreceptor complication of metabolic disease in the fetus, and sporadically or
for bone morphogenetic protein as part of an intracellular signalling recurrently, without overt cause, in siblings, including maternal
mechanism for synthesis of the peptide hepcidin. A smaller number half-​siblings. This latter observation indicates that conception by
 12.7.1 Hereditary haemochromatosis 2101

(a) (b)

(c) (d)

Fig. 12.7.1.2 Juvenile cardiac haemochromatosis. Histological appearances of explanted heart from a 27-year-old woman (patient 1) who underwent
orthotopic cardiac transplantation for refractory heart failure; hypogonadotrophic hypogonadism had been present for 8 years. Whole-mount sections
of left ventricular wall stained with haematoxylin and eosin (a) or (b), Perls’s ferrocyanide reagent, show iron deposits principally affecting sub-epicardium
and peripheral one-third of myocardium. High-powered microscopic views (×400: haemotoxylin and eosin, (c); Perls’s reagent, (d)) show widespread
punctate aggregates of stored iron in cardiac myocytes and interstitial cells. Note the absence of inflammatory changes. Although iron was most
abundant in the sub-epicardial zone, microscopic views show that degenerating myocytes containing iron deposits, some with hyperchromatic nuclei,
were distributed throughout the myocardium.
Reproduced from Kelly AL et al. (1998). Hereditary juvenile haemochromatosis: a genetically heterogeneous life-threatening iron-storage disease. QJM, 91, 607–618 with
permission from Oxford University Press.

the use of sperm donors in women who have had a previously af- although neonatal haemochromatosis appears to have a clear her-
fected infant should not be recommended. Although infants with editary basis, no predictive genetic test is yet available to inform the
neonatal haemochromatosis die of liver disease shortly after birth, outcome of at-​risk pregnancies for this devastating disease.
there are many instances where survival is associated with a com-
plete recovery and thereafter normal growth and development
with no signs of abnormal iron metabolism. Recently, it has been Prevalence and epidemiology
shown that the outcome of pregnancies at risk for neonatal haemo-
chromatosis is improved by treatment of the mother with high-​dose Juvenile and neonatal haemochromatosis are rare disorders that
intravenous infusions of pooled human immunoglobulin, thereby occur sporadically, but hereditary adult haemochromatosis is widely
suggesting the operation of a humoral factor and a significant disseminated and of global importance. Removal of toxic iron by re-
overlap with gestational alloimmune liver disease. However, the in- peated venesection improves the outcome for adult haemochroma-
volvement of genetic determinants, possibly of paternal origin, in tosis. If this treatment is instituted before irreversible tissue injury
an alloimmune response has not been excluded. In other pedigrees, occurs, venesection may restore health and a normal life expectancy.
2102 section 12 Metabolic disorders

For these reasons, there has been much discussion about the of iron in the diet appears to be much greater than in the average
early recognition of iron storage disease by the introduction of European population today, most middle-​aged male C282Y homo-
population-​based screening programmes, using genetic testing or zygotes appear to express at least one clinical manifestation of iron
phenotypic biochemical screening methods, that can be applied to storage disease. Similarly, a study of homozygous relatives (princi-
communities at risk. pally siblings) within pedigrees known to have haemochromatosis
In European populations, around 1 in 10 individuals carries one suggest that about one-​half of the men over 40 years of age, and
copy of an allele of the HFE gene that predisposes to iron storage about one in six of the women over 50 years of age, have at least
disease, and between 1 in 100 and 1 in 400 people in these popula- one haemochromatosis-​related clinical disorder. This latter survey,
tions are homozygotes or compound heterozygotes with biochem- conducted in the United States of America, suggests that an im-
ical abnormalities of iron storage that may lead to full-​blown clinical portant proportion of homozygous relatives of patients with estab-
haemochromatosis. Thus, the mutant allele, designated C282Y of lished haemochromatosis, especially men, have conditions such as
HFE, which is the principal determinant of iron storage disease, cirrhosis and arthropathy, as well as abnormalities of serum liver-​
occurs at polymorphic frequency and is one of the most common related tests that are not detected by spontaneous clinical referral.
genetic abnormalities leading to an autosomal recessive disease in Many reports of disease expression in haemochromatosis may,
populations of northern European origin. In European patients with however, be questioned because of the prevalence of cosegregating
iron storage disease due to hereditary haemochromatosis, the fre- genes within affected pedigrees, as well as early household environ-
quency of homozygosity for the C282Y HFE allele ranges from about mental factors common to siblings that may predispose to disease
35% in southern Italy to more than 90% in the British Isles, including expression. Studies in mice support this explanation, since it has
Ireland. In Australia, homozygosity for C282Y occurs in almost 100% been shown that several independent genetic determinants control
of patients with hereditary haemochromatosis. However, as discussed the extent of iron loading observed in mouse models of iron storage
later, although useful for diagnosis, homozygosity for the C282Y mu- disease generated by targeted disruption of the murine homologue
tation of HFE is not tantamount to a diagnosis of established iron of the HFE gene. In contrast, surveys conducted in outbred popu-
storage disease nor, therefore, of clinical haemochromatosis. lations, for example, in Jersey, show a great disparity between the
Clinical expression of haemochromatosis is highly dependent on predicted frequency of homozygosity for C282Y and the number
age and it is very rare for there to be detectable disease in adults of recorded cases with the disease attending local hospitals. These
below the age of 20 years. As clinical disease is much more common latter studies may reflect the underdiagnosis of haemochromatosis,
in men than women, it is likely to reflect environmental factors and and an inability to bring together the unitary clinical manifestations
the modification of disease expression due to blood loss associated of the disease into a unifying diagnostic category. However, widely
with menstruation and the investment in pregnancies, as well as the differing degrees of disease penetrance almost certainly account for
comparatively reduced dietary complement of iron in women. Other the apparent shortfall of diagnosed cases in populations at risk.
environmental factors, particularly the consumption of alcohol, ap- At present, no clear data in large unbiased population surveys are
pear to interact with predisposing genetic factors to induce the clin- available to assess disease penetrance and the modifying effects of
ical expression of iron storage disease in C282Y homozygotes. Most lifestyle factors such as alcohol, nutrition, and diet, as well as preg-
patients with the disease develop symptoms at, or above, the age of nancy and menstruation, that are likely to influence the effects and
40 years. However, studies of iron metabolism by biochemical meas- rate of iron storage in human C282Y homozygotes. Mortality figures
urements or tissue biopsy may reveal early evidence of iron storage show that death is rarely attributed to hereditary haemochroma-
in the long presymptomatic phase of this condition. With greater tosis in populations at risk. This fact contrasts starkly with the well-​
awareness of the diverse clinical manifestations of adult type heredi- established known complications of the full clinical syndrome, in
tary haemochromatosis, detection on the basis of early symptoms, which early death results from cirrhosis of the liver, hepatocellular
for example arthralgia and fatigue, may be possible. Thus, there is carcinoma, endocrine failure, or cardiac complications.
a marked disparity in populations in which C282Y homozygosity In a North American study of more than 41 000 individuals at-
is prevalent and the frequency with which symptomatic haemo- tending a health appraisal clinic, no evidence of an increased fre-
chromatosis is diagnosed. quency of symptoms was identified in those genetically predisposed
to iron storage disease. The only significant clinical history iden-
Phenotypic expression of disease tified in the at-​risk group was that of hepatitis or prior liver com-
For epidemiological purposes, since there is no internationally plaints. Only one of the 152 identified C282Y homozygotes had
agreed case definition of haemochromatosis, caution is needed in signs and symptoms of adult haemochromatosis. This provoca-
interpreting claims that haemochromatosis is the most common tive report, indicating a very low clinical penetrance (<1%) of the
inherited disorder affecting European peoples. Phenotypic expres- haemochromatosis genotype in an unusual group of adults over
sion of the disease may range from the established clinical syn- the age of 26 years, raises important questions about the introduc-
drome (which includes cutaneous pigmentation, cardiomyopathy, tion of mass population screening for this potentially treatable iron
endocrine failure—​especially diabetes mellitus and hypogonadism, storage disease by genetic or even biochemical methods. However,
arthritis, and pigment cirrhosis) to a slight abnormality of blood the high prevalence of impotence, joint symptoms, chronic fatigue,
parameters that reflect iron loading—​elevated serum transferrin and other complaints such as cardiac arrhythmias in the study group
iron saturation and serum ferritin measurements. Such studies as a whole, raises disturbing questions about the valid application of
that are available to determine the penetrance and expressivity this report to other populations. It is perhaps not surprising that in
of the haemochromatosis gene have provided widely varying re- a group where, on average, more than 40% complained of a general
sults in different populations. In Australia, where the mean intake limitation of their health and/​or joint symptoms, and in which more
 12.7.1 Hereditary haemochromatosis 2103

than 35% of the male participants scored positively on symptom en- diabetes with iron loading in the liver and pancreas, as well as the
quiry about impotence, a significant contribution from predisposing generation of (renal) carcinomas. Injections of iron salts induce local
haemochromatosis alleles could not be identified. Nonetheless, this sarcomas in experimental animals, with evidence of species sus-
large study raises key questions about the utility of screening for ceptibility. In humans, sarcomas or carcinomas have arisen, albeit
adult haemochromatosis as a genetic disease. rarely, at sites of therapeutic injections of iron, and it is possible that
To provide evidence for screening in haemochromatosis, other the complications of silicosis and asbestos exposure result from the
population surveys which address the morbidity and mortality of complement of iron associated with these particulates. A wealth of
individuals harbouring disease alleles, have been attempted. For ex- indirect but corroborative evidence indicates that the primary effect
ample, the effects of iron storage in C282Y homozygotes were re- of excess free iron is to promote the formation of oxygen free rad-
ported in a comprehensive study of about 30 000 individuals aged icals, which mediate the damage to cells and tissues that is observed
between 40 and 69 years from Melbourne, Australia. Of 203 subjects in iron storage disease. In established haemochromatosis, the iron-​
found to be homozygous for the C282Y allele, ‘iron overload-​ binding capacity of plasma transferrin may be exceeded, so that a
related disease’ occurred in 28% of the men and 1.2% of the women. proportion of the iron present in the blood remains reactive as a low
Longitudinal studies have shown that iron overload in C282Y homo- molecular weight species only loosely attached to plasma proteins.
zygotes is not always progressive and indeed may recede in some Nontransferrin iron in human plasma stimulates the peroxidation of
cases. In the Melbourne study, follow-​up for an average of 11.4 years unsaturated lipids and can form reactive complexes that react with
showed that the hazard ratio for death from any cause was 1.04 (con- DNA, thus suggesting a mechanism for genome toxicity and car-
fidence limits 0.67–​1.62) in C282Y homozygotes compared with cinogenesis related to iron overload. Iron is highly electroreactive,
subjects who did not harbour any copy of this mutant HFE allele. and coupling of the Fenton and Haber–​Weiss reactions leads to the
Not all individuals with mild iron loading require treatment and formation of hydroxyl radicals as a result of the catalytic interactions
this clearly has implications for the introduction of mass population between superoxide and ferric ions. Tissues with significant iron
screening programmes for HFE-​related haemochromatosis. storage show peroxidative injury in membrane lipid fractions.
The lysosomal compartment appears to be particularly suscep-
tible to iron-​mediated damage, since iron in the form of ferritin
Aetiology, pathophysiology, and pathology and its degradation product haemosiderin accumulates within
lysosomes to form the particulate ferrugineous granules known as
Young patients with haemochromatosis absorb an increased amount siderosomes. In haemochromatosis, there is an increased activity
of dietary iron in their upper intestine compared with normal con- of lysosomal enzymes with biochemical evidence of increased lyso-
trol subjects. In established iron storage disease, iron absorption somal fragility indicating disruption of the integrity of the lysosomal
continues at a rate that is inappropriate for the level of iron stores, as membrane by iron. These changes revert to normal when the tissue
reflected by serum ferritin and tissue iron determinations. iron is removed by venesection or by the use of specific iron chela-
In the absence of an effective excretory pathway, the increased ab- tors. It seems likely that the electrochemical reactivity of iron, and
sorption of iron by the intestine leads to a progressive accumulation its particular propensity to accelerate the formation of oxygen free
of the metal in the parenchymal cells of the liver, heart, endocrine radicals, mediate its injurious effects on cell membranes, and on
glands, and specialized type B synoviocytes. Excess iron accumu- the nuclear genome, leading to cancerous change. However, des-
lates in the pancreas where it is found in both acinar and endocrine pite great advances in the understanding of free-​radical chemistry,
cells of the islet, although there is a particular predisposition in the the cause-​and-​effect relationship between iron storage and tissue
early phases of iron loading to the islet β-​cell. Iron also accumulates injury is difficult to prove unequivocally. Nonetheless, much ex-
to toxic levels in the gonadotrophs of the anterior pituitary gland, perimental evidence points to the development of iron-​mediated
leading to hypogonadotropic hypogonadism. Iron may accumulate peroxidative injury of cellular membranes including the lysosome,
in the adrenal gland, where it is concentrated particularly in those as well as iron-​mediated genotoxicity. Whatever their physiochem-
cells that secrete aldosterone, in the zona glomerulosa. Iron accumu- ical basis might be, common mechanisms of iron toxicity clearly
lates in the cardiac myocytes and conducting tissue of the heart, in the exist, since the pathological and clinical manifestations of all iron
chief cells of the parathyroid, and in parenchymal cells throughout storage syndromes, including secondary haemochromatosis associ-
the body. The consequences of toxic iron storage include diabetes ated with blood transfusion and the iron-​loading anaemias, are al-
mellitus, cirrhosis of the liver, cardiomyopathy with or without con- most identical.
duction defects, hypogonadism, arthritis with chondrocalcinosis,
adrenocortical deficiency, and, rarely, hypoparathyroidism. Evidence Iron absorption
for the intrinsic toxicity of iron in haemochromatosis is provided by In established haemochromatosis, where the burden of iron may
the regression of the pathological changes following measures taken increase body iron stores by at least 10-​fold, measurements usu-
to reduce iron, for example, the use of iron chelators and removal of ally show that iron absorption is within the normal range. Studies
body iron by venesection. Venesection stimulates the mobilization in young patients with rapidly progressive disease show a markedly
and removal of iron from the storage compartment by increasing the increased absorption of iron. After depletion therapy, the rate of re-
demand for red cell production in the bone marrow. covery of iron stores is greatly enhanced for many years in patients
with haemochromatosis, reflecting a persistent homeostatic abnor-
Mechanism of iron toxicity mality in the retention of dietary iron. The daily absorption of be-
High concentrations of iron salts are toxic to cultured cells. The ad- tween 2 and 4 mg of iron over a period of 30 to 40 years accounts
ministration of iron chelates to experimental animals has induced for the degree of iron loading that occurs at presentation in patients
2104 section 12 Metabolic disorders

with haemochromatosis, and compares with the normal absorption studies in experimental animals identified a cytochrome-​containing
of 0.8 to 1.0 mg in men and in women, up to 2 mg daily. In effect, the ferrireductase that is also localized to the intestinal brush-​border
abnormal absorption of iron represents a disturbed regulation of the membrane; this reductase was cloned from murine intestine and
final common pathway for the acquisition of iron from the environ- its human homologue subsequently identified. Expression of mu-
ment by the small intestinal mucosa. cosal ferrireductase is specific to the apical microvillous membrane
A report, describing the transplantation of intestine and liver from of mammalian intestinal mucosa and appears to be induced in re-
an HFE C282Y homozygote into a recipient without haemochroma- sponse to nutritional iron deficiency. Mucosal ferrireductase re-
tosis, supports the small intestine as a key site of expression of the duces ferric irons derived from the diet in the lumen for delivery to
hereditary defect in adult haemochromatosis. The transplantation the DMT1 carrier protein, the final divalent pathway for inorganic
was associated with early iron overloading in the recipient, together iron uptake by intestinal mucosa. The mRNA species encoding
with raised serum transferrin iron saturations—​a phenomenon not murine DMT1 exist in two isoforms, one of which contains an
observed in recipients of hepatic allografts obtained from donors iron-​response element in its 3′ region, which would allow for the
later found to be homozygous for C282Y. In addition to recent evi- post-​transcriptional regulation of protein expression controlled by
dence for a principal role of the key hepatic iron regulator hepcidin, intracellular iron status. A similar translational control of transferrin
prior studies in vitro and in vivo have suggested that there is a quali- receptor expression has been described with the 3′ iron-​response
tative abnormality of the uptake and transfer of iron from the intes- element in the mRNA encoding the human transferrin receptor.
tinal lumen in patients with hereditary haemochromatosis that may Since the isoform of DMT1 containing the iron-​response element
represent a local HFE-​dependent mechanism. Previous studies of is preferentially expressed in the duodenum, it seems likely that
mutant strains of mice with abnormalities of iron metabolism shed changes in intracellular iron status regulate the expression of this
light on the iron-​absorption mechanism. The identification of a carrier protein in iron deficiency and haemochromatosis. Studies
single gene encoding the divalent metal transporter protein, DMT1, in Hfe knockout mice indicate that the functional expression of the
which is expressed in the upper small intestine and cells of the DMT1 protein is enhanced in the murine model of haemochroma-
erythron, provided a molecular understanding of the iron deficiency tosis, leading to increased iron uptake across the brush-​border
and the microcytic anaemia that occurs in the mk/​mk mouse strain. membrane of iron presented in the ferrous form. The action of rate-​
A single point mutation in the DMT1 gene interferes with the uptake limiting ferrireductases at the brush-​border membrane functionally
of ferrous iron, since it disrupts the cognate transmembrane carrier coupled to DMT1 activity appears to explain the enhanced isotopic
protein mainly expressed in the mucosa of the proximal small in- uptake of ferric iron in this model of haemochromatosis.
testine, at the site of iron absorption, and in the erythroid precursor Delivery of iron from enterocytes to the systemic circulation
cells. Since in vitro studies of the expressed protein DMT1 show that is mediated by the basolaterally expressed membrane protein
it serves only as a carrier of divalent cations, and that interference ferroportin. Ferroxidases including hephaestin, encoded on the X
with this pathway is sufficient to induce iron deficiency in a mam- chromosome and mutated in the sex-​linked anaemic mouse sla, me-
malian species, ferrous iron uptake is probably the main pathway by diate the transfer of iron across the intestinal mucosa in conjunction
which inorganic iron is acquired by the intestine. with ferroportin. It seems likely that, in hereditary haemochroma-
A variable, but often substantial, component of dietary iron is pre- tosis and physiological iron deficiency, post-​transcriptional control
sent in the organic form as haem. A full molecular understanding of carrier proteins responsible for the uptake and transfer of iron
of the uptake and transfer pathways for the absorption of iron com- occurs in the absorptive epithelium on the tips of the intestinal villi.
plexes to the porphyrias is also needed. Whole-​body studies show Thus, homeostatic mechanisms in the proximal intestine operate
that the absorption of the radiolabelled iron moiety of haemoglobin to bring about the coordinated transfer of iron presented in the in-
is enhanced in patients with adult-​type haemochromatosis. Early testinal lumen specifically to meet body requirements. Although
studies in dogs have shown that, in the presence of proteolytic di- functional interactions of HFE molecules with the identified com-
gestion products of globin, the haem complex is taken up intact by ponents of the absorptive pathway have yet to be clarified, the HFE
mucosal epithelial cells; free iron is then released by the action of protein probably influences iron status in intestinal stem cells within
intracellular haem oxygenases. The contribution of haemoglobin, the crypt. By these means, the expression of key absorptive proteins
myoglobin, and cytochromes to the iron overload in patients with such as DMT1 may be imprinted, thus influencing their subsequent
haemochromatosis has not been quantified, but iron complexed functional activity during ascent up the villus. How the antimicro-
to haem may well represent an important component of the total bial peptide hepcidin interacts with this machinery is uncertain. It
burden of body iron in symptomatic haemochromatosis. Recent is proposed that hepcidin is a negative stimulator of intestinal iron
identification of a putative transporter of haem iron on the brush absorption and that hepatic synthesis increases in response to iron
border of mammalian duodenum is a key advance. Haem carrier overload and inflammation but decreases in the iron-​deficient state;
protein 1 (HCP1) is up-​regulated in response to iron deficiency and hepcidin acts as a ligand for ferroportin whereby binding is thought
hypoxia, but its contribution to the dysregulated absorption of iron to abrogate iron export into the circulation.
in hereditary haemochromatosis is unclear.
The discovery of DMT1 immediately indicated a possible Genetics and molecular biology
role for this important protein in human haemochromatosis. The principal determinant of adult haemochromatosis has long
Overexpression of DMT1 mRNA had been identified in the intestinal been known to be tightly linked to the human MHC loci on the
mucosa of patients homozygous for the C282Y mutation with her- short arm of chromosome 6. In 1996, mutations in the HLA class I-​
editary haemochromatosis, as well as in mice with iron storage dis- linked haemochromatosis gene, HFE, were shown to predispose
ease due to targeted disruption of the HFE gene. Contemporaneous to the adult form of the disease. The most common mutation in
 12.7.1 Hereditary haemochromatosis 2105

the nonclassical MHC class I HFE protein affects a key cysteine for this effect. An action of hepcidin as an effector molecule after
residue, which contributes to the formation of the conserved α-​ hepatic signalling is central to the current favoured model of iron
3 helix that interacts cotranslationally with the β2-​microglobulin homeostasis (Fig. 12.7.1.6), but how the crypt programming hy-
protein. This association is required for the cell surface expression pothesis aligns with this model is not readily explained. Recent
of all class I MHC molecules. Most patients with haemochroma- experiments are unravelling the detailed pathways that influence
tosis are thus homozygous for a cysteine to tyrosine mutation at hepcidin synthesis within hepatocytes. A number of cell surface
codon 282 (C282Y) of the nascent HFE protein. An increased fre- interactions result in downstream signalling of hepcidin synthesis
quency of this mutation, in association with the more common via SMAD complexes (Fig. 12.7.1.7). Experimental work is focusing
H63D missense mutation, also occurs in adult haemochromatosis on possible novel molecular therapies—​for example, interfering
(Fig. 12.7.1.5). A minor variant, affecting the same region in the RNAs targeting TMPRSS6 have been shown to ameliorate iron over-
α1 helix, S65C, is also occasionally associated with the C282Y al- load in mouse models of haemochromatosis by increasing hepcidin
lele in compound heterozygotes with adult iron storage disease and expression.
indeed a number of uncommon pathogenic variants in HFE have
since been reported. Pathology of iron storage
Apart from reducing cell surface expression of the mutant Heavy deposits of iron in the tissues are associated with fibrosis
C282Y polypeptide, and thus the abundance of this protein within and cell death. Simple inspection reveals an overt rust-​like discol-
a population of cytoplasmic vesicles, a functional explanation for ouration of the liver, spleen, pancreas, heart, and lymph nodes. The
the qualitative abnormality of iron metabolism that characterizes liver is usually enlarged and haemosiderin is found in all cell types
haemochromatosis remains putative. Structural studies have pro- with the formation of fibrous septa and hyperplastic nodules. These
vided a molecular basis for an interaction between HFE and trans- nodules, which may be the forerunners of hepatocellular carcin-
ferrin receptor proteins. HFE may bind transferrin receptors, alter omas, contain little stainable iron, unlike the adjacent parenchyma.
the affinity for the receptor to transferrin, and in turn affect the de- The dominant site of iron deposition during the early phases is
livery of transferrin-​bound iron into cells. This interaction may be within hepatocytes, but soon iron loading may be observed in all cell
more specific in the case of TFR2, expression of which is restricted types, including the lining cells of biliary canaliculi, Kupffer cells,
to locations such as the hepatocyte membrane; here, an iron-​sensing and stellate cells (Figs. 12.7.1.3 and 12.7.1.4).
role is postulated. Similarly, in the pancreas there is fibrosis and iron deposition in
The recently identified peptide hepcidin has become the focus of the acini, ducts, and islets of Langerhans. Staining with Perls’ reagent
attention as the potential circulatory signal for body iron status with reveals marked haemosiderin deposition in the exocrine and endo-
a key role in the disturbed iron homeostasis of hereditary haemo- crine glands, including many cell types in the testes. Haemosiderin is
chromatosis. Rather than the expected compensatory increase, also markedly increased in the chief cells of the parathyroid, the an-
hepcidin expression is paradoxically decreased and unresponsive in terior pituitary, the zona glomerulosa of the adrenal, and the thyroid.
haemochromatosis caused by mutations in HFE, TFR2, and HJV. In the joints, there is loss of the intra-​ articular space with
The proteins encoded by these genes are predominantly synthesized chondrocalcinosis and deposits of haemosiderin in the synovium.
within the liver. Given that these types of haemochromatosis are Electron microscopy shows selective deposits of ferritin and
qualitatively similar and differ mainly in severity, it has been ar- haemosiderin within type B synoviocytes. Radiological examin-
gued that these observations point to a common pathway in hep- ation of the joints shows collapse of articular surfaces, subchondral
atocytes which signals hepcidin production downstream. In support cyst formation, and prominent formation of periarticular osteo-
of this argument, the distribution of tissue iron in HFE-​related phytes. In the heart, pericardial constriction with fibrosis may
haemochromatosis can be altered after inducing experimental
overexpression of hepcidin.
Many recent studies suggest that hepcidin production in hep-
atocytes is linked to a haemojuvelin-​dependent signalling pathway
which is responsive to plasma iron saturations. Recent studies also
suggest an effector function of hepcidin, whereby direct interaction
with ferroportin at the cell surface results in its internalization and
degradation with consequent reduced export of iron from macro-
phages and enterocytes. SLC40A1 mutations appear either to abro-
gate iron export function or interfere with the ability of membranous
ferroportin to bind hepcidin; differential effects on cellular iron ex-
port correlate with what appear to be the two discrete phenotypes
observed in type 4 haemochromatosis. Serum hepcidin concentra-
tions appear to be increased in ferroportin iron overload as opposed
to other forms of haemochromatosis.
In summary, a reduction in circulating hepcidin as a consequence
of haemochromatosis gene defects, or directly as a result of HAMP
Fig. 12.7.1.3 Low-​power needle-​biopsy appearance of liver specimen
gene mutations, appears to enhance plasma iron and subsequent stained with haematoxylin and eosin from a 67-​year-​old man with adult
tissue loading; it has been proposed that attenuated inhibition of haemochromatosis due to homozygosity for the HFE C282Y mutation.
macrophage and enterocyte ferroportin activity is responsible Note the large hyperplastic nodules and fibrosis.
2106 section 12 Metabolic disorders

LIVER
Fe
Haemojuvelin
GUT
HFE

Hepcidin
TfR2
Fpn

Tf

MACROPHAGES

Fig. 12.7.1.4 High-​power micrograph of the liver biopsy specimen Fpn

shown in Fig. 12.7.1.3 stained with Perls’ reagent. Note the extensive
deposits of ferric iron in all cell types including Kupffer cells, cells lining Fig. 12.7.1.6 Molecular regulation of iron homeostasis. This is
small biliary radicles, and in a punctate distribution within parenchymal maintained by hepcidin, a peptide released by hepatocytes into the
hepatocytes. Liver cells are hyperplastic. circulation under stimulatory control of a common pathway involving
HFE, haemojuvelin, and transferrin receptor 2. Hepcidin normally inhibits
iron export from enterocytes and macrophages via its interaction with
occasionally be observed, but the principal abnormality is seen
ferroportin. Mutations in haemochromatosis genes reduce hepcidin
in the myocardium with degeneration and vacuolation of cardiac expression and allow excess iron to enter the plasma compartment and
myocytes and intermyocyte fibrosis that involves conducting tissue bind to transferrin with consequent tissue iron loading.
in the septa. Surviving myocytes show eosinophilic degeneration
and evidence of hypertrophy. Microscopical examination shows
that, in established cases of haemochromatosis, all tissues except
the choroid plexus are affected by the iron storage process. In the
past, it was considered that transfusional and other types of sec- IRON
BMP6
ondary iron storage disease predominantly affected the cells of TMPRSS6 Neogenin
sHJV
the mononuclear macrophage system, such as the Kupffer cells of TFR1
TWSG1
the liver, rather than the parenchymal cells. Iron deposits in the TFR2
? IL-6
Haemojuvelin
GDF15 BMP-R HFE

H63D
SMAD 1/5/8
1
S HEPATOCYTE
2
S MEMBRANE

NH2 HAMP (hepcidin)

transcription
NUCLEUS

S S Fig. 12.7.1.7 Molecular signalling of hepcidin synthesis in hepatocytes.

2-Microglobulin 3
( 2m) S S Iron stimulates the binding of bone morphogenetic protein 6 (BMP6)
C282Y to the membrane-​bound BMP receptor for which haemojuvelin is a
coreceptor. This in turn activates the phosphorylation of SMAD proteins
which translocate to the nucleus to promote transcription of the HAMP
gene and synthesis of pro-​hepcidin. The BMP pathway is also activated
by neogenin but inhibited by the TMPRSS6 gene product matriptase-​2,
Plasma soluble haemojuvelin (sHJV), and twisted gastrulation 1 (TWSG1). Growth
membrane
and differentiation factor 15 (GDF15) inhibits SMAD phosphorylation.
Cytosol
HFE and transferrin receptor 2 (TFR2) act as an iron sensors and stimulate
HOOC the BMP/​SMAD pathway through an as yet unknown mechanism,
although recent studies suggest an interaction with the BMP type 1
Fig. 12.7.1.5 Diagram of nonclassical MHC class I-​like HFE molecule receptor ALK3. IL-​6 stimulates hepcidin production during inflammation,
shown in juxtaposition with the β2-​microglobulin. The location of the two independently of iron status.
frequent amino acid substitutions (C282Y and H63D) that predispose to Figure adapted from Medicine, Vol 39/​10, W. J. H. Griffiths, Haemochromatosis,
the development of adult haemochromatosis is indicated by the arrows. pp. 597–​601, Copyright (2011), with permission from Elsevier.
 12.7.1 Hereditary haemochromatosis 2107

macrophage system may be less damaging than in other cell types,

but it is difficult at present to relate evidence of iron-​mediated in-
jury to its cellular distribution. Progressive tissue injury follows the
long-​term cumulative toxicity of iron storage and its consequen-
tial effects on organ structure and cellular function. A striking, but
unexplained, feature of iron storage disease in the liver and other
tissues is the absence of overt necrosis. In cancer cell biology, the
novel term ‘ferroptosis’ describes iron-​dependent death distinct
from apoptosis, necrosis, and autophagy.

Quantitative aspects of iron storage disease

Chemical determination of tissue iron content yields useful infor-
mation about the severity of iron loading in haemochromatosis. In
normal individuals, the total concentrations of liver iron do not ex-
ceed 0.15% by dry weight, but in established haemochromatosis, the
value is usually 1% or more. In severely affected patients with un- Fig. 12.7.1.8 Arthropathy in a man with adult haemochromatosis
treated hereditary haemochromatosis or secondary haemochroma- forced to stop manual work because of painful arthritis, especially in the
tosis, the amount of iron may exceed 5% of the dry weight of tissue. second and third metacarpophalangeal joints. Note the increased skin
pigmentation.
The overall burden of body iron in patients with haemochromatosis
is usually in excess of 5 g in hereditary disease, a figure that rises
with age. Estimates indicate that the total burden in patients with manifestation of the condition for many years. The arthritis typic-
advanced haemochromatosis can be as much as 40 to 60 g, most ally affects the second and third metacarpophalangeal joints of the
of this accumulating in the liver. The pancreas and other organs hands and feet (Fig. 12.7.1.8). These joints show painful swelling
such as the lymph, thyroid, pituitary, and salivary glands typically without obvious inflammatory changes. Distal interphalangeal joint
show an increase of more than 10 times the normal iron content. disease is also recorded and is usually considered to be typical of
Other methods of iron quantification, other than the crude estima- osteoarthritis. Many joints, including the wrist, elbow, shoulder,
tion offered by serum ferritin concentrations, include histochemical and knee, may be affected and the changes in these joints are typ-
iron grading using Perls’ reagent, MRI techniques, and quantitative ically associated with chondrocalcinosis that is detected radio-
phlebotomy. logically. The affected joints show loss of joint space, subchondral
cysts, and, especially in the digits, prominent osteophyte formation
(Fig. 12.7.1.9). Recent studies show that premature and disabling
Clinical features arthritis in the hip and other large joints is a characteristic feature
of haemochromatosis.
Adult haemochromatosis The symptoms of haemochromatosis are notoriously nonspecific
The clinical features of adult haemochromatosis include skin pig- and slow in their progression. Fatigue is often reported and may be
mentation. The pigment may be manifest as a generalized slate-​grey a manifestation of hypogonadism and the onset of diabetes mellitus.
coloration, due principally to melanin, or localized bronzed pig-
mentation particularly of the lower limbs, associated with iron de-
posits in adnexal dermal structures, as well as melanin. Histological
examination of the skin reveals increased melanocyte activity in
conjunction with iron deposits, particularly in cutaneous sweat and
apocrine glands. Increased skin pigmentation is a common, but not
invariable, manifestation of haemochromatosis. It increases as the
disease progresses and may be a late manifestation of the condition.
Absence of pigmentation should consequently never be regarded as
a contraindication to the diagnosis of iron storage disease.
Iron storage disease invariably affects the liver, which is usually
enlarged and may be cirrhotic, but portal hypertension and spleno-
megaly are rare end-​stage features of haemochromatosis. The enlarged
liver, even in the absence of cirrhosis, may contain single or multifocal
hepatocellular carcinomas. Hypogonadism is often present and is typ-
ically preceded by a long history of fatigue, sexual asthenia, and impo-
tence, as well as premature menopause and loss of libido in women. In
Fig. 12.7.1.9 Radiograph of hands in a 51-​year-​old woman with
men, there is gynaecomastia, circumoral vertical skin wrinkling, and
haemochromatotic arthropathy of the hands for many years. Note
loss of body hair; the genitalia show premature atrophy. the loss of joint space, especially in metacarpophalangeal joints with
Many patients with haemochromatosis suffer from arthritis subchondral cyst formation and osteophyte growth. Chondrocalcinosis is
at an early phase in the illness and this may indeed be the sole present in the ulnar fibrocartilage at the wrist.
2108 section 12 Metabolic disorders

Atrial fibrillation may be an early manifestation of cardiomyop- Given the genetic variants that are now recognized as causes of
athy. Later, paroxysmal arrhythmias and cardiac failure supervene, haemochromatosis, it is clear that if any doubt exists as to the diag-
leading to shortness of breath and fatigue. Occasional patients with nosis, or molecular analysis of the HFE gene or of non-​HFE iron
haemochromatosis present with isolated features, such as abnormal overload genes fails to identify known pathogenic mutations, then
liver-​related tests detected during a routine examination for health tissue diagnosis is indicated. This is usually carried out by liver bi-
insurance, or with arthralgia and signs of arthropathy in association opsy with histochemical determination, and preferably chemical
with diabetes, impaired libido, or sexual failure. Cardiomyopathy quantification, of tissue iron content. Although a liver biopsy is asso-
with heart failure or isolated arrhythmias is an unusual lone presen- ciated with small but definable risks, it does offer a key opportunity
tation of the disease. for the evaluation of liver structure and of the injury consequent
The differential diagnosis of haemochromatosis is very wide, upon iron deposition. The finding of cirrhotic change carries with
but the presence of diabetes with abnormal liver function or it a worse prognosis. Cirrhotic change is also a major predictor of
hepatomegaly, or an association with endocrine failure or the occurrence of hepatocellular carcinoma, which occurs rarely
arthropathy, should prompt consideration of iron storage dis- in noncirrhotic subjects with iron storage disease (Fig. 12.7.1.10).
ease. Likewise, the presence of seronegative polyarthropathy with For C282Y homozygotes, liver biopsy may be reserved for those
pigmentation, hepatomegaly, or any of the associated endocrino- at risk of significant liver fibrosis. When serum aminotransferase
logical changes should initiate immediate testing for evidence of values are normal, hepatomegaly is absent and the serum ferritin is
haemochromatosis. below 1000 µg/​litre, the risk of significant fibrosis is negligible. This
In young patients with hypogonadism or cardiomyopathy, iron validated tool applies also to asymptomatic individuals identified
storage disease should be considered. Juvenile haemochromatosis through family screening or routine blood testing. More recently,
is often neglected by endocrinologists investigating young patients transient elastography has been shown to reduce the requirement
for infantilism or hypogonadotropic hypogonadism. The condi- for biopsy in at-​risk patients and can accurately classify severe fi-
tion may be responsible for cases of undiagnosed seronegative brosis in around 60% of homozygotes with ferritin above 1000 µg/​
polyarthropathy. Haemochromatosis should be considered in any litre and raised transaminases.
patient with signs and symptoms of chronic liver disease, including Serum iron-​saturation determinations, and particularly serum
those with sustained mild elevation of serum transaminase activ- ferritin concentrations, may signify conditions other than iron
ities, particularly since the liver is affected early in the course of the storage disease. Serum ferritin is elevated in inflammatory states,
iron overload. in certain malignancies such as Hodgkin’s disease and in any condi-
In fully established cases, skin pigmentation which may be either tion associated with significant necrosis of parenchymal liver cells.
of a grey colour, as a result of increased melanin, or, especially on the Under these circumstances liver biopsy is recommended, since it
shins, a yellow-​brown bronze colour. Pigmentation in association is most likely to provide a definitive diagnosis of iron storage dis-
with diabetes with or without arthropathy and hepatomegaly almost ease. Sometimes, however, liver biopsy is not possible, either be-
always signifies established iron storage disease. cause the patient will not consent to it, or because of the presence
of ascites and a bleeding disorder, especially thrombocytopenia.
Under these circumstances, MRI of the liver can demonstrate iron
Diagnosis storage if moderate or severe. A reduced signal on T2-​weighted

It is critically important to establish a diagnosis of haemochroma-

tosis at the earliest opportunity. There is strong evidence that if treat-
ment to remove iron before established structural injury occurs, then
tissue function and symptoms improve. Several studies indicate that
removal of iron from patients diagnosed in the precirrhotic phase of
adult haemochromatosis is associated with a normal or near-​normal
life expectancy.

Laboratory investigations
In adult haemochromatosis, the diagnosis can be usually established
by demonstrating abnormalities of iron metabolism (fasting serum
transferrin saturation with iron >55% in males and 45% in females)
together with a measurement of serum ferritin concentration that
provides evidence of increased iron stores. Molecular analysis of the
HFE gene for homozygosity for the common (C282Y) predisposing
allele to the development of adult haemochromatosis may be very Fig. 12.7.1.10 Adult haemochromatosis. Section of liver lobe after
useful in patients of European ancestry. There is an increased fre- surgical resection to remove a primary hepatocellular carcinoma arising
in an iron-​loaded but, unusually, noncirrhotic liver in this disorder.
quency of compound heterozygotes for the C282Y/​H63D or, more
The patient, aged 62 years, had been partially treated by venesection
rarely, C282Y/​S65C genotypes in patients with evidence of iron but recently noticed increasing lethargy. A raised serum α-​fetoprotein
storage disease. For patients with elevated ferritin but normal or low concentration led to the diagnosis. Moderate histochemical evidence of
transferrin saturation, ferroportin disease should be considered. iron storage was found in the nonmalignant tissue excised at surgery.
 12.7.1 Hereditary haemochromatosis 2109

imaging correlates with significant iron deposition and a crude as- In first-​degree relatives, in whom molecular analysis of the HFE
sessment of hepatic iron concentration is possible with dedicated or non-​HFE iron overload genes indicates a genetic predisposition
data manipulation. to the disease, periodic re-​evaluation is needed by clinical and bio-
If a liver biopsy is not possible and MRI of the liver does not chemical testing at intervals of not more than 5 years. In members
reveal increased ferromagnetic signals indicative of iron storage, of families affected by haemochromatosis due to mutations in the
there are two further options: measurement of urinary iron excre- HFE or non-​HFE iron overload gene who were not found to carry
tion after parenteral administration of desferrioxamine, and, where the predisposing mutations and whose ferritin and iron parameters
the patient will tolerate it, quantitative phlebotomy. Injection of are normal, liver biopsy is not mandatory and the risk of the devel-
500 mg of desferrioxamine intramuscularly in a patient with iron opment of significant iron storage disease in less than 5 or 10 years
overload will usually induce the daily excretion of more than 2 mg is extremely low. In patients with no known pregenetic disposition
of iron as the ferrioxamine complex in the urine. Ferrioxamine and normal tissue biopsy findings, further follow-​up screening is
excretion may be increased in patients with haemolytic anaemia not indicated.
but, when elevated, is generally indicative of iron storage disease. From the foregoing it can be seen that there is an urgent need
Weekly phlebotomy of 500 ml will remove approximately 225 mg to characterize the genotype–​phenotype relationship in both HFE
of iron, and thus provides a means of estimating the amount of iron and non-​HFE haemochromatosis. Unfortunately, no genetic locus
removed from the storage compartment when undertaken to in- has yet been identified for neonatal haemochromatosis, although
duce a mild hypochromic anaemia of approximately 10.5 to 11.0 g this is a subject of continuing research. In at-​risk pregnancies, neo-
of haemoglobin/​dl or a serum ferritin concentration of less than natal haemochromatosis may be occasionally recognized by MRI
30 µg/​litre. Iron overload exists when the estimated iron removed during the third trimester, which may show increased iron signals
by this method exceeds 1.5 g. in the fetal liver. After birth, biopsy of the oral mucosa on the gums
or inner lip may reveal histological evidence of iron storage in minor
Diagnosis in family members salivary glands of affected infants.
The diagnosis of haemochromatosis, whether it be of the adult or
juvenile form, has immediate implications for that individual’s first-​ Environmental cofactors and disease expression
degree relatives. All forms of haemochromatosis have a strong her- Many patients with adult haemochromatosis give a history of exces-
editary basis and even some forms of neonatal haemochromatosis sive current or prior alcohol consumption. In the past, physicians
may, in some families, be inherited as an autosomal recessive trait. have been tempted to attribute evidence of excess tissue iron in these
A dominant transmission pattern has been established in the case of individuals solely to the consumption of alcohol. In practice, how-
type 4 haemochromatosis. ever, it appears that those individuals who have biopsy-​proven evi-
Although the penetrance and expressivity of homozygosity for dence of hepatic iron storage usually prove to carry two predisposing
the various alleles that predispose to haemochromatosis is not yet alleles of the HFE gene and therefore have true haemochromatosis.
established, the risks of the disease in first-​degree family members Although no clear predictors for the expression of disease in first-​
is sufficiently high to warrant systematic study. Clearly, the impli- degree relatives at risk are available, disease expression is reduced
cations for asymptomatic or undiagnosed relatives of the index in women of reproductive age. Most practising clinicians consider
case are potentially very large. Hence, considerable care and sensi- that age and alcohol consumption are the main identifiable environ-
tivity are needed in the means of informing them about the condi- mental factors that contribute to disease expression in predisposed
tion through the identified index case. In large families there may homozygotes. Other comorbid factors, including heritable factors,
be formidable difficulties, so that the help of genetic counselling that may influence the expression of HFE mutations in homozy-
services, as well as formal assistance from physicians practised in gous subjects, include the presence of adult coeliac disease. There
medical genetics, may be needed. There can be little doubt, however, are few data that define the relationship between haemochromatosis
that at-​risk relatives should be offered the opportunity for further and coeliac disease, but subclinical coeliac disease may ameliorate
diagnostic and clinical evaluation in relation to iron storage disease. the long-​standing effects of iron loading in C282Y homozygotes.
The condition is readily susceptible to iron depletion therapy in its Cosegregation of haemochromatosis and coeliac disease has re-
early stages. Moreover, there may be additional considerations for cently been reported in a large Swedish study. Discriminatory
patients who wish to make reproductive choices and who will need polymorphisms in genes which modulate oxidative stress and other
to be reassured that appropriate testing can be carried out on their fibrogenic cytokine responses have been postulated as influencing
future offspring. expression of haemochromatosis in C282Y homozygotes. Recently,
In HFE haemochromatosis, molecular analysis of the HFE gene discrete genome-​wide association studies in HFE haemochroma-
may assist in assessing the risk of disease, particularly in asymptom- tosis have identified the transferrin gene as a significant modifier
atic siblings. Phenotypic screening, however, is useful at the level of iron status and proprotein convertase subtilisin/​kexin type 7
of clinical evaluation for evidence of liver disease, hypogonadism, (PCSK7) as a host risk factor for liver cirrhosis. The A736V TMPRSS6
arthritis, pigmentation, and diabetes. Determining the biochemical polymorphism may also influence the clinical expression of HFE
phenotype first involves assay of the serum parameters of disordered haemochromatosis as may a variant in the glyceronephosphate O-​
iron metabolism. Since the serum parameters may be abnormal be- acyltransferase (GNPAT) gene.
fore iron-​mediated tissue injury has occurred, liver biopsy should be The identification, since HFE, of several genes associated with
considered particularly if the serum ferritin is greater than 1000 µg/​ haemochromatosis has provided some insight into the pheno-
ml or the serum transaminases are raised. typic variation of primary iron overload. The phenotype of type 4
2110 section 12 Metabolic disorders

haemochromatosis certainly appears distinct. It is now apparent, how- access site. Where blood transfusion services can assume some, if
ever, that individuals with juvenile mutations may present later and not all, responsibility for the phlebotomy of haemochromatosis pa-
with milder disease than described historically for juvenile haemo- tients, the inconvenience of hospital-​based services can be circum-
chromatosis patients. Those with TFR2 mutations have occasionally vented and blood supplies can be enhanced safely.
presented young with a severe iron overload phenotype more rem- Not all patients require immediate treatment but it is vital to inter-
iniscent of juvenile haemochromatosis. Iron overload with varying vene if ferritin concentrations are above or approaching 1000 µg/​
severity has been accounted for by compound heterozygous forms of litre. Some patients will be at lower risk of morbidity and mortality,
HFE and juvenile mutations, termed digenic inheritance. Moreover, typically those presenting with lower iron indices, in older age or
C282Y homozygotes with the most severe iron overload may carry those who are female. Such patients could be observed initially or
an additional juvenile mutation to account for increased disease ex- indeed recommended to undergo blood donation with monitoring
pression. The classical haemochromatosis phenotypes overlap and if otherwise eligible. Of note, since October 2012 the National Blood
combinations of genetic alteration contribute to a spectrum of disease. Service in England and Wales has accepted selected haemochroma-
tosis patients for donation at up to 6-​week intervals. An Australian
study in homozygotes with ferritin concentrations of between 300
Management and 1000 µg/​litre comparing iron reduction with sham treatment is
currently underway.
Since it is the toxicity of iron that is responsible for the manifest-
ations of all forms of haemochromatosis, treatment is directed to the Duration of venesection therapy
removal of iron at the earliest possible stage. One 500 ml unit of peripheral blood contains approximately
225 mg of elemental iron. Thus most patients with established
Venesection haemochromatosis will require weekly phlebotomy for a period
In adult and juvenile haemochromatosis, the preferred method of of 1 to 2 years. The objective of this treatment is to restore serum
treatment is iron depletion by means of phlebotomy. This is best ferritin concentrations to within the low normal range and, if pos-
instituted by the removal of approximately 500 ml of venous blood sible, to induce a mild iron deficiency anaemia of approximately
each week by needle puncture of peripheral veins in the antecubital 11.5 g haemoglobin/​dl. Having thus achieved a satisfactory deple-
fossa. In young patients, it may be possible to increase the frequency tion of body iron stores, interval maintenance phlebotomy, carried
of venesection to twice per week after several once-​weekly proced- out according to ferritin measurements, four to six times per year
ures. In elderly patients and those with hypoalbuminaemia as well is usually sufficient to maintain normal iron stores with a serum
as end-​organ failure and heart disease, the frequency of venesection ferritin concentration less than 100 µg/​litre. Some authorities sug-
should be commuted to within the rate tolerated. Coincidental in- gest that serum ferritin values below 30 µg/​litre should ideally be
flammatory disease may impede the erythropoietin-​mediated drive achieved. In patients with juvenile haemochromatosis, who have
to haemopoiesis, and, particularly in the early phases of treatment, a higher than normal intestinal iron absorption, more frequent
mild haemorrhagic anaemia may ensure. Thus, adjustments need to phlebotomy may be needed to maintain a healthy iron balance.
be made according to the early responses to venesection therapy, Proton pump inhibitors appear to significantly reduce the need for
and regular monitoring of the haemoglobin concentration or haem- venesection, by reducing iron absorption through alkalization of
atocrit is advisable. the stomach, although currently are not recommended for this sole
Difficulties may arise in delivering this deceptively simple treat- purpose.
ment as a result of poor organization of health service provision
and of unavailability of suitable healthcare personnel to carry out Iron chelation therapy
the venesection procedure. Every practical effort should be made Alternative methods of iron removal are needed for patients with
to ensure that the procedure is convenient for the patient, who is severe clinical manifestations of haemochromatosis, such as life-​
often a young or middle-​aged person in full-​time employment, and threatening cardiac arrhythmias and those with severe liver dis-
who may find regular access to the treatment centre problematic. In ease and hypoalbuminaemia, who are incapable of withstanding
cold weather, or in patients with poor circulation or inconspicuous frequent phlebotomy. The preferred alternative involves chelation
superficial venous access, the use of topical local anaesthetics such as therapy with the parenteral agent desferrioxamine. As indicated in
lidocaine cream or even local diffusable preparations of glyceryl tri- Chapter 22.6.4, the subcutaneous administration of desferrioxamine
nitrate, applied 30 to 60 min before the venesection procedure, may brings about the removal of a maximum of 20 to 25 mg of iron daily
greatly improve venous access. Likewise, the simple technique of and is thus generally less efficient than vigorous weekly phlebotomy.
immersing the arm in warm water to improve peripheral blood flow However, desferrioxamine may gain access to cellular pools of iron
may be critical for establishing confidence in treatment staff. Since that are important in the pathogenesis of tissue injury in established
patients with haemochromatosis usually harbour a large burden of iron storage disease, and therefore may offer particular benefit in pa-
iron, requiring repeated phlebotomy over a period of several years, tients critically ill with arrhythmias due to haemochromatotic car-
every effort should be made to preserve the integrity of their per- diomyopathy. Although the nature of this so-​called chelatable iron
ipheral veins. In the authors’ view, the use of a local anaesthetic is pool is unknown, there is strong circumstantial evidence that its
usually unwarranted since it involves further tissue invasion in the depletion by means of intravenous desferrioxamine treatment may
region of the antecubital fossa with needles. Moreover, repeated in- reverse the life-​threatening consequences of terminal iron storage
jections of the irritant fluid often lead to sclerosis around the venous disease in patients with haemochromatosis. Moreover, the removal
 12.7.1 Hereditary haemochromatosis 2111

of 140 mg of chelatable iron per week represents about two-​thirds of subsequent maintenance of normal iron homeostasis. Most patients
the amount that can be removed by weekly phlebotomy. A biological experience an improvement in well-​being on iron depletion therapy
advantage may also be gained by therapeutic access to a reactive, low and, during its early phases, there is evidence that hypogonadotropic
molecular weight, chelatable fraction responsible for the injurious hypogonadism may improve with this therapy. Similarly, the mani-
effects of cellular iron overload. festations of cardiomyopathy with intractable cardiac failure or
Parenteral desferrioxamine may be given intravenously for life-​ tachyarrhythmias can improve after the removal of iron.
threatening cardiac disease, as described in Chapter 22.6.4, or, in The cirrhosis of haemochromatosis appears not to be reversible,
the nonemergent situation, by subcutaneous infusion using portable although the earlier precirrhotic manifestations of hepatic disease
infusion pumps for 12 to 14 h, five or six times per week. It must be improve greatly on the removal of iron with an apparent restoration
stressed, however, that chelation therapy is not the preferred option of normal life expectancy. Indeed, there is mounting evidence that
for the treatment of established haemochromatosis and should be re- hepatic fibrosis, short of cirrhosis, can reverse following iron deple-
stricted to those patients unable to tolerate phlebotomy as a result of tion. In all patients, there is at least a twofold increase in the survival
anaemia or hypoalbuminaemia, or in whom life-​threatening cardio- rate at 5 years from the point of diagnosis with the introduction of
myopathy or liver disease is present. Newer oral iron chelators with phlebotomy. In patients studied during the 1950s and 1960s, the
promising safety profiles are becoming established for secondary 5-​year survival rate improved from 18% to more than 65% in all
iron overload. One such chelator, deferasirox, has been shown to be haemochromatosis subjects treated.
efficacious in an early phase study in genetic haemochromatosis, re- In patients diagnosed with haemochromatosis but without cir-
peated in a further phase II study published very recently. rhosis, iron depletion therapy is associated with a near normal or
normal life expectancy compared with a sex-​and age-​matched con-
General measures trol cohort derived from the same population. It is notable, however,
Attention should be given in patients with haemochromatosis to that the indolent nature of this storage disorder and the long-​term
the diagnosis and treatment of end-​organ failure. This particu- survival of patients who are affected by it has, so far, rendered long-​
larly applies to the management of diabetes mellitus by diet and term controlled studies of the effects of phlebotomy on eventual out-
insulin where necessary, as well as hormone replacement therapy come almost impossible to achieve. However, a wealth of evidence,
for hypogonadism (see Chapter 13.6.2). In men, intramuscular based on the understanding of the pathogenesis and documented
depot injections of testosterone enantate (250 mg every 2–​3 weeks) responses to iron depletion in individual patient cohorts, indicates
are recommended to improve libido and inhibit the development that early removal of iron is highly desirable—​indeed, it may be de-
of premature osteoporosis. Similarly, conventional sex hormone cisive in determining a good outcome from all forms of human iron
replacement therapy should be used in women with premature storage disease, including all subtypes of hereditary haemochroma-
gonadal failure as a result of haemochromatosis. Cardiac failure tosis so far established.
in patients with haemochromatosis due to cardiomyopathy and Hepatocellular carcinoma occurs mostly in patients with iron
hepatic failure consequential upon pigmentary cirrhosis should storage disease who have established cirrhosis and the risk appears to
be treated by standard methods. Organ transplantation may be persist despite removal of iron. Although hepatocellular carcinoma
used successfully, but correction of systemic iron overload should and cholangiocarcinoma have been reported in noncirrhotic pa-
be undertaken as soon as practicable to restore normal function tients with haemochromatosis, these are rare phenomena. Systematic
in all organ systems. Rarely, end-​organ hormone deficiencies re- ultrasonographic surveillance is vital if liver cancer is to be detected
sult from thyroid infiltration and parathyroid and adrenocortical at a stage where potentially curative treatment can be offered. Since
disease. These deficiencies should be vigorously sought for in the all the evidence suggests that patients with haemochromatosis are
clinical evaluation of the patient at presentation. The appearance more likely to have diabetes mellitus and other manifestations of the
of lethargy, faintness due to postural hypotension, or symptomatic disease, every encouragement should be given to the prompt diag-
hypocalcaemia demands immediate investigation and institution nosis of the condition and early institution of iron depletion therapy.
of appropriate replacement therapy. Patients with cirrhosis should Increasingly, it has been recognized that the arthropathy of haemo-
undergo 6-​monthly surveillance by ultrasonographic examination chromatosis can be disabling, whether or not it is associated simply
and α-​fetoprotein estimation for early detection of hepatocellular with joint pain (arthralgia) or progressive and noninflammatory
carcinoma. joint destruction. The disease is associated with a loss of cartilage
and, in many large joints, chondrocalcinosis. Although the re-
sponse of the arthropathy to iron depletion therapy is controver-
Prognosis sial, the weight of observation indicates that, once established, the
arthropathy of haemochromatosis progresses independently of
The main causes of death in untreated patients with haemo- body iron status and of iron depletion treatment. It seems intrin-
chromatosis are hepatocellular failure, primary carcinoma of sically likely that effective removal of excess body iron stores before
the liver (including hepatocellular carcinoma), and, rarely, the development of joint symptoms will prevent their onset and pro-
cholangiocarcinomas. Cardiac failure due to haemochromatotic gression. However, at present only cross-​sectional data are available
cardiomyopathy and untreated diabetes also contribute to death. to support this contention.
Although not categorically proven, evidence from retrospective In summary, observations in adult haemochromatosis suggest
surveys suggest that life expectancy is improved by removing iron that once the disease is established in association with cirrhosis or
from patients with haemochromatosis of whatever cause and the diabetes mellitus, it diminishes life expectancy. In fact, a more recent
2112 section 12 Metabolic disorders

study demonstrated that among treated C282Y homozygotes those abnormal biochemical genotype, the manifestations of the clinical
with serum ferritin levels greater than 1000 µg/​litre at diagnosis had disease are variable and protean. Moreover, as pointed out earlier,
a fivefold relative risk of death. The prognosis for cardiomyopathy no internationally agreed case definition of haemochromatosis
in juvenile haemochromatosis is very poor but it may be improved exists, which creates additional difficulties for the introduction of
by early diagnosis and the early institution of vigorous iron deple- public health measures and appropriate policy review of nationwide
tion therapy. In several cases, the outcome has been improved by screening procedures.
allogeneic cardiac transplantation. In adult patients with established
pigment cirrhosis, hepatic transplantation has been undertaken
and, provided the other systemic manifestations of haemochroma- Future directions
tosis have been adequately treated, the procedure is associated with
a good overall prognosis. Although startling progress has been made in the discovery of
many components that serve to regulate iron homeostasis in hu-
mans, more information is needed before a full molecular under-
Prevention and control standing of the mechanisms of iron homeostasis can be achieved.
The genetic basis of some neonatal and further variant forms of
The importance of early recognition and the institution of iron de- adult haemochromatosis has yet to be fully explored. The inter-
pletion therapy in all forms of haemochromatosis cannot be over- actions between iron regulatory molecules on the hepatocyte
emphasized. Molecular analysis of the HFE gene, together with membrane are not fully resolved but this interplay and the asso-
biochemical characterization using serum transferrin iron satur- ciated downstream signalling pathway for hepcidin appear key
ation estimations and serum ferritin concentrations, has the power to body iron homeostasis—​thus a promising target for future
to assist greatly in the detection of presymptomatic first-​degree rela- therapeutic intervention. A challenging task will be the detailed
tives of patients with haemochromatosis. understanding of how environmental cofactors determine the ex-
In relation to whole populations in which mutations in the HFE pression of iron storage disease in genetically predisposed indi-
gene are frequent, the health implications based on mass screening viduals. Alcohol is a long-​standing candidate, but the mechanism
remain contentious. Superficially, adult hereditary haemochroma- by which it leads to increased delivery of toxic iron to the tissues
tosis due to mutations in the HFE gene appears to be an ideal con- is, at present, poorly understood. Recognizing genetic modifiers
dition for DNA-​based mass population screening. The condition of disease expression may, in future, inform natural history and
is attributable to a single gene, and a single mutation of diagnostic treatment decisions in asymptomatic individuals at risk from iron
significance is prevalent (gene frequency 5–​10%). Disease-​related storage disease. Greater understanding of these issues and of pene-
mutations in HFE (especially C282Y) are easily tested for by means trance in particular populations will determine local screening
of techniques based on the polymerase chain reaction. At the same practices for disease prevention.
time, HFE-​ mediated haemochromatosis has a long incubation
period without symptoms, and all the evidence suggests that the in-
stitution of treatment for presymptomatic disease is cheap, simple, Newly identified iron storage diseases
and effective.
On the other hand, genetic identification of at-​risk individuals By general agreement, the term haemochromatosis is used to de-
is associated with problems of stigmatization, increased anxiety, scribe systemic syndromes of pathological iron storage that affect
and potential life insurance weighting, all of which are familiar many tissues and disturb the function of diverse organ systems.
aspects in well-​rehearsed debates about genetic testing in the gen- Conversely, several distinct clinical syndromes of local iron tox-
eral population. These aspects must be considered, together with icity have been identified, especially in the eye and brain. Although
the age-​related penetrance of the homozygous state for HFE C282Y these syndromes are individually rare, they are important because
variants and, as yet, unknown combined genetic and environmental they are potentially accessible to measures that reduce cellular free
influences on disease expression. Uncertainty as to the significance iron (e.g. metal chelation, mentioned earlier), and because they
of these factors has held back the introduction of mass population demonstrate the central importance of metabolic iron in selected
screening by DNA-​based methods. In light of the present state of tissues. A fuller understanding of these disorders, and the cognate
knowledge, it is clear that homozygosity for the C282Y allele of HFE cell metabolic pathways they affect, may well shed light on ill-​
cannot be considered to be tantamount to a diagnosis of hereditary understood aspects of tissue iron physiology. Additional informa-
haemochromatosis. tion is available by reference to the OMIM website at http://​www.
More information is needed from outbred populations, rather ncbi.nlm.nih.gov/​omim.
than from homozygotes identified as a result of screening family
members of index cases having full-​blown clinical disease. Family Hereditary hyperferritinaemia cataract syndrome
studies provide a false measure of disease expressivity, presumably (OMIM 600886)
as a result of shared environments and of the cosegregation of po- The sole clinical manifestation of this condition is of congenital
tential disease-​modifying genes within defined pedigrees. Finally, it bilateral ferrugineous nuclear cataracts due to the disposition of
must be emphasized that difficulties also occur for the evaluation excess ferritin light chain polypeptide in the ocular lenses. The
of the burden of haemochromatosis in the population at large. serum ferritin concentrations are moderately elevated but no evi-
Although there are definitions of iron storage disease that reflect the dence of systemic iron storage is found. The disorder is caused
 12.7.1 Hereditary haemochromatosis 2113

by mutations in the 5′ noncoding iron-​response element of the or indeed parenteral chelation therapy with desferrioxamine or
ferritin light-​chain (FTL) gene that leads to unregulated transla- trientine, especially in the early evolution of the neurological syn-
tional overexpression of ferritin light chains. These polypeptides drome, has not yet been established. The interplay between copper
accumulate in the lenses and disturb their tissue organization and and iron metabolism is well illustrated by this severely disabling
refractile properties. The hyperferritinaemia cataract syndrome illness. Acaeruloplasminaemia illustrates the particular sensitivity
is, as expected for an overexpression disease, inherited as a dom- of the basal ganglia to disturbances of iron metabolism. In this con-
inant trait. Measurement of serum ferritin concentrations may text, it is notable that caeruloplasmin expression is abundant in glia
identify at-​risk family members. The gene encoding ferritin light in the brain microvasculature juxtaposed to the pigment-​containing
chain polypeptide maps to chromosome 19q3.3-​qter. Latterly, a dopaminergic neurones of the substantia nigra and inner layer of
syndrome without cataracts has been identified due to mutations the retina.
in exon 1 of the FTL gene—​this forms an important differential
in individuals with unexplained hyperferritinaemia with normal Hallervorden–​Spatz disease: pantothenate kinase-​
transferrin saturation. associated neurodegeneration (OMIM 234200)
This disease has been familiar to neurologists and neuropatholo-
Adult-​onset basal ganglia disease (OMIM 606159) gists since its original description by two, now discredited, German
A single pedigree has been identified with a dominantly inherited neuroscientists of the Nazi period. The clinical features indicate
disorder showing features of late-​onset extrapyramidal dysfunction basal ganglia disease and dementia with retinal degeneration
resembling parkinsonism or Huntington’s disease. Imaging and aut- leading to optic atrophy. The disorder often presents with club foot
opsy studies revealed cavitation of the basal ganglia with deposition deformity in children and adolescents; extrapyramidal rigidity pre-
of iron and ferritin protein in adjacent tissue, especially in the pu- ceded by choreoathetosis usually follows rapidly. Dementia, optic
tamen and the globus pallidus. The macroscopic appearances showed atrophy, and generalized seizures occur in the later stages, and
widespread reddish discolouration of affected tissues. This disorder death usually ensues by the age of 30 years. Although late-​onset
was mapped to chromosome 19q13.3 and a single mutation, a point forms of the disease are known, a striking feature is the presence of
insertion of a single adenine at nucleotide 461, was identified in iron pigment in the basal ganglia and substantia nigra, now easily
exon 4 of the FTL gene. The mutation is predicted to disrupt the C-​ recognized by MRI. The heredofamilial nature of this syndrome
terminal sequence of the ferritin light-​chain molecule and disturb has been known since its first description. Hallervorden–​Spatz dis-
the iron-​binding core of the hetero-​or homomeric protein. Serum ease is now known to be an autosomal recessive trait due to mu-
ferritin concentrations were found to be abnormally low in affected tations in the pantothenate kinase 2 gene (PANK2) that maps to
heterozygotes. Although this disorder has so far only been identified chromosome 20p13.
in a single large pedigree, it further illustrates the importance of fer- Pantothenate kinase 2 is abundant in the retina and target regions
ritin in tissue iron metabolism and, especially, in selective regions of of the brain and regulates the formation of coenzyme A. Deficiency
the brain. This disorder has been termed a ‘neuroferritinopathy’ and of pantothenate kinase 2 would deplete sensitive neural tissues with
may be the first of several diseases affecting cellular iron pathways in a high metabolic rate of coenzyme A; the defect may also lead to a
iron-​rich brain tissue. consequential accumulation of cysteine, which normally condenses
with the enzyme product, phosphopantothenate. In the presence
Acaeruloplasminaemia with iron deposition of high concentrations of free iron, excess cysteine may accelerate
(haemosiderosis) in basal ganglia (OMIM 277900) the formation of cytotoxic oxygen free radicals. For some years,
This disorder is associated with mild systemic iron deposition and cysteine accumulation has been independently observed in the
deficiency of the plasma copper-​binding protein, caeruloplasmin. iron-​rich nigrostriatal regions of the brain affected by this disorder.
Caeruloplasmin has long been known to possess ferroxidase activity Identification of PANK2 mutations offers the hope of improved diag-
and the ability to enhance the mobilization and delivery of iron to nosis of this neurodegenerative disorder, and, more importantly,
and from macrophages and hepatocytes. It promotes iron loading the prospect of specific therapy using supplementation to enhance
of intact ferritin micelles. Acaeruloplasminaemia, due to mutations local coenzyme A activity and phosphopantothenate concentra-
in the gene encoding caeruloplasmin on chromosome 3q21–​24, is an tions in affected neural tissue. Latterly, the term ‘neurodegeneration
autosomal recessive trait. The deficiency is associated with diabetes with brain iron accumulation’ (NBIA) has been coined to encom-
mellitus, dementia, and extrapyramidal features including parkin- pass several inherited neurological disorders with basal ganglia
sonism, with choreoathetosis as well as cerebellar ataxia. MRI shows involvement—​nine genes have thus far been implicated including
altered signals in the basal ganglia, and retinal degeneration may PANK2 and FTL. The accelerated interest in this field is leading to
be apparent by fundoscopy. Excess systemic iron is demonstrable trials of iron chelation in Parkinson’s disease.
by examination of liver tissue and the serum ferritin concentra-
tion is moderately elevated; however, low serum iron transferrin
saturations with hypochromic microcytic anaemia, reminiscent of Further practical information
copper deficiency, are usually present.
Infusions of plasma or purified caeruloplasmin may correct the Many patients’ associations and societies exist to serve the needs of
systemic abnormalities of iron metabolism, but probably do not patients in their respective countries. In the United Kingdom, useful
influence the dementia or the other neurological deficits, at least information can be obtained from The Haemochromatosis Society,
once these are established. The role of caeruloplasmin replacement Haemochromatosis UK, PO Box 6356, Rugby, CV21 9PA.
2114 section 12 Metabolic disorders

Haemochromatosis UK is a working name of The Haemo­

Kelly AL, et al. (2001). Classification and genetic features of neonatal
chromatosis Society (a registered charity). Office: office@huk.org.uk;
haemochromatosis: a study of twenty-​seven affected pedigrees and
Helpline:helpline@huk.org.uk; Telephone: +44 (0)3030401102. molecular analysis of genes implicated in iron metabolism. J Med
The society’s website (http://​www.haemochromatosis.org.uk) in- Genet, 38, 599–​10.
cludes links to similar societies in other parts of the world. Le Gac G, et al. (2004). The recently identified type 2A juvenile haemo-
chromatosis gene (HJV), a second candidate modifier of the C282Y
homozygous phenotype. Hum Mol Genet, 13, 1913–​18.
Legros L, et al. (2015). Non-​invasive assessment of liver fibrosis
FURTHER READING
in C282Y homozygous HFE hemochromatosis. Liver Int, 35,
Adams P, et al. (2009). Screening for iron overload: lessons from the 1731–​8.
HEmochromatosis and IRon Overload Screening (HEIRS) Study. McCance RA, Widdowson EM (1937). Absorption and excretion of
Can J Gastroenterol, 23, 769–​72. iron. Lancet, 233, 680–​4.
Adams PC, Speechley M, Kertesz AE (1991). Long-​term survival McKie AT, et al. (2000). A novel duodenal iron-​regulated transporter,
analysis in hereditary haemochromatosis. Gastroenterology, 101, IREG1, implicated in baso-​lateral transfer of iron to the circulation.
368–​72. Mol Cell, 5, 299–​309.
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 12.7.2 Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease 2115

to the liver where it is avidly removed from the circulation. The liver
12.7.2 Inherited diseases of copper utilizes some copper for metabolic needs, synthesizes and secretes
the copper containing the protein caeruloplasmin, and excretes ex-
metabolism: Wilson’​s disease and cess copper into the bile (Fig. 12.7.2.1).

Menkes’​ disease
Michael L. Schilsky and Pramod K. Mistry Wilson’s disease (OMIM 277900)

Introduction and historical perspective

ESSENTIALS Wilson’s disease (hepatolenticular degeneration) was first described
Copper is an essential metal that is an important cofactor for many in detail in 1912 by Kinnear Wilson as progressive lenticular de-
proteins and enzymes. Two related genetic defects in copper trans- generation, a familial, lethal neurological disease accompanied by
port have been described, each with distinct phenotypes. chronic liver disease leading to cirrhosis. Over the next few decades,
the role of copper in pathogenesis was established, and the pattern of
Wilson’s disease inheritance was determined to be autosomal recessive.
An uncommon disorder (1 in 30 000) caused by autosomal re- Wilson’s disease was uniformly fatal until treatments were devel-
cessive loss-​of-​function mutations in a metal-​transporting P-​type oped just over half a century ago, when it became one of the first
ATPase (ATP7B) that result in defective copper excretion into bile liver diseases for which effective pharmacological treatment was
and hence copper toxicity. Typical presentation is in the second and identified. The first chelating agent, introduced in 1951 for the treat-
third decade of life with liver disease (ranging from asymptomatic ment of Wilson’s disease, was the intramuscularly administered
to acute fulminant hepatic failure or chronic end-​stage liver dis- compound British Anti-​ Lewisite (BAL or dimercaptopropanol).
ease) or neurological or psychiatric disorder (dystonia, dysarthria, The identification and testing of an orally administered chelator,
parkinsonian tremor, movement disorder, a spectrum of psychiatric d-​penicillamine, by John Walsh in 1956 revolutionized treatment.
ailments). While no single biochemical test or clinical finding is suf- Other treatment modalities have since been introduced, including
ficient for establishing the diagnosis, typical findings include low the use of zinc salts to block enteral copper absorption, trientine
serum caeruloplasmin, high urinary copper excretion, and elevated and tetrathiomolybdate to chelate copper, and liver transplantation,
liver copper content. Corneal Kayser–​Fleischer rings may be seen. which may be life-​saving and curative because the liver is the pri-
Treatment is with copper chelating agents and zinc. Liver transplant- mary site of the metabolic disorder.
ation is required for fulminant hepatic failure and decompensated
liver disease unresponsive to medical therapy. Genetic defect
Menkes’ disease In 1993, the gene defect in Wilson’s disease was identified. The ATP7B
gene encodes a metal-​transporting P-​type ATPase, which is expressed
A rare disorder (1 in 300 000) caused by X-​linked loss-​of-​function
mainly in hepatocytes and functions in the transmembrane transport of
mutations in a P-​type ATPase homologous to ATP7B (ATP7A) that
copper. The absent or reduced function of ATP7B protein leads to im-
result in defective copper transport across intestine, placenta, and
paired excretion of excess copper into the bile, leading to copper accu-
brain and hence cellular copper deficiency. Clinical presentation is
mulation and toxicity. Eventually copper is released into the bloodstream
in infancy with facial dimorphism, connective tissue disorder, hypo-
and deposited in extrahepatic tissues. Failure to incorporate copper into
pigmentation, abnormal hair, seizures, and failure to thrive, usually
caeruloplasmin is an additional consequence of the loss of functional
followed by death by age 3 years (although some variants with a
ATP7B protein. Caeruloplasmin devoid of copper, apocaeruloplasmin,
milder phenotype result from milder mutations, e.g. occipital horn
has a short half-​life, which causes decreased plasma levels found in most
syndrome). Treatment, which is only effective when presymptomatic
patients with Wilson’s disease (Fig. 12.7.2.1).
diagnosis is made in a sibling after florid presentation in a previous
Wilson’s disease occurs worldwide with an average incidence
affected sibling, is with intravenous copper histidine.
of approximately 30 per million. The carrier frequency is approxi-
mately 1 in 90. However, a recent study of the frequency of ATP7B
mutations in the United Kingdom suggested that this established
Introduction figure may underestimate the frequency of affected individuals and
carriers, and estimated a disease incidence of 1:8000.
Copper is an essential metal that is an important cofactor for many
proteins and copper-​containing enzymes involved in cellular res- Clinical features
piration, antioxidant defence, pigment production, neurotrans- There is protean phenotypic presentation comprising various com-
mitter formation, connective tissue synthesis, and iron homeostasis. binations of liver disease, progressive neurological disorder, and
Therefore, in states of impaired copper homeostasis resulting in psychiatric disorder. Presentation with liver disease occurs more
copper excess or copper deficiency, tissue injury and organ dysfunc- frequently in children and younger adult patients than in older
tion ensue. The average diet provides substantial amounts of copper, adults. Overt liver disease is the most common presenting feature
typically between 2 and 5 mg/​day, most of which is eventually ex- in childhood with the most common age of presentation between
creted in the bile and then in the stool. Copper is absorbed by en- 10 and 13 years, but manifestations may be present as early as age 3
terocytes mainly in the duodenum and proximal small intestine and to 5 years in rare individuals. In contrast, neurological disease oc-
transported in the portal circulation bound to albumin and histidine curs as the initial presenting feature in adults, usually in the third
2116 section 12 Metabolic disorders

Hepatocyte Cu-albumin Enterocyte Cu

caeruloplasmin
hCTR hCTR
basolateral membrane apical membrane
Endosome ATP7B Cu Cu
Cu
Lysosome +Cu
ATOX1 ATOX1
−Cu +Cu Golgi
Cu

Trans Golgi Cu CPN Cu

bile Cu bile Trans Golgi
Golgi

+Cu −Cu
Cu-GSH Cu
cMOAT

canalicular hCTR basolateral

membrane membrane hCTR

ATP7B Cu ATP7A

Fig. 12.7.2.1 Cellular copper trafficking in the hepatocyte and enterocyte depicting the contrasting metabolic defects in Wilson’s disease and
Menkes’ disease. ATP7B is the major copper transporter in the hepatocyte, and ATP7A fulfils this role in the enterocyte. Copper gains access to both
cell types via copper transporter 1, hCTR, and is delivered by the copper chaperone ATOX1 to ATP7B and APT7A, respectively, residing in the trans-​
Golgi network. Increasing cell copper content is associated with trafficking of ATP7B towards the apical canalicular membrane and copper excretion
in bile in the hepatocyte. In contrast, in the enterocyte, increasing dietary copper leads to net absorption of copper via the basolateral surface. While
significant amounts of ATP7B expression are relatively restricted to hepatocytes and a few other cell types, ATP7A expression is more ubiquitous
except that it is minimally expressed in the liver. In the other cells that express ATP7A, the basolateral presence of ATP7A when copper is abundant,
and this protein’s copper transport activity, result in the cellular excretion of excess copper. In the kidney, ATP7A and ATP7B are active in copper
reabsorption or excretion from the body.

or fourth decade of life. This sequence reflects the natural history hepatomegaly, to acute fulminant hepatic failure or chronic end-​
of primary hepatic involvement followed by neurological and other stage liver disease. Children may be entirely asymptomatic, with
extrahepatic organ dysfunction. Symptoms at any age can be non- hepatomegaly or abnormal serum aminotransferases found only in-
specific and there is considerable overlap between distinct hepatic cidentally. Some patients may have a brief clinical illness resembling
and neurological presentations frequently cited in the literature. an acute viral hepatitis or mononucleosis, and others may present
A patient presenting with liver disease aged between 5 and with features indistinguishable from autoimmune hepatitis. Some
40 years with decreased serum caeruloplasmin and detectable may present with only biochemical abnormalities or histological
Kayser–​Fleischer rings represents the classic form of Wilson’s dis- findings of steatosis on liver biopsy and many others with signs of
ease. However, about one-​half of patients presenting with liver dis- chronic liver disease with advancing fibrosis and inflammation and
ease do not possess two of these three criteria and pose a challenge evidence of compensated or decompensated cirrhosis. Patients may
in trying to establish the diagnosis. Moreover, as with other liver dis- present with isolated splenomegaly due to clinically unapparent cir-
eases, patients may not come to medical attention when their clin- rhosis and portal hypertension.
ical disease is comparatively mild. Wilson’s disease may also present as acute fulminant hepatic
Even when presymptomatic siblings are excluded, the age at which failure with an associated Coombs’-​negative haemolytic anaemia
Wilson’s disease may present is both younger and older than generally and acute kidney injury. Some patients have transient episodes of
appreciated, though most present between the ages of 5 and 35 years. jaundice, due to haemolysis. Low-​grade haemolysis may be associ-
Wilson’s disease is increasingly diagnosed in children younger than ated with Wilson’s disease when liver disease is not clinically evident.
5 years old, with atypical findings in children under 2 years old that
include cirrhosis in a 3-​year-​old and fulminant hepatic failure in a Neurological presentations
5-​year-​old. The oldest patients diagnosed with Wilson’s disease were Neurological manifestations of Wilson’s disease typically present later
in their early 70s. With new molecular testing capabilities, testing for than the liver disease, most often in the third decade of life. However,
Wilson’s disease can be performed even in utero or in newborns, and earlier subtle findings may appear in paediatric patients, including
cases are now being diagnosed earlier than ever before. changes in behaviour, deterioration in school work or the inability to
perform activities requiring good hand–​eye coordination. Patient may
Liver presentations exhibit small handwriting as in Parkinson’s disease (micrographia).
The diversity of liver disease encountered in patients with Wilson’s Other common findings in those presenting with neurological dis-
disease is summarized in Table 12.7.2.1. ease include tremor, lack of motor coordination, drooling, dysarthria,
Wilson’s disease should be considered in the differential diag- dystonia, and spasticity or athetosis. Because of pseudobulbar palsy,
nosis of patients with unexplained liver disease and when neuro- transfer dysphagia may also occur, with a risk of aspiration if severe.
logical and/​or psychiatric symptoms occur concurrently with liver Dysautonomia may be present, but usually in concert with other
disease. Liver involvement can range from asymptomatic, with neurological findings. Migraine headaches and insomnia may be re-
only biochemical abnormalities or an isolated clinical finding of ported, but seizures are infrequent. Along with behavioural changes,
 12.7.2 Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease 2117

Table 12.7.2.1 Clinical patterns of hepatic, neurological, and

psychiatric disease in patients with Wilson’s disease

Hepatic Asymptomatic hepatomegaly

Isolated splenomegaly
Persistently elevated serum aminotransferase activity
(AST, ALT)
Fatty liver
Acute hepatitis
Resembling autoimmune hepatitis
Cirrhosis—​compensated or decompensated
Fulminant hepatic failure Fig. 12.7.2.2 Florid Kayser–​Fleischer ring in a patient with Wilson’s
Neurological Movement disorders (tremor, involuntary movements)
disease.
Courtesy of Dr Susan Hall Forster, Yale School of Medicine.
Drooling, dysarthria
Rigid dystonia findings in a medically treated patient in whom these had previously
Pseudobulbar palsy disappeared suggests noncompliance with therapy.
Dysautonomia
Diagnostic testing
Migraine headaches
A diagnosis of Wilson’s disease should be considered in any patient with
Insomnia
unexplained liver disease, especially if associated with neurological and
Seizures psychiatric disease; patients with acute fulminant liver failure, especially
Psychiatric Depression if haemolysis is present; and first-​degree relatives of affected patients.
Neurotic behaviours No single biochemical test or clinical finding is sufficient to establish
Personality changes the diagnosis. A combination of clinical and biochemical evaluation is
necessary to make the diagnosis, and this has led to the use of a scoring
Psychosis
system that uses these findings and tests to determine the probability of
Other systems Renal abnormalities: aminoaciduria and nephrolithiasis
establishing a diagnosis of Wilson’s disease (Leipzig criteria).
Skeletal abnormalities: premature osteoporosis and
arthritis Biochemical liver tests
Cardiomyopathy, dysrhythmias Serum aminotransferase activities are generally abnormal in Wilson’s
Pancreatitis disease except at a very early age. In many patients, the degree of ele-
Hypoparathyroidism vation of aminotransferase activity may be mild compared to other
Menstrual irregularities; infertility, repeated miscarriages liver injuries and does not reflect the severity of the liver disease.
Measures of liver synthetic function such as coagulation factors and
proteins such as albumin may be reduced significantly in such cases.
other psychiatric manifestations include depression, anxiety, and even
frank psychosis. Many but not all individuals with neurological or Caeruloplasmin
psychiatric manifestations may have cirrhosis, but frequently they are Caeruloplasmin is a 132-​kDa protein synthesized mainly in the
not symptomatic from their liver disease. liver and is also an acute phase reactant. The vast majority of
caeruloplasmin is secreted into the circulation from hepatocytes
Eye manifestations as a copper-​carrying protein containing six copper atoms per mol-
Kayser–​ Fleischer rings represent deposition of copper in the ecule (holocaeruloplasmin), and the remainder as the protein lacking
Descemet’s membrane of the cornea (Fig. 12.7.2.2). When they copper (apocaeruloplasmin). Caeruloplasmin is the major carrier for
are visible by direct inspection, they appear as a band of golden-​ copper in the blood, accounting for 90% of the circulating copper in
brownish pigment near the limbus. A slit-​lamp examination by an normal individuals. It is also a ferroxidase and a nitric oxide oxidase, so
experienced observer is required to identify Kayser–​Fleischer rings it influences nitric oxide homeostasis. Levels of serum caeruloplasmin
in most patients. Rarely, they may be found in patients with chronic may be measured enzymatically by their copper-​dependent oxidase
cholestatic diseases and in children with neonatal cholestasis; how- activity towards these substrates, or by antibody-​dependent assays.
ever, these disorders can usually be distinguished from Wilson’s dis- Results generally are regarded as equivalent, but it should be noted
ease on clinical grounds or on histology. Kayser–​Fleischer rings are that immunological assays routinely in clinical use may overestimate
present in approximately 95% of patients with a neurological presen- caeruloplasmin concentrations since they do not discriminate be-
tation but in only approximately 40 to 50% of patients with predom- tween apocaeruloplasmin and holocaeruloplasmin.
inant hepatic disease at the time of diagnosis. A serum caeruloplasmin level of less than 200 mg/​L (<20 mg/​dl,
Sunflower cataracts, also found by slit lamp examination but with a although the lower level of the normal range can vary between la-
lower frequency, represent deposits of copper in the lens. These typic- boratories) is considered consistent with Wilson’s disease. Low
ally do not obstruct vision, and—​along with Kayser–​Fleischer rings—​ caeruloplasmin levels are found in approximately 95% of cases.
will gradually disappear with effective medical treatment or following However, serum caeruloplasmin alone as a screening test for Wilson’s
liver transplant. Reappearance of either of these ophthalmological disease in patients referred with liver disease has a low positive
2118 section 12 Metabolic disorders

predictive value (approximately 6%), although the very lowest values Detection of copper in hepatocytes by orcein or rhodanine staining
have a slightly higher predictive value than levels near or at the lowest is highly variable. In extreme cases, nodules lacking histochemically
limit of normal. Moreover, a low caeruloplasmin level is found in detectable copper are found next to cirrhotic nodules with abundant
20% of healthy heterozygote carriers of Wilson’s disease, and in other copper, and negative histochemistry for copper does not exclude the
disorders including protein-​losing states (gut and kidney), poor diagnosis. Electron microscopy reveals characteristic mitochondrial
hepatocellular synthetic function, and in another genetic disorder abnormalities, dilated cristae and crystalline deposits, in hepatocytes
where the caeruloplasmin gene is affected, acaeruloplasminaemia. in the early phase of the disease (when steatosis is evident).

Serum copper Neurological findings and radiological imaging of the brain

Although a disease of copper overload, the total serum copper in Neurological disease may manifest with parkinsonian features of
Wilson’s disease is usually decreased in proportion to the decreased dystonia, hypertonia, and rigidity, with tremors and dysarthria.
caeruloplasmin in the circulation. In patients with severe liver injury, Muscle spasms, which can lead to contractures, dysarthria, dys-
serum copper may be within the normal range or even elevated des- phonia, and dysphagia can be incapacitating. Movement disorder
pite a decreased serum caeruloplasmin level. In the setting of acute may be present as well. At this stage of the disease, MRI or CT scan-
fulminant hepatic failure due to Wilson’s disease, levels of serum ning of the brain may detect structural abnormalities in the basal
copper may be markedly elevated due to the sudden release of the ganglia. Most frequently found are increased density on CT and
metal from tissue stores. Normal or elevated serum copper levels in hyperintensity on T2-​weighted MRI in the region of the basal gan-
the face of decreased levels of caeruloplasmin indicate an increase in glia, but other regions of the brain may be involved.
circulating ‘free’ or noncaeruloplasmin-​bound copper.
Genetic studies
Urinary copper excretion
ATP7B mutation analysis can be difficult because of the multiplicity
The amount of copper excreted in the urine in a 24-​h period, which of mutations, the occurrence of mutations in noncoding sequences,
reflects the amount of noncaeruloplasmin copper in circulation, and the large size of the gene that spans around 80 kb. Pedigree ana-
may be helpful for diagnosing Wilson’s disease and for monitoring lysis using haplotypes of polymorphisms flanking the Wilson’s dis-
treatment. Basal measurements can provide useful diagnostic infor- ease gene can be used but it is mostly replaced by methods relying on
mation so long as copper does not contaminate the collection ap- high-​throughput sequencing. Most patients are compound heterozy-
paratus (this is less problematic with current plastic disposables) gotes. Currently, over 500 mutations of ATP7B have been identified.
and the urine collection is complete. Basal 24-​h urinary excretion of Mutation analysis is an especially valuable diagnostic strategy
copper in Wilson’s disease is typically more than 100 µg (1.6 µmoles) for certain well-​defined populations harbouring prevalent ATP7B
in symptomatic patients, but a level above 40 µg (>0.6 µmoles) may mutations. Populations with a single predominant mutation in-
indicate Wilson’s disease and requires further investigation. clude those of Iceland, Japan, Korea, Sardinia, Spain and the Canary
Liver copper concentration Islands, and Taiwan. Certain populations in Eastern Europe also
show predominance of the H1069Q mutation, accounting for nearly
Liver copper content of more than 250 µg/​g dry weight provides crit- 40% of disease alleles. Genotype–​phenotype correlation is imperfect
ical diagnostic information and should be obtained in cases where the as in most other inherited metabolic diseases of the liver, indicating
diagnosis is not straightforward and in younger patients. In untreated an important role for modifier genes and environmental factors in
patients, normal hepatic copper content (<40–​50 µg/​g dry weight) the determination of phenotypic characteristics. However, a large
almost always excludes a diagnosis of Wilson’s disease. Further diag- multinational study and a meta-​analysis suggest that homozygosity
nostic testing is indicated for patients with intermediate copper con- for the H1069Q mutation is associated with neurological presenta-
centrations (70–​250 µg/​g dry weight), especially if there is active liver tion in adults. The H1060Q Wilson ATPase resides in a highly con-
disease or other symptoms of Wilson’s disease. The major problem with served sequence in the cytoplasmic loop, SEHPL, and appears to
attempting diagnosis based on hepatic parenchymal copper concentra- result in defective trafficking of the mutant protein.
tion is that in the later stages of Wilson’s disease distribution of copper
within the liver is often inhomogeneous. Furthermore, copper con- Diagnostic considerations in specific target populations
centrations may seem falsely low in those with significant amounts of Liver diseases which mimic Wilson’s disease
fibrosis in the biopsy, and—​since this is a weight-​based measurement—​
the error is potentially greater in smaller specimens. Patients with Wilson’s disease, especially younger ones, may have clin-
ical features and histological findings on liver biopsy indistinguishable
Liver biopsy findings from autoimmune hepatitis. All children with apparent autoimmune
The earliest histological abnormalities in the liver include hepatitis and any adult patient with the presumptive diagnosis of
microvesicular and macrovesicular steatosis, glycogenated nu- autoimmune hepatitis failing to respond appropriately to cortico-
clei, and focal hepatocellular necrosis. The liver biopsy may show steroids must be evaluated for Wilson’s disease. Hepatic steatosis in
classic histological features of autoimmune hepatitis. With pro- Wilson’s disease is rarely as severe as in nonalcoholic fatty liver dis-
gressive parenchymal damage, fibrosis and subsequently cirrhosis ease. Nevertheless, occasional patients with Wilson’s disease closely
develops and is frequently found in most patients by the second resemble nonalcoholic fatty liver disease or have both diseases.
decade of life. Cirrhosis is usually macronodular, although occa-
sionally micronodular. In the setting of fulminant hepatic failure, Acute fulminant liver failure
there is marked hepatocellular degeneration, hepatocytes apoptosis, A high level of clinical suspicion is essential because transplant re-
and parenchymal collapse, typically on the background of cirrhosis. ferral is required given the poor prognosis for medical management
 12.7.2 Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease 2119

of these patients, and there are disease-​specific management and and should be used as primary screening tool, especially for sibling
family screening that should follow. Most patients with the ful- screening once the proband is identified. Treatment should be initi-
minant hepatic failure presentation of Wilson’s disease have a char- ated for all individuals over 3 years old identified as patients by family
acteristic pattern of clinical findings: screening, and individualized for younger patients.
• Coombs’-​ negative haemolytic anaemia with features of acute
Perspective on diagnosis
intravascular haemolysis
• Coagulopathy unresponsive to parenteral vitamin K administration Over the years, diagnostic advances have enabled a more system-
• Rapid progression to renal failure atic evaluation of individuals suspected to have Wilson’s disease, and
unlike the early description by Wilson, many patients are now diag-
• Relatively modest rises in serum aminotransferases (typically
nosed before they develop neurological symptoms. These include
<2000 IU/​litre) from the beginning of clinical illness
the recognition of corneal Kayser–​Fleischer rings, 50% of patients
• Normal or markedly subnormal serum alkaline phosphatase (typ-
with hepatic presentations, and 98% of those with neurological or
ically <40 IU/​litre) with alkaline phosphatase to bilirubin ratio of
psychiatric presentation of disease. Molecular diagnostic studies
less than 4:1.
have made it feasible to identify presymptomatic and symptomatic
• AST-​to-​ALT ratio of greater than 2:1. individuals by analysing for disease-​specific mutations of the ATP7B
• Female-​to-​male ratio of greater than 2:1. gene. However, since de novo genetic diagnosis is currently expen-
Serum caeruloplasmin is usually decreased, but the predictive sive, not universally available, and (most importantly) sometimes
value of this test in the setting of acute liver failure is poor. Serum inconclusive, a combination of clinical findings and biochemical
copper and 24-​h urinary excretion of copper are greatly elevated. testing is still necessary to establish the diagnosis of Wilson’s disease.
The serum copper is usually greater than 200 µg/​dl (31.5 µmol/​litre).
Kayser–​Fleischer rings may be identified to support the diagnosis Treatment
of Wilson’s disease but are absent in approximately 50% of these pa- In general, the approach to treatment is dependent upon whether
tients. Expeditious diagnosis is critically important since, without there is active disease or symptoms, whether neurological, psychiatric,
timely liver transplantation, death is almost inevitable. Management or hepatic, or whether the patient is identified prior to the onset of
of these patients awaiting transplantation includes measures to sup- clinical symptoms. This distinction helps in determining the choice of
port their liver injury and specifically is geared to reduce the removal therapy and the dosages of medications utilized. The recommended
of the excess circulating copper to prevent further liver and renal initial treatment of symptomatic patients or those with active disease
injury, reduce haemolysis, and help stabilize the patient. is with chelating agents. The largest treatment experience worldwide is
with penicillamine; however, there is more frequent consideration of
Family screening trientine for primary therapy. Combination therapy, in which zinc is
First-​degree relatives of any patient newly diagnosed with Wilson’s utilized in conjunction with a chelating agent (temporally separated),
disease must be screened. Assessment should include serum copper, has a theoretical basis in both blocking copper uptake and eliminating
caeruloplasmin, liver function tests, slit-​lamp examination of the eyes excess copper. Past studies of the use of tetrathiomolybdate as an alter-
for Kayser–​Fleischer rings, and basal 24-​h urinary copper. Individuals native chelating agent for the initial treatment of neurological Wilson’s
without Kayser–​Fleischer rings who have subnormal caeruloplasmin disease suggest that this drug may be useful as initial therapy for pa-
and abnormal liver tests undergo liver biopsy to confirm the diag- tients presenting with neurological symptoms, and newer studies are
nosis. Molecular analysis of the ATP7B gene is increasingly available underway to revisit this treatment (Table 12.7.2.2).

Table 12.7.2.2 Pharmacological treatments of Wilson’s disease

Drug/​dose in adults Mode of action Neurological deterioration Side effects Comments

Penicillamine 750–​1500 mg in General chelator 10–​20% during the initial Fever, rash, proteinuria, lupus-​like Reduce dose for surgery to
2 or 3 divided doses; requires Induces cupruria phase of treatment reaction promote wound healing
supplemental pyridoxine Aplastic anaemia and during pregnancy to
Leucopenia reduce teratogenicity
Thrombocytopenia
Nephrotic syndrome
Degenerative changes in skin;
Elastosis perforans serpiginosa
Serous retinitis
Hepatotoxicity
Colitis (rare)
Trientine 750–​1500 mg in 2 or General chelator 10–​15% during the initial Gastritis; aplastic anaemia rare Reduce dose for surgery to
3 divided doses Induces cupruria phase of treatment Sideroblastic anaemia promote wound healing
Colitis (rare) and during pregnancy
Zinc 75–​150 mg in 3 divided Metallothionein inducer Can occur during the initial Gastritis; biochemical pancreatitis; No dosage reduction for
doses Blocks intestinal phase of treatment; infrequent zinc accumulation; possible changes surgery or pregnancy
absorption of copper hepatic decompensation in immune function
Tetrathio-​molybdate 120 mg Chelator Reports of rare neurological Anaemia; neutropenia Experimental in the United
in 6 divided doses (with meals Blocks copper deterioration during the initial Hepatotoxicity States of America and
and apart from meals) absorption treatment Europe
2120 section 12 Metabolic disorders

Once the disease symptoms or biochemical abnormalities have by the large size of ATP7A (150 kb) and diversity of mutation types,
stabilized, typically in 2 to 6 months after the initiation of therapy, including large deletions and chromosomal rearrangements.
a reduced dosage of chelators or zinc therapy can be used for main- A useful test for neonatal diagnosis of Menkes’ disease has been
tenance treatment. Patients presenting without symptoms may be developed involving the measurement of serum neurotransmitter
treated with either maintenance dosages of a chelating agent or with levels. Dopamine-​β-​hydroxylase converts dopamine to noradren-
zinc from the outset. Failure to comply with lifelong therapy has led aline and these transmitters in turn can be further metabolized to
to recurrent symptoms and liver failure, the latter requiring liver dihydroxyphenylacetic acid to dihydroxyphenylglycol, respectively.
transplant for survival. Monitoring of therapy includes monitoring In Menkes’ disease, deficiency of dopamine-​β-​hydroxylase (an en-
for compliance as well as for potential treatment-​induced side effects. zyme that depends on copper for its activity) leads to a high ratio
of dopamine to noradrenaline as well as of dihydroxyphenylacetic
Liver transplantation acid to dihydroxyphenylglycol. These characteristic abnormal-
Liver transplantation is the only effective option for those with ities can be used to identify presymptomatic disease, allowing pre-​
Wilson’s disease who present with acute fulminant hepatic failure emptive therapy with copper histidine and resulting in delay in the
and is indicated for all Wilson’s disease patients with decompensated development of typical neurodegeneration and other changes, but
liver disease unresponsive to medical therapy. In acute fulminant most often not the arrest of the disease. Trials of gene therapy are in
liver failure due to Wilson’s disease, interventions to rapidly reduce development.
elevated free circulating copper may reduce secondary organ injury Occipital horn syndrome is a milder allelic variant of Menkes’ dis-
while the patient awaits a suitable organ donor. Liver transplantation ease that may present later in life without the same neurodegenerative
corrects the hepatic metabolic defects of Wilson’s disease and over changes observed in the typical early presentation described
time reverses extrahepatic copper disposition. Living donor liver preiously. Clinical features include skeletal deformity (including
transplantation has been successfully performed for Wilson’s dis- exostoses of the occipital bone—​the ‘horns’), looseness of the skin,
ease, including the use of donor livers from heterozygote carriers for and joint laxity, features which previously led the condition to be
Wilson’s disease. One-​year survival following liver transplantation considered a variant of Ehlers–​Danlos syndrome.
ranges from 79 to 87%, and those who survive this early period con-
tinue to survive long term.
A liver transplant is not recommended as the primary treatment FURTHER READING
for neurological Wilson’s disease since the liver disease is stabilized Bandmann O, Weiss KH, Kaler SG (2015). Wilson’s disease and other
by medical therapy in most of these individuals and outcomes with neurological copper disorders. Lancet Neurol, 14, 103–​13.
a liver transplant in the setting of advanced neurological disease are Beinhardt S, et al. (2014). Long-​term outcomes of patients with Wilson
not always beneficial. disease in a large Austrian cohort. Clin Gastroenterol Hepatol,
12, 683–​9.
Coffey AJ, et al. (2013). A genetic study of Wilson’s disease in the
Menkes’ disease (OMIM 309400) United Kingdom. Brain, 136, 1476–​87.
Ferenci P. (2014). Phenotype-​genotype correlations in patients with
Menkes’ disease is an X-​linked recessive neurodegenerative disorder Wilson’s disease. Ann N Y Acad Sci, 1315, 1–​5.
presenting in infancy due to mutations in the ATP7A gene, which Ferenci P, et al. (2012). EASL Clinical Practice Guidelines: Wilson’s
disease. European Association for Study of Liver. J Hepatol, 56,
encodes a P-​type ATPase homologous to ATP7B (Fig. 12.7.2.1). The
671–​85.
pathology and disease manifestations reflect decreased activities
Guillaud O, et al. (2014). Long term results of liver transplantation
of enzymes that require copper as a cofactor, such as dopamine-​β-​ for Wilson’s disease: experience in France. J Hepatol, 60, 579–​89.
hydroxylase, cytochrome c oxidase, and lysyl oxidase. Kaler SG (2011). ATP7A-​related copper transport diseases-​emerging
Affected infants appear healthy at birth but by the age of approxi- concepts and future trends. Nat Rev Neurol, 7, 15–​29.
mately 2 months develop hypotonia, seizures, skin and joint laxity, Kaler SG, et al. (2008). Neonatal diagnosis and treatment of Menkes
hair twisting (pili torti), and failure to thrive, usually followed by disease. N Engl J Med, 358, 605–​14.
death by 3 years of age from end-​stage neurodegenerative disease. Lorincz MT (2018). Wilson disease and related copper disorders.
Treatment with daily injections of copper histidine may im- Handb Clin Neurol, 147, 279–​92.
prove the outcome if started presymptomatically soon after birth. Lutsenko S (2014). Modifying factors and phenotypic diversity in
However, newborn screening is not routinely available and early Wilson’s disease. Ann N Y Acad Sci, 1315, 56–​63.
detection is difficult because clinical abnormalities in affected new- Roberts EA, Schilsky ML, American Association for Study of Liver
borns are absent or subtle, hence this type of pre-​emptive treatment Diseases (2008). Diagnosis and treatment of Wilson disease: an up-
is only possible when presymptomatic diagnosis is made in a sibling date. Hepatology, 47, 2089–​111.
Schilsky ML (2017). Wilson disease: diagnosis, treatment and follow-​
after florid presentation in a previous affected child.
up. Clin Liver Dis, 21, 755–​67.
The usual biochemical markers, low serum copper and caerulo­
Zimbrean PC, Schilsky ML (2014). Psychiatric aspects of Wilson dis-
plasmin, are unreliable in the neonatal period. Molecular diagnosis ease: a review. Gen Hosp Psychiatry, 36, 53–​62
is the preferred option when available, but this is rendered difficult
12.8
Lysosomal disease
Patrick B. Deegan and Timothy M. Cox

ESSENTIALS essential. Diagnosis is confirmed by biochemical methods including

examination of urine metabolites or specific enzymatic assays on
Lysosomal function and classification of diseases leucocytes or cultured fibroblasts, histochemical stains of existing bi-
The lysosome is a ubiquitous, single membrane-​bound intracellular opsy material, and/​or next-​generation DNA sequencing studies.
organelle which continuously recycles biological macromolecules: it
Particular lysosomal diseases
not only breaks down cell components but has a dynamic role in nu-
trient and energy sensing that, through regulatory signalling, is critical Fabry’s and Gaucher’s diseases (glycosphingolipidoses) are prob-
for homeostasis and metabolic economy of the cell. ably the most frequent in the general population, but certain lyso-
More than 80 lysosomal diseases caused by single gene defects somal diseases are over-​represented in particular groups where
are known. These are classified according to the nature of the pri- consanguinity or endogamy is high (e.g. the high frequency of
mary storage molecules (biochemical classification) or according to non-​neuronopathic Gaucher’s disease, infantile and late-​onset Tay–​
the defective molecular cell physiology (functional classification), or Sachs disease (GM2 gangliosidosis), and Niemann–​Pick disease type
(more usefully) a combination of these classification systems that in- A (neuronopathic) in Ashkenazi Jews).
corporates genetic information. Fabry’s disease—​an X-​ linked disorder caused by deficiency of
Biochemical classification identifies (1) sphingolipidoses; α-​galactosidase A, which leads to the accumulation of globo­
(2) mucopolysaccharidoses; (3) glycoproteinoses; (4) glycogenosis, triaosylceramide (Gb3), typically manifests in early childhood with
with or without lysosomal debris derived from subcellular organ- lancinating pain and background burning sensations in the extrem-
elles due to impaired autophagy; and (5) miscellaneous condi- ities. Other features include diarrhoea, lack of peripheral sweating,
tions with multiple classes of storage material such as the neuronal impotence, high-​ tone deafness, angiokeratomas, chronic kidney
ceroid lipofuscinoses. Functional classification describes deficiency disease, hypertrophic cardiomyopathy, and stroke. Enzyme therapy
of (1) a specific acid hydrolase activity, (2) an activator protein, with recombinant human α-​galactosidase A is very costly but im-
(3) a lysosomal membrane protein or transporter, or (4) abnormal proves neuropathic pain and cardiac hypertrophy.
post-​translational modification of lysosomal proteins, and (5) ab- Gaucher’s disease is ​an autosomal recessive trait caused by func-
normal biogenesis of lysosomes. A unified classification will emerge tional deficiency of acid glucocerebrosidase. Characteristic manifest-
from genetic characterization integrated with clinicopathological ations of the most frequent form—​‘adult non-​neuronopathic’ (type
manifestations of the individual disorders. 1)—​include pancytopenia, splenic enlargement, and bone pain with
osteoporosis and episodic osteonecrosis. Parenteral administration
Clinical features and diagnosis of enzyme therapy with imiglucerase (Cerezyme), velaglucerase
About one in 5000 live-​born infants have a lysosomal disorder. alfa (VPRIV), taliglucerase alfa (Elelyso) or oral substrate reduction
Clinically diverse, the lysosomal diseases can appear at any age but therapy with miglustat (Zavesca) or eliglustat (Cerdelga) is extremely
are very rarely present at birth. Diagnosis is usually suspected on the expensive but clinically effective.
basis of key clinical presentations of progressive neurodegenerative Other diseases discussed in this chapter include (1) cystinosis,
disease, often combined with visceral enlargement (especially (2) the mucopolysaccharidoses, (3) Pompe’s disease (glycogen
splenomegaly), connective tissue and skeletal disease, or particular storage disease type II), (4) Niemann–​Pick diseases, (5) lysosomal acid
syndromic appearances. lipase deficiency, (6) Danon’s disease, and (7) diseases more recently
As with all disorders with strong hereditary determinants, diagnosis attributed to primary defects in lysosomes and related organelles.
is crucial for prognosis and genetic counselling, because specific ther-
Treatments
apies may have disease-​modifying effects, and to prevent inappro-
priate interventions (e.g. removal of an enlarged spleen). A detailed Despite some striking therapeutic advances in several lysosomal
family history, including careful analysis of the extended pedigree, is conditions such as Gaucher’s disease, there is no specific or curative
2122 section 12 Metabolic disorders

within the endosomal lumen and thus enter the lysosome upon
treatment for most lysosomal disorders. Supportive and palliative
fusion. In contrast, structural or transporter proteins bound for
measures are nonetheless of great benefit.
incorporation into the lysosomal membrane remain within the
Advanced cell and molecular therapies can have striking benefits
limiting membrane of the endosome and form part of the lyso-
in several lysosomal diseases: these include bone marrow (haem-
somal membrane on fusion.
atopoietic stem cell) transplantation, specific augmentation with
Two multicomponent macromolecular complexes, CORVET
receptor-​targeted recombinant human lysosomal enzymes, sub-
(core subunit vacuolar/​endosome tethering complex) and HOPS
strate biosynthesis inhibitors, pharmacological chaperones, and sub-
(homotypic fusion and protein sorting), bring about vacuolar fu-
strate dissolution stratagems. Gene therapy is in a promising phase of
sion with the endosomal, lysosomal, and autophagosome com-
clinical development for this group of disorders.
partments. Recently, a few patients with destabilizing mutations in
HOPS components have been investigated. While the cell biology
is incompletely understood, these patients will be instructive
Lysosomal function since the complex phenotype of Turkic patients with mutations in
the vacuolar protein-​ sorting associated protein, VP33A, clearly
Since their discovery more than 65 years ago by the late Nobel has pathological lysosomal storage with features resembling a
prize winner Christian de Duve, lysosomes and their associated mucopolysaccharidosis (MPS) despite a full complement of lyso-
endosomal structures have been at the centre of research into mo- somal acid hydrolases. Further investigations of such extraordinary
lecular cell biology and membrane dynamics. Lysosomes are an in- patients are likely to reveal much about the functional dynamics of
tegral part of the intracellular digestive system (see Chapter 3.1) and lysosome–​endosome pathways in cell biology and their relevance to
acquire complex macromolecules for breakdown and recycling by medicine.
three main pathways: (1) receptor-​mediated endocytosis, (2) en-
gulfment and fusion (phagocytosis), and (3) autophagy. Greater Phagocytosis
understanding of lysosomal function has arisen from biochemical Lysosomes are also involved in a specialized process for the degrad-
definition of cellular macromolecules that accumulate when the or- ation of exogenous particulates and proteins, including microbes
ganelle is affected by hereditary diseases. and effete cells such as erythrocytes and neutrophils. Although
Many other molecular components that bring about trafficking this engulfment and fusion process involving phagolysosomes is a
and membrane-​ fusion events, for example, Rab proteins and feature of many cells, it is particularly active in macrophages and
SNARE proteins, are localized to, and interact with, the lysosome. dendritic cells.
These proteins form complexes that bring about the ebb and flow In macrophages, cell surface components on bacteria and yeast,
of substrates and digestive products as they move between com- as well as exogenous cells, are recognized and bound by specific
partments in the greater lysosomal network within the cell. Live-​ receptors on the plasma membrane. The phagocytes engulf for-
cell imaging techniques reveal a highly dynamic constellation of eign material to form large vesicles in which acidification and
particles that are continuously moving and fusing as a result of the proteolysis, as well as the secretion of degradative molecules
release of phosphate-​bond energy through the action of GTPases. (including reactive oxygen and nitrogen species), is initiated. The
This chemical bond energy is used to drive the continuous traf- phagolysosome fuses with lysosomes and further acidification oc-
ficking of membrane constituents involved in the innumerable tran- curs, so that the acid hydrolases are activated to effect destruction
sient interactions of the endosomal, lysosomal, and autophagosome of the ingested material.
compartments. A specialized phagolysosome variant occurs in osteoclasts that are
derived from myeloid cells of mononuclear phagocyte origin. The
Endocytosis and membrane flow osteoclastic resorptive vacuole serves as a large exteriorized lyso-
Receptor-​mediated endocytosis occurs by means of clathrin-​coated somal compartment which is independently acidified for resorption
pits, a process by which molecules are delivered after internaliza- of bone.
tion to a peripheral, and later to a perinuclear endosomal compart-
ment, ‘the endolysosome’. The endolysosome undergoes maturation Autophagy
to form a lysosome after the loss of certain membrane components Autophagy occurs within cells: microautophagy describes the
and further acidification. degradation of cytosolic components trapped during invagin-
Some molecules acquired by receptor-​ mediated endocytosis ation of endosomes and lysosomes, while macroautophagy de-
(e.g. apolipoprotein B in low-​density lipoproteins) are specifically scribes the engulfment of relatively large volumes, including
retrieved and returned ultimately to the cell surface, having des- organelles.
patched their cargo to the lysosome. Other molecules that are not In a constant process of membrane fusion and flow, the endo-
retrieved are ultimately degraded by fusion with mature lysosomes plasmic reticulum (reticulophagy), ribosomes, mitochondria
and enzymatic hydrolysis (e.g. the epidermal growth factor receptor (mitophagy), peroxisomes and other lysosomes, and particulate ma-
system). terial such as macromolecular complexes of glycogen are engulfed by
The endosomal system also mediates the traffic of nascent autophagic vacuoles. Formation of these vacuoles is initiated when
acid hydrolases from the trans-​Golgi network to the lysosome, a flattened cisterna composed of membrane, the phagophore, encir-
employing a specific mannose 6-​ phosphate receptor targeting cles cytoplasm to form a double-​layered vesicle, the autophagosome:
system. Plasma membrane proteins bound for degradation in the acidified late endosomes and lysosomes fuse with the nascent vacu-
lysosomal system are incorporated into membrane-​bound vesicles oles to form an autolysosome.
 12.8 Lysosomal disease 2123

With progressive acidification, the complement of lysosomal is activated by dephosphorylation of TFEB, indirectly after inhib-
hydrolases effects breakdown of the inner membrane and digestion of ition of the master-​regulator mTOR, a kinase that is controlled
the vacuolar contents. After digestion is completed, the autolysosome in part by the effects of low cytoplasmic concentrations of leu-
acquires an electron-​ dense—​and often autofluorescent—​ core cine and arginine as well as low-​energy charge during periods of
known as a residual body. When lysosomal function is impeded, starvation.
the breakdown of endogenous macromolecules is impaired; this, Deficiency of the activity of one lysosomal enzyme usually leads
together with a failure to break down exogenous macromolecular to a coordinated upregulation of many proteins including those en-
substrates, results in a characteristic pattern of pathological storage coded by genes containing CLEAR sequences that coordinate lyso-
of the biological residue. Disturbed autophagy is a spectacular fea- somal function and autophagy.
ture of cystinosis, Pompe’s disease, and Danon’s disease, but prob-
ably drives much of the pathogenesis of many, if not all, lysosomal Degradation and recycling of complex macromolecules
diseases, including those involving cells where autophagy is particu- Of the 400 or so proteins found in the lysosome, including membrane
larly active, as in neurons. proteins, there are at least 50 lysosomal hydrolases. These include
Recent exploration of the central signalling pathway that controls proteases, glycosidases, sulphatases, phosphatases, nucleases, lipases,
tissue and cell growth, the mechanistic target of rapamycin com- and phospholipases. These enzymes require an acidic pH for optimal
plex 1 (mTORC1), has shown that under nutrient-​rich conditions function, which in the lysosome is maintained at a pH of 4 to 5.5 by the
this complex is recruited to the cytoplasmic surface of the lyso- ATP-​dependent proton transporter V-​ATPase. The lysosomal mem-
some where it interacts with a large assembly of proteins including brane and the acidic pH optimum of the hydrolases protect other cell
a small guanine triphosphatase, Rheb, which is itself regulated by components, at neutral pH, from indiscriminate autodigestion.
the prevailing energy charge, oxygen availability, and growth factor Lysosomes display a range of pH values, properties that are linked
signalling. Under conditions in which amino acids are not abun- to their position in the living cell (e.g. perinuclear or peripheral).
dant, mTORC1 dissociates from the membrane and is inactive. The Live-​cell microscopic imaging reveals highly dynamic structures
energy-​requiring acidifying molecule, vacuolar (V)-​ATPase, which that move rapidly in three dimensions with oscillating acidities that
pumps protons into the lysosome, is also part of the assembly and may reflect functional transients which change according to the flux
may be influenced by amino acid abundance. The condition of X-​ of different substrates. Intralysosomal pH values could influence
linked myopathy with excess autophagy illustrates the role of the the rate of substrate hydrolysis according to the differential pH op-
nutrient-​sensing feedback loop that controls autophagy; defects timum of particular reactions and thus the exchange of macromol-
in a chaperone, VMA21, that assembles the V-​ATPase give rise to ecular substrates between distinct organelle populations during the
inadequate lysosomal acidification and reduced release of nutrient digestive sequence.
amino acids, thus leading to upregulated autophagic processes.
Autophagy retrieves the basic building blocks of cellular compo- Targeting of hydrolases
nents and proceeds hand-​in-​hand with de novo synthesis and the re- About 60 known soluble lysosomal enzymes and activator proteins
newal of intracellular compartments throughout life; as summarized continually digest and recycle cellular macromolecules. Most of
earlier, the process is stimulated under conditions of starvation and these components are targeted to the lysosome by the mannose 6-​
disuse—​for example, in immobilized muscles or during involution phosphate cotranslational pathway. Immediately after biosynthesis,
of the anterior pituitary or mammary gland after pregnancy and lac- N-​linked oligosaccharides on lysosomal proteins are modified spe-
tation. When starvation is prolonged, macroautophagy slows down cifically to generate the principal mannose 6-​phosphate recognition
in favour of the lysosomal uptake of a class of large cellular proteins marker with the addition of a phosphate group on the sixth carbon
harbouring particular amino acid sequences which are recognized of mannose residues. The appropriately phosphorylated proteins
by receptors that mediate import into the organelle. The intrinsic bind to mannose 6-​phosphate receptors in the trans-​Golgi network
and highly glycosylated lysosomal membrane protein, LAMP2, is and the ligand–​receptor complexes enter clathrin-coated transport
implicated in the uptake of such cytosolic proteins. LAMP2 is mu- vesicles that traffic to an acidic prelysosomal compartment where
tated in the X-​linked disorder Danon’s disease in which liver as well the ligands dissociate. Soluble lysosomal proteins enter the lyso-
as cardiac and skeletal muscle show prominent vacuoles engorged somal matrix and most of the receptors recycle back to the trans-​
with glycogen and other debris, including remnants of cellular Golgi network to repeat the intracellular delivery process.
organelles. About 20% of the mannose 6-​phosphate receptors traffic to the cell
surface, where their complement of protein ligands is released but
Common regulation of autophagy, lysosomal biogenesis, where fresh binding and hence recapture is stochastically possible.
and lysosomal function This creates the potential for glycoproteins harbouring the appro-
A common regulatory system based on a transcription factor, TFEB, priate hexosyl phosphate recognition signal that are discharged into
upregulates many of the processes required for integrated function the fluid phase to be distributed and recaptured by cell surface man-
of autophagy: formation of vesicles, production of factors necessary nose 6-​phosphate receptors. While this process may have a physio-
for cargo recognition and fusion of the autophagosome and lyso- logical role, for example, in regulating insulin-like growth factor
some, synthesis of lysosomal enzymes, membrane proteins, and (IGF) concentrations in plasma, because the cation-independent
pH pumps. M6P receptor also functions as the IGF2 receptor its greatest signifi-
Phosphorylation of TFEB prevents its entry into the nucleus cance is to provide the foundation for functional complementation
and hence its actions on the transcription of genes harbouring the of lysosomal diseases due to deficiency of soluble proteins (in this
responsive binding sequences in the CLEAR element. The system example, iduronate sulphatase).
2124 section 12 Metabolic disorders

Activator proteins antigens to generate peptide fragments. In antigen-​presenting cells,

Activator proteins are required for several lysosomal en- where abundant expression of several of these proteases is necessary,
zymes: saposin C is required for the in vivo catalytic function of peptide fragments of the cognate antigens are presented in associ-
glucocerebrosidase, deficiency of which causes Gaucher’s disease. ation with major histocompatibility complex (MHC) class II mol-
Indeed, a Gaucher’s disease-​like phenotype has been observed in ecules as a key step in the pathway that orchestrates the adaptive
the rare individuals with saposin C deficiency. The small protein, immune response. In mouse models of autoimmunity, deficiency of
GM2 activator, is absolutely required for the digestion of GM2 acid proteases—​such as cathepsins B and S, generated experimen-
ganglioside by ß-​hexosaminidase A and deficiency of the GM2 tally by gene disruption technology—​can ameliorate many of the
activator causes a disease with clinical features similar to Tay- disease manifestations.
Sachs disease.
Another vivid example of a crucial activator for many lysosomal
enzymes is sulphatase-​modifying factor 1 (SUMF1), an enzyme ex- Definition and classification of lysosomal diseases
pressed in the endoplasmic reticulum that catalyses the oxidation of
a conserved cysteine residue within a protein domain of all known Definition
sulphatases, many of which are involved in the breakdown of glyco- Lysosomal diseases result from inherited defects in lysosomal
saminoglycans and sulphated glycosphingolipids in the lysosome. hydrolases and the mechanisms for delivering them to the organelle,
Homozygous or compound heterozygous mutations in the human lysosomal enzyme activators and cofactors, lysosomal membrane
SUMF1 gene lead to multiple sulphatase deficiency (Austin’s disease) proteins, and carrier systems for the transport of the substrates and
with features of MPS and metachromatic leukodystrophy as well products of lysosomal digestion between the organelle and the cyto-
as very dry skin, ichthyosis, due to defective activity of cutaneous plasm. Most of the enzymatic defects are restricted to the activity of
steroid sulphatase. a single hydrolase, but defects of activators and cofactors, as well as
proteins involved in the processing of nascent lysosomal enzymes
Transporter proteins
for organellar delivery, can lead to generalized defects of lysosome
Transporter proteins of the lysosomal membrane are less well function.
characterized than the acid hydrolases. Maintaining a proton gra-
dient with a concentration of protons approximately 1000-​fold Classification
greater than that in the ambient cytosolic pH depends on the pres- Lysosomal disorders have been classified according to the nature of
ence of a V-​type H+ ATPase in the lysosomal membrane. Other the primary storage compounds (biochemical classification) or ac-
membrane transporters exist for the crucial counter-​exchange of cording to the nature of the physiological defect (functional classifi-
ions, including the chloride channel, CLCN7. This channel is ex- cation). A combination of two classification systems, incorporating
pressed in the endosome–​lysosomal membranes of all cells but genetic characterization, may allow a clearer description of the
is abundant on the ruffled border of the osteoclast. Mutations in pathological basis of the condition.
the CLCN7 gene are responsible for dominantly inherited and se- As the clinical manifestations of the 80 or more diseases associ-
vere autosomal recessive forms of osteopetrosis due to a failure to ated with inborn errors of lysosomal function are very diverse, the
acidify the subosteoclastic vacuole, an externalized lysosomal as- reader is referred to specialized literature for further information
sembly of enzymes critical for modelling bone matrix during os- (see ‘Further reading’).
sification and maintenance of skeletal integrity throughout life. In
the recessive variants, mutations of CLCN7 are also responsible for Biochemical classification
neurodegeneration.
Other channels include those that transport Ca2+ (LAAT1), Sphingolipidoses
as well as the egress of small molecules generated by hydrolytic Sphingolipids are amphiphilic compounds with a lipophilic
digestion of the macromolecular substrates in the lysosome—​ moiety based on the amino-​alcohol sphingosine (usually linked to
for example, cystinosin (cystine), CblF (cobalamin), and sialin a long-​chain fatty acid to form ceramide) and a polar hydrophilic
(sialic acid) which are implicated respectively in cystinosis, mono-​or oligosaccharide chain; in sphingomyelins, which are the
methylmalonic acidaemia due to defective intracellular vitamin most abundant sphingolipids, the charged head group is either
B12 transport, and Salla disease. Transporters are required to ex- phosphorylcholine or phosphorylethanolamine. Sphingolipids are
port the products of lysosomal digestion, such as amino acids, found in all plasma membranes and concentrated in large aggre-
monosaccharides, nucleosides, and ions, for reuse in cellular me- gates: the lipophilic moiety is often anchored by structural proteins
tabolism. Recent research has identified mucolipin as a channel such as tubulin in the lipid bilayer and the carbohydrate element or
for monovalent cations; impaired function of which causes head group extends into the extracellular space.
mucolipidosis IV. The protein CLN3, deficiency of which results Sphingolipids mediate diverse cellular functions and serve as spe-
in a juvenile type of neuronal ceroid lipofuscinosis type 3 (‘Batten’s cific receptors and cell recognition markers. They are continuously
disease’), has been implicated in the egress of arginine. delivered to the lysosomal compartment in the course of mem-
brane turnover in endocytosis, phagocytosis, and by autophagy.
Antigen presentation Deacylated forms of the sphingolipids (β-​d-​glucosylsphingosine,
Proteases of lysosomal origin, particularly the cysteine proteinases a ‘psychosine’, is the deacylated form of glucosylceramide), are
or cathepsins, are responsible for the cleavage of endocytosed protein water-​soluble and hence diffusible. Exploration of the roles of
 12.8 Lysosomal disease 2125

such lysolipids and other lipid molecules, such as sphingosine 1-​ removal of sulphate moieties from glycosaminoglycans, glycolipids,
phosphate and ceramide, in signal transduction and other cellular and glycopeptides—​require the conversion of a conserved cysteine
processes is an expanding field of research and holds promise for a residue to formylglycine for their activation. Genetic defects in the
more comprehensive understanding of the molecular pathogenesis enzyme, sulphatase-​modifying factor (SUMF1), which mediates
of sphingolipid diseases. this conversion in the endoplasmic reticulum, leads to Austin’s dis-
ease (multiple sulphatase deficiency)—​a condition which usually
Mucopolysaccharidoses resembles late-​infantile metachromatic leukodystrophy but with
Mucopolysaccharides, or glycosaminoglycans, are complex linear prominent clinical and biochemical features of a complex MPS as
polysaccharides, composed of repeating units of polar disaccharides well as ichthyosis, due to an accompanying deficiency of steroid
which are strongly negatively charged under physiological condi- sulphatase.
tions; glycosaminoglycans contain amino sugars substituents and Deficiency in the precursor of the small sphingolipid acti-
are often sulphated. When associated with a linear core protein, the vator proteins leads to loss of activity of the cognate hydrolases,
glycosaminoglycans form even larger three-​dimensional complexes, whose activity depends on interaction with the activators saposins
known as proteoglycans. A to D. Depending on the selectivity of the defect, a distinct dis-
By virtue of their negative charge and extended structure, proteo- ease complex, characterized by accumulation of a broad panel of
glycans attract water molecules and have important gel-​like proper- glycosphingolipids, occurs when these proteins are deficient.
ties. Proteoglycans are essential components of ground substance in A genetically and biochemically distinct activator, GM2 acti-
intercellular spaces and connective tissue, including cartilage, vit- vator protein, interacts crucially to form a ternary complex with
reous humour, and synovial fluid. the two subunits of hexosaminidase A and its specific natural sub-
Lysosomal degradation of the carbohydrate moieties requires strate in the lysosome, GM2 ganglioside. Deficiency of this activator
the participation of several glycosidases orchestrated in series. protein gives rise to a phenocopy of the severe neurodegenerative
Lysosomal diseases associated with the failure to digest heparan sul- disorder Tay–​Sachs disease, but characteristically the activity of
phate in particular, such as Hunter’s disease and Sanfilippo’s diseases hexosaminidase A, when determined with the usual fluorogenic
(MPS II and MPS III subtypes), are all associated with prominent substrates, is unimpaired. A similar phenomenon occurs in the dis-
neurological disease. orders due to saposin deficiencies and may render correct diagnosis
difficult for the unwary.
Glycoproteinoses Most acid hydrolases are glycoproteins that are specifically tar-
Glycoproteins are proteins to which one or more oligosaccharide geted to the lysosomal system through interaction between a
chains are attached covalently. The carbohydrate moiety is often mannose-​phosphate moiety and membrane mannose-​phosphate
branched and complex, mediating specific recognition by cell sur- receptors. Failure to generate the mannose-​phosphate signal gives
face receptors. As with the glycosaminoglycans, lysosomal degrad- rise to widespread mistargeting of hydrolases and intralysosomal
ation of the carbohydrate element requires the ordered participation deficiency of the respective activities with consequent accumu-
of several glycosidases operating in sequence. Deficiency of one lation of many substrates (I-​cell disease); characteristically, body
glycosidase, in effect, blocks the subsequent release of sugars in the fluids, including plasma, have increased activities of many lysosomal
reaction series, thus causing accumulation of oligosaccharides and hydrolases and although the disease shares many features of a MPS,
other complex glycan molecules. the urine is usually free of glycosaminoglycans.

Glycogenosis (Pompe’s disease) Miscellaneous

Deficiency of α1,4-​ glucosidase, acid maltase, causes intra-​and Please see Table 12.8.1 for details.
extralysosomal accumulation of glycogen in muscle and other tis- Functional classification
sues. This storage molecule is common to conditions of impaired
autophagy (e.g. Danon’s disease) but is prominent in Pompe’s disease Classification based on the nature of the defect in cell biological
and confirms the role of the lysosome in constitutive and continuous terms is particularly relevant in relation to potential therapeutic ap-
remodelling of glycogen macromolecules. proaches. Examples of the type of defects listed here are given in the
‘Biochemical classification’ section, in Table 12.8.1, and throughout
Multiple classes of storage material the text:
Several lysosomal hydrolases are not specific to one substrate: β-​ • Deficiency of a specific acid hydrolase activity
galactosidase deficiency, for example, leads to accumulation of a • Deficiency of an activator protein
glycosphingolipid (GM1 ganglioside) and glycosaminoglycans • Deficiency of a lysosomal membrane protein or transporter
(keratan sulphate and β-​galactosyl oligosaccharides) with greatly • Abnormal post-​translational modification of lysosomal proteins
divergent clinical manifestations. This enzyme deficiency is respon-
• Abnormal lysosomal biogenesis
sible for a range of phenotypes, extending from a predominantly
neurodegenerative disease, GM1 gangliosidosis, to the skeletal dis- Deficiency of an acid hydrolase may come about either as a result
order of Morquio B (MPS IVB) in which neurological impairment of a mutation that reduces catalytic activity, or as a result of a muta-
is typically absent. tion that impedes correct folding of the protein and delivery of the
All eukaryotic sulphatases, including the eight sulphatases mutant enzyme to the lysosome. This has implications for pathogen-
destined for the mammalian lysosome—​where they catalyse the esis and potential therapeutic approaches.
2126 section 12 Metabolic disorders

Table 12.8.1 Representative classification of lysosomal diseases

Disease Synonym OMIM Locus, gene Gene product and functional Storage material
classification
Sphingolipidoses
Farber Lipogranulomatosis 228000 8p22 Acid ceramidase Cer
ASAH Acid hydrolase
Fabry Anderson–​Fabry 301500 Xq22 α-​Galactosidase A Gb3
GLA Acid hydrolase
Gaucher Glucosylceramidosis 606463 1q21 Glucocerebrosidase GlcCer
230900 GBA Acid hydrolase
231000
230800
GM1 gangliosidosis 230500 3p21 β-​Galactosidase GM1
230600 GLB1 Acid hydrolase
Tay–​Sachs GM2-​gangliosidosis B 272800 15q23 β-​Hexosaminidase α-​subunit GM2
HEXA Acid hydrolase
Sandhoff GM2-​gangliosidosis O 268800 5q13 β-​Hexosaminidase β-​subunit GM2
HEXB Acid hydrolase
Tay–​Sachs AB variant GM2 gangliosidosis AB 272750 5q32 GM2 activator protein GM2
GM2A Activator protein
Krabbe Globoid cell leukodystrophy 245200 14q31 β-​Galactosylceramidase GalCer
GALC Acid hydrolase
Metachromatic Arylsulphatase A deficiency 250100 22q13 Arylsulphatase A Sulphatide
leukodystrophy ARSA Acid hydrolase
Prosaposin deficiency 176801 10q22 Prosaposin Multiple lipids
PSAP Activator protein
Saposin B deficiency Metachromatic 249900 10q22 Saposin B Sulphatide
leukodystrophy variant PSAP Activator protein
Saposin C deficiency Gaucher variant 610539 10q22 Saposin C GlcCer
PSAP Activator protein
Niemann–​Pick types 257200 11p15 Acid sphingomyelinase SM
A and B 607616 SPMPD1 Acid hydrolase
Other lipidoses
Niemann–​Pick type C1 257220 18q11 NPC1 Cholesterol, GSL
NPC1 Probable transmembrane
transporter
Niemann–​Pick type C2 607625 14q24 NPC2 Cholesterol, GSL
NPC2 Soluble transporter
Wolman Cholesteryl ester storage 278000 10q23.2 Acid lipase Cholesteryl esters
disease LIPA Acid hydrolase
Mucopolysaccharidoses (MPS)
MPS I Hurler 607015 (MPS IH) 4p16 α-​Iduronidase DS, HS
Hurler/​Scheie, Scheie 607015 (MPS IHS) IDUA Acid hydrolase
607016 (MPS IS)
MPS II Hunter 309900 Xq28 Iduronate sulphatase DS, HS
IDS Acid hydrolase
MPS IIIA Sanfilippo A 52900 17q25 Heparan N-​sulphatase HS
SGS Acid hydrolase
MPS IIIB Sanfilippo B 252910 17q21 N-​acetyl glucosaminidase HS
NAGLU Acid hydrolase
MPS IIIC Sanfilippo C 252930 8p11 α-​Glucosaminide acetyl-​CoA HS
TMEM76 transferase
HGSNAT Acid hydrolase
MPS IIID Sanfilippo D 252940 12q14 N-​acetylglucosamine HS
GNS 6-​sulphatase
Acid hydrolase
MPS IVA Morquio A 253000 16q24 Galactosamine 6-​sulphatase KS,CS
GALNS Acid hydrolase
MPS IVB Morquio B 253010 3p21 Acid β-​galactosidase KS
GLB1 Acid hydrolase
 12.8 Lysosomal disease 2127

Table 12.8.1 Continued

Disease Synonym OMIM Locus, gene Gene product and functional Storage material
classification
MPS VI Maroteaux–​Lamy 253200 5q12 Arylsulphatase B DS
ARSB N-​Acetyl galactosamine
4-​sulphatase
Acid hydrolase
MPS VII Sly 253220 7q21 Glucuronidase DS, HS, CS
GUSB Acid hydrolase
MPS IX Hyaluronidase deficiency 601492 3p21 Hyaluronidase 1 HA
HYL1 Acid hydrolase
Glycogen storage disease
Pompe Glycogen storage disease 232300 17q25 α-​Glucosidase Glycogen
type II GAA Acid hydrolase
Multiple substrate storage due to single gene defects
Multiple sulphatase Austin disease 272200 3p26 Formyl-​glycine Sulphatide,
deficiency SUMF1 generating enzyme mucopolysaccharides
Post-​translational modification
Galactosialidosis 256540 20q13 Protective protein GSL, polysaccharides
PPCA Cathepsin A
Acid hydrolase
Mucolipidosis type II I-​cell disease 252500 12q23 UDP-​GlcNac Multiple lipids and
GNPTAB Phospho transferase α/​β unit oligosaccharides
Post-​translational modification
Mucolipidosis type IIIa Classic pseudo-​Hurler’s 252600 12q23 UDP-​G1cNac Multiple lipids and
polydystrophy GNPTAB Phosphotransferase α/​β unit oligosaccharides
Post-​translational modification
Mucolipidosis type IIIb Pseudo-​Hurler’s 352605 16p UDP-​G1cNac Multiple lipids and
polydystrophy GNPTG Phosphotransferase γ-​subunit oligosaccharides
Post-​translational modification
Mucolipidosis type IV 252650 19p13 Mucolipin-​1 cation channel Multiple lipids and
MCOLN1 Transporter oligosaccharides
VP33A deficiency Mucopolysaccharidosis plus 610034 12q24.31 VP33A is a common component Glycosaminoglycans,
syndrome of the heterohexameric especially heparan
Turks and Yakut tethering complexes involved sulphate; increased
in endocytic-​lysosomal acidification
fusion: HOPS (homotypic fusion
and vacuole protein sorting)
and the Rab GTPase-​dependent
CORVET (class C core vacuole/​
endosome tethering)
Glycoproteinoses
Aspartylglucosaminuria 208400 4q32 Glycosyl-​asparaginase Aspartyl-​glucosamine
AGA Acid hydrolase
Fucosidosis 230000 1p34 α-​Fucosidase Oligosaccharides
FUCA Acid hydrolase
α-​Mannosidosis 248500 19q12 α-​Mannosidase Oligosaccharides
MAN2B1 Acid hydrolase
β-​Mannosidosis 248510 4q22 β-​Mannosidase Oligosaccharides
MANBA Acid hydrolase
Sialidosis Sialidase deficiency 256550 6p21 α-​Sialidase (neuraminidase) Oligosaccharides
Mucolipidosis type 1 NEU1 Acid hydrolase
Schindler NAGA deficiency 609242 22q13 α-​N-​acetyl galactosaminidase Oligosaccharides
Kanzaki’s disease 609241 NAGA Acid hydrolase
Lysosomal transport defects
Cystinosis Abderhalden–​Kaufmann–​ 219800 17p13 Cystinosin, a transmembrane Cystine
Lignac disease 219900 CTNS protein
219750 Cystine efflux
Transporter
Methylmalonic aciduria Vitamin B12 lysosomal 277380 Unknown Vitamin B12 carrier (Cb1F) Vitamin B12
release defect Transporter
(continued)
2128 section 12 Metabolic disorders

Table 12.8.1 Continued

Disease Synonym OMIM Locus, gene Gene product and functional Storage material
classification
Salla Sialuria 604322 6q14 Sialin Sialic acid
SLC17A5 Transporter
Lysosomal protease defect
Pycnodysostosis 265800 1q21 Cathepsin K Collagen fibrils
CTSK Acid hydrolase (osteoclasts)
Autophagy defects (with glycogenosis)
Danon Pseudoglycogenosis II 300257 Xq24 LAMP2 Vacuoles,
LAMP2 Membrane protein macromolecular
debris, glycogen, and
membrane
RNASET2 Leukoencephalopathy, cystic 612951 6q27 Ribonuclease T2 deficiency Unknown in humans:
without megalencephaly; (glycoprotein with but implicated
RNase T2-​deficient endoribonuclease activity and in reticulophagy
leukoencephalopathy acid optimum) (endoplasmic reticulum
autophagy)—​authentic
zebrafish model shows
accumulated rRNA in
neurons
X-​linked myopathy with 310440 Xq28 VMA21 Vacuole
excessive autophagy XMEA Membrane protein
Vacuolar myopathy Muscular dystrophy with 601846 19p13 MDRV Vacuoles
vacuoles MDRV Unknown function
Autophagy defects
X-​linked vacuolar MEAX 310440 Xq28 VMA 21, chaperone for the Vacuoles
myopathy with excessive lysosomal V-​ATPase.
autophagy (XMEA)
Neuronal ceroid lipofuscinosis (NCL)
CLN1 (infantile, late-​ Haltia–​Santavuori 256730 1p32 PPT1 palmitoyl protein SAPs (sphingolipid
infantile, juvenile, adults) CLN1/​PPT1 thioesterase 1 activator proteins)
Acid hydrolase
CLN2 Jansky–​Bielchowsky 204500 11p15 TPP1 tripeptidyl peptidase 1 SCMAS (subunit c
(late infantile/​juvenile) CLN2/​TPP1 Acid hydrolase mitochondrial ATP
synthase)
CLN3 Spielmeyer–​Sjögren Batten 204200 16p12 CLN3 (Battenin) SCMAS
( juvenile) CLN3 transmembrane protein—​
endosomes, lysosomes as well as
synaptic vesicles
CLN4A Kufs type A—​adult 204300 15q23 CLN6 SCMAS
(adult) (autosomal recessive) CLN6 Membrane transporter
CLN4B Kufs, Parry disease 162350 20q13.33 Soluble, cytoplasmic cysteine SAPs
(autosomal dominant) (DNAJC5) string protein alpha—​
palmitoylation reduced
CLN5 Finnish 256731 13q22.3 CLN5—​a complex but soluble SCMAS
(late infantile, juvenile, adult) CLN5 glycoprotein
CLN6 Lake–​Cavanagh 601780 15q23 CLN6 SCMAS
Late infantile, adult—​Kufs CLN6 Transmembrane protein possible
type A variant ER transporter
CLN7 vLINCL 610951 4q28.2 CLN7/​MFSD8 SCMAS
(Turkish and others) MSFD8 Transmembrane protein
CLN8 Northern epilepsy 600143 8p23 CLN8 SCMAS
CLN8 Transmembrane protein transfers
lysosomal enzymes from Golgi
to endoplasmic reticulum
[CLN9] Original Serbian-​German 609055 (obsolete) N/​A N/​A N/​A
Obsolete pedigree reclassified as
CLN5 after genetic studies
CLN10 Congenital with 610127 11p15 Cathepsin D SAPs
microcephaly, neonatal and CTSD Acid hydrolase
late infantile CLN
(very rare juvenile and adult
variants)
 12.8 Lysosomal disease 2129

Table 12.8.1 Continued

Disease Synonym OMIM Locus, gene Gene product and functional Storage material
classification
CLN11 Autosomal recessive 614706 17q21.31 Progranulin Intraneuronal
(note: heterozygotes with GRN ubiquitin-​positive
GRN mutations develop autofluorescent
autosomal dominant lipofuscin and
frontotemporal dementia rectilinear inclusions
with TDP43-​inclusions—​ on electron
OMIM 607485) microscopy
CLN12 Juvenile (note: recessive 610513 1p36.13 ATPase type 13A2
mutations in ATP13A2 CLN12/​ATP13A2 Lysosomal membrane protein
also cause Kufor–​Rakeb
syndrome, PARK9, juvenile-​
onset atypical Parkinson’s
disease with supranuclear
gaze palsy, spasticity and
dementia (OMIM 606693))
CLN13 Adult CLN (sometimes 615362 11q13.2 Cathepsin F Autofluorescent
known as Kufs B—​autosomal CTSF Soluble acid hydrolase material
recessive)
CLN14 Infantile—​progressive 611725 7q11.21 Potassium channel Fingerprint or
myoclonic epilepsy CLN14 (KCTD7) tetramerization domain rectilinear as well
containing protein 7—​a putative as osmiophilic
cytoplasmic regulator of deposits by electron
potassium conductance microscopy
Disorders in extended lysosomal apparatus (melanosomes, lamellar bodies)
Chédiak–​Higashi 214500 1q42 LYST Enlarged vacuoles
LYST Biogenesis defect Melanosomes
MYOV Griscelli type 1 214450 15q21 Myosin 5A Melanin granules
MYO5A Biogenesis defect
RAB27A Griscelli type 2 603868 15q21 RAB27A Melanin granules
RAB27A Biogenesis defect
Melanophilin Griscelli type 3 609227 2q37 Melanophilin Melanin granules
MLPH Biogenesis defect
HPS-​1 Hermansky–​Pudlak type 1 604982 10q23 HPS-​1 Multiple vacuoles
HPS1 Biogenesis defect
HPS-​2 Hermansky–​Pudlak type 2 608233 5q14 AP3 β-​subunit Multiple vacuoles
AP3B1 Biogenesis defect
HPS-​3 Hermansky–​Pudlak type 3 606118 3q24 HPS-​3 Multiple vacuoles
HPS3 Biogenesis defect
HPS-​4 Hermansky–​Pudlak type 4 606682 22q11 HPS-​4 Multiple vacuoles
HPS4 Biogenesis defect
HPS-​5 Hermansky–​Pudlak type 5 607521 11p15 HPS-​5 Multiple vacuoles
HPS5 Biogenesis defect
Biogenesis defect Multiple vacuoles
HPS-​6 Hermansky–​Pudlak type 6 607522 10q24 HPS 6
HPS6 Biogenesis defect
HPS-​7 Hermansky–​Pudlak type 7 607145 6p22 Dysbindin Multiple vacuoles
DTNB1 Biogenesis defect
HPS-​8 Hermansky–​Pudlak type 8 609762 19q13 BLOC1S3 Multiple vacuoles
BLOC1S3 Biogenesis defect
HPS-​9 Hermansky–​Pudlak type 9 614171 15q1.21 Pallidin
BLOC1S6 Biogenesis defect
HPS-​10 Hermansky–​Pudlak 617050 19p3.3 Biogenesis defect
type 10 AP3D1
Surfactant metabolism SMPD3 610921 16p13 ABCA3 transporter Alveolar proteins
dysfunction-​4 ABCA3
Congenital and lamellar Harlequin fetus 242500 2q34 ABCA12 transporter Abnormal keratin
ichthyosis 601277 ABCA12

Cer, ceramide; CS, chondroitin sulphate; DS, dermatan sulphate; Gb3, globotriaosylceramide; GlcCer, glucosylceramide; HA, hyaluronan; HS, heparan sulphate; KS, keratan sulphate;
SM, sphingomyelin.
2130 section 12 Metabolic disorders

Psychosines (glucosylsphingosine and galactosylsphingosine) ap-

Pathophysiology
pear to interact with receptors on the plasma membrane of human
monocytic-​lineage cells. Latterly, multiple myeloma, which occurs at a
Lysosomal storage of primary substrates
greatly increased frequency in Gaucher’s disease, has been reported to
In the initial period of discovery of lysosomal diseases, limited avail- result from a T-​follicular helper type 2 (TFH2)-​mediated B-​cell prolif-
ability of investigative tools influenced how the conditions were erative response directed against the pathological glycosphingolipids
viewed. Pathological examination and microscopy showed not only present in serum (especially ß-​glucosylsphingosine), with clonal para-
organ enlargement but intracellular ‘storage’ bodies of remarkable protein antibody reactivity directed against this circulating lipid mol-
appearance. Biochemical characterization of storage compounds ecule in patients with Gaucher’s disease. Up to one-​third of patients
guided research into discovery of enzyme activities and gene prod- with spontaneous monoclonal gammopathy apparently unrelated
ucts. This led to a somewhat simplistic view of the pathogenesis of to Gaucher’s disease have been reported to have specific antibody
lysosomal storage diseases as being related to the expansion of cells reactivity to ß-​glucosylsphingosine or other sphingolipids such as
and organs containing relatively inert ‘storage’ material. In most lysophosphorylcholine.
cases, the contribution of storage material to organ enlargement is Another deacylated glycosphingolipid, lyso-​globotriaosylceramide
quantitatively very small and the widespread effects of lysosomal (lyso-​GB3), has been identified in the plasma of patients with Fabry’s
diseases on cell–​cell interactions with paracrine, inflammatory, and disease. This induces smooth muscle proliferation and is thus impli-
immunological consequences, remain unsolved. Latterly, the patho- cated in the severe systemic and cerebrovascular manifestations that
genesis of lysosomal diseases in relation to so-​called secondary characterize the condition.
metabolites and their specific roles in signalling and cell biology is These biochemical findings may signify new approaches to the
receiving attention; investigations are also underway into the effects understanding of several lysosomal disorders associated with
of storage on membrane flow and trafficking within the cell. cell loss due to apoptosis and fibroinflammatory responses; since
Although the amount of storage material that accumulates within lysolipids diffuse readily from their site of formation, different ap-
lysosomes in the lysosomal diseases may be several hundred-​or proaches to their treatment other than targeted enzyme replacement
thousand-​fold greater than normal, the absolute amount of material may be appropriate.
may amount to only a few grams, even in an enlarged viscus such as
the spleen, which may exceed 5 kg in some disorders. For example, Cellular effects
the presence of a few grams of the sphingolipid, sphingomyelin, in The cellular reaction associated with lysosomal storage is often re-
Niemann–​Pick disease types A and B, is associated with massive vis- stricted and stereotypical. In neural tissue, several pathological hall-
ceral enlargement with accompanying inflammatory, ischaemic, and marks such as meganeurite formation and ectopic dendritogenesis
other destructive changes due to the presence of storage cells. Similarly, accompany the accumulation of a wide assortment of storage com-
marked pathological injury occurs: in the viscera and bone marrow pounds. It appears that lysosomal storage gives rise to a general-
spaces of patients with Gaucher’s disease; in the heart and skeletal ized defect in the complex traffic flow mediated by the endosomal
muscles of patients with α-​glucosidase deficiency (with glycogen ac- system with effects on autophagy, signal propagation at the synapse,
cumulation in the sarcoplasm of striated and cardiac myocytes); in axonal transport, myelin formation, and arborization of dendrites.
the kidney and heart of patients with Fabry’s disease; and affecting Lipid rafts, detergent-​resistant islands within the plasma membrane,
neurons throughout the nervous system of patients with ceroid neur- contain high local concentrations of gangliosides and play an im-
onal lipofuscinosis, Tay–​Sachs disease, and GM1 gangliosidosis. portant role in many cell signalling events. Disordered lateral move-
ment and recycling of raft components as part of a general or specific
Secondary metabolites and their effects endosomal ‘traffic jam’ may have profound effects on cell signalling,
Although there often appears to be an anatomical relationship be- as well as recycling processes mediated by autophagy.
tween the extent of lysosomal storage and the development of overt As an example of such cellular cascades, Niemann–​Pick C1 dis-
disease in a particular organ, at present there is little mechanistic ease has been linked to a sequence of events in which sphingosine
understanding of this relationship in molecular terms. Sphingolipids accumulation causes depletion of acidic compartment calcium
participate in cell recognition events and receptor biology; sphingo- stores, leading to accumulation of various lysosomal lipids including
lipid metabolites (the deacylated lysosphingolipids) also function cholesterol. Disorders in which autophagy is markedly disturbed,
as signalling molecules in apoptotic and proliferative responses. particularly those affecting the nervous system, can lead to mito-
However, in two striking instances (Gaucher’s and Krabbe’s dis- chondrial dysfunction as a result of impaired clearance of effete and
eases, due to acid β-​glucocerebrosidase and β-​galactocerebrosidase damaged organelles (defective mitophagy).
deficiencies, respectively), multinucleated macrophages resem- The causative link between Gaucher’s disease and Parkinson’s
bling the pathognomonic Gaucher’s or globoid cell can be induced disease remains to be established, but one area of active research
in vitro by the water-​ soluble molecules glucosylsphingosine and implicates the overproduction of mutant protein which then fails
galactosylsphingosine (psychosine), which are overproduced in these to fold correctly, accumulating within the endoplasmic reticulum,
diseases. At pathophysiological concentrations in culture, psychosines activating the unfolded protein response, the final effects of which
and related glycolipids inhibit cytokinesis and for this reason are im- may include apoptosis. Individuals who are heterozygous for
plicated in the molecular pathways responsible for the presence of pathological GBA1 mutations not only develop parkinsonian fea-
large macrophage-​like cells with several nuclei in the brain of patients tures but also Lewy body dementia: in such patients, the Lewy
with Krabbe’s disease (‘globoid cells’) and in the marrow, spleen, and bodies costain for α-​synuclein, the mutant ß-​glucosylceramidase
other viscera in Gaucher’s disease (‘Gaucher cells’). and ubiquitin.
 12.8 Lysosomal disease 2131

Tissue and organ malfunction episodes may punctuate this process, giving rise to a step-​wise im-
In a scientific era that offers powerful analytical techniques to ex- pairment of function, such as occurs with the osteonecrosis that
plore complex functional networks which lead to tissue pathology, typically affects the epiphyses of the long bones in Niemann–​Pick
the lysosomal diseases represent a promising field for investiga- disease type B or Gaucher’s disease.
tion using large-​scale, high-​throughput methods to investigate al- Organomegaly and disturbed visceral function
tered protein and gene expression in the context of cell signalling
responses. An early application of this work has been the use of Those disorders that affect metabolically active organs such as the
authentic experimental models of some of the more severe storage liver and kidney often cause functional impairment, including the
diseases generated by gene knockout technology, which facilitate re- manifestations of liver failure, portal hypertension, and—​in the case
search on otherwise inaccessible tissues such as the brain during the of the kidney—​rickets and metabolic acidosis, for example, as a con-
development of the storage phenotype. sequence of Fanconi’s syndrome in cystinosis. Cardiac involvement
Gene expression profiling experiments conducted during periods leads to hypertrophy, diastolic dysfunction, conduction and rhythm
of neuronal cell death have shown upregulation of genes related to disturbances, as well as thickening of the valves. Respiratory mani-
the inflammatory process in the nervous system of mice that serve festations of the mucopolysaccharidoses are usually first evident
as a model of GM2 gangliosidosis. The activation of local microglia as a result of narrowing of large airways, but restricted ventilation
is shown by the signature of upregulated macrophage expression due to skeletal disease often supervenes. Splenomegaly, complicated
markers and lymphocyte chemoattractants, as well as genes encoding by marked functional hypersplenism, is characteristic of untreated
antigen-​presenting MHC class II molecules. Since Krabbe’s disease Gaucher’s disease.
modelled in mice is mitigated by bone marrow transplantation, Skeletal manifestations
which supplies a population of genetically competent immune cells
(and which is accompanied by the use of powerful immunosuppres- Skeletal effects predominate and are particularly cruel in several
sion), it seems probable that the altered immunity accompanying of the mucopolysaccharidoses. Severe growth retardation, joint
bone marrow transplantation may itself modify the clinical expres- stiffness, and atlantoaxial instability impair the quality and dur-
sion of lysosomal diseases affecting the brain, and such an effect may ation of life. In Gaucher’s disease, diverse osseous manifestations
be independent of the storage material. include marrow infiltration, osteoporosis, osteonecrosis, lytic
Several indirect studies have indicated the release of inflamma- ­lesions, pathological fractures, and occasional plasmacytoma or
tory cytokines in at least one lysosomal storage disease (Gaucher’s frank myelomatosis (Fig. 12.8.1).
disease), which may explain the metabolic and plasma protein ab- Neurological features
normalities associated with a sustained inflammatory response that
characterizes the clinical syndrome. Hypertrophy and fibrosis char- Lysosomal diseases are a prominent cause of progressive neuro-
acterize the organ responses in many lysosomal diseases. Whether logical and mental deterioration in patients whose disease starts
the response is mediated at a cellular, paracrine, or endocrine level during adolescence up to mature adult life, and they should always
remains unclear. In Fabry’s disease, lyso-​Gb3 is a promising candi- be considered in the differential diagnosis of such presentations.
date for an elusive, endocrine-​like factor in the cardiac and vascular Ataxia is a feature of GM1 and GM2 gangliosidoses, and
aspects of this condition. a flaccid paraparesis in young children might suggest meta-
The clinical presentation of malfunctioning organs in lysosomal chromatic leukodystrophy. Widespread white-​ matter disease in
storage disorders generally resembles the pathological outcomes of association with frontal dementia and spastic paraparesis is a char-
hypertrophy, fibrosis, and organ failure observed in other chronic acteristic presentation of juvenile and adult forms of metachrom-
conditions. Neurological syndromes vary with the anatomical site atic leukodystrophy and Krabbe’s disease. Polyneuropathy and
of greatest injury and with the relative involvement of grey or white pyramidal signs are superimposed in both disorders. Early-​onset
matter (neuronopathic or myelination defects). leukodystrophy is caused by metachromatic leukodystrophy, mul-
tiple sulphatase deficiency, and Krabbe’s disease. The latter is a rare
but important diagnostic entity in this group since the disease may
be partially ameliorated by allogeneic marrow transplantation in
Clinical presentation very early life.
Lysosomal diseases with prominent neurological manifestations
Natural course and severity range are often associated with progressive mental deterioration, with or
All lysosomal diseases disturb the catabolism of complex molecules without the onset of spasticity, myoclonic seizures, and optic atrophy.
in numerous tissues and their manifestations are usually progres- Extrapyramidal signs including parkinsonism, athetoid movements,
sive and permanent. They show no relationship to food intake and and dystonia are also frequent.
are generally independent of intercurrent illness. The rate of de- Corneal opacities suggest cystinosis, I-​cell disease, mucopoly­
terioration depends in part on the degree of residual activity of saccharidoses, mannosidosis, Fabry’s disease, and galactosialidosis,
the deficient enzyme or process: subtotal deficiencies present early as well as one form of Gaucher’s disease with neuronopathic features
in childhood with rapid evolution of disease; partial deficiencies (the D409H type IIIc variant). Perifoveal pallor with the appearance
emerge more slowly and often present in later childhood or adult of pigmentation in the macula (the ‘cherry-​red spot’ in white per-
life. The disease may be insidious, as in the indolent splenomegaly of sons) is a hallmark of Tay–​Sachs disease and other gangliosidoses
adults with Gaucher’s disease, the renal impairment of Fabry’s dis- affecting infants and young adults. Specific syndromes are described
ease, or the muscle weakness of adult-​onset Pompe’s disease. Acute in later sections.
2132 section 12 Metabolic disorders

(a) (b)

Fig. 12.8.1 (a) A 35-​year-​old male with α-​mannosidosis. (b) A 20-​year-​old male with α-​
mannosidosis and coincident glutaric aciduria type 1. Facial appearance includes prominent
brow, depressed nasal bridge, and prognathism. Note hearing aids.

general physicians, haematologists, nephrologists, neurologists,

Diagnosis
gastroenterologists and hepatologists, dermatologists, and even
orthopaedic surgeons may be the first to evaluate the patient—​all
Clinical suspicion and family history
of whom should be able to identify the condition by following diag-
Even in the critically ill, it is essential (whenever possible) to estab- nostic pathways appropriate to their specialty. In any event, the diag-
lish the definitive diagnosis where a lysosomal disease is suspected, nosis of lysosomal storage diseases is rarely difficult, provided the
for several reasons: (1) specific treatment may be possible—​enzyme expertise of trusted laboratory services is available for the conduct
replacement therapy, bone marrow transplantation, or even oral of biochemical assays, diagnostic DNA studies, and wide-​ranging
substrate reduction and enzyme enhancement therapies may be histopathological examination. The value of good communication
available; (2) these disorders are inherited either as X-​linked or as between laboratory staff and clinical investigators, to whom these
autosomal recessive traits, which has important consequences for patients are referred, cannot be overestimated.
reproductive choice in other family members; and (3) the diagnosis
may clarify unexplained symptoms in at-​risk relatives. Pattern of inheritance
The key to making the diagnosis of a rare lysosomal disease is A detailed family history, taking care to investigate the extended
often informed suspicion combined with dogged persistence. In pedigree, is of critical importance for these high-​penetrance mono-
most circumstances, once suspected, the lysosomal disease can be genic diseases. Most lysosomal diseases are inherited as autosomal
identified with relative ease by referral to a specialized regional ref- recessive traits and patients have biallelic mutations at the locus pri-
erence laboratory for the diagnosis of metabolic disorders: senior marily implicated. The differential diagnosis narrows substantially
laboratory staff will usually advise about the handling of appro- if there is evidence of X-​linked inheritance characteristic of Fabry’s
priate tissue material for diagnostic studies, including the means for disease, MPS II (Hunter’s disease), or Danon’s disease. At-​risk family
securing a genetic diagnostic by molecular analysis of genomic DNA members will be identified, often living with presymptomatic or
(see ‘Molecular diagnosis’). undiagnosed disease. Tracing family members is best carried out
In the first instance, simple histochemical stains of existing biopsy sensitively in cooperation with professional genetic counselling
material and examination of urine metabolites, including lipids and services and with the general oversight of patient representative
oligosaccharides, may narrow down the diagnosis. More commonly, organizations.
specific enzymatic assays are used. These are generally carried out
on leucocytes isolated from fresh heparinized blood samples, or on Particular populations
fibroblasts cultured from small biopsy specimens of skin; the latter While the possibility of frank consanguinity should be explored (usu-
are particularly valuable since, once established, fibroblast cultures ally from pairings between cousins), it is helpful to be aware of rare
can be stored indefinitely for repeated and definitive study. diseases that are over-​represented in small populations with high
Fabry’s disease, Niemann–​Pick disease types B and C, as well as endogamy. Examples include the high frequency of Hermansky–​
Gaucher’s disease have often come to light in young or adult patients Pudlak syndromes 1 and 3 among Puerto Ricans and certain isolated
with particular syndromic presentations. Apart from paediatricians, Swiss communities. Lysosomal diseases are also more frequent than
 12.8 Lysosomal disease 2133

expected in Ashkenazi Jews, including Hermansky–​Pudlak type 3,

Niemann–​Pick disease (type A), and type 1 (non-​neuronopathic)
Gaucher’s disease. Type 3 (chronic neuronopathic) Gaucher’s dis-
ease is frequent in parts of arctic Sweden and in one caste group
in Pakistan, among which several hundred patients have been
identified.
The high frequency of several mutant alleles of the HEXA gene re-
sponsible for Tay–​Sachs disease in Ashkenazi Jews has led to greatly
enhanced awareness of the disorder in this population, with suc-
cessful international programmes for carrier detection. The birth of
infants soon to be affected by Tay–​Sachs disease is now exceptional
in the Ashkenazim, but infantile as well as attenuated, late-​onset
forms of the disease occur with a high frequency in isolated popu-
lations such as Moroccan Jews, French settlers in Quebec (Canada),
the Cajun people of Louisiana (United States of America), and the
Canadian Metis Indian population.
Sandhoff ’s disease, due to mutations in the HEXB gene and the
other major form of GM2 gangliosidosis, is not over-​represented
in Jews but occurs at high frequency in the aboriginal population
in the district of Cordoba (Argentina) and in the Arabic followers
of the Syriac Maronite Church in Lebanon, Syria, and Northern
Cyprus.
Infantile Krabbe’s disease occurs with a very high carrier fre-
quency among the Druze people of Northern Israel and Lebanon Fig. 12.8.2 T2-​weighted MRI of the brain of a young woman with
and appears to be more frequent in Scandinavian countries and adult-​onset metachromatic leukodystrophy—​psycho-​cognitive variant.
other parts of Northern Europe but an adult variant arising from Notice the high signal intensity, especially in the frontal white matter and
a single missense mutation in the GALC gene is occurs at high fre- periventricular regions. This patient presented with bizarre behaviour
due to a frontal-​type dementia; there were no neurological signs or
quency Catania, Italy.
symptoms. Near total loss of short-​term memory with lack of planning
Radiology and higher executive functions were prominent features of her illness.

Ultrasonography, MRI, and CT may reveal visceral enlargement

Pathology
and infiltration, for example Niemann–​Pick disease, mucopoly­
saccharidoses, and Gaucher’s disease. Skeletal radiographs may Although lysosomal defects occur in all tissues, the principal focus
reveal bone expansion in vertebrae and in the phalangeal and long of each disease is manifest in those tissues with the most rapid turn-
bones, sometimes associated with infarction and collapse, par- over of the parent macromolecule of which degradation is impaired.
ticularly in Niemann–​Pick disease type B and Gaucher’s disease. For example, in Gaucher’s disease the turnover of parent glycolipids
Echocardiography may reveal thickening and calcification of the appears to be greatest in the mononuclear phagocytes. Here the ac-
cardiac valves (particularly of the aortic ring), infiltration of cardiac cumulation of glycolipids derived from the breakdown of complex
muscle causing ventricular hypertrophy in Pompe’s disease, Fabry’s sphingolipids present in white cell and red cell membranes present
disease, mucopolysaccharidoses I, IV, and VI, and, often strikingly, in the formed blood elements occurs. With mild or moderate im-
in Danon’s disease. pairment of the responsible enzyme, glucocerebrosidase (acid ß-​
Neuroradiology is informative, particularly in patients with glucosylceramidase), the pathology is restricted principally to the
mucopolysaccharidoses and in Morquio’s syndrome as well as MPS macrophage-​containing tissues of the liver, spleen, bone marrow,
syndromes I, II, and VI where instability of the atlantoaxial joint and (occasionally) the lung. When inherited defects further impair
may cause fatal subluxation as a consequence of connective tissue the activity of the enzyme, the nervous system becomes a site of dis-
disease abutting the dens. MRI of the cervical spine in MPS is critical ease: here the main source of accumulating glucosylceramide and
for assessing when to carry out posterior fusion to stabilize the joint. glucosylsphingosine is derived from the recycling of the endogenous
Similarly, investigations of the lower spine may determine the cause cellular sphingolipids, particularly gangliosides present in neuronal
of progressive spinal deformity due to lumbar kyphosis and assist in membranes.
the evaluation of the need for surgery. Microscopic pathology shows storage within dilated vesicular
MRI of the brain is invaluable in the assessment of dementing spaces, which represent diseased lysosomes. Sphingolipids, being
illnesses: cortical and/​or white matter disease may be delineated. amphipathic molecules, tend to accumulate in whorls known as
Imaging plays a key part in diagnosis of the striking white matter ‘membranous cytoplasmic bodies’ where they assume a lamellar
changes of Krabbe’s disease, multiple sulphatase deficiency, and structure within lysosomal spaces. Paracrystalline and crystal-
metachromatic leukodystrophy (Fig. 12.8.2). Extensive white matter line material in distended lysosomes may also be seen under elec-
lesions and eventual cerebral atrophy also characterize the advanced tron microscopy, for example, in the accumulation of the charged
stage of the neurological aspects of Fabry’s disease (Fig. 12.8.3). glycolipid, sulphatide, that occurs in metachromatic leukodystrophy
2134 section 12 Metabolic disorders

(a) (b)

(c)

Fig. 12.8.3 Macroscopic and microscopic appearances of the brain of a patient with Fabry disease. The patient died 15 years after a successful
renal transplant, aged 62 years and with a cardiac pacemaker, of a dementing illness having suffered multiple stroke-​like events. (a) CT examination
of the brain demonstrating extensive white matter lesions. Cerebral atrophy characterizes the advanced stage of the neurological aspects of Fabry
disease; ectopic calcification within the basal ganglia, cerebral cortex, and cerebellum is thought to locate to the media of small penetrating arteries.
(b) Postmortem examination demonstrating cortical atrophy, ventricular dilatation, and white matter focal cavitation. (c) Histological examination of
the brain demonstrating striking calcification of hypertrophic media of penetrating arteries, with associated leukoencephalopathy.
Courtesy of Dr G. Alistair Lammy, Cardiff University.

(arylsulphatase A deficiency). With more water-​soluble substrates, MPS VI); staining with a periodic acid–​Schiff reagent may reveal
granular material accumulates within the vesicular spaces. These diastase-​resistant glycolipid storage in the kidney and other organs
spaces represent distended and often fused lysosomes, filled, for ex- in Fabry’s disease and other glycosphingolipidoses. The presence of
ample, with undegraded glycogen macromolecular complexes in metachromatic storage material in nervous tissue, including periph-
acid maltase deficiency (Pompe’s disease). eral nerves, is characteristic of the sphingolipidosis, metachromatic
As emphasized earlier, the pathological manifestations of the leukodystrophy (Fig. 12.8.4). The secondary effects of lysosomal ex-
lysosomal diseases are diverse. They may range from enlargement pansion related to upregulation of lysosomal proteins through the
of viscera with infiltration by abnormal macrophages containing TFEB/​CLEAR transcriptional pathway include increased staining
storage material (foam cells of Niemann–​Pick disease or Gaucher for tartrate-​resistant (type 5) acid phosphatase, hexosamindases
cells) to bone infarction, neuronophagia, vacuolation of renal and other lysosomal markers, and intrinsic membrane proteins, for
tubular cells, and diverse tissue infiltrates. Inclusion bodies may be example, LAMP1.
observed in metachromatic-​stained cells of the urine deposit or in Ultrastructural examination is often diagnostic for lysosomal dis-
circulating neutrophils and lymphocytes (Maroteaux–​Lamy disease, eases: membrane-​bound vesicles containing storage material that
 12.8 Lysosomal disease 2135

established by confirming reduced or absent activity of the cognate

lysosomal acid hydrolase.
Specialized laboratories carry out panels of these assays depending
on the clinical details provided by the clinician. Most assay systems
are based on the cleavage of synthetic fluorescent analogues of the
natural substrate in question. Accurate clinical information greatly
assists the laboratory in deciding which enzyme activity, of many, to
assay. The usual sample is a peripheral blood leucocyte preparation
made from whole blood, although fibroblast cultures obtained from
skin biopsies or biopsy specimens of other tissues may be required.
For some conditions, including Gaucher’s disease, Fabry’s disease
Pompe’s disease and lysosomal acid lipase deficiency, accredited la-
boratories offer diagnostic assays based on dried blood spots on card.
These developments, partly initiated and funded by the pharma-
Fig. 12.8.4 Sural nerve biopsy stained with toluidine blue from a patient
with metachromatic leukodystrophy. Note the brown-​staining granular ceutical industry, have the advantage of convenience for transport to
material within Schwann cells and perineurial macrophages typical of this the diagnostic lab in a stable form, but the diagnostic performance
disorder due to the deposition of the glycolipid sulphatide. and reliability compared with conventional fluid-​phase assays car-
Courtesy of Dr J. Xuereb, Addenbrooke’s Hospital. ried out on fibroblast suspensions or blood leucocytes has yet to be
completely established. There is increasing interest in development
may show a crystalline or concentric appearance, or—​in the case of of newborn screening for lysosomal diseases, but so far this has been
glycogen in Pompe’s disease—​vacuoles with a granular appearance. limited to a few specific geographic regions, such as Krabbe’s disease
The appearance of concentric arrays of material strongly suggests in Illinois, Kentucky, Missouri, New York, Ohio, Pennsylvania, and
a sphingolipidosis. Complete absence of platelet d ​ ense granules Tennessee (all United States of America) and Taiwan (particularly
by electron microscopy is characteristic in Hermansky–​ Pudlak for Pompe’s disease).
syndromes. The biochemistry laboratory has a further role in determining
the presence and concentration of markers of disease activity.
Blood film examination Such biomarkers play an increasing role in clinical management,
Blood film examination is an often neglected but simple diag- pharmaceutical development, and research. Markers in clinical
nostic screening procedure that may indicate the diagnosis of practice include chitinase, chitotriosidase, and the chemokine
a lysosomal disease. Amorphous material accumulates within CCL18/​PARC as markers of the presence and extent of tissue in-
the lysosomal vacuoles in the ceroid neuronal lipofuscinoses, filtration by the eponymous cell in Gaucher’s disease. Particular
mucopolysaccharidoses, and glycoproteinoses. In Chédiak–​Higashi lipid substrates (including lysolipids), in addition to their puta-
disease, giant granules are readily visible in neutrophils, eosinophils, tive mechanistic role, are used as potential biomarkers for diag-
and granulocytes. nosis and monitoring therapeutic effects: the unacylated, partly
Smaller pathological bodies may be evident in circulating white water-​soluble congeners of the primary storage glycosphingolipid,
blood cells and are typical of several mucopolysaccharide diseases, lysoglobotriasolceramide, and ß-​ glucosylsphingosine are in-
particularly MPS I (Hurler–​Scheie), MPS VI (Maroteaux–​Lamy), creasingly used in the clinical monitoring of Fabry’s disease and
and MPS VII (Sly’s syndrome) diseases in which granular deep Gaucher’s disease, respectively.
lilac-​staining inclusions (the Alder–​Reilly abnormality) are readily
detected in all leucocyte subtypes after staining by the Leishman Molecular diagnosis
method. Molecular analysis of genes encoding lysosomal enzymes may often
Pathological vacuolation is prominent in peripheral blood support the enzymatic diagnosis, and may, on occasion, provide a
lymphocytes in ceroid neuronal lipofuscinosis type 3 and Pompe’s rough prediction about the behaviour of the disease. DNA-​based
disease (the latter in which the vacuoles stain with periodic studies are of particular value for future prenatal diagnosis in a par-
acid–​Schiff reagent before, but not after, exposure to diastase). ticular pedigree, and for the diagnosis of carrier status in at-​risk fe-
Lymphocyte vacuolation is reported in other lysosomal diseases males for heterozygosity in the X-​linked diseases such as Hunter’s,
(GM1 gangliosidosis, galactosialidosis, Salla disease, neuramin- Danon’s, and Fabry’s diseases.
idase deficiency, alpha mannosidosis, fucosidosis, I cell disease, and In the last 20 years, there has been a strong and justified trend
Niemann–​Pick disease type A). in favour of specific enzymatic and genetic diagnoses, rather than
those based on the examination of biopsy material by light micros-
Diagnostic biochemistry copy with or without the additional use of special histochemical
For most lysosomal storage diseases, the suspected diagnosis can stains. Ultrastructural examination of biopsy material may be of
be confirmed by biochemical studies. Storage compounds can, as particular value in recognizing the type of disorder but is rarely cru-
in the case of the glycoproteinoses and mucopolysaccharidoses, be cial for a specific diagnosis. Hitherto, histochemical and histopatho-
detected in the urine. Initial colorimetric screening methods may logical methods have led to diagnostic inaccuracies, but it must
confirm the presence of elevated concentrations of glycosaminogly- be admitted that many cases of lysosomal disease—​particularly
cans but are not specific; chromatographic separation of individual as they affect adults—​have in the past come to light as a result of
glycoconjugates will assist further. More often, the diagnosis is bone marrow examinations, liver and muscle biopsies, and other
2136 section 12 Metabolic disorders

procedures carried out in an attempt to arrive at a diagnosis in an Orphan drug development in lysosomal
otherwise puzzling condition. diseases: fortunes and misfortunes
High-​throughput diagnostic DNA sequencing is now in use in Encouraged by the success of several ‘blockbuster’ products such as
several laboratories, either in the form of single gene sequencing to recombinant human growth factors and erythropoietin, the orphan
address a unitary suspected diagnosis or ‘panels’ of genes associated drug industry has grown rapidly. An early adopter of these oppor-
with a clinical presentation of interest. Research initiatives such as tunities, Genzyme Therapeutics, the corporation that first jointly de-
the ‘100,000 Genome Project’ in the United Kingdom aim to enu- veloped macrophage-​targeted enzyme therapies with the National
merate sequence variants and predict the causative mutations in rare Institutes of Health in the United States of America, and with sub-
or unexplained metabolic conditions. Whole-​exome sequencing is stantial financial support from the National Gaucher Foundation,
also gaining traction in the practice of metabolic diseases, especially introduced highly effective treatment for this disease within the aegis
among paediatricians, but attribution of causation to innumerable of the Orphan Drug Act. By 2009, alglucerase (Ceredase) followed
sequence variants that emerge from such broad searches remains by imiglucerase (Cerezyme) for Gaucher’s disease, supplied 5000
a considerable logistical challenge and many ‘diagnoses’ cannot be patients in more than 90 countries. The company, then the third lar-
validated. gest biotechnology corporation, reported revenues of about $4 bil-
lion, of which about one-​third were due to Cerezyme; revenue from
agalsidase alfa (Fabrazyme) for Fabry’s disease was $424 million.
Treatment Commercial success on such a scale supported continuing invest-
ment in even more challenging disorders, including Pompe’s dis-
Supportive and palliative therapy ease. Delivery of the therapeutic protein Myozyme (recombinant
No specific or curative treatment is available for most of the lyso- human acid α-​glucosidase (maltase)) to a large bulk of diseased skel-
somal disorders and as a consequence, the psychological and social etal muscle, to which it is targeted by surface expression of mannose
burdens are pervasive. As discussed earlier, the organ response to 6-​phosphate residues, was a major challenge. The therapeutic de-
the metabolic defect is often stereotypical and similar to that seen in livery required administration of gram quantities of the remodelled
other diseases, with treatment limited to those supportive and pal- recombinant glycoprotein at each infusion. The scale of the manu-
liative measures shared with other chronic diseases. Occasionally, facturing resources required for the developmental Pompe’s disease
organ transplantation is required to deal with heart, liver, or kidney clinical trial programme led to a lack of secure reserve stocks of the
failure. Orthopaedic surgical techniques, such as joint replacement corporation’s leading products.
surgery and stabilization of kyphosis using Harrington rods, are By mid 2009, a vesiviral infection impaired the viability of the re-
frequently required and beneficial. Patients with obstructive hydro- combinant Chinese hamster cells in the bioreactors that synthesize
cephalus benefit from the placement of shunts for cerebrospinal Cerezyme and Fabrazyme. Manufacture was rapidly shut down
fluid. Middle ear effusions and glue ear are also treated convention- with the immediate consequence of a ‘global supply restraint’ in
ally with grommets. Physiotherapy for restricted joint movement which treatment for Gaucher’s disease and Fabry’s disease became
and muscle weakness is valuable. Mobility aids and ventilatory sup- critically limited. Many patients were without treatment for nearly
port add to the range of expensive and invasive measures required in 2 years. Fortunately, licensed products already in development
the absence of definitive treatment. were accelerated through the industrial scale-​up and regulatory
approval processes, and with expanded compassionate use and ac-
The search for specific treatments cess programmes the manufacturing void was gradually filled. Of
Lysosomal diseases have been the focus of several prominent note, the Genzyme corporation was purchased by Sanofi and full-​
therapeutic discoveries. The cooperation of informed patient scale manufacturing and its global supply capacity was restored by
groups, applied medical research funded by government organiza- late 2012.
tions, and the commercial interest of medium-​sized pharmaceut- This biopharmaceutical shut-​off of therapeutic supply was un-
ical companies has been promoted by the introduction of Orphan precedented in scale and totally unexpected. The episode revealed
Drug legislation. First enacted in the United States of America an inevitable but concealed risk associated with orphan drug legis-
in 1983, and adopted in principle in Europe in 2001, the legisla- lation. While the orphan drug initiative serves as a powerful and
tion has facilitated the early exclusive licensing of products for successful incentive for drug development in neglected diseases
rare diseases and has greatly enhanced corporate pharmaceutical with clear unmet needs, the rewards for market authorization of a
investment. first-​in-​class orphan agent with demonstrable efficacy and justifiable
Orphan diseases are variously defined as those affecting fewer safety are essentially anticompetitive.
than 1 in 2000 of the population (Europe) or fewer than 200 000 Beyond marketing credibility for any given company and the bio-
individuals (United States of America); each lysosomal disease is, pharmaceutical industry overall, there are deeper consequences of
in effect, an ultra-​orphan disorder, that is, a disease affecting fewer the events described: (1) the episode should instruct all stakeholders
than 1 in 50 000 individuals. Despite attracting great attention as of the need for any manufacturer to support and maintain adequate
a result of the high individual costs of treatment, the total national reserve stock, with shared costs as a result; (2) the value of sustained
burden of treatments for these diseases in countries with devel- competition in therapeutic development, even in the realm of ultra-​
oped healthcare systems is low (in England, the costs of specific rare; and (3) the intellectual domination of the global community as
treatments for lysosomal diseases amounts to about 0.1% of the a consequence of ‘life-​changing’ enzyme therapy in Gaucher’s dis-
health budget). ease opened up and exposed a vulnerable global patient community
 12.8 Lysosomal disease 2137

Table 12.8.2 Lysosomal diseases with approved enzyme therapies biochemical defects thus permitted an early classification of distinct
complementation groups among the MPS syndromes, often before
Disease with approved therapy Disease with trial completed but
drug not approved
the individual enzymatic defects had been characterized.
Specific receptor pathways for the biosynthesis and uptake of
Acid lipase deficiency Krabbe disease (peripheral)
Anderson–​Fabry disease Metachromatic leukodystrophy nascent lysosomal proteins during the course of organelle biogen-
Gaucher disease types I and III (intrathecal) esis have been identified: the process is usually brought about by
α-​Mannosidosis MPS type IIIA (intrathecal) the so-​called recognition marker, mannose 6-​phosphate. This ter-
MPS type I
MPS type II
minal sugar is generated by a specific mechanism involving two
MPS type IVA post-​translational modifying enzymes during the biosynthesis of
MPS type VI soluble glycoproteins destined for the lysosomal matrix. Receptors,
MPS type VII
Neuronal ceroid lipofuscinosis type II
serving as intracellular lectins for mannose 6-​phosphate ligands
Pompe disease are densely expressed on prelysosomal membranes and mediate
uptake of suitably labelled nascent proteins into the developing or-
ganelle. However, this trafficking process is not foolproof and 10 to
20% of newly formed soluble lysosomal proteins are misdirected to
to the risk of corporate collapse and treatment withdrawal, although the plasma membrane from which they are released; by the same
this nightmare scenario was avoided in this instance. token, an appreciable population of cation-​independent mannose 6-​
Current therapeutic landscape phosphate receptors is expressed on the plasmalemma, serving the
function of regulatory uptake of IGF. The ‘leakiness’ of this targeting
At present, about 20 recombinant human enzyme preparations are system represents a default pathway for lysosomal protein secretion
in use or in late clinical investigation. Several companies are ex- and recapture—​as well as mutual complementation between dif-
panding interest in this rarefied field, with additional recombinant ferent cells and tissues.
proteins (including biosimilar, modified, and semisynthetic mol- Functional complementation of lysosomal storage disorders by
ecules), small-​molecule products, and even gene therapy in robust supplying particular molecular isoforms of the enzymes that are
competitive development (Table 12.8.2). deficient in individual diseases provides a scientific justification for
The magnification of interest that has accompanied successful enzyme replacement treatment. Successful application of enzyme-​
medical research into this area has generally been a model of replacement is dependent on an understanding of glycoprotein
utility and progress. It continues to provide for many patients and chemistry, receptor-​mediated endocytosis, and the molecular cell
their families the hope that definitive relief might be forthcoming. biology of lysosomal biogenesis: identification of the secretion and
Nevertheless, given the high cost per patient, decision-​ making recapture mechanism has provided further practical underpinning.
bodies such as the United Kingdom National Institute for Health and The mannose 6-​phosphate pathway is not the only mechanism for
Care Excellence (NICE) continue to look closely at the health eco- delivering proteins to the lysosome; indeed, the first successful en-
nomic benefits of individual treatments for rare diseases, operating zyme replacement therapy for Gaucher’s disease employed human
as they do in healthcare systems that are financially constrained. glucocerebrosidase that was modified specifically to reveal ter-
Specific treatments and their mechanisms minal unphosphorylated mannose residues that greatly enhanced
delivery of the therapeutic protein to cells of the macrophage lin-
Augmentation of deficient activity eage that are the principal focus of the disease. Characterization of
Early experiments by Elizabeth Neufeld and colleagues using lysosomal recognition markers occurred at a time when other cell
fibroblasts in which glycosaminoglycans accumulate due to surface glycoprotein recognition systems were being identified: the
mucopolysaccharidoses such as Hurler’s disease (MPS I, autosomal re- asialoglycoprotein receptor, the first mammalian lectin identi-
cessive) and Hunter’s syndrome (MPS II, X-​linked), showed that the fied by Ashwell and Morell, can mediate the uptake of modified
rate of degradation—​rather than the rates of synthesis or secretion—​of plasma proteins by parenchymal liver cells in vivo. Recent studies
35S sulphate-​labelled substrate is severely disrupted. When (initially as a show that in some cells, for example, in the inner ear and brain, as
result of a laboratory error) fibroblasts obtained from these genetically well as lymphocytes (but not fibroblasts or macrophages), delivery
distinct storage disorders were co-​cultured, the pathological accumu- of nascent acid glucocerebrosidase to lysosomes is dependent on a
lation of glycosaminoglycans in lysosomes was prevented. The biosyn- unique tissue-​specific chaperone function supplied by a lysosomal
thetic labelling technique was also used to show that degradation of membrane protein (LIMP2). Mutations in the human LIMP2 gene
the substrates was restored to normal in these co-​culture experiments. appear to account for some atypical cases of Gaucher’s disease with
Further investigation of this phenomenon by the Neufeld group neurological manifestations (including myoclonic epilepsy), kidney
demonstrated that each of the fibroblast cultures elaborated and de- disease, and perplexing enzymology when examined in periph-
livered a specific corrective factor to the medium, which ultimately eral blood cells and cultured skin fibroblasts; in these patients, acid
proved to be a high molecular weight form of the hydrolases that were glucocerebrosidase deficiency occurs in fibroblasts but not leuco-
specifically lacking in fibroblasts from the corresponding disease. cytes or tissue macrophages.
These corrective factors were identified in several comparable experi-
ments using fibroblasts derived from other mucopolysaccharidoses Haematopoietic stem cell transplantation
and also several different classes of lysosomal disease; when taken Cellular complementation, by providing a source of wild-​type enzyme
up from the medium, the factors restore the impaired intracellular delivered from allogeneic bone marrow transplantation, has also had
degradation of cognate substrates. Functional correction of the spectacular successes in several lysosomal disorders. In Gaucher’s
2138 section 12 Metabolic disorders

disease, where the pathogenic cell is of haematopoietic origin, bone in Milan provide convincing evidence of some neurological benefit
marrow transplantation was effective in the past. Successful engraft- or ‘rescue’ compared with historical and sibling control patients
ment led to full correction of the biochemical defect and reversal of with early-​onset disease not so treated. It is not certain whether
most of the visceral and haematological effects of the condition that transplantation of haematopoietic stem cells from healthy matched
had not already progressed irrevocably. Now that a safer treatment related donors give comparable or inferior results. Despite the dif-
in the form of enzyme replacement is available, bone marrow trans- ficulty in determining efficacy directly in the gene therapy studies,
plantation, with its attendant risks, is very rarely indicated. remarkably the disease did not manifest or progress in the first eight
In diseases due to deficiency of soluble hydrolases, donor cells of nine patients who underwent the autologous gene therapy pro-
that repopulate the microglia (the brain equivalent of tissue macro- cedure. What is clear, however, from worldwide experience not only
phages) may participate in the secretion-​recapture mechanism, and of haematopoietic stem cell transplantation but genetically modified
in this form of cell replacement therapy would be expected to pro- autologous stem cell therapy, is that compelling clinically signifi-
vide a source of enzyme to vicinal cells. cant benefit is almost solely restricted to recipients who undergo the
Haematopoietic stem cell transplantation has shown efficacy at an intervention in the presymptomatic phase of this disease.
early stage of disease in several of the neurodegenerative lysosomal The other stratagem under active development for clinical applica-
disorders, such as Hurler’s disease (MPS I); very young infants, par- tion in the lysosomal diseases employs vectors based on the use of re-
ticularly in the immediate neonatal period, with Krabbe’s disease combinant nonpathogenic ‘passenger’ adeno-​associated picornavirus
and, as described previously, in chronic neuronopathic Gaucher’s dis- of several serotypes with preferential ability to transduce certain cell
ease. As a result of improved outcomes of the intervention in general, types, known as ‘tropisms’. These tropisms can be harnessed to facilitate
treating physicians are re-​evaluating the potential of haematopoietic delivery and expression of the cognate therapeutic transgene DNA to
stem cell transplantation in conditions where its role had previously particular tissues such as the liver or neural cells. Each vector system
been questioned, such as Hunter’s syndrome (MPS II). has potential advantages and shortcomings, which are discussed in the
suggested ‘Further reading’ material at the end of this chapter.
Gene therapy At the time of writing, several trials using direct injection of re-
Gene therapy has long been discussed in relation to lysosomal dis- combinant adeno-​associated viral vectors expressing the cognate
eases since the capacity to transduce a focus of cells using vectors corrective human proteins into the brains of children with two other
expressing the deficient enzyme or protein within a tissue is an at- neurological lysosomal diseases have been safely completed. Early
tractive possibility for sustained functional complementation. This safety and efficacy outcomes of the Sanfilippo’s disease type A (MPS
approach has shown spectacular benefit in several different spontan- IIIA) trial using rAAV rh10 have been reported: the safety criterion
eous and transgenic animal models that are genetically and clinically was met with an indication of stabilization in three of the four patients
coherent with their human counterparts. At present, two principal and possible improvement in one. Following the recent licensing of
stratagems—​both dependent on viral vectors—​are being explored the vector, a more definitive phase III trial is planned. Encouraging
in lysosomal diseases; mainly those with life-​threatening features outcomes of a phase I/​II trial using intracranial rAAV vectors serotype
including neurological disease. 5 in four children aged 20 to 53 months with Sanfilippo’s disease type B
Third-​generation lentiviral vectors are able to transduce dividing (MPS IIIB) have been reported. Not only were the safety requirements
cells such as haematopoietic stem cells and integrate into the host-​ met, but over 24 months neurocognitive progression was improved in
cell nuclear genome. Adeno-​associated viral vectors do not integrate all patients compared to that expected. N-​acetylglucosamine activity
into the nuclear DNA but remain episomal and direct biosynthesis of was detected in lumbar cerebrospinal fluid and was 15 to 20% of that
therapeutic transgene products in nonmitotic cells, including neural in unaffected children. Other phase I/​II clinical trials are in active de-
cells. In the case of haematopoietic stem cells, the genetically cor- velopment for other lysosomal diseases.
rected autologous cells of haematopoietic origin can be reinfused into
the donor after transduction ex vivo. Here after engraftment they are Enzyme replacement therapy
able to deliver the corrective protein function (wild-​type enzyme) to Discovery of the mechanism by which lysosomal proteins are delivered
the tissues in circumstances where these migratory cells of haemato- to the nascent organelle have gone hand-​in-​hand with the hope of treat-
poietic origin slowly populate the sites of disease, such as the brain ment based on the targeting of therapeutic enzymes to diseased tissues.
and spinal cord. It is believed that they give rise to macrophages and The first commercial preparation of glucocerebrosidase (alglucerase,
lymphoid cells with the potential to secrete corrective factors for up- Ceredase) was not licensed until 1991 and 1994 by the Food and Drug
take and functional complementation of local disease. Administration (FDA) in the United States of America and by the
Reconstitution of bone marrow-​ derived cells, engineered by European Medicines Agency, respectively, after decades of painstaking
lentiviral gene transfer to overexpress the wild-​type enzyme (in- research. This was purified from placentae and its glycan structure
tended to deliver an abundance of soluble enzyme), are being ex- modified enzymatically to reveal terminal mannose groups that bind
plored and efficacy has been shown in late-​infantile and juvenile the mannose receptor on cells of macrophage origin. It mitigated many
metachromatic leukodystrophy. Retroviral vectors and gene con- features of Gaucher’s disease when given parenterally.
structs were used to introduce the desired DNA sequence encoding The therapeutic and commercial success of alglucerase, along
arylsulphatase A into autologous explanted haematopoietic stem with potential difficulties in maintaining the supply of suitable
cells of young, presymptomatic subjects with metachromatic placentae, stimulated the demand for a recombinant preparation
leukodystrophy, and the genetically corrected cells were expanded (imiglucerase, Cerezyme). Expansion of the approach to include
in culture and then returned to the patient’s circulation. Phase I/​II diseases that would be targeted using mannose 6-​phosphate, the
clinical trial results reported by Dr Alessandra Biffi and colleagues more familiar lysosomal recognition marker, followed.
 12.8 Lysosomal disease 2139

Since 2001, recombinant protein therapies have become avail- cotranslational processing, it leads to an operational deficiency of
able for Fabry’s disease (two products), Hurler–​Scheie disease (MPS protein function at the point of action.
I), Hunter’s disease (MPS II), Maroteaux–​Lamy disease (MPS VI), Pharmacological chaperones are molecules which bind to mutant
Pompe’s disease (glycogen storage disease type II) and Morquio’s dis- proteins in a stable complex and thus assist delivery to the site of
ease type A (MPS IVA), and more recently lysosomal acid lipase de- action in the correct cellular compartment. In the case of lysosomal
ficiency (Wolman’s disease, the infantile form, and cholesteryl ester enzymes, the candidate chaperone molecule is usually a competitive
storage disease, the later-​onset form). Velmanase alfa (Lamzede) has inhibitor of the nascent enzyme at neutral pH and designed to dis-
recieved marketing authorisation by the European Medicines Agengy sociate from the mature lysosomal enzyme on arrival at the acidic
in 2018 for the treatment of Alpha-Mannosidosis. Trials of intra- environment of the organelle.
thecal enzyme therapy are in progress for several lysosomal disorders Pyrimethamine, a licensed oral antiprotozoal folate antagonist,
that cause neurodegeneration, including MPS II and metachromatic has chaperone-​like effects in cells harbouring some HEXA muta-
leukodystrophy. Universal availability of these treatments is limited tions from some patients with attenuated forms of Tay–​Sachs and
by their very high cost (licensed doses cost upwards of $200 000 per Sandhoff ’s diseases. This drug, which traverses the blood–​brain
annum for an average adult) and by the requirement for a sophis- barrier, has undergone small phase I/​II clinical trials in which its
ticated healthcare infrastructure to support the delivery and moni- efficacy has mainly been disappointing. However, the authors have
toring of the therapy. Thus, even imiglucerase (Cerezyme), which has seen one patient with juvenile Sandhoff ’s disease in whom pyri-
been available for over 15 years and whose efficacy is clear, is available methamine induced a large increase in enzyme activity in cultured
to fewer than 20% of patients globally for whom it is indicated. skin fibroblasts, with more mature hexosaminidase protein in the
Analogous biological products have now been approved for treat- lysosomal compartment together with partial clearance of the cog-
ment of Gaucher’s disease. Velaglucerase alfa (VPRIV) is produced nate substrate (GM2 ganglioside); improved cognitive power and
by specific upregulation of the endogenous gene sequence in a fibro- neuropsychological test scores were seen on oral exposure to the
sarcoma cell line cultured in the presence of an inhibitor of post-​ drug (with calcium folinate supplements) over a 5-​year period.
translational glycosylation to express human glucocerebrosidase Several iminosugars correct the misfolding of mutant lysosomal
decorated by high-​mannose glycans. After an extensive clinical trial glucocerebrosidases in experimental cell systems, including cul-
programme and aided by the supply limitation of imiglucerase, it tured fibroblasts obtained from Gaucher’s patients: one of these,
received marketing approval in 2010. Taliglucerase alfa is produced isofagomine, underwent clinical evaluation but failed to demonstrate
using recombinant technology in cultured carrot cells and has re- sufficient efficacy. Equally, clinical trials of single-agent chaperone-​
ceived authorization as Elelyso by the FDA in the United States of based therapy in Pompe’s disease failed to show benefit. Clinical trials
America (but not by the European Union). have completed with another iminosugar (1-​deoxygalactonojirimycin,
Two enzyme products are approved by the European Medicines migalastat) in patients with Fabry’s disease in whom in vitro studies
Agency in Fabry’s disease. Agalsidase alfa (Replagal) is generated by indicate the potential for functional enhancement of several mutant
targeted overexpression of the human AGAL gene in a human fibro- α-​galactosidase variants. One trial in treatment-​naïve subjects dem-
sarcoma cell line and is marketed at a dose of 0.2 mg/​kg every other onstrated a modest reduction in storage vacuoles on kidney biopsy. In
week. Agalsidase beta (Fabrazyme) is a traditional recombinant a separate switch study in patients already receiving enzyme therapy,
product generated in Chinese hamster ovary cells and marketed at subjects’ kidney function remained stable. In both studies, interesting
a dose of 1 mg/​kg every other week. Agalsidase alfa did not secure and potentially salutary effects were noted on left ventricular mass by
marketing approval in the United States of America. echocardiography. On the basis of these findings, migalastat received
Development continues of an alglucosidase modified by the marketing authorization in the European Union in 2016 and in the
chemical addition of mannose phosphate ligands: avalglucosidase United Kingdom has also received approval by NICE for reimburse-
alfa is in phase III trials in Pompe disease. A clinical trial programme ment. Phase three trials are in progress to examine a combination of
in Fabry’s disease using an agalsidase modified by addition of poly- a chaperone and a second-generation enzyme therapy for Pompe dis-
ethylene glycol adducts—​pegylation—​has been initiated, with evi- ease. In this case the aim of the chaperone is to act extracellularly to
dence of different biodistribution and cell uptake characteristics. improved the stability and delivery of the therapeutic enzyme.
The therapeutic position of newer enzyme products for other con- Although the use of pharmacological chaperones is an attractive
ditions will evolve, but it must be recognized that in general the con- concept for the oral treatment of lysosomal diseases, hitherto—​
ditions for which they are licensed are heterogeneous and, it appears, outside the use of neopterin in phenylketonuria and other vitamin
more intractable than the visceral and haematopoietic features of cofactors such as pyridoxine for homocystinuria—​no small mol-
Gaucher’s disease. It seems likely that internalization of glycoproteins ecule has shown true clinical efficacy in a putative misfolding disease.
decorated by mannose 6-​phosphate signals is less rapid and effective
in vivo than the uptake and delivery of those displaying terminal man-
nose residues recognized by the mannose receptor on macrophages. Restriction (or rebalancing) of substrate flux (‘substrate
reduction therapy’)
Pharmacological chaperone therapy For many years, the accumulation of storage material within lyso-
This stratagem is based on the ability of small molecules to bind to somes has been considered to be the precipitating factor for the
key regions of mutant proteins that are misfolded and thus prema- development of tissue injury and the inflammatory response that
turely degraded in the endoplasmic reticulum and Golgi network. accompanies the lysosomal storage disorders. By analogy with the
Aberrant protein folding is increasingly recognized as a molecular development of atherosclerosis due to impaired catabolism of chol-
mechanism in inherited diseases since, as a result of disrupted esterol bound to low-​density lipoproteins, it is principally a failure
2140 section 12 Metabolic disorders

of degradation or export from the lysosome that leads to the patho- P450 (CYP) genotyping since the agent is extensively metabolized
logical storage. Thus, like the statins which inhibit the first committed by the CYP2D6 and to some extent CYP3A4 systems. Eliglustat (as
step in the biosynthesis of cholesterol, the concept of depleting the Celderga) has received marketing authorization by the FDA in the
supply of macromolecular substrate to prevent the accumulation of United States of America as an oral first-​line agent for adults with
injurious material has been developed experimentally and brought type 1 (non-​neuronopathic) Gaucher’s disease, is authorized by the
to clinical practice in the sphingolipid disorders. European Medicines Agency, and is approved by NICE for reim-
Two classes of inhibitor are prominent in therapeutic bursement by the National Health Service (as in many other regions).
studies: iminosugars derived from naturally occurring compounds Eliglustat is a substrate for the P-​glycoprotein MDR1 efflux
(acting principally as sugar mimetics) and synthetic pyrrolidino com- transport system, and thus does not distribute effectively to the
pounds (acting as analogues of the ceramide moiety of sphingolipids). brain. With the recognition that there remains a large need for
small molecule drugs that traverse the blood–​brain barrier to exert
Iminosugars therapeutic effects in those lysosomal diseases with neurological
Some iminosugars related to deoxynojirimycin are inhibitors of effects, and that the biosynthesis of glucosylceramide represents
the ceramide-​specific UDP-​glucosyltransferase reaction as the first a common target for several disabling sphingolipid disorders, the
committed step in the biosynthesis of glycosphingolipids. Following Sanofi Genzyme company has identified an additional inhibitory
experimental studies in cultured cells with pathological storage of molecule, venglustat, for clinical conditions requiring systemic
glycolipids in lysosomes and in murine models of debilitating human and/​or neurological targeting. A phase I/​II clinical trial of this
glycosphingolipidoses, clinical trials of N-​butyldeoxynojirimycin agent has been completed in Fabry’s disease, and similar trials are
(miglustat, Zavesca, a particular analogue of iminosugars) were underway in adults with type 3 (chronic neuronopathic) Gaucher’s
conducted in in Gaucher’s disease. Evidence of disease regression disease and in patients with Parkinson’s disease who are heterozy-
was obtained in an open-​labelled trial with reduction in visceral en- gous for pathological mutation in the GBA1 gene. Given the bio-
largement, enzymatic markers of Gaucher’s disease activity (plasma chemical relationships of glucosylceramide with the gangliosides
chitotriosidase activity), and a slow improvement in haematological that accumulate in Tay–​Sachs and Sandhoff ’s diseases, as well as
parameters. The drug gained marketing authorization in 2002 as an GM1 gangliosidosis, chronic forms of these neurological diseases
orally active second-​line treatment for type 1 Gaucher’s disease in are potential therapeutic targets for this drug class.
adults unable or unwilling to receive enzyme therapy. Although ap-
proved as a first-​in-​class inhibitor of substrate biosynthesis, further
research now suggests that among the off-​target effects of miglustat, Examples of lysosomal disorders
its action as a more potent inhibitor of a neutral glucocerebrosidase
involved in sphingolipid recycling contributes to its therapeutic ef- Gaucher’s disease
fects in non-​neuronopathic Gaucher’s disease. This disorder may occur at any age and has been regarded as the
Since the iminosugars are small molecules with the potential to most frequent of the lysosomal storage diseases, although recent
penetrate the blood–​brain barrier, the possibility of their use (either evidence suggests that Fabry’s disease, particularly in its attenu-
as a monotherapy or as a synergistic treatment with enzyme therapy) ated forms, is substantially more frequent. The condition is usu-
for neuronopathic Gaucher’s disease has been raised, as well as for ally due to a catalytic deficiency of glucocerebrosidase, although
the treatment of the otherwise intractable glycosphingolipidoses that rare cases of deficiency of its cognate sphingolipid activator protein
cause severe neurological disease. However, miglustat was found not (SAP-​C) may cause a severe disorder usually similar to the subacute
to be effective in young patients suffering from the neurological ef- neuronopathic form of true Gaucher’s disease. Numerous mutations
fects of type 3 (chronic neuronopathic) Gaucher’s disease who were responsible for the enzymatic deficiency have been identified in the
receiving imiglucerase, but it appeared to improve pulmonary mani- human glucocerebrosidase gene and the reader is referred to the
festations which usually fail to respond to enzyme therapy alone. specialist literature for those genotype/​phenotype correlations that
Miglustat has also received marketing authorization in Europe for broadly apply to this protean disorder. The mature protein contains
treatment of Niemann–​Pick disease type C, having shown delay in 497 amino-acid residues; a 39 amino-acid lead peptide is cleaved
progression of the neurological features in a randomized, open-​label from the initially-translated polypeptide that contains 536 initial
clinical trial. amino acids. A recent change in nomenclature now considers the
position of amino-acids relative to the beginning of the 536 amino-
Synthetic pyrrolidino compounds acid peptide, rather than the 497 amino-acid mature protein. Thus
Eliglustat, a pyrrolidino compound that is a ceramide analogue with the most frequent mutations, known previously as N370S and L444P,
a highly selective and potent inhibitory action on glucosylceramide are now referred to as p.Asn409Ser and p.Leu483Pro respectively.
biosynthesis, has demonstrated strong therapeutic effects in non-​
neuronopathic Gaucher’s disease. Encouraging 4-​year phase III and Gaucher’s disease type 2 and type 3
8-​year phase II clinical studies and 1400 patient-​years of clinical Rarely, infants are born with an almost complete lack of gluco­
trial exposure support its position for most adult patients with type cerebrosidase activity: they die within a few days of birth or are still-
1 (non-​neuronopathic) Gaucher’s disease as an alternative first-​line born due to skeletal deformities and/​or dehydration as a result of
agent to enzyme therapy. The oral activity in once-​or twice-​daily loss of skin integrity (collodion babies).
dosing, represents an important advantage over intravenous infu- Infantile Gaucher’s disease (classified as acute neuronopathic or
sions of enzyme therapy given every 2 weeks. Prescription requires type 2 disease) is a rare neuronopathic disease with bulbar palsy,
specialist monitoring, with dosing guided principally by cytochrome opisthotonus, and minor visceral enlargement. It is invariably fatal
 12.8 Lysosomal disease 2141

in the first 2 years of life and does not respond to either systemic or
intrathecal enzyme replacement therapy.
While neurological disease may occur in children, adolescents,
and young adults with Gaucher’s disease, it is less severe than in the
infantile variant and is termed subacute neuronopathic or type 3 dis-
ease. In such patients the disease is associated with supranuclear gaze
palsies, ataxia, nerve deafness, myoclonus, and (occasionally) seizures.
In type 3 disease the neurological condition usually deterior-
ates slowly but is exacerbated if splenectomy is performed for the
accompanying splenomegaly and associated pancytopenia. Where
possible, and with vigorous enzyme therapy, splenectomy is best
avoided, although partial splenectomy may be carried out to ameli-
orate pressure effects and life-​threatening thrombocytopenia.
Subacute neuronopathic disease is not always fatal and often
improves with bone marrow transplantation and enzyme replace-
ment therapy, although the effects of the latter are restricted to the
systemic, non-​neurological aspects. Affected children may show
striking visceromegaly, with the associated gaze palsies often playing
a small part in the clinical presentation.
Fig. 12.8.5 T2-​weighted MRIs obtained from the lower femur and
Although juvenile subacute neuronopathic Gaucher’s disease upper tibia of a 30-​year-​old woman with non-​neuronopathic Gaucher’s
(type 3) occurs sporadically in all populations, there is a small iso- disease experiencing pain due to acute avascular necrosis of bone. Note
late in Northern Sweden where all individuals are homozygous for the geographical areas of increased signal intensity on the T2-​weighted
a single point mutation in the glucocerebrosidase gene (L444P) that image due to increased tissue water representing oedema surrounding
has arisen by descent from a common ancestor. the necrotic tissue.
Courtesy of Professor D. Lomas, Addenbrooke’s Hospital.
Gaucher’s disease type 1
The most frequent form of Gaucher’s disease is the so-​called adult
non-​neuronopathic form (type 1). This is found in all populations
but is over-​represented in Jews of Ashkenazi origin. Although the
condition does not commonly affect the nervous system, visceral
and skeletal manifestations are prominent.

Clinical features
Characteristically, Gaucher’s disease presents with pancytopenia,
with bleeding due to thrombocytopenia and splenic enlargement.
Acutely painful episodes also occur in the bones, particularly
during growth, and these episodes are followed by the evolving
MRI appearances of osteonecrosis with consequential effects on
the integrity of large joints, including the hip, knee, and shoulder
(Fig. 12.8.5). The increased frequency of infarction events is an
important aspect of Gaucher’s disease that, as yet, has not been ex-
plained, and bone necrosis remains an aspect of the condition that
often persists despite enzyme therapy.
In the era before enzyme replacement therapy, splenectomy was often
carried out during childhood to relieve the pressure effects of the en-
larged organ and to ameliorate the effects of accompanying cytopenias.
Although there appears to be a striking temporal association between
splenectomy and the development of severe bone disease, it is unclear
as to whether this is directly due to the effects of the splenectomy or the
consequential manifestations of disease severity. Nonetheless, splen-
ectomy is best avoided where at all possible. Splenectomy in Gaucher’s
disease carries a greatly enhanced risk of overwhelming infection;
this includes infection with protozoa, such as babesia and malaria, as
well as capsulated bacteria, for example, Streptococcus pneumoniae,
Haemophilus influenzae, and Neisseria meningitidis.
Fig. 12.8.6 Expanded lytic lesion at the distal end of the femur in a
In addition to the effects of osteonecrosis, the osseous manifest- 44-​year-​old woman with severe Gaucher’s disease complicated by
ations of Gaucher’s disease are very diverse and include the presence osteoporosis, osteonecrosis, and, as shown, expanded lytic lesions in long
of expanded bone lesions (Fig. 12.8.6) with surrounding cortical bones leading to local infiltration of the marrow space by Gaucher tissue.
2142 section 12 Metabolic disorders

thinning related to Gaucher cell infiltrates within the bone marrow the mutant alleles. The odds ratio for any glucocerebrosidase mu-
(‘Gauchomas’). Diffuse osteoporosis accompanied by pathological tation in patients with Parkinson’s disease compared with controls
fractures may also compound the skeletal manifestations. Kyphosis was 5.43. When compared with patients with Parkinson’s disease
due to crush fractures of vertebrae are common in untreated adults, who did not carry a GBA mutation, those with a mutation had
particularly in postmenopausal women. an earlier presentation with the disease, were more likely to have
Gaucher’s disease may rarely be associated with pulmonary infil- affected relatives, and were more likely to have atypical clinical
trates, including reticulonodular opacities, restrictive lung defects, manifestations.
and various abnormalities of the pulmonary circulation, causing
Relationship to B-​ cell malignancy Gaucher’s disease abnor-
pulmonary hypertension. The hepatopulmonary syndrome, ac-
malities include a polyclonal immunoglobulin response that may
companied by platypnoea and associated with severe scarring liver
progress to monoclonal gammopathy, amyloidosis, or even frank
disease or cirrhosis and portal venous hypertension, has also been
myeloma and B-​cell lymphoma, with an estimated 20-​to 40-​fold in-
reported in severely affected adults.
creased risk compared with heathy subjects without Gaucher’s dis-
In its untreated state, Gaucher’s disease is a miserable condi-
ease. These malignant complications are now an important cause of
tion leading to progressive skeletal deformity, pancytopenia, and
death in adult patients with type 1 Gaucher’s disease. Their cause
visceral enlargement with failing organ function punctuated by
appears to be related to the clonal expansion of B cells that specif-
painful visceral bone crises. The mean age of death in a single
ically secrete antibodies directed against the pathological complex
large series reported from Pittsburgh, Pennsylvania, was 60 years
lipids and that are driven, at least initially, by a subclass of follicular
during the pretreatment era, but this does not take into account
B helper T cells (TFH2) recognizing the glycosphingolipids presented
the poor quality of life of most affected individuals. Some homo-
by the CD1d molecule.
zygotes for ‘mild’ missense mutations in the glucocerebrosidase
gene (especially the widespread mutation, N370S) may escape Other plasma and metabolic abnormalities Low-​density lipopro-
detection and remain asymptomatic throughout a long adult life. tein and high-​density lipoprotein cholesterol fractions are abnormal
Detailed investigation reveals only a mild thrombocytopenia in the plasma. Basal metabolic rate is increased. Some lysosomal
and trivial splenomegaly in some cases. However, monoclonal enzymes are elevated, including tartrate-​ resistant acid phos-
gammopathy is frequently present after the age of 45 years. It is phatase, hexosaminidase, and a human chitinase, chitotriosidase.
uncertain as to what extent the presence of such mutations in the Chitotriosidase may reflect the severity of the disease and has
population at large (homozygosity for N370S occurs in about one proved to be very useful for monitoring Gaucher’s disease activity
in 960 Ashkenazi Jews) contributes to the development of β-​cell in response to treatment. The enzyme is elevated, sometimes several
lymphoproliferative disorders, such as B-​cell lymphoma and mye- hundredfold above normal, in the untreated condition.
loma, in this at-​risk group.
Pathology
Other clinical aspects The pathognomonic abnormality is the presence of large storage
Parkinsonism and Gaucher’s disease—​ a complex relation- cells, which are activated macrophages (Gaucher cells), typically
ship Approximately 5% of patients develop extrapyramidal found in the splenic sinusoids. The Gaucher cells (Figs. 12.8.7 and
disease resembling parkinsonism in middle life. The response 12.8.8) replace the Kupffer cells of the liver, alveolar macrophages of
to dopaminergic agents is often less clear than in classical idio- the lung, and in the bone marrow.
pathic Parkinson’s disease and the disorder may progress more
rapidly. This complication may reflect the emerging strong but ill-​
understood relationship between mutant glucocerebrosidase al-
leles and Parkinson’s disease and especially Lewy body-​associated
diseases and α-​synucleinopathies in several populations: heterozy-
gous mutations in the gene encoding glucocerebrosidase represent
the commonest single genetic association with Parkinson’s disease
in all populations studied. It appears that there is at most a small
gene-​dosage effect and Parkinson’s disease appears to be little more
frequent in patients with Gaucher’s disease than in their heterozy-
gous parents.
An international study by Sidransky and colleagues involved
the search for two frequent missense GBA1 mutations, L444P and
N370S, in patients with Parkinson’s disease attending 16 centres.
A total of 5691 patients with Parkinson’s disease (780 Ashkenazi
Jews) and 4898 control subjects (387 Ashkenazi Jews) were geno-
typed. Among Ashkenazi Jewish subjects, either mutation was
found in 15% of patients but only 3% of control subjects; among
non-​Ashkenazi Jewish subjects, either mutation was found in 3% Fig. 12.8.7 Light micrograph of a Leishman-​stained bone marrow
biopsy obtained from a 23-​year-​old man with type 1 Gaucher’s disease.
of patients and less than 1% of controls. GBA1 was fully sequenced Note that the large, pale-​blue staining Gaucher cells with striated
in 1983 non-​Ashkenazi Jewish patients, and mutations were iden- cytoplasm replace the Kupffer cells of the liver, alveolar macrophages of
tified in 7%, showing that limited mutation screening can miss half the lung, and of the bone marrow.
 12.8 Lysosomal disease 2143

is reconstituted for intravenous infusion, given most commonly

every 2 weeks. After a few weeks of enzyme administration, most
patients show an improvement in the blood parameters of disease
activity and a reduction of the chronic inflammatory response
that accompanies the condition. The platelet count rises and there
is correction of the hypersplenic blood picture, with reduction in
hepatosplenomegaly. There is improvement in asthenia and quality-​
of-​life measures. Similar salutary effects are noted with the use of the
more recently licensed enzyme therapies.
Since most patients express the protein antigen endogenously,
hypersensitivity and immune reactions are very rare. Apart from
the inconvenience of periodic intravenous infusions, treatment is
well tolerated and many patients in Europe and the United Kingdom
choose to take their treatment as self-​ administered infusions
at home.
Fig. 12.8.8 Electron micrograph showing the cytoplasm of a Gaucher Controversy remains as to the appropriate dose of enzyme
cell in the spleen of a 56-​year-​old man removed because of life-​ therapy, whether in the form of imiglucerase or the newer products
threatening thrombocytopenia and pain due to a recent splenic infarct. velaglucerase alfa or taliglucerase, but most authorities agree that
Note the vesicular spaces filled with fibrillary glycolipid storage material.
administration of the enzyme should be lifelong. There are several
schools of thought as to whether enzyme therapy should be admin-
Diagnosis istered at a high dose to start with, perhaps then reducing as evidence
of disease regression becomes clear, or whether a more variable but
The diagnosis of Gaucher’s disease is based on white-​cell acid
lower dose be given and altered according to response. Disease
β-​glucosidase activity, which may be accompanied by the elevation
activity is assessed by objective parameters, including visceral en-
of one or more related marker enzymes such as chitotriosidase or
largement, and by determination of surrogate biomarkers such as
tartrate-​resistant acid phosphatase in the serum. Spleen tissue, liver
chitotriosidase and blood counts. The application of simple defined
biopsy material, or bone marrow aspirates may show the character-
therapeutic goals with close monitoring of individual patients has
istic oligonucleate storage cells demonstrating striated cytoplasm on
much to recommend it. Achievement of key goals and amelior-
Leishman staining (Fig. 12.8.7), but which appear as pink sheets in
ation of disease-​associated parameters is more rapid when high-​
tissue sections stained with haematoxylin and eosin. Molecular ana-
dose enzyme therapy is administered. In patients with the subacute
lysis of the glucocerebrosidase gene may identify widespread mutant
neuronopathic form of the condition (type 3), international guide-
glucocerebrosidase alleles and may assist in the diagnosis and inves-
lines suggest that a dose of at least 60 units of enzyme/​kg bodyweight
tigation of family members at risk for this recessive disorder.
per month is necessary to secure disease regression. This is very ex-
Treatment pensive, costing as much as £200 000 per year for an adult.
Until recently, the treatment for Gaucher’s disease was palliative. Substrate reduction therapies
Bone marrow transplantation has been undertaken in a few infants
Miglustat When taken for several months, miglustat (Zavesca;
and children with rapidly progressive disease, including those with
N-​butyldeoxynojirimycin) appears to reduce the content of gan-
the subacute neuronopathic form type 3. When successful, this may
gliosides in circulating white cells and has salutary effects on key
correct most of the systemic manifestations of the condition and
laboratory and clinical parameters of Gaucher’s disease activity. It is
restore growth, and some observers believe that it may arrest fur-
licensed in the United States of America and Europe for use in mild
ther neurological deterioration. However, bone marrow transplant-
to moderate type 1 Gaucher’s disease, albeit with certain restric-
ation is no longer in routine use because of the accompanying severe
tions. Short-​duration unwanted effects (including diarrhoea due to
risk resulting from the procedures and constraints in the supply of
inhibition of intestinal disaccharidases) are frequent, although they
donors, especially MHC-​matched, first-​degree relatives. Steady im-
usually respond well to dietary adjustments. The occurrence of per-
provement in the outcome of stem cell transplantation in general
ipheral neuropathy after long-​term administration may restrict the
raises the possibility that this stratagem could be re-​evaluated in
indications for its use. A trial to determine whether or not Zavesca
patients with chronic neuronopathic Gaucher’s disease in circum-
is inferior to maintenance therapy with Cerezyme in patients with
stances where health services resources will not sustain the long-​
type 1 Gaucher’s disease after stable control of their disease who then
term costs of high-​ cost molecular therapies (whether enzyme
switch to the oral agent has shown that for some patients the disease
therapy or other potential chronic therapies should, for example,
remains stable, but many discontinued the medication either as a re-
venglustat prove to be safe and effective).
sult of adverse effects or re-​emergent features of disease.
Enzyme augmentation therapy Eliglustat In the ENGAGE trial, 40 patients were randomized
Enzyme augmentation therapy was introduced during the early to eliglustat or placebo for 9 months. Salutary changes in the key
1990s in the form of a natural product extracted from the human parameters of spleen and liver volume, haemoglobin, and platelet
placenta, alglucerase (Ceredase). The recombinant glycoform, count were observed, to the degree expected of enzyme therapy.
imiglucerase (Cerezyme), is supplied as a lyophilized powder which In the ENCORE study, 160 patients were randomized to receive
2144 section 12 Metabolic disorders

eliglustat (n = 106) or continued enzyme therapy (n = 54) after at The acroparaesthesias are often attributed to Raynaud’s phenomenon,
least 3 years of enzyme therapy. The trial met its primary endpoint which is indeed associated with Fabry’s disease, but this relationship is
demonstrating noninferiority of eliglustat in composite haemato- unclear. Nonetheless, many of the symptoms of Fabry’s disease can be
logical and visceral parameters over 12 months, and 4-​year follow-​ explained by neuropathy affecting autonomic nervous tone.
up data showed safe stabilization in most patients. Use is restricted Patients with Fabry’s disease have disturbing gastrointestinal
to individuals who are not ultra-​rapid metabolizers of the drug by symptoms, characterized by diarrhoea shortly after eating; attacks of
the CYP2D6 enzyme. Complex drug–​ drug interactions require abdominal pain associated with unexplained fever also occur. These
careful prescribing practice, but safety and tolerability have been ac- abdominal symptoms may also be related to autonomic neuropathy.
ceptable in the clinical trial programme, with no sustained or major Most men with established ‘classical’ disease notice a striking ab-
safety concerns hitherto. sence of peripheral sweating, and often suffer erectile dysfunction.
They often have a characteristic facial appearance (Fig. 12.8.9).
Other aspects of treatment High-​tone loss of hearing is also a common feature of Fabry’s dis-
Treatment for Gaucher’s disease should include appropriate immun- ease, which appears to reflect selective injury to cochlear neurons.
ization and antimicrobial prophylaxis in the fortunately diminishing Affected male hemizygotes have small, raised, red vascular skin le-
number of patients who have undergone splenectomy. Osteoporosis sions (angiokeratomas) particularly around the buttocks and genital
may be an indication for bisphosphonate drugs. Patients may require region (Fig. 12.8.10). These lesions are often detected in limited
joint replacement surgery to ameliorate the effects of bone infarction areas of affected heterozygous females and reflect X-​chromosome
crises and, in rare instances, liver transplantation for end-​stage liver inactivation patterns in the skin.
disease. All surgical procedures carry a risk of haemorrhage in the With increasing age, progressive tubular, interstitial, and glom-
face of thrombocytopenia, platelet dysfunction, or blood coagula- erular disease leads to proteinuria and renal failure. Many patients
tion factor abnormalities. It is thus critically important to engage require renal support, including haemodialysis, peritoneal dialysis,
expert assistance from a haematologist in planning surgical inter- or kidney transplantation.
ventions. Bone marrow transplantation probably does not have a Cardiac hypertrophy, especially of the left ventricle, occurs with
role today, except in rare circumstances. conduction defects leading to a shortened PR interval and a pro-
Evidence of metabolic bone disease complicating the disorder longed QRS complex, later accompanied by tachyarrhythmias and
should be always sought and osteoporosis should be treated promptly complete heart block. Left ventricular hypertrophy may be associ-
with enzyme replacement therapy, with the additional consideration ated with functional limitation due to diastolic dysfunction. The use
of orally active or parenteral bisphosphonates. Where present, a defi- of MRI has drawn attention to typical patterns of fibrosis in the mid-​
ciency of 25-​hydroxyvitamin D should probably be treated with ap- wall of the myocardium in particular regions of the left ventricle.
propriate supplements. Some patients develop deficiency of vitamin This fibrosis may progress in the absence of cardiac hypertrophy,
B12 and this should be sought for and treated promptly. particularly in women. It is associated with risk of arrhythmia and
On account of the increased risk of infection due to intrinsic reduced response to specific therapy.
chemotactic and phagocytic defects as well as splenectomy, patients There is an increasing recognition of variant forms of Fabry’s
with Gaucher’s disease undergoing surgery or with systemic infec- disease, which appear to be predominantly manifested by
tion should be promptly treated, preferably with parenteral anti- cardiomyopathy—​ without the ‘classical’ acroparaesthesia,
microbial agents. anhidrosis, and angiokeratomas—​in older patients with appreciable
residual α-​galactosidase activity.
Fabry’s disease Disease of capillaries and medium-​sized vessels in the brain is
Fabry’s disease is an X-​linked disorder, unlike many of the lyso- associated with unusual microvascular changes, particularly in the
somal diseases, apart from Danon’s and Hunter’s disease (MPS posterior cerebral circulation, and also causes stroke.
II). Deficiency of α-​galactosidase A causes the accumulation of Disease expression in many carrier females, who may rarely de-
ceramide trihexoside (otherwise known as globotriaosylceramide) velop renal failure, is often accompanied by angiokeratomas that are
and related compounds including the deacylated equivalent lyso-​ seen to be restricted to certain dermatomes on careful examination,
GB3, which principally derives from the breakdown of lipids present and asymptomatic corneal opacification with whorl-​like cataracts
in senescent red cells. A notable feature is the presence of clinical on slit-​lamp examination.
signs and symptoms in most heterozygous female carriers of the Sudden cardiac arrhythmias, stroke, and renal failure are the most
condition. Although these manifestations are usually less severe common causes of death in patients with Fabry’s disease. In men with
and of later onset than in affected hemizygous males, florid and life-​ the classical form of the condition and in the absence of specific or
shortening clinical disease has often been observed (and ignored) in supportive treatment, death occurs at a median age of 48 to 49 years,
affected women. with a greatly reduced quality of life during the antecedent symp-
tomatic period. Life expectancy in affected heterozygous women
Clinical features and prognosis is also shortened. Sometimes the lancinating acroparaesthesias are
The most characteristic symptoms of the ‘classical’ or severe form of sufficient to cause severe depression and even suicide.
the disease, usually indicative of absent or very low enzyme activity,
are the onset in early childhood of lancinating pain with background Diagnosis
burning sensations in the extremities that are made worse by exercise Diagnosis is made by demonstrating the abnormal glycolipid in
and exposure to extremes of temperature. These attacks can be very urine or plasma, as well as by assay of α-​galactosidase A in tears,
disabling and represent neuropathic pain, which is difficult to control. plasma, white cells, dry blood spots, or other tissue material.
 12.8 Lysosomal disease 2145

(a) (b) (c)

(d) (e) (f)

(g) (h) (i)

Fig. 12.8.9 Facial images of nine men with the classical form of Fabry disease; although subtle, the facial appearances include periorbital
oedema, depressed nasal bridge, prominent brow ridge, and full lips.
2146 section 12 Metabolic disorders

(a) (b)

Fig. 12.8.10 Two patients with Fabry disease showing (a) diffuse telangiectatic lesions over
flank and abdomen, and (b) hemispheric papules in suprapubic area.
Reproduced with permission from Mulliken J. Capillary Malformations, Hyperkeratotic
Stains, Telangiectasias, and Miscellaneous Vascular Blots. From: Mulliken and Young's Vascular
Anomalies: Hemangiomas and Malformations, 2nd edition. Ed. John B. Mulliken, Patricia E. Burrows, and
Steven J. Fishman. 2013. Courtesy of Dr Harley A. Haynes.

Molecular analysis of the α-​galactosidase A gene on the long arm of renal function, and ventricular mass, as well as conduction defects
the X chromosome is worthwhile because it allows the unambiguous that represent infiltrative cardiomyopathy, but substantial reversal of
detection of female heterozygotes and may thus be useful during the established organ malfunction has not been achieved.
reproductive period, particularly for antenatal diagnosis. Despite Unlike Gaucher’s disease, targeting to the affected cells and tis-
the presence of active disease, ceramide trihexoside concentrations sues in Fabry’s disease probably results from receptor-​mediated
and α-​galactosidase A assays are often within normal limits in af- uptake of protein molecules harbouring the common lysosomal
fected female heterozygotes. recognition marker, mannose 6-​phosphate, a less efficient and less
specifically targeted system. In one remarkable instance, therapy
Treatment
with galactose infusions appears to have mitigated this condition by
Supportive care stabilizing the nascent mutant enzyme, thereby enhancing residual
Hitherto, the treatment for Fabry’s disease has been palliative, α-​galactosidase A activity with slow clearance of cardiac glycolipid
involving the use of anticonvulsants (including gabapentin) for the storage. Clinical trials of the pharmacological chaperone1-​
acroparaesthesias and neuropathic pain. Gastrointestinal symptoms deoxyglactonojirimycin, migalastat, which is predicted to stabilize
sometimes respond to antimotility agents or to pancreatic enzyme certain residual α-​galactosidase A variants in Fabry’s disease and, by
supplements, but these agents have not been subjected to controlled preventing misfolding, increase their delivery to the lysosome, have
trials. Renal failure is managed by dialysis or by renal transplant- been reported.
ation; occasionally, cardiac transplantation has been required for In patients naïve to therapy, who were found to have mutations
cardiomyopathy; pacemakers and antiarrhythmic drugs may also be amenable to the chaperone effect, statistically significant albeit
needed. modest reductions in the storage material were seen on histological
analysis of kidney biopsy samples. In patients already on enzyme
Specific therapies therapy, a further trial demonstrated that no additional decline
To date, two preparations of recombinant human α-​galactosidase in renal filtration function took place in the group randomized to
A have been licensed: agalsidase-​alfa (Replagal—​not approved in the migalastat. In both trials, reductions in left ventricular mass index
United States of America) and agalsidase-​beta (Fabrazyme). These were observed, although the full therapeutic meaning and clin-
may differ slightly in their post-​translational glycosylation status for ical impact of this finding needs to be established. Migalastat has
delivery to endothelial, epithelial, and other cells that represent the received marketing approval in the United States of America and
pathological focus of this disease. Administration of these prepar- Europe. Because of its distinct mechanism of action, which requires
ations to male hemizygotes has improved lipid accumulation in the the binding of this inhibitory molecule to the active site of the en-
plasma and in renal biopsy samples. Both products have also been zyme to achieve better folding, the drug is given in an alternate-​day
shown in double-​blind, placebo-​controlled trials to improve clinical regimen to permit disengagement of the inhibitor from the enzyme
endpoints of the disease, including neuropathic pain, stabilization of once it has reached the lysosome.
 12.8 Lysosomal disease 2147

Mucopolysaccharidoses
These disorders are caused by a deficiency of lysosomal hydrolases
that catalyse the cleavage of complex glycosaminoglycans, which are
macromolecular components of connective tissues including joints,
bones, heart, and major arteries. Clinical manifestations of each of
these disorders reflect an individual enzymatic deficiency and the
resulting accumulation of mucopolysaccharide derivatives, of which
dermatan-, keratan-, chondroitin-, and heparan sulphates are the
principal components. In general, the accumulation of the complex
substrates that are normally linked to proteins to form proteoglycans
is associated with visceral enlargement, heart valve disease—as well
as bony abnormalities, joint stiffness, corneal clouding and short
stature. The accumulation of heparan sulphate may particularly be
associated with the development of brain disease, including thick-
ening of the leptomeninges, hence hydrocephalus is an often neg-
lected factor in cerebral impairment that may also be attributed to
lysosomal storage affecting neurons of the brain and peripheral gan-
glia as well as the retina.

Clinical features and pathology

Typically, these disorders are associated with coarse facial features Fig. 12.8.12 Twenty-​year-​old female patient with Morquio A syndrome
(MPS IV) with marked skeletal deformity and growth retardation.
(Figs. 12.8.11 and 12.8.12), bone shortening, and skeletal abnor-
malities, as well as disturbances of dentition, the gums, and middle
ear. Abnormalities of the tracheobronchial cartilages and upper air- Excess urinary excretion of glycosaminoglycan products,
ways may be associated with respiratory infections and obstructive including dermatan sulphate and heparan sulphate, character-
lung disease. The coronary arteries and cardiac valves may be infil- istically occur in the mucopolysaccharidoses. This abnormality
trated by glycosaminoglycans, leading to coronary artery occlusion should immediately prompt further investigations by enzymatic
and aortic and mitral valve malfunction. Similar changes may occur and genetic studies in blood leucocytes and/​or fibroblasts obtained
in peripheral arteries, particularly those supplying the viscera. In from cultured skin biopsy samples. The inheritance pattern of the
the eye, the basal layers of the cornea show swelling, cytoplasmic mucopolysaccharidoses is typical of autosomal recessive traits with
vacuolization, and storage granules leading to opacification. Scleral the exception of Hunter’s disease (MPS II, which is due to iduronate
thickening may impinge upon the optic nerve. sulphatase deficiency) that maps to the X chromosome and is ex-
pressed predominantly in boys and men. Female heterozygotes for
Hunter’s disease only very rarely show evidence of neurological im-
pairment or connective tissue abnormalities.

Treatment
Palliative treatment is a very important aspect of the management of
these diseases and should include the provision of multidisciplinary
support for children and young adults with the accompanying devel-
opmental disabilities. Sustained provision for the long-​term man-
agement of the condition in affected families is desirable.

Surgical procedures
Corneal transplantation may be required to improve vision where
retinal degeneration is not dominant. Carpel tunnel syndrome with
compression neuropathy of the median nerve is very common and,
when indicated, surgical treatment is often beneficial.
Particular care is required in patients with mucopolysaccharidoses
such as Hurler’s syndrome when surgical procedures under general
anaesthetic are required for relief of hydrocephalus, myringotomy,
hernia repair, relief of airways obstruction due to laryngeal disease,
and corrective spinal or joint surgery. Infiltration of the soft tissues
of the upper and lower airways, as well as the heart and cervical
Fig. 12.8.11 Facial image of a male patient aged 20 years with MPS spine (which may include subluxation of the atlanto-​occipital joint),
I (Hurler’s syndrome) who underwent a bone marrow transplant at the is associated with high perioperative mortality. Tracheostomy may
age of 1 year; some coarsening of the facial appearance persists. be required to avoid life-​threatening complications of intubation,
2148 section 12 Metabolic disorders

but complications may arise with general anaesthesia beyond that Questions still arise of how clinical benefits and an improved
of difficulties with endotracheal intubation. Extensive preoperative quality of life can be best assessed. However, encouraging results
assessment should therefore be conducted whenever an anaesthetic showing an improved quality of life, mobility, nutrition, and educa-
is required for any procedure, particularly to assess the stability of tional achievements have already been documented in several MPS
the atlantoaxial joint, the airway, and the presence of coronary artery disorders in response to enzyme therapy, even where pre-​existing
disease (that may predispose to perioperative myocardial infarc- developmental effects and mental retardation are established.
tion). Where possible, an anaesthetist experienced in the manage-
ment of patients with MPS disorders should be consulted. Pompe’s disease
Glycogen storage disease type II, due to acid maltase deficiency,
Specific treatments otherwise known as Pompe’s disease, is an autosomal recessive dis-
order of glycogen metabolism caused by deficient activity of lyso-
Bone marrow transplantation Bone marrow transplantation
somal acid maltase—​α-​glucosidase. Acid maltase deficiency was the
using HLA-​identical sibling and HLA-​matched nonsibling donors
first of the lysosomal storage diseases to be so characterized by H.-​G.
has been investigated extensively in the mucopolysaccharidoses.
Hers, a colleague of de Duve. The disease occurs in many countries
Long-​term clinical trials have confirmed the beneficial effects of
and ethnic groups. The prevalence of this disorder is one in about
successful transplantation with reversal of hepatosplenomegaly
150 000 and males and females are affected equally.
and obstructive airways disease. In some cases there is improved
longevity, with a possible reduction also in the incidence of sec- Clinical features and pathology
ondary hydrocephalus. However, at present, transplantation does
Pompe first reported infants with massive cardiac hypertrophy and
not cure the condition and is unable to reverse established brain
skeletal weakness with hypotonia, enlargement of the tongue and
injury and most of the crippling skeletal manifestations. If it is to
liver, and a uniformly fatal outcome. Acid maltase releases glucose
be considered, bone marrow transplantation should therefore be
units from the carbohydrate storage macromolecule, glycogen, as
carried out early in the course of these diseases. The therapeutic
well as from the disaccharide, maltose. The enzyme is profoundly
position of bone marrow and cord blood-​derived stem cell therapy
deficient in infants with Pompe’s disease and partial deficiencies in
is most clearly established for Hurler’s disease (the more severe
the enzyme, detectable in all cells, are responsible for later-​onset
variant of MPS I).
forms in children, adolescents, and adults. No clear correlation be-
Enzyme replacement therapies Enzyme replacement therapy has tween the degree of enzyme deficiency and the severity of disease is
long been under investigation in MPS I (Hurler’s syndrome, Hurler–​ possible.
Scheie syndrome, and Scheie’s syndrome), which was one of the first Pathological accumulation of glycogen within vacuolar lyso-
of such disorders to be subjected to intensive laboratory study. In somal spaces occurs in skeletal muscles and (on occasion) other
clinical trials, recombinant human α-​l-​iduronidase, now licensed tissues, but it is noteworthy that in certain muscles, microscopic
as laronidase (Aldurazyme) given by weekly infusion intravenously, examination may be normal or show only trivial abnormalities,
after 1 year clearly showed a reduction in lysosomal storage: liver especially in patients with late-​onset disease. Hence, the diagnosis
volume decreased and there was an improved rate of growth as well of late-​onset Pompe’s disease may be difficult and routine muscle
as improvement in the range of joint movements at sites character- biopsies may not identify all those affected. The combined use of
istic of connective tissue infiltration in this condition. With a reduc- muscle biopsy with biochemical assays and molecular analysis of
tion in the storage material in the upper airways, there was also an the acid glucosidase gene (at least for the common IVS1 mutation)
improvement in episodes of hypoventilation during sleep. After a should be considered in patients with unclassified myopathy. Acid
few weeks of enzyme treatment, urinary glycosaminoglycans abnor- maltase is normally responsible for constitutive autophagy and mo-
malities were corrected. Although many patients developed serum lecular remodelling of intracytoplasmic glycogen; when deficient,
antibodies, only transient immune reactions, including urticaria, abnormal glycogen accumulates within the lysosomal vacuole and
occurred during the infusions. elsewhere in the cell. In pathways not yet completely understood,
Enzyme replacement therapies have received market authoriza- this pathological accumulation is associated with tissue injury, but
tion for patients suffering from MPS II (Hunter’s syndrome with large cytoplasmic collections of autophagic debris appear to disrupt
iduronate sulphatase deficiency) and MPS VI (Maroteaux–​Lamy the contractile apparatus. Since glycogen is a storage molecule abun-
disease due to arylsulphatase B deficiency) following successful dant in muscle cells, it is these cells that are the principal focus of
clinical trials. Enzyme therapy with elosulfase alfa for MPS IVA acid maltase deficiency.
(Morquio A) has been evaluated in clinical trials: benefits are re- Patients with infantile onset of symptoms have predomin-
ported in clinical measures of endurance and lung function and antly skeletal muscle disease, hypertrophic cardiomyopathy, or
the therapy has received marketing approval in the United States of macroglossia; hepatomegaly is not a feature of Pompe’s disease in
America and Europe, although the complexities of funding delayed the absence of cardiac failure. Onset of disease in children and adults
patient access in the United Kingdom. Favourable responses to en- with weakness and poor athletic performance is associated with de-
zyme replacement therapy have also been reported in animal models layed achievement of developmental motor milestones. Ultimately
of related disorders, including the cone-​head mouse that represents the clinical appearance is dominated by proximal muscle weakness
a faithful model of MPS VII (Sly’s disease), due to deficiency of acid with lordosis of the spine; patients adopt the Gower manoeuvre in
β-​glucuronidase. Following results of a clinical trial in the exception- rising from the squatting position.
ally rare MPSVII, vestronidase alfa (MEPSEVII) received marketing Late-​onset forms observed in adults usually present as a progres-
authorisation from the U.S. Food and Drug Administration in 2017. sive proximal myopathy with the variable addition of diaphragmatic
 12.8 Lysosomal disease 2149

and respiratory muscle paralysis leading to respiratory failure, but to the lysosomal compartment of skeletal muscle. The Genzyme
the rate of progression is unpredictable. The onset of symptoms (Sanofi) agent is a form of α-​glucosidase modified chemically to
varies between the age of 10 and 60 years. In most patients there display many times more mannose phosphate than the parent com-
is a history of longstanding proximal weakness with involvement pound, Myozyme.
of the truncal muscles and weakness in the hips in advance of the Even with specific treatment, the role of physical therapy, respira-
upper limb girdle. Poor physical strength and failure in gymnastic tory assessment and support, nutritional care, and measures aimed
activities may be the clue. In children and adolescents, the condition at general rehabilitation remain crucial for functional outcome and
may be misdiagnosed as a late-​onset muscular dystrophy or even improved quality of life.
polymyositis, leading to inappropriate treatment. Ultimately the
progressive proximal weakness is apparent and associated with re- Niemann–​Pick diseases
spiratory failure: the latter is presaged by fatigue, breathlessness on Niemann–​Pick disease types A and B
exertion, and sleepiness due to marked ventilatory failure—​carbon Niemann–​Pick disease types A and B are, respectively, neuronopathic
dioxide retention causes morning headaches. Occasionally, dys- and non-​ neuronopathic variants of acid sphingomyelinase de-
phagia for solids may result from weakness of voluntary pharyngeal ficiency, a sphingolipid disorder leading to the accumulation of
muscles that initiate swallowing. sphingomyelin. The condition resembles many of the manifest-
ations of Gaucher’s disease, with a characteristic secondary storage
Treatment cell which is also a macrophage. The Niemann–​Pick cell has a foamy
Alglucosidase alfa (Myozyme) has been developed as a mannose appearance rather than the characteristic striated cytoplasm of the
6-​phosphate-​ containing recombinant human acid α-​glucosidase Gaucher cell: there is prominent infiltration of the lungs as well as
(rhGAA) for the treatment of patients of any age with Pompe’s dis- the marrow cavity, liver and spleen.
ease (GSD II). Enzyme replacement therapy is administered to re- Niemann–​ Pick disease type A is associated with disabling
store enzymatic activity, deplete accumulated glycogen, and prevent neuronopathic features and dementia in infants and young chil-
its further accumulation to allow repair of damaged myocytes. dren. Niemann–​Pick disease type B may occur in adults who have
In the very severe infantile form of the condition, where survival only trivial splenomegaly and minor pulmonary infiltrates that are
beyond 1 year of age is unusual, treatment with Myozyme has been only exacerbated at times of intercurrent chest infection; they are
associated with prolonged survival. In a trial of rhGAA in infants at risk from osseous disease related to marrow infiltration, as with
aged 6 months or younger, all were alive at 18 months whereas only Gaucher’s disease.
2% of the historical cohort group survived to this age. Most patients At present, no specific treatments are available apart from the
treated with rhGAA had normal growth and significant motor de- prompt treatment of pulmonary infection and the management of
velopment during the treatment period. In another report, two se- the consequences of skeletal infiltrates and episodes of avascular ne-
verely affected (wheelchair-​and ventilator-​ dependent) patients crosis. Some patients, including those previously misdiagnosed as
remained stable during an 8-​year period of enzyme therapy, and in a having Gaucher’s disease, may have undergone splenectomy to relieve
third, moderately affected patient, muscle strength improved mark- pressure symptoms or the haematological effects of hypersplenism.
edly and the ability to walk was regained. Since this disease is primarily a disorder of macrophages, it should
In some instances, however, the outcome has been disappointing be susceptible to enzymatic complementation using the mannose
and, in general, better outcomes are seen with early treatment and in receptor. At the time of writing, clinical research to develop recom-
patients who do not develop high-titre antibody responses to the re- binant human acid sphingomyelinase is well advanced. Clinical
combinant protein. Recently, in infants predicted to form high-titre, trials were delayed to address safety concerns from studies in animal
neutralising antibody responses on the basis of mutation analysis, models in which high-​dose therapy led to a fatal inflammatory reac-
immune-​modifying treatments have been given at the outset of en- tion, believed to be due to release of bioactive ceramide, the product
zyme therapy in an attempt to tolerize the immune system. Taken as of the catalytic reaction.
a whole, the efficacy of enzyme replacement therapy for acid maltase After the completion of a gradual dose escalation study to min-
deficiency emphasizes the need for prompt clinical recognition and imize release of ceramide product from accumulated substrate, a trial
diagnosis, especially in infants and young children. in adult patients with Niemann Pick type B disease is now continuing
Several studies have confirmed the therapeutic efficacy of rhGAA as an open-​label phase II/​III clinical trial to evaluate the safety and
in patients suffering from attenuated forms of Pompe’s disease. In efficacy of different doses of recombinant acid sphingomyelinase
the present authors’ experience with adult patients suffering from when administered once every 2 weeks. In children up to the age of
acid maltase deficiency, improvements in skeletal and respiratory 18 years with this condition, a one-​year phase I and II multicentre,
muscle function are seen in the first year of treatment, with stability open-​label clinical trial to evaluate the safety and tolerability of
or a slower rate of decline maintained thereafter. It is unclear if, once recombinant human acid sphingomyelinase administered paren-
lost, diaphragmatic function can be regained; we contend that re- terally once every 2 weeks is recruiting patients. It is intended that
stricting treatment to those with severely weak and wasted limbs this agent will be started at 0.3 mg/​kg dose, gradually increasing to
and respiratory failure due to diaphragmatic paralysis will greatly a maximum of 3 mg/​kg. The outcome of these long-​awaited studies
underestimate its capacity to improve life quality or restore the func- to advance the understanding of investigational enzyme therapy
tion of injured muscles. will be received with great interest in this very rare but severe dis-
A second-​generation enzyme preparation is undergoing clinical ease. Unfortunately, since the biosynthesis of sphingomyelin is not
trial evaluation with the aim of improving the delivery of enzyme regulated by the uridine diphosphate-​glucosylceramide synthase
2150 section 12 Metabolic disorders

reaction, and so far no clinical inhibitors of this biosynthetic step marketing approval of the drug by the European Medicines Agency,
are available, any exploration of substrate reduction therapy for the but it has yet to be approved for use in Niemann–​Pick disease type C
severe neuronopathic manifestations of Niemann–​Pick disease type by the FDA in the United States of America. Treatment of Niemann–​
A will be long in coming. Pick C disease is currently the principal use of this agent, rather than
type 1 Gaucher’s disease, the original indication.
Niemann–​Pick disease type C Recently, two candidate products for preclinical development
Niemann–​Pick disease type C is a distinct disease that may pre- in Niemann–​Pick type C have been identified. One is the recom-
sent with jaundice in infants or children; the initial hepatitic illness binant human heat-​shock protein HSP70, and the other is an orally
usually resolves but may lead to fatal liver failure with cholestatic available small molecule, arimoclomol, that serves to induce heat-​
features. Intractable and progressive neurological disease occurs in shock proteins, including HSP70. These candidates have produced
childhood and early adult life, with ataxia, seizures, (vertical) supra- encouraging biochemical and disease-​ modifying effects in the
nuclear gaze palsy, and progressive diffuse cortical injury. Death Niemann–​Pick type C mouse model through their actions on lyso-
usually occurs in the third or fourth decade. somal integrity and on scrambled or denatured endogenous mol-
Niemann–​Pick disease type C is not due to a primary defect of ecules. The compounds have completed toxicity studies and clinical
acid sphingomyelinase but to mutations in two distinct lysosomal trial results are awaited.
proteins, NPC1 and NPC2, that when mutated produce subtypes of Cyclodextrins are complex ring structures that can solubilize
the disease. The physiological role of the NPC1 transmembrane pro- lipids and are widely used domestic chemicals. When given system-
tein remains unclear, as is the pathological cellular cascade that leads ically and into the central nervous system, cyclodextrin was associ-
to NPC disease. Some investigators propose a lipid transport role for ated with slowing and/​or prevention of neurodegeneration in both
NPC1, others a role in lipid-​sensing, while some evidence points to a mouse and feline model of the disease. A multicentre phase III
a complex involvement in endosomal calcium flux and other sec- clinical trial of the intrathecal use (via lumbar puncture) of VTS-​
ondary and downstream effects. 270 (2-​hydroxypropyl-​β-​cyclodextrin) is underway, as is a phase I/​
Niemann–​Pick disease type C is also associated with the appear- IIa trial of its use in patients with neonatal hepatitis. Cyclodextrin
ance of foam cells in the macrophages; the Kupffer cells of the liver infusions, especially via intrathecal administration, are a laborious
may be enlarged and a cholesterol trafficking defect is apparent in and challenging intervention and it remains unclear how paren-
most cells. A rare complication is inflammatory bowel disease which teral cyclodextrin will find its therapeutic position in the long-​term
has many features in common with Crohn’s disease and a prominent management of this disease, but orally active analogues are being
infiltrate of storage macrophages in the inflamed tissue. explored for later application in this disease.
The molecular defect in this disease, though not manifest in the
skin, may be detected in skin-​derived fibroblasts after culture and ex- Cholesteryl ester storage disease and Wolman’s disease
posure to low-​density lipoprotein cholesterol: in Niemann–​Pick dis- These are late-​onset (cholesteryl ester storage disease) and infantile
ease type C, cholesterol is taken up and accumulates in intracellular (Wolman’s disease) forms of lysosomal acid lipase deficiency, which
droplets that stain positively with the fluorescent dye filipin. Within causes the accumulation of cholesteryl esters in the lysosome.
the brain, Niemann–​Pick disease type C causes neuronophagia and Wolman’s disease is a devastating, fatal illness in which the infant
the accumulation of gangliosides and other complex sphingolipid fails to thrive, has massive hepatomegaly, adrenal calcification, and
storage products that may induce neuronal injury. intestinal malabsorption. Death is almost inevitable within the first
The use of statins and other agents that interfere with cholesterol year of life. Cholesteryl ester storage disease, by contrast, manifests
metabolism has not been effective in arresting the course of this as a more indolent liver disease, with hepatic steatosis, progressing
cruel illness. in many cases to fibrosis and cirrhosis. Patients have accelerated and
Clinical trials using N-​butyldeoxynojirimycin (miglustat, often severe atherosclerosis with dyslipidaemia characterized by low
Zavesca) have followed the delayed onset and increased survival of plasma high-​density lipoprotein cholesterol and variably high low-​
mice homozygous for a spontaneous mutation in the NPC1 gene density lipoprotein cholesterol concentrations. It can be difficult to
that serves as an authentic model, recapitulating many features of distinguish cholesterol ester storage disease from other commoner
the human disease. A randomized controlled trial and several co- causes of fatty liver disease, except that the usual risk factors for
hort studies have reported improvements in or stabilization of sac- the latter (overweight, diabetes, and other features of the metabolic
cadic eye movements during 1 to 5 years of therapy. Swallowing was syndrome) are normally absent and on histological analysis of liver
also shown to improve or remain stable during the randomized trial biopsy specimens the lipid droplets are small, indicating lysosomal
(up to 2 years). These findings were supported by long-​term obser- rather than cytosolic location: microvesicular steatosis is thus a hall-
vational cohorts (up to 6 years). A meta-​analysis of dysphagia—​a mark of cholesterol ester storage disease and macrovesicular stea-
clinically important therapeutic endpoint for the disease since as- tosis reflects the spectrum of nonalcoholic liver disease.
piration pneumonia is a frequent cause of hospitalization and An enzyme preparation, sebelipase alfa, has been subject to in-
death—​demonstrated a clear survival benefit with miglustat that tensive clinical trials for these disorders. The phase I clinical study
was accompanied by improved swallowing. Serial studies showed demonstrated clear and early pharmacodynamic effects in patients
decrease in calbindin in cerebrospinal fluid during treatment, sug- with cholesteryl ester storage disease. Favourable outcomes of an
gesting reduced cerebellar Purkinje cell loss, and MRI studies dem- international, randomized, double-​blind, placebo-​controlled phase
onstrated a protective effect on cerebellar and subcortical structure III trial of sebelipase alfa in children and adults with lysosomal acid
that correlated with clinical symptom severity. This research led to lipase deficiency, and the phase II/​III trial of sebelipase alfa in infants
 12.8 Lysosomal disease 2151

with Wolman’s disease were reported in 2014. In summary, in 66 chil- Ceroid lipofuscinosis, neuronal type 1 (CLN1) is due to mutations
dren and adults with lysosomal acid lipase deficiency administration in a gene encoding palmitoyl:protein thioesterase 1, an enzyme in-
of the enzyme met the primary endpoint of restoring of serum alanine volved in lysosomal degradation of acetylated proteins. CLN2 is
aminotransferase (used as a biomarker of liver injury) to the healthy due to defects in the gene encoding the acid hydrolase, tripeptidyl-​
reference range. The agent was administered parenterally on alternate peptidase. CLN3 is the most frequent form and particularly common
weeks at 1 mg/​kg for the double-​blind treatment period of 20 weeks. in Nordic countries; it was the first lysosomal disease ever to have
The median age of patients enrolled in the trial was 13 years of age been reported in the literature (in a Norwegian family) in 1826, and
(range 4–​58) and fibrosis or cirrhosis was documented in all 32 pa- is due to deficiency of a lysosomal transmembrane protein that may
tients who had had baseline liver biopsy samples. In a continuing open-​ serve as a transporter molecule.
label follow-​up study, relative to placebo, markers of dyslipidaemia Childhood forms of these disorders are almost invariably inherited
and liver fat content improved, with sustained reduction in markers as recessive traits and result in a progressive dementia combined
of liver injury and further improvements in low-​density lipoprotein with epilepsy (sometimes myoclonic), blindness, and early death.
cholesterol. Worldwide marketing approval has been granted on the The family history may, however, suggest dominant transmission of
basis of these results. At the time of writing, funding for this treat- CLN11, a puzzling recessive disease caused by mutations in the GRN
ment is available in some countries and is under negotiation in others gene encoding progranulin, with confusion arising because hetero-
(including the United Kingdom). There is evidence that sustained use zygotes develop frontotemporal lobar degeneration with ubiquitin-​
of sebelipase may lead to a substantial reversal of fibrosis in this condi- positive inclusions (Online Mendelian Inheritance in Man (OMIM)
tion and in the authors’ view, the life-​saving effects in children make a 607485). In only one of these conditions, Kufs adult-​onset neuronal
compelling case for authorized reimbursement. lipofuscinosis, is inheritance of a single copy of the mutant CLN4/​
DNAJC5 gene both necessary and sufficient to cause disease, which
Danon’s disease
is always transmitted as an autosomal dominant.
In 1981, two cases of cardiomyopathy in male infants with skeletal In several instances, neuronal ceroid lipofuscinoses represents
myopathy and mental retardation were reported by Danon and col- defects in elements of intralysosomal protein catabolism, indi-
leagues. The skeletal pathology suggested type II glycogenosis but no cating that the turnover of the cognate proteins is very high in cor-
deficiency of acid maltase activity was present. Mutations in the gene tical neurons. Realization that the neuronal ceroid lipofuscinoses
encoding LAMP2, located on the X-​chromosome, have been iden- represent inherited disorders of lysosomal protein metabolism is
tified. LAMP2 is a highly glycosylated integral membrane protein very recent, but the discovery clearly has important consequences
of the lysosome with a role in mediating fusion of the autophagic for better understanding the pathology of this family of cruel
vacuole with the lysosome. Deficiency leads to accumulation of neurodegenerative disorders and for developing better diagnostic
vacuoles containing autophagic debris, including mitochondria and tools (especially for prenatal application) as well as innovative
granular deposits of glycogen. treatments
In affected males, the clinical features include a dramatic hyper- The most familiar form of these diseases has, in Anglophone coun-
trophic cardiomyopathy, a mild skeletal myopathy, and mild to mod- tries, been widely termed ‘Batten’s disease’. In 1915, Dr F.E. Batten
erate learning difficulties. The cardiomyopathy is particularly prone had, at a time when these disorders fell into the descriptive category
to give rise to malignant ventricular arrhythmias. Before the intro- of ‘familial amaurotic idiocy’, correctly differentiated infantile neur-
duction of implanted defibrillation devices, the median age of death onal ceroid lipofuscinosis from Tay–​Sachs disease. However, with
of classically affected hemizygotes was about 20 years. A milder identification of the biochemical causation and responsible genetic
phenotype, apparently restricted to the heart, is seen in heterozy- loci, this terminology and many other eponymous terms from the
gous women. Apart from supportive measures, no specific treatment medical literature of the 19th and 20th centuries now has little prac-
is currently available, although a few hemizygous male patients have tical value in the enlarging canon of lysosomal disorders.
been successfully treated by cardiac transplantation. The striking pleiotropic effects of mutations at loci responsible for
Mutations in the LAMP2 gene have been found at high frequency the neuronal ceroid lipofuscinoses reflect the severe impairments of
(6%) in men with unexplained severe hypertrophic cardiomyopathy. multiple lysosomal functions which cause this class of exclusively
Diseases recently attributed to lysosomal dysfunction neurodegenerative diseases. Several of the genes encode lysosomal
proteins, including acid hydrolases (CLN1, CLN2, CLN10, CLN13);
The characterization of lysosomal defects in several ill-​understood a soluble lysosomal protein in CLN11; a protein, progranulin, that
disorders with diverse clinical manifestations continues to reveal functions in the secretory pathway; two cytoplasmic proteins that
much about the role of the lysosome in cellular functions of sig- interact with lysosomal membranes (CLN4, CLN14); and many
nificance in medicine and molecular physiology. Several recently transmembrane proteins with diverse subcellular locations (CLN3,
studied lysosomal diseases in this category are briefly described here. CLN6, CLN7, CLN8—​and the lysosomal ATPase, type 13A2 in
Neuronal ceroid lipofuscinoses CLN12).
Pathological studies show the characteristic accumulation of
Clinical features, genetic basis, and pathology autofluorescent storage debris (lipofuscin) within neurons and
The neuronal ceroid lipofuscinoses are the most common group of lysosomes in other cells; this material consists of several oxidized
progressive brain diseases that usually affect children and young and ubiquitinated proteins and often includes soluble cytochrome
adults; 13 independent genetic groups have so far been identified C derived from the mitochondrial F1ATPase complex and saposin
with an estimated incidence of 1 in 12,500 live births. fragments. The storage of this material occurs preferentially in
2152 section 12 Metabolic disorders

lysosomes of the nervous system and is associated with progressive of decisive benefit in patients whose seizures are otherwise very
neuronal death leading to a marked atrophy of the brain; cerebral challenging.
atrophy is particularly obvious in the early-​onset forms of the neur- Myoclonus may be exacerbated by carbamazepine and gabapentin
onal lipofuscinoses. (and pregabalin) as well lamotrigine, hence careful reduction of the
anticonvulsant regimen may help to control this often distressing
Diagnosis manifestation. Zonisamide has been reported to control myoclonus,
Diagnosis of these diseases requires clinical persistence, which is and levetiracetam and piracetam may also have therapeutic effects.
driven by the need for clarity and to provide genetic and prognostic Spasticity requires prompt and enthusiastic use of physiotherapy
advice to family members and carers. The electroencephalogram is and sometimes splinting to prevent or mitigate the tendency for
usually informative with early development of occipital spike poten- development of fixed flexural deformities with painful spasms and
tials after photic stimulation. MRI shows atrophy, characteristically emergence of pressure sores. Local use of botulinum toxin may as-
first in the cerebellum and vermis but which progresses to general- sist in severe cases. The spasmolytic agents baclofen and tizanidine
ized cerebral atrophy, ultimately with profound shrinkage (unlike can be effective, and there are preliminary reports that tetrahydro-
GM2 gangliosidosis from which the CLN syndromes need to be cannabinol may be useful in some patients. Benzodiazepines are no
distinguished). longer popular since their unwanted effects (excessive drowsiness
The presence on a blood smear of vacuoles in lymphocytes in a and dribbling) are so unwelcome.
juvenile disorder would be typical of CLN3 disease. Enzymatic tests
conducted on white cell pellets can readily define suspected CLN1 Experimental and specific therapies
or CLN2 disease. Ultrastructural studies by electron microscopy
Cysteamine In vitro studies suggested that the use of the
in blood cells and fibroblasts may demonstrate the characteristic
lysosomotropic thiol agent, cysteamine, may activate residual
storage deposits, usually in lysosomal structures, in blood cells or
palmitoyl-​protein thioesterase activity in patients with CLN1 or
tissue specimens. Advances in molecular diagnostics allow the iden-
solubilize the intralysosomal ceroid in this disease. Cysteamine
tification of defective genes and their protein products in several dis-
bitartrate (Cystagon), used in the treatment of cystinosis, was ex-
tinct clinical phenotypes.
plored in a 7-​year, open-​label, substrate-​reduction therapy trial in
Supportive and symptomatic management four patients with atypical, juvenile-​onset CLN1. Five untreated pa-
tients with the same CLN1 mutations, three of whom were siblings,
This clinically heterogeneous family of relentless neurodegenerative
were included as controls. The treatment substantially decreased
diseases poses great challenges: the provision of continuing care for
the storage material in peripheral lymphocytes in a dose-​dependent
what in most cases is a chronic, cruel, and fatal disease affecting chil-
manner, and a minor slowing of the disease progression compared
dren and young adults. As described, neuronal ceroid lipofuscinoses
to the controls was observed in three out of the four treated patients.
are characterized by dementia (one of the most frequent causes in
A long-​term pilot trial of oral cysteamine bitartrate and N-​
young persons), epilepsy, motor deterioration, and visual loss, and
acetylcysteine was conducted in 10 children below 3 years of age
for most there is currently no specific therapy and little prospect of
with any two of the seven most lethal CLN1 mutations. Outcomes in
therapy. Discovery of the genetic basis of 14 clinical variants permits
nine patients after follow-​up for 8 to 75 months were compared with
prenatal and postnatal diagnosis in affected pedigrees by molecular
the reported natural history of the disease and that of affected older
analysis of genomic DNA that is of key importance for provision of
siblings. While no trial participant acquired new skills and retinal
genetic counselling.
function decreased progressively, the average time to an isoelectric
Beyond an experimental therapy, and one approved molecular
EEG (52 months) was longer than in historical controls (36 months),
therapy, palliative measures are employed for symptom relief. Much
and parents and physicians reported less irritability, improved alert-
distress accompanies loss of the ability to swallow and vocalize and
ness, or both in seven patients. It seems unlikely that this treatment
of independent movement. While the use of feeding gastrostomies is
will be used widely.
critical for maintaining hydration and giving regular medication to
treat epilepsy and muscle spasms, death is usually inevitable in CLN2 Enzymatic augmentation and gene therapy in CLN2 Recombinant
by the early-​mid teenage years, often from aspiration pneumonia. human tripeptidyl peptidase 1 was investigated as a potential treat-
The response to anticonvulsant medication is best judged by the ment for CLN2 disease in children aged 3 to 16 in an open-​label,
level of symptomatic relief and the minimum effective dose for rea- multicentre clinical trial. The protein, termed cerliponase-​alfa, at
sonable clinical control should be used. Complex drug regimens, 30, 100, and 300 mg was initially infused at 2-​weekly intervals into
especially those that use more than two drugs, often compound cerebral ventricles through an in-​dwelling device, later maintained
the unwanted effects and are counterproductive. Sodium valproate at 300 mg over at least 96 weeks. Outcome was determined by de-
and lamotrigine are preferred, and phenytoin, carbamazepine, and cline in a motor-​language disease score, with data compared with a
vigabatrin (and topiramate in CLN2 disease) are probably best study conducted on the course of the disease in historical controls.
avoided in patients with neuronal ceroid lipofuscinoses. The mean (± standard deviation) unadjusted rate of decline in the
In generalized persistent seizures, diazepam and/​or lorazepam motor-​language score per 48-​week period was 0.27 ± 0.35 points
are used in the short term to gain control. Under these circum- in treated patients and 2.12 ± 0.98 points in 42 historical controls
stances there may be a place for introducing phenobarbitone for (mean difference, 1.85). Cerliponase alfa received global marketing
frequent severe attacks, and myoclonic seizures may also respond approval as Brienura from the FDA (for children >3 years) and
to ethosuximide. Another valuable measure, when frequent severe European Medicines Agency in 2017 for patients at any age. At the
attacks occur, is the introduction of a ketogenic diet, which is often time of writing in the United Kingdom, NICE has given provisional
 12.8 Lysosomal disease 2153

approval for Brienura with limited reimbursement from the National The type 5 acid phosphatase is a readily measured lysosomal en-
Health Service in England under a managed access programme. zyme expressed in osteoclasts and pathological macrophages. In
Anecdotal reports and post-​marketing information provides some healthy persons, the enzyme is also abundant in Langerhans and
reassurance that this intensive and laborious intervention provides dendritic cells. Apart from its ability to degrade skeletal phospho-
clinically useful benefit and stabilization of disease in otherwise proteins, including osteopontin, it probably modulates the effector
stricken children. It is not yet known whether the therapy will delay pathways of phagocytic activation or antigen presentation.
the onset of blindness. There is little or no evidence of ‘storage’: the disease illustrates the
Two small-​scale early-​phase clinical trials of gene therapy have been extraordinary diversity of lysosomal functions in the whole animal
conducted in infants with CLN2 using recombinant adeno-​associated and how genetic disturbances can induce wide-​ranging clinical ef-
vectors delivered intracranially. Two distinct vector serotypes with fects. Enchondromatous lesions are seen in long bones with sclerosis
potentially different cellular tropisms have been used. At the time of and irregularity of the metaphyseal plate. Lateral spine radiographs
writing no beneficial outcomes have been reported from either trial. reveal platyspondyly and irregularity of the vertebral endplates. There
is intracranial calcification in the basal ganglia, thalami and deep
Papillon–​Lefèvre syndrome cerebral gyri. The manifestations of autoimmunity are characterized
This is an unusual syndrome, inherited as an autosomal reces- by elevated antinuclear antibody and anti-​double-​stranded DNA
sive trait, resulting in periodontal disease with tooth loss and antibody titres with hypocomplementaemia. The clinical course in
palmoplantar keratosis that is associated with a selective deficiency patients is varied but generally florid, with hypothyroidism, vitiligo,
of cathepsin C activity within the azurophil granules of neutrophilic thrombocytopenia requiring splenectomy, autoimmune haemolytic
polymorphonuclear leucocytes. Several mutations have been identi- anaemia, hepatosplenomegaly, nonerosive arthropathy, and vascu-
fied within the gene encoding cathepsin C, which is an exo-​cysteine litic skin eruptions.
protease, also known as dipeptidyl peptidase I, that serves as a multi-
faceted scaffold on which numerous chymotrypsin-​like proteases Defects of organelle assembly: Chédiak–​Higashi, Griscelli’s,
are activated during neutrophil maturation. These include granule and Hermansky–​Pudlak syndromes
serine peptidases such as elastase, cathepsin G and proteinase 3 in Inherited defects of protein complexes that participate in the bio-
neutrophils, and chymase and tryptase in mast cells; a partial role in genesis of lysosomes and their related secretory organelles such
the activation of granzyme B, a key effector system of natural killer as melanosomes are increasingly being recognized. The organ-
cells, has been suspected from animal studies but only described elles with specialized functions that closely resemble lysosomes
in one affected human pedigree. Deficiency of antimicrobial pep- are termed lysosome-​related organelles and include δ-​granules in
tides released during the normal inflammatory process has also platelets; Weibel–​Palade bodies of endothelial cells; lytic granules
been shown. A more severe allelic variant known as Haim–​Munk and vesicles implicated in the immune ‘synapse’ in lymphocytes;
syndrome, originally reported from Cochin in Southern India, is basophil and azurophil granules in polymorphonuclear leucocytes;
associated with onychogryphosis, pes planus, arachnodactyly, and lamellar bodies in type 2 pneumocytes; neuromelanin granules in
osteolysis involving the distal phalanges (acro-​osteolysis). the catecholaminergic neurones of the nigro-​strial pathway, and the
It appears that the enzyme deficiency leads to the failure of bac- melanosomes of the iris, choroid, and skin. Most of these organelles
terial clearance in the gums, thereby causing destructive periodon- maintain an acidic intra-​organellar milieu, but while they often em-
titis and tooth loss. The corresponding role of cathepsin C within the ploy the lysosomal recognition marker, mannose 6-​phosphate, they
dermal epithelium is not known, but a failure of cathepsin C activity do not necessarily have a full complement of lysosomal membrane
reproducibly leads to epithelial abnormalities and thickening of the proteins such as LAMP1 and LAMP2 and other characteristics.
skin, particularly on the soles of the feet. Chédiak–​Higashi, Griscelli’s, and Hermansky–​Pudlak syndromes
Some patients with disabling skin manifestations have obtained are rare conditions inherited as autosomal recessive traits. All
benefit by the use of retinoids, with or without antimicrobial cause oculocutaneous albinism, often in association with abnormal
therapy. These agents are, however, unlikely to improve early-​onset platelet granules and melanosomes in the skin and eyes: partial al-
destructive periodontal disease which leads to loss of primary and binism is frequent.
secondary dentition. Recurrent oral infection with Aggregatibacter
actinomycetemcomitans infection has been reported. Chédiak–​Higashi and Griscelli’s syndromes
The importance of the Papillon–​Lefèvre syndrome rests not only Chédiak–​Higashi syndrome is caused by mutations in the lyso-
on the identification of lysosomal cathepsin C as an important com- somal trafficking regulator gene located on chromosome 1q44. It
ponent of immune defences against bacteria that preferentially in- predisposes to microbial infection and there are giant lysosomal
vade the privileged periodontal site, but also on the involvement of granules in peripheral blood granulocytes; ceroid storage occurs in
this enzyme in the normal turnover of keratinized skin as well as the nervous system and lungs. The clinical phenotype results from
defence against microbial invasion. a complex set of immune defects affecting natural killer cells and
neutrophilic leucocytes. Natural killer cell cytotoxicity is absent.
Spondyloenchondrodysplasia with immune dysregulation Neutrophils, melanocytes, neurons, muscle cells, and Schwann cells
This autosomal recessive skeletal dysplasia with intracranial calcifi- show giant inclusion bodies.
cation had been long recognized, but association with deficiency of Recurrent cutaneous and systemic pyogenic infections occur with
the lysosomal tartrate-​resistant iron-​containing purple (type 5) acid defective neutrophil and monocyte migration. Neurodegeneration
phosphatase and diverse clinical manifestations of autoimmunity, is a prominent feature in young adults, but death often results from
including lupus erythematosus, has been recent. a rapidly progressive lymphoproliferative disorder.
2154 section 12 Metabolic disorders

The Griscelli’s syndrome(s) are three unusual variants: one (type Oculocutaneous albinism may require aids for poor vision due
III) is a simple form of albinism, and the others combine albinism to retinal photoinjury, especially at school, and protection against
with defective immunity (type II) or neurological deficits (type I). high-​intensity ultraviolet and visible light-​induced damage, with
Griscelli’s syndrome type II with immunological defects is caused by skin carcinoma, should be offered.
mutations in Rab27a, a soluble GTPase, which regulates the flow of Haemorrhagic manifestations may require platelet transfusions
melanosomes in melanocytes and regulates exocytosis of lytic gran- and parenteral desmopressin (DDAVP—​1-​desamino-​8-​d-​arginine
ules at the point of the ‘immune synapse’ in cytotoxic T lympho- vasopressin) to improve platelet function in the short term. Aspirin
cytes. Deficient Rab27a thus causes dysfunctional T lymphocytes and other nonsteroidal drugs should be avoided if possible.
and pigmentary abnormalities. The Griscelli’s syndrome type I, Serious microbial infections with bacteria are common in affected
which also has neurological symptoms, is caused by mutations in children and fungal infections due to Candida or Aspergillus also
the motor protein, myosin Va, which may cooperate with Rab27a to occur. Immunization for common viral and bacterial infections,
transport melanosomes along actin filaments but apparently does including influenza, Haemophilus influenzae, and pneumococci,
not participate in the exocytosis of lytic T cell granules. should be given, and appropriate antimicrobial drugs used promptly
where infection is likely.
Hermansky–​Pudlak syndrome Established pulmonary fibrosis proceeds rapidly and may require
Nine genetically distinct Hermansky–​Pudlak disorders are known. treatment with domiciliary supplemental oxygen in the home, and
Hermansky–​Pudlak syndrome type 2 is caused by mutations in lung transplantation may be successful in selected cases. A smoke-​
the β-​3A adaptin gene which is associated with altered trafficking free environment is likely to be advantageous.
of lysosomal proteins in melanosomes, lysosomes, and platelet-​
dense granules leading to storage pool deficiency. The gene maps
to chromosome 10q. Inheritance is autosomal recessive. Although
FURTHER READING
very rare, one of the Hermansky–​Pudlak syndromes occurs at a high The study of lysosomal diseases is burgeoning: critical cellular func-
frequency in the Swiss Alps and the Puerto-​Rican population where tions carried out in the lysosomal compartment place the study of
it is the most common single-​gene defect. this organelle at the heart of contemporary molecular cell biology.
The sheer pace of discovery and involvement of the lysosome in many
Clinical features include a bleeding tendency due to abnormal
pathological conditions and processes, with or without an overt gen-
platelets; diminished pigmentation of the skin, iris, and hair; and
etic basis, means that comprehensive sources of up-​to-​date infor-
diverse inflammatory complications including granulomatous col-
mation are hard to find. Here we principally identify references of
itis, cardiomyopathy, and severe pulmonary fibrosis. The pulmonary immediate application in the clinical field.
disease appears to be related to defective release of surfactant by type
2 pneumocytes. Books
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12.9
Disorders of peroxisomal metabolism
in adults
Anthony S. Wierzbicki

deafness, ataxia, polyneuropathy, ichthyosis, and cardiac arrhyth-

ESSENTIALS
mias. Treatment is by restriction of dietary phytanic acid, with or
The peroxisome is a specialized organelle which employs molecular without its elimination by plasmapheresis or apheresis.
oxygen in the oxidation of complex organic molecules including
lipids. Enzymatic pathways for the metabolism of fatty acids, including
very long-​chain fatty acids (VLCFA), enable this organelle to carry out
β-​oxidation in partnership with mitochondria. A peroxisomal Neuropsychiatric adult peroxisomal disorders
pathway for isoprenoid lipids derived from chlorophyll, such as
phytanic acid, utilizes α-​oxidation, but a default mechanism involving Historical perspective
ω-​oxidation may also metabolize phytanic acid and its derivatives.
The likely first description of X-​linked adrenoleukodystrophy (X-​
The biochemical manifestations, molecular pathology, and di-
ALD; OMIM 300100) was in 1910 when a 6-​year-​old child devel-
verse clinical features of many peroxisomal disorders have now been
oped abnormal eye movements, apathy, and mental deterioration.
clarified, offering the promise of prompt diagnosis, better manage-
His gait then deteriorated and skin darkening was noted prior to
ment, and useful means to provide appropriate genetic counselling
his death a few months later. Examination of the brain by Schilder
for affected families. At the same time, specific treatments including
showed central demyelination, perivascular lymphocytes, foam cells,
rigorous dietary interventions and plasmapheresis to remove
and gliosis which he termed encephalitis periaxalis diffusa. Other
undegraded toxic metabolites offer credible hope of improvement
cases he later described are likely due to other leukodystrophies.
and prevention of disease in affected individuals.
Adrenoleukodystrophy was defined in 1970, with its characteristic
Inborn errors of peroxisomal metabolism usually present in in-
adrenal changes of excess very long-​chain fatty acids (VLCFAs) and
fancy and childhood, but some disorders typically become manifest
cholesterol esters present in cell inclusion bodies. These VLCFAs
later in life and in adults, in whom the progress is often slow.
were later recognized as pathognomonic and identifiable in plasma
Particular adult peroxisomal disorders samples and the primary defect was identified as an inability to me-
X-​linked adrenoleukodystrophy (X-​ALD)—​due to mutation in the gene tabolize them. The gene was mapped to Xq18 and identified as a
for an ATP-​binding cassette (ABC) protein of unknown function and member of the ATP-​binding cassette (ABC) transporter family. X-​
characterized by accumulation of unbranched saturated VLCFAs, ALD was localized to the peroxisome. Subsequently, mouse models
particularly hexacosanoate (C26), in the cholesterol esters of brain have been developed which show some clinical features of human
white matter, adrenal cortex, and certain sphingolipids of the brain. disease such as adrenomyeloneuropathy but typically lack the cere-
The disease has multiple phenotypes: it may present in adolescence bral changes seen in man.
with slowly progressive stiffness, clumsiness, weakness, weight loss, Aetiology
and skin pigmentation typical of Addison’s disease; it may present
in adults with primarily psychiatric manifestations. Most cases de- Adrenoleukodystrophy is characterized by the accumulation of un-
velop increasing handicap; management is palliative and supportive branched saturated VLCFAs with a chain length of 24 to 30 carbons,
in most instances. particularly hexacosanoate (C26), in the cholesterol esters of brain
Adult Refsum’s disease—​due in most cases to mutations in the gene white matter, in the adrenal cortex, and in certain sphingolipids of
for phytanoyl-​CoA hydroxylase (PHYH) such that patients are un- the brain. The disorder shows X-​linked inheritance with expression
able to detoxify phytanic acid by α-​oxidation and have greatly ele- in female heterozygotes. The disruptive effects of the accumulation
vated levels of this in their plasma. Usually presents in late childhood of VLCFAs, especially hexacosanoic acid (C26:0), on cell membrane
with progressive deterioration of night vision, the occurrence of structure and function may explain the neurological manifestations
progressive retinitis pigmentosa, and anosmia; late features include seen in adrenoleukodystrophy patients. VLCFAs cause alterations in
membrane fluidity and affect cortisol secretion from cultured cells
2158 section 12 Metabolic disorders

of adrenal cortical origin. In addition, albumin has only one C26 Rare presentations include olivopontocerebellar atrophy which
binding site compared with more than six for shorter fatty acids, so has been described as X-​ALD ataxia in Japanese. Other uncommon
limiting its efficacy as a reverse transport protein for excess VLCFAs. presentations include unilateral masses which can mimic brain
tumours and cases of spontaneous remission of neurological
Clinical features symptoms.
X-​ALD is heterogeneous: seven phenotypes occur in males and five A clinical syndrome that mimics features of ALD is acyl-​coenzyme
are recognized in females. Childhood cerebral adrenoleukodystrophy A (CoA) oxidase deficiency but most cases present with severe neo-
presents between the ages of 5 and 10 years with emotional lability, natal disease.
hyperactivity/​withdrawal, and mental deterioration, mimicking at-
tention deficit disorder which evolves to parietal lobe dysfunction Neuropathology
with apraxia, astereognosis, and later dementia. MRI shows a char- There are two distinct forms of neuropathology associated with X-​
acteristic pattern of symmetric involvement of the posterior parieto-​ ALD. Pure adrenomyeloneuropathy is a distal axonic neuropathy
occipital white matter in 85% of patients, frontal involvement in while the cerebral forms are associated with inflammation. In cere-
10%, and an asymmetric pattern in the rest. The clinical phenotype bral X-​ALD, brain pathology is often grossly normal though with
of X-​ALD shows a variable progression which may be interrupted by signs of cerebral atherosclerosis. Grey matter is unaffected but white
periods of arrest on MRI sometimes lasting 5 to 10 years. matter disease occurs in a rostrocaudal direction with demyelination
The adolescent form is adrenomyeloneuropathy which presents prominent in the parieto-​occipital cortex and the cerebellum. The
with slowly progressive stiffness, clumsiness, weakness, weight loss, detailed pathology shows oligodendroglial cell loss, astrocytosis, and
and skin pigmentation typical of Addison’s disease. Autonomic a perivascular inflammatory infiltrate. In the noncerebral form, de-
function including micturition and erectile function are affected myelination is seen in the corticospinal tracts with no obvious in-
later. Somatosensory, auditory, and brainstem evoked potential are flammation and only mild gliosis and occasional macrophages. In the
abnormal with some cases of abnormal visual and peripheral nerve adrenal cortex, cells are filled with lamellar deposits of cholesterol es-
conduction abnormalities. Brain MRI scans are abnormal in 50% ters with primary cortical atrophy and no evidence of inflammation
of men and 80% of women, usually affecting corticospinal tracts or antibodies, with milder changes in the adrenomyeloneuropathy
with later parenchymal changes. Depression and emotional lability form. In men with X-​ALD, the testes show Leydig cell alterations,
are common. Adult cerebral adrenoleukodystrophy is a variant of again with lamellar deposits. It has been estimated that at least 10% of
adrenomyeloneuropathy occurring after age 20 without spinal cord males with Addison’s disease (adrenocortical failure) have X-​linked
symptoms. The primary signs are psychiatric with a presentation of adrenomyeloneuropathy or unrecognized X-​ALD.
psychotic mania and may include schizophrenia or dementia.
Some cases show a pure initial Addisonian picture with no Metabolism of VLCFAs
neurological involvement; all are autoantibody negative. The onset VLCFAs are derived from the diet and endogenous synthesis, with
of Addison’s disease is usually in childhood but the neurological between 20 and 80% derived from synthesis depending on the
changes follow in 20 to 30 years. Subtle hyper-​reflexia or impaired study. The synthetic pathway occurs in brain microsomes with re-
vibration sense and subtle MRI or neurophysiological signs may be peated additions of malonyl-​CoA units to palmitic (C16:0) or stearic
detected earlier in these cases. (C18:0) acid precursors. There are probably separate pathways for
It had been considered that neurological changes were mild C20:0 and C22:0 (behenic) fatty acids with the C22:0 pathway also
or absent in carriers of X-​ALD, but up to 20% are symptom- elongating C22:1 (erucic) acid.
atic. Women who are X-​ALD heterozygotes usually present with Synthesis of VLCFAs starts with use of a specific activator pro-
adrenomyeloneuropathy at age 30 to 40. Subtle signs are often de- tein SLC27A4—​the fatty acid transport protein 4 (FATP4). The
tected prior to presentation but eventually the full picture occurs, synthesis of saturated VLCFA, monounsaturated VLCFA (MUFA),
with late-​onset dementia. A recent prospective study of 46 fe- and polyunsaturated fatty acids (PUFAs) occurs in the endoplasmic
male carriers found an age-​dependent phenotype of myelopathy reticulum by four distinct enzymes; elongation of very long-​chain
occurring in 63% and faecal incontinence in 28% independent of fatty acids ligase (ELOVL), 3-​ketoacyl-​CoA reductase (HSD17B12),
X-​inactivation status. These were associated with abnormalities in 3-​hydroxyacyl dehydratase (HACD3), and trans-​2,3,-​enoyl-​CoA
plasma VLCFAs and decreased fibroblast β-​oxidation of VLCFAs. reductase (TECR). The initial condensation reaction catalysed
In female adrenoleukodystrophy heterozygotes, adrenal by ELOVL is usually rate limiting. Mammals have seven different
cortical insufficiency rarely develops, although isolated min- ELOVL enzymes (ELOVL1–​7) but only a single enzyme has been
eralocorticoid insufficiency may occur but may be difficult to identified so far for each synthetic pathway. ELOVL1, ELOVL3,
diagnose. Furthermore, adrenoleukodystrophy heterozygotes are ELOVL4, and ELOVL6 are involved in the synthesis of saturated
predisposed to hypoaldosteronism related to the use of nonsteroidal and monounsaturated fatty acids and ELOVL2, ELOVL4, ELOVL5,
anti-​inflammatory drugs (NSAIDs). A subclinical decrease in gluco- and ELOVL7 are essential for PUFA metabolism. The synthesis of
corticoid reserve, as measured by synthetic ovine corticotropin-​ C24:0 and C26:0 VLCFAs is carried out by the concerted action of
releasing hormone testing, may be present in most of these women. ELOVL6 (C18:0–​C22:0) and ELOVL1 (C24:0–​C26:0) of which the
Aldosterone levels should be included in ACTH stimulation latter is the key rate-​limiting step.
testing done to detect adrenal insufficiency in affected women. Degradation of VLCFAs occurs by β-​oxidation within peroxi-
NSAIDs should be considered a risk factor for the develop- somes after activation by specific acyl-​CoA ligases which are chain-​
ment of hypoaldosteronism in women who are heterozygous for length specific. Again, FATP4 plays a key role in activating the
adrenoleukodystrophy. fatty acid.
 12.9 Disorders of peroxisomal metabolism in adults 2159

Molecular genetics: the X-​ALD protein and been described (http://​www.x-​ald.nl) of which 51% are missense,
its homologues 28% frame-​shift, and 12% nonsense mutations; 6% are small in-
The X-​ALD gene was mapped to a region of the X-​chromosome sertions/​deletions and 13% are exon deletions. About 75% of all
close to the glucose-​6-​phosphate dehydrogenase gene. The gene was nonrecurrent ABCD1 mutations result in the absence of ABCD1
established to code for an ABC protein of still unknown function protein (http://​www.x-​ald.nl). Nonsense and frame-​shift mutations
but likely to involve the translocation of a variety of substrates across as well as large deletions lead to a truncated protein. Many missense
extra-​and intracellular membranes, including lipids, sterols, and mutations result in unstable protein whose detection is likely to be
drugs. The ABCD1 protein (adrenoleukodystrophy protein) maps dependent on the specificity and sensitivity of the method used. The
to Xq28 and is mutated in X-​ALD. lack of anti-​ABCD1 immunofluorescence (IF) using microscopy
ABCD1 is a member of the ABC transporter superfamily. It ex- in cultured fibroblasts is commonly used to assess ABCD1 pro-
presses a half transporter which is located in the peroxisome. The tein expression. However, fibroblasts express relatively low levels of
gene has an open reading frame of 2235 bases which encodes a 745-​ ABCD1 and so this method may miss ABCD1 expression detectable
amino acid protein with 38.5% amino acid identity and 78.9% simi- by the more sensitive western blot methods. Re-​investigation of ‘IF
larity to another peroxisomal protein (ABCD3). negative’ cell lines using improved techniques has confirmed this
Mutations in ABCD1 result in X-​ALD in animal models, with supposition, hence some previously suspected cases may require
elevated VLCFAs. ABCD1 is one of four related peroxisomal trans- re-​analysis. Disease-​associated missense mutations are not equally
porters that are found in the human genome, the others being ABCD2 distributed over the ABCD1 protein. Analysis of 300 missense mu-
(adrenoleukodystrophy related protein) (OMIM 601081), ABCD3 tations showed clustering in two major regions (Fig. 12.9.1).
(peroxisomal membrane protein 70) (OMIM 170995), and ABCD4 Epidemiology
(P70R/​PMP69) (OMIM 603214). The adrenoleukodystrophy pro-
tein and the adrenoleukodystrophy-​related protein are expressed on Screening and diagnostic records suggest that the prevalence is a
oligodendroglia, while the adrenoleukodystrophy-​related protein minimum of 1 in 22 500 to 1 in 62 000. In contrast, the use of the
and peroxisomal membrane protein 70 are found in neurons of the Hardy–​Weinberg approach and genetic frequency data suggests a
central nervous system. These genes are highly conserved in evolu- combined male to female frequency of 1 in 18 000 similar to phenyl-
tion, and two homologous genes are present in the yeast genome, ketonuria (1 in 12 000).
PXA1 and PXA2, which also transport long-​chain fatty acids. The Differential diagnosis
80-​kDa protein encoded by this gene is absent in patients with X-​
The differential diagnosis of neuropsychiatric abnormalities is
ALD, in whom X-​ALD mRNA was undetectable. Most of the ABCD1
shown in Table 12.9.1. X-​ALD can mimic attention deficit disorder,
mutations (>450) in X-​ALD are point mutations, but large deletions
multiple sclerosis, organic dementias, and psychoses among neuro-
have been described. There is no correlation between genotype and
logical diseases, and Addison’s disease and hypogonadism among
phenotype. In 15 to 20% of obligate female heterozygotes, false-​
endocrine disorders (Table 12.9.2). The critical clinical differential
negative results occur for plasma VLCFAs. Mutation analysis is the
element is the finding of abnormal ACTH concentrations and skin
only reliable method for the identification of heterozygotes.
pigmentation with neurological signs, however subtle.
Overexpression of the adrenoleukodystrophy protein and its
homologue, the adrenoleukodystrophy-​related protein (ABCD2), Clinical investigation
can restore the impaired peroxisomal β-​oxidation in the fibro-
blasts of adrenoleukodystrophy patients. However, it seems that Clinical biochemistry
functional replacement of the adrenoleukodystrophy protein by The primary abnormality in X-​ALD is an accumulation of VLCFAs
adrenoleukodystrophy-​ related protein is not due to stabiliza- (>C22) which occur in myelin. C26:0 can account for up to 5% of
tion of the mutated adrenoleukodystrophy protein. Similarly, the brain cerebrosides and sulphatides. In X-​ALD, both saturated and
adrenoleukodystrophy-​related protein and peroxisomal membrane unsaturated forms of C26:0 (cerotic) and C24:0 (lignoceric) acids ac-
protein 70 could restore the peroxisomal β-​oxidation defect in the cumulate with reductions in C24:1(n-​9) (nervonic) acid. Normally,
liver of adrenoleukodystrophy protein-​deficient mice by stimulating shorter fatty acids accumulate in brain cholesterol esters, but in
Aldr and Pmp70 gene expression through a dietary treatment with X-​ALD, by contrast, these are mostly C26:0 and are enriched in
the peroxisome proliferator fenofibrate. These results suggested that a myelin and in areas of demyelination. Similarly, C26:0 accumu-
correction of the biochemical defect in adrenoleukodystrophy might lates in white matter phosphatidylcholine phospholipids, C24:0 and
be possible by drug-​induced overexpression or ectopic expression of C24:1 in gangliosides. Erythrocytes, plasma, and cultured fibroblasts
the adrenoleukodystrophy-​related gene. The adrenoleukodystrophy all contain a 2-​to 10-​fold excess of VLCFAs. The diagnostic test re-
protein transporter may facilitate the interaction between per- lies on measurement of C26:0 levels and the ratios of C26 to C22:0
oxisomes and mitochondria, the two sites within the cells where (docosahexaenoic acid) and C26:0 to C24:0 (tetracosanoic acid).
β-​oxidation of VLCFAs occurs. The phenotype of X-​ ALD was Some neonatal paediatric screening programmes have begun to
thought to be based on microglial activation for cerebral effects, implement screening for C26:0 phosphatidylcholine as a marker of
while inflammation is less involved in adrenomyeloneuropathy but X-​ALD in their dried blood spot analysis programmes.
transcriptome studies show that a combination of effects of the defi- Results can be confirmed by fibroblast studies or by the use of
ciency on oxidative phosphorylation and adipocytokine and insulin sequencing techniques. Highly elevated VLCFA levels are also found
signalling are responsible for the phenotypes. in peroxisomal biogenesis disorders but these show a different clinical
Many papers have described mutations in the ABCD1 gene in X-​ presentation to X-​ALD or transiently with ketogenic diets for seizures.
ALD patients, indeed more than 600 different mutations have now False-​negative results may occur in patients consuming excess C22:1;
2160 section 12 Metabolic disorders

10 100

(% AA identity per block of 10 amino acids)

Number of disease-causing mutations
8 80

per block of 10 amino acids

Evolutionary conservation
6 60

4 40

2 20

0 0
50 100 150 200 250 300 350 400 450 500 550 600 650 700 750

N Transmembrane domain C

mPTS Walker A Walker B

Fig. 12.9.1 The degree of interspecies conservation and location of human mutations in
the ABCD1 gene. The first region of conservation/​disease-​causing mutations is located in the
transmembrane domain region (amino acids 83–​344) and the second is located in the ATP-​
binding domain (amino acids 500 and 668). The N-​terminal 73 amino acids and the C-​terminal
50 amino acids are mostly spared, hence caution is warranted when interpreting sequencing
data suggesting missense mutations outside these key regions.
Reproduced with permission from Wiersinger C, Eichler FS, Berger J. The genetic landscape of X-​linked
adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis. Appl Clin Genet. 2015; 8: 109–​
121. Copyright © 2015 Wiesinger et al.

Table 12.9.1 Psychiatric signs and inborn errors of metabolism in adolescents and adults

Disorder Confusion Mental Behavioural Catatonia Visual Psychosis Depression

retardation disturbance hallucination
Urea cycle defect + +/​–​ + + + + +
Homocysteine disorders + + + + + +/​–​ +
Porphyria + + + +/​–​ +/​–​
Wilson’s disease +/​–​ + +/​–​ +
CTX + + + +
MLD + +
GM2 gangliosidosis + + + + +
Mannosidoses + + + + +
X-​ALD + + +
Acyl-​CoA oxidase (pseudoneonatal + + +
adrenoleukodystrophy)
Nonketotic hyperglycinaemia + +
Monoamine oxidase A deficiency + +
Creatine transporter deficiency + +
Succinic semi-​aldehyde dehydrogenase + +
deficiency
Niemann–​Pick C + + + + +

CTX, cerebrotendinous xanthomatosis; MLD, metachromatic leukodystrophy; X-​ALD, X-​linked adrenoleukodystrophy.

Reproduced from Sedel F et al. (2007a). Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. J Inherit Metab Dis, 30, 631–​41, with permission.
 12.9 Disorders of peroxisomal metabolism in adults 2161

Table 12.9.2 Differential diagnosis of X-​ALD the five patterns of disease visible on MRI is used to determine severity
and prognosis and is used as a decision aid prior to bone marrow
Presentation Differential diagnosis
transplantation. The presence of demyelination and gadolinium en-
Childhood neurological with Hyperactivity, attention deficit disorder hancement are used to differentiate stable from likely progressive in-
normal endocrinology
Epilepsy/​seizures flammatory changes on MRI scanning (Fig. 12.9.2c). Proton magnetic
Brain tumour resonance spectroscopy shows only mild reduction in N-​acetyl aspar-
Metachromatic/​globoid leukodystrophy tate, normal choline and myo-​inositol, and normal lactate in patients
Postencephalitic syndromes, e.g. subacute
sclerosing panencephalitis
(a)
Myelinoclastic diffuse sclerosis
(A) (B)
Childhood neurological with Addison’s disease with post-​hypoglycaemic
hypoadrenalism damage
X-​linked glycerol kinase deficiency
Central pontine myelinolysis
Glucocorticoid deficiency with achalasia
Hypoadrenalism Secondary causes of hypoadrenalism
Adrenomyeloneuropathy Multiple sclerosis
Familial or other spastic parapareses
Spinocerebellar/​olivopontocerebellar
degeneration
Cervical spondylosis
Spinal cord tumour, e.g. ependymoma
(C) (D)
Adult cerebral Schizophrenia
Depression
Epilepsy/​organic psychosis
Alzheimer’s disease or other dementias
Brain tumour
Heterozygote with symptoms Multiple sclerosis
Chronic spinal disease
Spinal cord tumour
Cervical spondylosis

ω-​9 (erucic acid; Lorenzo’s oil) which is found in mustard and rapeseed Fig. 12.9.2 (a) MRI of the brain in a case of childhood cerebral
oils. A few affected males (0.1%) have borderline normal C26:0 levels adrenoleukodystrophy (ALD) showing characteristic extensive white
and 15% of obligate female carriers have normal results. Effective mu- matter changes in the parieto-​occipital region and internal capsules on
tation detection in these families is therefore fundamental to the un- FLAIR sequences (A). This area is initially affected in about 80% of cases
ambiguous determination of genetic status. Of particular concern are of cerebral ALD. The rim enhances after administration of gadolinium
on T1 sequences (B). In about 20% of cases the site of initial involvement
female members of kinships with segregating X-​ALD mutations, be- in cerebral ALD is the frontal white matter as shown on this FLAIR
cause normal levels of VLCFA do not guarantee a lack of carrier status. image of a different patient with cerebral ALD (C), with prominent rim
Prenatal diagnosis is possible from cultured amniocytes or chorionic enhancement after administration of gadolinium on a T1-​weighted
villus cells. Abnormal liver function tests are a common finding in image (D). (b) MRI of the brain in a patient with adrenomyeloneuropathy
adrenoluekodystrophies and occur secondary to disturbances in di-​ showing increased signal in the pyramidal tracts on T2-​weighed coronal
(A) and axial (B) images indicative of Wallerian degeneration. (c) MRI
and trihydroxycholestanoic acid (DHCA and THCA) metabolism.
of the brain (T2 (A) and FLAIR (C) images; T1 with gadolinium (B, D))
Radiology of a patient with adrenomyeloneuropathy who rapidly deteriorated
clinically with new symptoms of cognitive decline. On MRI, extensive
A MRI scan often reveals biochemical changes before the develop- white matter changes were seen in the parieto-​occipital white matter
ment of clinical symptoms. Eighty per cent of childhood cerebral and corpus callosum (A), but no enhancement of the lesion after
adrenoleukodystrophy patients have symmetric periventricular administration of gadolinium (B). A follow-​up MRI about 3 months
later shows progression of the white matter lesion (C) and there is
white matter changes in the posterior parietal and occipital lobes now faint enhancement of the rim of the lesion after gadolinium
with a dorsocaudal progression with time (Fig. 12.9.2a). Patients with administration (D).
adrenomyeloneuropathy typically have abnormalities in the pyramidal Reproduced with permission from Engelen M, Kemp S, de Visser M, van Geel
tracts (Fig 12.9.2b). Contrast studies show up areas of active demye- BM, Wanders RJ, Aubourg P, Poll-​The BT. X-​linked adrenoleukodystrophy (X-​ALD):
clinical presentation and guidelines for diagnosis, follow-​up and management.
lination, inflammation with breakdown of the blood–​brain barrier, Orphanet J Rare Dis. 2012 Aug 13;7:51. doi: 10.1186/​1750-​1172-​7-​51.
and gliosis. The Loes score (34-​point X-​ALD severity score) based on Copyright © 2012 Engelen et al.; licensee BioMed Central Ltd.
2162 section 12 Metabolic disorders

(b) Endocrinology
(A) (B) Overt hypoadrenalism occurs in 40% of patients with child-
hood cerebral adrenoleukodystrophy and 80% have a deficient
cortisol response on Synacthen testing. In childhood disease,
80% show abnormal adrenal stimulation test results, while in
adrenomyeloneuropathy, between 30 and 50% show normal re-
sponses. Clinical Addison’s disease is found in 1% of female hetero-
zygotes. In adrenoleukodystrophy heterozygotes, adrenal cortical
insufficiency rarely develops, although hypoaldosteronism may
occur, especially if NSAIDs are being used. ACTH levels are in-
creased in male patients. Levels of follicle-​stimulating hormone or
luteinizing hormone are increased in 50 to 70% of patients with
adrenomyeloneuropathy, while testosterone levels are reduced in
20% with low normal levels of dehydroepiandrosterone sulphate.
(c)
(A) (B) Neurophysiology
Hearing is normal but brainstem auditory evoked potentials are
abnormal in 95% of adrenomyeloneuropathy patients and 42% of
heterozygote patients. Abnormalities in visual evoked potentials
are also found as latencies and are increased in 20% of men with
adrenomyeloneuropathy but in more than 70% with childhood cere-
bral disease. Electroretinograms are normal. Subtle demyelination
and axonal loss patterns of nerve conduction are found in 90% of
men and 67% of women with adrenomyeloneuropathy, usually af-
fecting the legs more than the arms. Neuropsychological tests can
show up deficits in parieto-​occipital function affecting visuospatial
parameters and auditory processing, while frontal lobe lesions affect
executive functions, emotions, problem solving, and anticipatory
(C) (D)
processing.

Treatment
The progressive nature of X-​ ALD means that comprehensive
family and professional management support services are required.
Leukodystrophies are associated with progressive learning diffi-
culties, psychiatric disturbance, and increasing disability. Painful
muscle spasms are common and should be managed with diazepam,
baclofen, or gabapentin. Bulbar muscle function may be lost with
disease progression, thus requiring special attention to feeding to
reduce the risk of aspiration pneumonia. The routine management
of patients with X-​ALD includes regular clinical reviews allied with
Fig. 12.9.2 Continued MRI scanning at approximately 3–​6-​month intervals depending
on the rate of progression. Endocrine assessment is performed at
with arrested as compared with progressing disease where N-​acetyl baseline and repeated if the clinical syndrome includes features of
aspartate levels are significantly reduced while choline compounds, hypoadrenalism.
myo-​inositol, and lactate are raised. 18Fluorodeoxyglucose positron Dietary therapy was based on the restriction of the intake of
emission tomography shows increased glucose uptake in the frontal C26:0 to less than 15% of normal intake, but early trials showed
lobes with decreased activity in the temporal lobes and cerebellum in no effect of this on levels of VLCFA levels. Addition of oleic acid
patients with X-​ALD. The increase in frontal activity correlated with normalized VLCFA levels in fibroblasts and oral glyceryl trioleate
scores from psychological evaluations. reduced VLCFA levels by 50% with an improvement in nerve con-
Proton spectroscopy using N-​acetyl aspartate shows up neuronal duction measures. A 4:1 combination of glyceryl trioleate and
loss, while choline compound studies assaying phosphocholine and trierucate (Lorenzo’s oil) normalized VLCFA levels within 1 month
glycerophosphocholine indicate membrane turnover and demyelin- and prompted mass use of this intervention. No evidence of a clin-
ation, and myo-​inositol compounds seem to be indices of gliosis. ically relevant benefit from dietary treatment with Lorenzo’s oil has
The presence of lactate indicates the anaerobic metabolism of the been seen in many studies of patients with neurological involvement
inflammatory cell infiltrate. In the adrenomyeloneuropathy brain, and X-​ALD, and asymptomatic thrombocytopenia was noted in
MRIs may be normal in 50% of men and 80% of women but diffuse 30% of patients. The fatty acid composition of the plasma and liver,
spinal cord atrophy is present. but not that of the brain, improves with this therapy, suggesting that
 12.9 Disorders of peroxisomal metabolism in adults 2163

little erucic acid crossed the blood–​brain barrier. Thus, dietary sup- Statins (3-​HMG-​CoA reductase inhibitors) are capable of nor-
plementation with Lorenzo’s oil is of limited value in correcting the malizing VLCFA levels in primary skin fibroblasts derived from
accumulation of saturated VLCFAs in the brain of patients with es- X-​ALD patients. They block the induction of proinflammatory cyto-
tablished neurological adrenoleukodystrophy. kines through effects on rho kinase. Twelve patients with X-​ALD
In a study of 89 asymptomatic boys with X-​ALD who had normal were treated with lovastatin for up to 12 months. Levels of C26:0
MRI scans, Lorenzo’s oil and moderate fat restriction were pre- declined from pretreatment values and stabilized at various levels
scribed for 6.9 ± 2.7 years. Plasma fatty acids and clinical status during a period of observation of up to 12 months, which does not
were followed as measures of outcome. Twenty-​four per cent devel- correlate with the type of adrenoleukodystrophy gene mutation. In
oped MRI abnormalities and 11% developed neurological and MRI six patients, erythrocyte C26:0 levels fell by 50%. All patients with
abnormalities. The trial concluded that the reduction of C26:0 by adrenomyeloneuropathy remained neurologically stable. However,
Lorenzo’s oil was associated with a reduced risk of developing MRI follow-​up trials have been unsuccessful.
abnormalities. Lorenzo’s oil therapy is indicated in asymptomatic The PPAR-​α agonist-​mediated induction of ABCD2 expression
boys with X-​ALD who have normal brain MRI scans. Experience seems to be indirect and possibly mediated by the sterol-​responsive
with other adrenoleukodystrophy patients indicated that total fat in- element-​binding protein 2 in mice. In addition PPAR-​α is involved
take in excess of 30 to 35% of total calories may counteract or nullify in the regulation of ELOVL1, a key step in VLCFA synthesis. In vitro
the C26:0-​reducing effect of Lorenzo’s oil. CoA esters of both bezafibrate and gemfibrozil inhibit ELOVL1 and
Patients who develop progressive MRI abnormalities should be could form starting points for novel drug development. However, a
considered for haematopoietic stem cell transplantation, but the study of the pan-​PPAR agonist bezafibrate in 10 male patients failed
5-​year mortality is 38% and survival is increased by 8 months on to show any effects of plasma or erythrocyte VCLFA concentrations
average. despite reducing plasma triglyceride levels as predicted. Studies in
Results in 283 boys with X-​ALD who received haematopoietic animal models have suggested that the PPAR-​γ (with some PPAR-​α
cell bone marrow transplantation showed that the estimated 5-​ activity) agonist pioglitazone may reduce axonal degeneration but
year survival was 66%. The leading cause of death was disease pro- there have been no studies in humans.
gression. Donor-​derived engraftment occurred in 86% of patients. Sodium 4-​phenylbutyrate reduces VLCFA levels through its ef-
Demyelination involved parietal–​occipital lobes in 90%, leading to fects on peroxisomal function and increases adrenoleukodystrophy-​
visual and auditory processing deficits in many boys. Bone marrow related protein levels. However, human studies have failed to show
transplantation must be considered very early, even in a child consistent beneficial effects.
without symptoms but with signs of demyelination on MRI, if a suit- ω-​Oxidation is an alternative oxidation route for VLCFAs. These
able donor is available. There are few data on the usefulness of bone fatty acids are substrates for the ω-​oxidation system in human liver
marrow transplantation in adrenomyeloneuropathy. microsomes and are converted into ω-​hydroxy fatty acids and further
Adrenal function must be monitored since 80% of asymptomatic oxidized to dicarboxylic acids via cytochrome P450 (CYP)-​mediated
patients with adrenoleukodystrophy develop evidence of adrenal reactions. The high sensitivity towards the specific CYP inhibitor
insufficiency and adrenal hormone replacement therapy should be 17-​octadecynoic acid suggested that ω-​hydroxylation of VLCFAs
provided when indicated by laboratory findings. is catalysed by the CYP4A/​F subfamilies, particularly CYP4F2 and
Given the inflammation associated with X-​ALD, a number of CYP4F3B, and that therapies capable of increasing ω-​oxidation
immunosuppressive regimens have been investigated. Studies of may have the potential to reduce the progression of the disease.
cyclophosphamide, immunoglobulin, and interferon-​β have been Previously gene therapy has been attempted for X-​ALD using lenti-
unsuccessful. virus transformation of white cells and 9 to 14% of cells showed re-
constitution of ABCD1 expression over 24 months. A more modern
Prognosis gene therapy approach using an adeno-​associated virus construct
The prognosis in X-​ALD depends on the presentation. As yet, there AAV-​9/​ABCD1 shows appropriate neurological tropism following
are no methods of determining which type of disease will result intracerebroventricular or intravenous injection and reduces plasma
from a given mutation as genotype–​phenotype correlation is poor. and brain VLCFA levels in Abcd1-​deficient mice.
Once leukodystrophy begins, the prognosis is poor as progression is Given the extensive oxidative stress associated with demyelin-
inevitable. Data from inherited error bone marrow transplant regis- ation in X-​ALD there has been interest in antioxidant therapies
tries shows prolongations in life with transplantation in X-​ALD but in the treatment of X-​ALD. A combination of the antioxidants α-​
do not record improvements in quality of life. tocopherol, N-​acetyl-​cysteine, and α-​lipoic acid reduced demyelin-
ation in Abcd1-​deficient mice. There are no studies of this approach
Future developments in humans.
Other potential therapeutic approaches to X-​ALD include the use of There has been an explosion of interest in novel therapeutic strat-
lipid-​lowering drugs. Lowering cholesterol activates human ABCD2 egies for inherited errors of metabolism. Classical enzyme replace-
in cultured cells. In mice, a sterol regulatory element exists in the ment therapy for X-​ALD is impossible given the need to replace a
Abcd2 promoter and overlaps sites for liver X receptor/​retinoid X peroxisomal transporter molecule, but other strategies utilizing
receptor heterodimers. Adipose Abcd2 is induced by SREBP1c, technologies such as stabilized mRNA technology combined with
whereas hepatic Abcd2 expression is down-​regulated by concur- liposome or other shielded delivery technologies allied with various
rent activation of liver X receptor-​α and SREBP1c. Hepatic Abcd2 methods of delivering tissue specificity may be more successful.
expression in liver X receptor-​α/​β mice is inducible to levels vastly These show promise in cell culture models but no studies have yet
exceeding wild type. been performed in human X-​ALD. None of these technologies
2164 section 12 Metabolic disorders

have reached animal models let alone human trials in peroxisomal 50% of cases in one series were shown not to be linked to chromo-
diseases. some 10 but to chromosome 6. Eventually, the novel defect was iden-
tified as a variant of rhizomelic chondrodysplasia punctata type 1
and caused by mutations in peroxin 7. In parallel with this discovery,
Neuro-​ophthalmic adult peroxisomal disorders three patients were described in 1997 with a phenotype of sensory
neuropathy and a subtle bile acid disorder but whose families in-
Introduction cluded siblings with a Refsum’s-​like syndrome which was identified
Though survival is improving for peroxisomal biogenesis disorders as due to a deficiency in α-​methylacyl-​CoA racemase. A clinical
and more subtle defects are now diagnosed, most still present in the phenocopy associated with polyneuropathy, hearing loss, ataxia, ret-
neonatal period or in infancy. This is also true for most single en- initis pigmentosa, and cataract (PHARC) (OMIM 612674) has re-
zyme peroxisomal deficiencies. Only one group of disorders presents cently been described. In contrast to other Refsum-​like syndromes,
later, with the onset of symptoms often in early teenage years but, phytanic acid levels are normal in this condition.
due to delays in diagnosis, many are not identified until they reach
adulthood. In contrast to the neuropsychiatric or endocrine pres- Clinical features
entation associated with adrenoleukodystrophy, these peroxisomal In contrast to Zellweger’s syndrome (OMIM 214100), neonatal
disorders present as central and peripheral neuropathies—​a neuro-​ adrenoleukodystrophy (OMIM 202370), infantile Refsum’s dis-
ophthalmic picture. They are often termed Refsum’s disease though, ease (OMIM 266500), and rhizomelic chondrodysplasia (OMIM
given the multiple underlying genetic defects, it would be better to 601757), adult Refsum’s disease usually presents in late childhood
refer to them as Refsum’s syndrome. The syndrome comprises three with progressive deterioration of night vision, the occurrence
genetic disorders: phytanoyl-​ CoA hydroxylase deficiency (clas- of progressive retinitis pigmentosa, and anosmia (Table 12.9.3).
sical adult Refsum’s disease), atypical rhizomelic chondrodysplasia Anosmia, contrary to early reports, is a constant feature of adult
punctata type 1, and the newly described α-​methylacyl-​CoA Refsum’s disease. After 10 to 15 years, deafness, ataxia, polyneur-
racemase deficiency. opathy, ichthyosis, and cardiac arrhythmias can occur. Short meta-
carpals or metatarsals are found in about one-​third of patients. Rare
Historical perspective findings include psychiatric disturbance and proteinuria. Premature
Adult Refsum’s disease (OMIM 266510), also called heredopathia death may result from cardiac arrhythmias.
atactica polyneuritiformis, is a hereditary sensory motor neur- α-​
Methylacyl-​ CoA racemase (OMIM 604489) presents with
opathy type IV. It was first described in 1947, but only recognized adult-​onset sensorimotor neuropathy (Table 12.9.3). It may be ac-
as a syndrome by Refsum in 1962. He described a constellation of companied by retinitis pigmentosa, visual field restriction and loss
signs comprised of retinitis pigmentosa, anosmia, deafness, ataxia, of acuity, axonal sensorimotor neuropathy, and myopathy-​like adult
and polyneuropathy allied with raised levels of protein in the cere- Refsum’s disease. Other features described have included primary
brospinal fluid. The biochemical defect was identified in 1963 when hypogonadism, hypothyroidism, spastic paraparesis, epileptic seiz-
phytanic acid was noted in the plasma of affected patients and de- ures, and mild developmental delay. More severe childhood-​onset
fective α-​oxidation was later suggested as the cause of adult Refsum’s cases have shown a phenotype of defects in bile acid synthesis al-
disease. This disease was thought to be unifactorial with admittedly lied with fat-​ soluble vitamin deficiencies, coagulopathy, and
some rare aberrant complementation studies until 1995 when, after cholestatic liver disease and a resemblance to a Niemann–​Pick type
the localization of the gene for phytanoyl-​CoA hydroxylase, up to C phenotype.

Table 12.9.3 Comparison of clinical features of underlying metabolic defects associated with adult Refsum’s disease

Adult Refsum’s disease Rhizomelic chondrodysplasia α-​Methylacyl-​CoA racemase PHARC

(n c. 300) (n c.5) (n c.6) (n c.30)
Retinitis pigmentosa Age >12 Age >12 Age >20 Age >30
Cataract Age >30 Age >30 ? Age >5
Anosmia All All ? Absent
Sensorineural deafness Age >40 Age >40 ? Age >5
Sensory neuropathy Age >20 Age >20 Age >30 Age >30
PA dependent PA dependent Axonal/​ Variable progressive
demyelinating
Ataxia Age >20 Age >20 Variable Progressive
PA dependent PA dependent
Cholestasis No No Yes No
Biochemistry: >300 >100 <200 Normal (<10)
Phytanic acid <0.2 <0.2 >10 Normal (0.5–​3)
Pristanic acid
(μmol/​L)

PA, phytanic acid; PHARC, polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract.
 12.9 Disorders of peroxisomal metabolism in adults 2165

PHARC shares many clinical features of Refsum’s disease but lacks metabolized by this route due to the presence of a β-​methyl group.
the anosmia and possibly the osteological changes (Table 12.9.3). Instead, phytanic acid is metabolized either by α-​oxidation to
Some mitochondrial disorders in the Leigh’s syndrome spectrum, pristanic acid, or by ω-​oxidation from the other end of the molecule.
including neurogenic muscle weakness, ataxia, and retinitis pig- Using radiolabelled [14C]-​phytanic acid as a substrate, an enzyme
mentosa (NARP), caused in many cases by mutations in mitochon- activity responsible for the α-​oxidation of phytanic acid in cell lys-
drial MT-​ATP6, may also share some clinical features with adult ates was described in 1967. This activity was eventually localized
Refsum’s disease. within peroxisomes and, after 30 years, the pathway responsible for
α-​oxidation has been clarified.
Aetiology
Phytanic acid (3R,S,7R,11R,15-​tetramethylhexadecanoic acid) is an α-​Oxidation of phytanic acid
isoprenoid lipid derived from the phytol side chain of chlorophylls Most phytanic acid metabolism occurs in the liver and kidney by
by bacterial degradation in ruminants, invertebrates, or pelagic fish α-​oxidation, though skin fibroblasts are used for clinical diagnostic
(see Fig. 12.9.3). Phytol can be oxidized to an unsaturated fatty acid, purposes. Phytanic acid from plasma enters the peroxisome in asso-
phytenic acid, and this is saturated to phytanic acid by a pathway ciation with the sterol carrier protein-​2 (SCP-​2) and is metabolized
involving fatty aldehyde dehydrogenase 10 (FALDH-​10) in micro- by a four-​step initial α-​oxidation pathway (Fig. 12.9.4).
somes. The significance of this pathway in humans is unclear though Unusually, it appears this pathway can metabolize two stereoiso-
high phytanic acid levels have been described in some patients defi- mers of its substrate equally well. One carbon atom is then removed
cient in FALDH-​10 with Sjögren–​Larsson syndrome. Most phytanic from the latter in a lyase reaction to give pristanal and formyl-​CoA.
acid is ingested from the adipose tissue and muscle of herbivores or Pristanal is then oxidized to pristanic acid which is thio-​esterified
pelagic fish. The average human daily dietary intake of phytanic acid using CoA to give a racemic mixture. The action of α-​methylacyl-​
in Western societies is between 50 and 100 mg, of which about 50% CoA racemase converts the (2R)-​epimer to the (2S)-​epimer. Further
is absorbed and metabolized. degradation of (2S)-​pristanic acid by the stereospecific β-​oxidation
Phytanic acid is transported in plasma bound to very low-​density pathway then occurs, with the release of propionyl and acetyl-​CoA
lipoprotein and later low-​density lipoprotein, with its elimination units. Further β-​oxidation reactions (including epimerization) are
allied to reverse cholesterol transport (high-​density lipoprotein). required to generate the dimethylundecanoic and dimethylnonanoic
Phytanic acid is preferentially taken up by the liver and may account and methyl-​heptanoic acid derivatives, which are finally exported
for up to 50% of the free fatty acid pool in hepatocytes. This pool is for mitochondrial β-​oxidation.
labile and can be acutely mobilized by stress, infection, or starva-
tion, resulting in rapid phytanic acid release. Plasma phytanic acid Disordered ω-​oxidation of phytanic acid
concentrations are less than 10% of the levels found in adipose tissue Patients with adult Refsum’s disease are unable to detoxify phytanic
and neurons, which accumulate phytanic acid because of its hydro- acid by α-​oxidation, and so the ω-​oxidation pathway is the only
phobicity. The elimination half-​life of total body phytanic acid is metabolic pathway available for its degradation (Fig. 12.9.5).
usually between 1 and 2 years. This pathway produces 3-​methyladipic acid as the final metab-
Most fatty acids are metabolized by the β-​oxidation path- olite, which is excreted in the urine. Thus, 3-​methyladipic acid
ways in peroxisomes and mitochondria. Phytanic acid cannot be concentrations can be used as an index of the molar activity of the

16

14

12
RP
Number of patients

10 Anosmia
Neuropathy
8
Deafness
6 Ataxia
Ichthyosis
4

0
0 10 20 30 40 50 60
Age (years)

Fig. 12.9.3 Cumulative incidence of clinical features on presentation of 15 patients with Refsum’s
disease. RP, retinitis pigmentosa.
Reproduced from Wierzbicki AS, et al. (2002). Refsum’s disease: a peroxisomal disorder affecting phytanic acid alpha-​
oxidation. J Neurochem, 80, 727–​35, with permission.
2166 section 12 Metabolic disorders

Fig. 12.9.5 ω-​Oxidation mediated by a microsomal CYP4A enzyme

yields phytane 1,16 dioic acid which can be metabolized to a wide
spectrum of metabolites by β-​oxidation.
Reproduced with permission from Wanders RJA, Komen J, Ferdinandusse S. Phytanic
Fig. 12.9.4 Metabolic pathway for α-​oxidation of phytanic acid acid metabolism in health and disease. Biochimica et Biophysica Acta (BBA) -​Molecular
and β-​oxidation of pristanic acid producing 4,8 dimethynonanoyl-​ and Cell Biology of Lipids. Copyright © 2011 Elsevier B.V.
CoA, propionyl CoA, and acetyl-​CoA as end-​products. This pathway
is integrated with PXMP-​2 porin responsible for transport of small
molecules, PMP34 for ATP, and a transporter for phytanoyl-​CoA.
Reproduced with permission from Wanders RJA, Komen J, Ferdinandusse S. Phytanic ω-​oxidation pathways. Excess phytanic acid is excreted by low-​
acid metabolism in health and disease. Biochimica et Biophysica Acta (BBA) -​Molecular
and Cell Biology of Lipids. Copyright © 2011 Elsevier B.V. affinity pathways. Phytanic acid can be glucuronidated and it can
also be lost nonspecifically in the urine as nephropathy is a feature of
adult Refsum’s disease.
ω-​oxidation pathway. After ingestion of a test load of phytanic acid, The enzymology of the ω-​oxidation pathway in adult Refsum’s
3-​methyladipic acid is detected in the urine of healthy controls and disease has been clarified and occurs through the microsomal
adult Refsum’s disease heterozygotes showing that ω-​oxidation plays CYP4A system as well as the peroxisome. The capacity of the ω-​
a significant role in postprandial metabolism of phytanic acid in oxidation pathway has been measured by the excretion of 2,6-​
humans. dimethyloctanedioic acid (the C10 ω-​2-​methyl thioester derivative
The activity of the ω-​oxidation pathway is approximately doubled of phytanic acid) at 30 mg phytanic acid (89 µmol) per day. However,
in patients with adult Refsum’s disease, but this microsomal pathway other studies measuring 3-​methyladipic acid excretion showed a far
has considerable reserve capacity. The balance of intake of phytanic lower capacity of 6.9 mg (20.4 µmol) per day. These differences in
acid and its ω-​oxidation is likely to determine long-​term concentra- activity may reflect the metabolic fates of the respective markers.
tions of the lipid. Patients with adult Refsum’s disease often clinically Both 2,6-​ dimethyloctanedioic acid and 3-​ hexanedioic acid are
relapse during episodes of illness or drastic weight loss. Fasting in- products of the initial steps of ω-​oxidation and may be dependent
duces ketosis and lipolysis and acute mobilization of phytanic acid on carnitine ester formation for activation and further metabolism.
in hepatocyte and adipocyte fatty acid pools. This process can in- The initial steps of ω-​oxidation appear to have a greater capacity
duce a release of 5000 mg (c.15 mmol) per day of phytanic acid (50 than that of the whole pathway when measured by the final product
times normal). In experimental ketosis, following acute starvation, 3-​methyladipic acid.
phytanic acid doubled in 29 h in patients with adult Refsum’s dis-
ease and an 80% rise was seen in urinary 3-​methyladipic acid levels, Molecular toxicology of Refsum’s syndrome
indicating that ω-​oxidation was buffering part of this rise. Phytanic The exact mechanism of the toxicity of phytanic acid to neuronal,
acid concentrations can exceed the capacity of the residual α-​ and cardiac, and bone tissue is gradually being clarified. Structural
 12.9 Disorders of peroxisomal metabolism in adults 2167

homology between phytanic acid and vitamin A, vitamin E, geranyl mislocalization of phytanoyl-​CoA hydroxylase in contrast to the
pyrophosphate, and farnesyl pyrophosphate has been noted and it other peroxin 7 imported proteins.
has been suggested that phytanic acid may have a role in the regu-
lation of isoprenoid metabolism and protein prenylation. Recent Epidemiology
studies have identified that phytanic acid and also pristanic acid are Neuropathic adult peroxisomal disorders are rare, with a prevalence
direct toxins to mitochondria and it has been found that phytanic of 1 in 106 in Europe and, for unexplained reasons, 10-​fold less in
acid has a rotenone-​like action in uncoupling complex I in the oxida- the United States of America. As with all recessive conditions, they
tive phosphorylation chain in the mitochondrial inner membrane, are more common in cultures or localities with strong founder ef-
with subsequent likely production of reactive oxygen species, causes fects where consanguineous marriages are frequent. The classical
secondary calcium-​driven changes through GPR40, and induces Refsum’s phenotype is usually found in genetic ophthalmic services
apoptosis in neuronal cells through a histone deacetylase-​mediated where it may represent 1% of retinitis pigmentosa cases. No sur-
mechanism. This metabolic toxicity may explain why neuronal or veys have been performed on the incidence of α-​methylacyl-​CoA
allied retinal pigment tissues rich in mitochondria are the prime tis- racemase among patients with neuropathy.
sues affected in adult Refsum’s disease.
The molecular toxicology of pristanic acid is unknown, although Differential diagnosis
it is likely that the mild ophthalmic features seen in some cases may The differential diagnoses of the neuropathic disorders and relevant
relate to phytanic acid toxicity as for phytanoyl-​CoA hydroxylase signs and investigations are shown in Tables 12.9.4 and 12.9.5. With
deficiency. Although both di-​and trihydroxycholestanoic acids classical adult Refsum’s disease, the differential diagnosis includes
levels are elevated in α-​ methylacyl-​CoA racemase, there is no the various genetic retinitis pigmentosa syndromes if neurological
phenotype of itching associated with this disorder. The cause of the signs are subtle and other rare neurological disorders (Table 12.9.6).
sensory neuropathy in α-​methylacyl-​CoA racemase still remains to
be determined. Clinical investigation
The key investigations in the case of suspected neuropathic adult
Molecular genetics Refsum’s disease are the measurement of phytanic acid (for adult
The defect in adult Refsum’s disease was soon identified as being Refsum’s disease) and pristanic acid (for suspected α-​methylacyl-​
due to the lack of an α-​oxidase. It took 30 years for the enzyme CoA racemase). These are diagnostic.
responsible, phytanoyl-​CoA hydroxylase, to be identified. Two For clinical staging purposes, electroretinograms are often
groups identified the gene for phytanoyl-​CoA hydroxylase simul- performed but often show flat responses characteristic of well-​
taneously in 1997. The phytanoyl-​CoA hydroxylase gene includes established retinitis pigmentosa. Visual fields should be assessed
nine exons and codes for a 338-​amino acid protein including the regularly as functional diplopia is a long-​term complication of adult
30-​amino acid signal domain, which is cleaved on entry into the Refsum’s disease. Slit-​lamp examination for cataracts is also indi-
peroxisome. Like all the peroxisomal targeting sequence type cated, as these can be treated. Ideally, retinal photography should
2 proteins, phytanoyl-​CoA hydroxylase is transported into the be performed so that the extent of retinitis pigmentosa and its pro-
peroxisomes by the protein transporter peroxin 7. Deficiency in gression can be monitored on a long-​term basis. Anosmia can be
this transporter is responsible for rhizomelic chondrodysplasia detected by screening using the standard four-​bottle smell test, but
punctata (RCDP) type 1. Phytanoyl-​CoA hydroxylase is an iron is best quantified by more extensive profiles (e.g. the University of
(II) and 2-​oxoglutarate-​dependent oxygenase, with little overall Pennsylvania smell identification test). Auditory function should be
sequence similarity to other human oxygenases. Numerous point assessed by auditory evoked potentials and hearing tests and moni-
and splice mutations in phytanoyl-​CoA hydroxylase have now tored every 5 years. Peripheral neuropathy should be investigated
been described in adult Refsum’s disease patients, many of which by peripheral nerve conduction studies for somatosensory poten-
affect 2-​oxoglutarate conversion. Significantly, all cause complete tials and electromyography. A nonspecific demyelination pattern
inactivation of the protein; no partial function mutations have yet is typical of adult Refsum’s disease. Osteo-​or chondrodysplasia is
been identified. best identified by a radiological survey of hands and feet for short
Genetic mapping studies have shown that in most cases, but not metatarsals and knee radiology for signs of current or previous
all, classical adult Refsum’s disease maps to chromosome 10. The chondrodysplasia.
locus for the second form of adult Refsum’s disease, comprising Subtler signs that may accompany these definitive tests include
about 10% of cases, was localized to chromosome 6q22–​q24 and an electrolyte profile showing mild hypokalaemia and a Fanconi-​
biochemical studies of fibroblasts from patients with adult Refsum’s like aminoaciduria which can occur in adult Refsum’s disease.
disease established that these patients have subtle deficiencies of per- Liver function tests should be performed. If bilirubin is raised or
oxisomal targeting sequence type 2-​dependent enzyme functions α-​methylacyl-​CoA racemase is suspected, a detailed bile acid profile
(plasmalogen synthesis) consistent with mild variants of RCDP, should be performed by mass spectrometric methods. As the differ-
though they lack any clinical signs specific to childhood-​onset ential diagnoses include vitamin deficiencies, vitamin A and E levels
form of RCDP where significant deficiencies in plasmalogen syn- should be measured to exclude retinol-​deficiency retinopathy and
thesis result in intellectual impairment and other neurological signs. tocopherol-​deficient ataxia. Vitamin B12 and folate determinates are
Ironically, one of the original patients described with adult Refsum’s used to exclude cobalamin/​folate deficient neuropathy.
disease turned out to have the RCDP variant. A limited number of To differentiate phytanoyl-​CoA hydroxylase from peroxin 7 adult
mutations have been described that cause Refsum’s–​RCDP and it is Refsum’s disease, it is necessary to measure plasma VLCFAs and
unclear why these mutations should preferentially lead to specific plasmalogens. However, often the deficiencies are subtle and these
2168 section 12 Metabolic disorders

Table 12.9.4 Differential diagnosis of treatable adult neuropathies caused by inborn errors of metabolism

Disease Onset Neurology Signs Chemistry Treatment Screening

Fabry’s disease 10–​20 Small fibre, Stroke; cardiomyopathy; Low ERT WBC
sensory renal α-​galactocerebrosidase α-​galactocerebrosidase
Serine deficiency 10–​20 Axonal Growth delay; ichthyosis Low CSF/​plasma serine Serine Plasma amino acids
Cerebrotendinous 10–​40 Axonal, Mental retardation; Cholestanol Chenodeoxycholate Cholestanol
xanthomatosis demyelination, ataxia, spastic paraparesis.
sensorimotor Tendon xanthomata
Adult Refsum’s 10–​50 Demyelination, Retinitis pigmentosa, Phytanic acid Low phytanic acid diet Phytanic acid
disease/​syndrome sensorimotor ataxia, anosmia
Porphyrias 10–​50 All Neuropsychiatric PBG and δALA Various PBG and δALA
Dermatological
Wilson’s disease 15–​50 Axonal, Movement disorder Copper/​caeruloplasmin Chelation Copper/​
demyelination, caeruloplasmin
sensorimotor

CSF, cerebrospinal fluid; δALA, δ-​aminolaevulinic acid; PA, phytanic acid; PBG, porphobilinogen.
Reproduced from Sedel F et al (2007) Peripheral neuropathy and inborn errors of metabolism in adults. J Inherit Metab Dis, 30, 642–​53, with permission.

investigations may appear normal. For a definitive diagnosis, a skin normal <30 µmol/​litre), in contrast to other peroxisomal disorders
biopsy should be taken, fibroblasts grown, and detailed enzyme and where levels are usually lower and other metabolic abnormalities are
immunofluorescence profiles examined in a specialist peroxisomal also present. Unlike in rhizomelic chondrodysplasia punctata or the
laboratory. peroxisomal biogenesis disorders, no intellectual defects are seen,
bone abnormalities are mild (if present at all), and there is no de-
Criteria for diagnosis fect in plasmalogen synthesis. In infantile Refsum’s disease, which
The pathognomonic finding in adult Refsum’s disease is greatly ele- is a mild clinical variant of the peroxisomal biogenesis disorder
vated phytanic acid concentrations in the plasma (>200 µmol/​litre; encompassing Zellweger’s disease as its most severe form, numerous

Table 12.9.5 Differential diagnosis of other adult neuropathies caused by inborn errors of metabolism

Disease Age of Neuropathy Signs Chemistry Treatment Screening

onset
Mitochondrial 15–​50 All Retinitis pigmentosa, CSF/​plasma lactate None Lactate, muscle
myopathy epilepsy, ataxia biopsy
Metachromatic 15–​50 Demyelination, Psychiatry, ataxia Aryl-​sulphatase A None/​bone Aryl-​sulphatase A
leukodystrophy sensorimotor marrow transplant
Krabbe’s disease 15–​50 Demyelination, Spastic paraparesis WBC None/​Bone WBC
sensorimotor galactocerebrosidase marrow transplant galactocerebrosidase
GM2 gangliosidosis 15–​50 All Psychiatry; ataxia, Hexosaminidase None WBC hexosaminidase
AMACR 10–​50 Demyelination, Retinitis pigmentosa, Pristanic acid, D/​ Low PA diet Pristanic acid
sensorimotor ataxia, anosmia, IQ THCA
Abetalipoproteinaemia 5–​20 Axonal, sensory, Ataxia, movement disorder, Low cholesterol, low Vitamins A and E Apolipoprotein B
sensorimotor retinitis pigmentosa, apolipoprotein B,
acanthocytes vitamins A and E
Vitamin E deficiency 10–​20 Axonal, Ataxia, movement disorder, Vitamin E Vitamin E Vitamin E
demyelination, retinitis pigmentosa,
sensorimotor acanthocytes
Homocysteine 15–​50 Axonal, motor Psychiatric, stroke, Homocysteine; Folate, vitamins B12 Homocysteine
metabolism (CblC) neuron disease, leukoencephalopathy; methylmalonic acid and B6, betaine
sensorimotor Macrocytosis
X-​ALD 15–​50 Axonal, Neuropsychiatric Very long-​chain fatty ?Lorenzo’s oil Very long-​chain fatty
demyelination, leukoencephalopathy; acids acids
sensorimotor adrenal failure
NARP 5–​20 Demyelination, Retinitis pigmentosa ataxia Mitochondrial—​MT-​ None; supportive Mitochondrial DNA
sensorimotor ATP6
PHARC 10–​30 Demyelination, Retinitis pigmentosa ataxia, Endocannabinoid(?) None None
sensorimotor cataract

AMACR, α-​methylacyl-​CoA racemase; CSF, cerebrospinal fluid; D/​THCA, di-​/t​ rihydroxycholestanoic acid; PA, phytanic acid; WBC, white blood cell.
Adapted from Sedel F, et al. (2007). Peripheral neuropathy and inborn errors of metabolism in adults. J Inherit Metab Dis, 30, 642–​53, with permission.
 12.9 Disorders of peroxisomal metabolism in adults 2169

Table 12.9.6 Differential diagnosis of retinitis with neurological signs (apart from adult Refsum’s disease)

Presentation OMIM Neurological and other signs

Abetalipoproteinaemia 200100 Ataxia, movement disorder, retinitis pigmentosa, acanthocytes
Vitamin E deficiency 600415
Ornithine aminotransferase deficiency 258870 Gyeate atrophy
Myopathy
Usher’s syndrome Ia 276900 Congenital deafness, ataxia
Usher’s syndromes II 276901 Moderate progressive deafness
Bardet–​Biedl–​Moon syndrome 209900 Polydactyly
Truncal obesity
Hypogonadism
Short stature
Mental retardation
Kearns–​Sayre syndrome 530000 Ophthalmoplegia
Cardiomyopathy
Ceroid lipofuscinosis (Batten’s disease) 204300 Seizures
Dyskinesia
Dementia
X-​linked macular degeneration 304020 Ataxia
Myoclonic encephalopathy
NARP 551500 Neurogenic proximal muscle weakness
Ataxia
Dementia
Seizures
PHARC 612674 Polyneuropathy
Hearing loss
Ataxia
Cataract

OMIM, Online Mendelian Inheritance in Man.

subtle peroxisomal defects are present and the condition presents least so ataxia, and it has uncertain effects on the progression of ret-
from birth. initis pigmentosa, anosmia or deafness, although it seems to sta-
In α-​methylacyl-​CoA racemase neuropathy, the pathognomonic bilize these signs.
findings are raised levels of pristanic acid (>100 µmol/​litre) allied
with increases in di-​and trihydroxycholestanoic acids. A secondary Prognosis
elevation of phytanic acid may be seen, but levels are usually be- The prognosis in adult Refsum’s disease depends on the degree to
tween 50 and 100 µmol/​litre. which phytanic acid concentrations are decreased. In untreated
disease, presentation is with progressive weakness and neuropathy
Treatment usually following an acute infective illness which leads to anorexia
Long-​term prospects for the treatment of adult Refsum’s disease (or and acute hepatic phytanic acid release exacerbating the condition.
at least for some forms) are good as it is one of the few inherited Concentrations of phytanic acid in the plasma usually exceed 1000
disorders of metabolism with an exogenous precipitating cause. The µmol/​litre. Left untreated, cardiomyopathy and sudden death can
disease is treated symptomatically by restriction of phytanic acid in- occur. If phytanic acid levels are reduced by plasmapheresis and
take in the diet or its elimination by plasmapheresis or apheresis. by adequate parenteral nutrition, and then a low phytanic acid
These regimens reduce plasma phytanic acid levels by between 50 diet is followed, prognosis is good. Any myopathy usually resolves
and 70%, to values typically around 100 to 300 µmol/​litre, and can within 2 to 3 weeks, though acute visual and auditory deterioration
eliminate phytanic acid completely from fat stores in some patients. may be irrecoverable. In long-​term cases, patients are blind, deaf,
There is long-​term efficacy and safety data for a phytanic acid re- and anosmic, have extensive peripheral myopathy, and are often
strictive diet and to a lesser extent for plasmapheresis/​apheresis, wheelchair bound.
which are used in a few centres. Treatment is generally most effective In acute adult Refsum’s disease, once phytanic acid levels fall to less
in resolving symptoms of ichthyosis, less so sensory neuropathy and than 500 µmol/​litre, ichthyosis resolves followed by improvement in
2170 section 12 Metabolic disorders

myopathy and neuropathy. If phytanic acid levels can be restored to

PHARC (polyneuropathy, hearing loss, ataxia,
normal values, then it is likely that ophthalmological changes will be
retinitis pigmentosa, and cataract) syndrome
minimal or slow, but sudden step-​like deteriorations can occur. The
principal long-​term disability is increasing loss of visual field with
A phenocopy sharing many features of adult Refsum’s disease has
subsequent diplopia and progressive cataract formation. Auditory
recently been described (Table 12.9.3). This disorder forms part of
function generally remains good unless phytanic acid levels are sub-
a newly designated group of phospholipid, sphingolipid, and fatty
stantially raised, in which case audiological deterioration occurs
acid synthesis disorders. The synthesis of phospholipids involves
with the need for cochlear implants. Although acute myopathy re-
multiple steps from dihydroxyacetone phosphate (DHAP) and gly-
solves, patients may have muscle spasms or contractures which may
cerol (Fig. 12.9.6).
be either related to the adult Refsum’s disease or secondary to the
osteodystrophy. Splints and the surgical correction of osteopathy Clinical features
may be required.
PHARC is a progressive syndrome and has the key clinical features of
polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cata-
Other issues
ract (MIM 612674). It is marked by early-​onset cataract and hearing
Adult Refsum’s disease is a potentially treatable cause of retinitis pig- loss, retinitis pigmentosa, and involvement of both the central and
mentosa or neuropathy. The average delay to diagnosis is 12 years peripheral nervous systems, including demyelinating sensorimotor
and a simple biochemical screening test exists for these disorders. polyneuropathy and cerebellar ataxia. Approximately 30 cases have
Given that earlier implementation of dietary restriction of phytanic been described. Most seem to have an adult Refsum’s disease-​type
acid would likely arrest the disease process before retinitis is estab- phenotype but lack the key feature of anosmia which is universally
lished, screening for phytanic and pristanic acidaemias should be present in adult Refsum’s disease. PHARC seems to be a progressive
considered as an important investigation in retinitis pigmentosa or disorder, unlike adult Refsum’s disease, and seems not to show tem-
peripheral neuropathy. poral or environmental variability in symptoms.
Clinically, the onset of retinitis pigmentosa seems to be later in
Future developments PHARC than in adult Refsum’s disease (approximately age 35–​40 vs
The causes of neuropathic adult peroxisomal disorders are in- 15–​20 years), cataracts occur earlier (age 20–​30 vs 30–​50 years), and
completely delineated. Cases of pristanic acidaemia with an adult early-​onset deafness is common (age <15 years vs 50 years in adult
Refsum’s disease phenotype exist for which no cause has yet been Refsum’s disease).
found. Similarly, all cases of adult Refsum’s disease currently de- Patients have a demyelinating neuropathy and develop chronic
scribed are null-​function variants, so the phenotype associated ataxia at varying ages. Cerebellar atrophy is more common on
with low partial function has not been identified. It may be entirely MRI (25%) than in adult Refsum’s disease, but milder phenotypes
normal, but it is possible that some cases of retinal dystrophy or have retinitis pigmentosa associated with only mild sensorineural
peripheral neuropathy may actually be caused by mild phytanoyl-​ hearing loss and cataract and no other signs or symptoms.
CoA hydroxylase mutations. No cases of deficiency of phytanic
acid lyase have been described, although the condition should show Diagnosis
signs of an adult Refsum’s disease phenotype with some overlap The biochemical profile differs from adult Refsum’s disease or
into the α-​oxidation pathway-​associated features of α-​methylacyl-​ other α-​oxidation disorders in showing no abnormality in phytanic
CoA racemase and possibly non-​neurological effects of 2-​hydroxy-​ or pristanic acid concentrations or in any other peroxisomal
fatty acid deficiency. A number of lyase enzymes with peroxisomal metabolites.
targeting signal motifs remain to be placed on the α-​oxidation PHARC was originally mapped to chromosome 20 and is caused
pathway and these may be associated with neuropathy or retinitis by mutations in α/​β hydrolase-​12 (ABHD12), an enzyme involved
pigmentosa syndromes. in hydrolysing the endocannabinoid 2-​arachidonyl-​glycerol and
Reduction of dietary phytanic acid is already successful in ameli- possibly other structurally related substrates including very long
orating most nonophthalmic symptoms in long-​term studies with chain fatty acids. ABDH12 can be inhibited by triterpenoids (e.g.
diet and to a lesser extent apheresis. Orlistat has been shown to re- betulonic acid). Phytol and phytanic acid are diterpenes. The me-
duce phytanic acid in some patients. Newer, more efficacious, ther- tabolism of 2-​arachidonyl-​glycerol in the brain is complex as 85% is
apies are still required to fully reverse the progression of this disease. metabolized by mono-​acylglycerol lipase (MAGL) or ABDH6, while
The signalling pathways which regulate α-​oxidation in humans ABDH12 has a far greater role in microglial 2-​arachidonyl-​glycerol
are unclear. In rodents, the retinoid X receptor β and peroxisomal metabolism suggesting that microglial dysfunction is the patho-
proliferator-​activating receptor α pathways control α-​oxidation and genic mechanism behind PHARC. Both ABDH12 and ABDH16 are
thus fibrate (PPAR-​α agonist) therapy increases activity, but this involved in cellular lyso-​phosphatidylserine metabolism and modu-
does not seem to be true in humans. As ω-​oxidation is capable of late cytokine production. How these biochemical findings relate to
large increases in activity and is principally mediated through CYP causing the full clinical phenotype is unclear.
enzymes, it forms a good candidate for therapeutic interventions to
induce enzyme activity and reduce phytanic acid levels in Refsum’s Treatment
disease. However, at the present time, no drug therapy trials of com- No specific treatment has been defined for PHARC. Symptomatic
pounds capable of modulating either the α-​or the ω-​oxidation path- treatment is recommended for individual deficits. The effective-
ways have been conducted in humans. ness of a dietary restriction of phytanic acid in this condition is
 12.9 Disorders of peroxisomal metabolism in adults 2171

Dihydroxyacetone
Glycerol-3-phosphate Glycerol
3-phosphate
Acyl CoA
1
CoA-SH
4 Monoacylglycerol
Lysophosphatidic Acid
Acyl CoA 1
ADP ATP
CoA-SH
2
Phosphatidic Acid CTP

PPi
3 4 14
15
ADP CDP Diacylglycerol Phosphoglycero-
Triacylglycerol Diacylglycerol phosphate
ATP
5
CDP- 19 Phospho- 18 16
Phosphatidyl choline
choline choline
Serine 8
6 Myoinositol
7 CMP
ADP ATP Phosphatidyl-
CMP Glycerol
Phosphatidyl
Phosphatidyl
Phosphatidyl Choline
Ethanolamine 17
Inositol

CH2 CH2
O C O
O P O P O
O H HO
9 + 10 Phospho- O
O
glycerol CH2 CH2
H2O
Lyso- CO CH CO
phospholipids CH
11 CH2
Fatty acid CH2
9 O
O CO
Diacylglycerol CO
H2O
12 COOH
Fatty Prostaglandins
acid
13 Cardiolipin
2-Arachidonoyl Arachidonic
Glycerol Acid
H2O Glycerol
Leukotriens

Fig. 12.9.6 Major reactions involved in phospholipids biosynthesis: CDP, cytidyldiphosphate; CMP,
cytidylmonophosphate; CoA, coenzyme A; CTP, cytidyltriphosphate. Phospholipids are synthesized de novo
from glycerol or from glyceraldehyde 3-​phosphate and dihydroxyacetone phosphate (DHAP). Glycerol-​
3-​phosphate is esterified twice with acyl-​CoA by acyl-​CoA transferase (1) to form lysophosphatidic
(LPA) acid and then phosphatidic acid (PA). In adipose, muscular tissues, and skin, LPA is converted into
PA by α/​β-​hydrolase-​5 (ABHD5) (2). In mitochondria, PA and LPA are obtained from monoacylglycerol
(MAG) and diacylglycerol (DAG), respectively, a reaction catalysed by acylglycerol kinase (4). PA can be
converted either into DAG by phosphatidic acid phosphatase (3), or into CDP-​DAG by phosphatidic
acid cytidyltransferase (14). DAG is an essential inter-​mediate for the synthesis of triglycerides and
of various phosphoglycerides: phosphatidyl serine (PS) by PS-​synthase (5), which is transformed to
phosphatidyl ethanolamine (PE) by PS-​carboxylase (6), phosphatidyl inositol (PI) by PI-​synthase (7) and
phosphatidyl choline (PC) by PC-​synthase (8). On the other side, CDP diacylgly-​cerol is converted, by
the sequential action of phosphatidic acid glycerol phosphate synthase (15) and phosphatase (16), into
phosphatidylglycerophosphate—​a precursor of cardiolipin, an important phospholipid of the mitochondrial
membrane. This is catalysed by cardiolipin synthase (17) and enriched by linoleic acid by the remodelling
enzyme, monolysocardiolipin acyl transferase (also called tafazzin). The alternative pathway for DAG and
fatty acids synthesis is their release from membrane phospholipids by specific phospholipases (PLA2) (9) and
lysophospholipases (Neuropathy target esterase) (10). Phospholipase C (11) leads to the membrane release
of DAG and its further conversion by diacylglycerol lipase (12) into 2-​arachidonoyl glycerol, which can
be hydrolysed into arachidonic acid by α/​β-​hydrolase-​12 (ABDH12) (13). Arachidonic acid is the starting
molecule of many complex fatty acids like prostaglandins and leukotrienes.
Reproduced with permission from Lamari, F., Mochel, F., Sedel, F. et al. J Inherit Metab Dis (2013) 36: 411. https://​doi.org/​
10.1007/​s10545-​012-​9509-​7. Copyright © 2012 SSIEM and Springer.
2172 section 12 Metabolic disorders

unknown, but unlikely to be completely efficacious given the dif-

Jansen GA, et al. (1997). Refsum disease is caused by mutations in the
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Kamat SS, et al. (2015). Immunomodulatory lysophosphatidylserines
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Aubourg P, et al. (1993). A two-​year trial of oleic and erucic acids Biophys Acta, 1822, 1465–​74.
(‘Lorenzo’s oil’) as treatment for adrenomyeloneuropathy. N Engl J Lamari F, et al. (2013). Disorders of phospholipids, sphingolipids and
Med, 329, 745–​52. fatty acids biosynthesis: toward a new category of inherited meta-
Baldwin EJ, et al. (2010). The effectiveness of long-​ term dietary bolic diseases. J Inherit Metab Dis, 36, 411–​25.
therapy in the treatment of adult Refsum disease. J Neurol Neurosurg Loes DJ, et al. (2003). Analysis of MRI patterns aids prediction of pro-
Psychiatry, 81, 954–​7. gression in X-​linked adrenoleukodystrophy. Neurology, 61, 369–​74.
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linked adrenoleukodystrophy. Biochimie, 98, 135–​42. plantation for childhood cerebral X-​linked adrenoleukodystrophy: a
Brown PJ, et al. (1993). Diet and Refsum’s disease. The determination comparison study. Lancet Neurol, 6, 687–​92.
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12.10
Hereditary disorders of oxalate
metabolism: The primary hyperoxalurias
Sonia Fargue, Dawn S. Milliner, and Christopher J. Danpure

ESSENTIALS Introduction
Primary hyperoxalurias (PHs) are rare inherited disorders character- Oxalate, hyperoxaluria, and oxalosis
ized by an increased endogenous synthesis of oxalate caused by
a deficiency in one of several liver enzymes involved in glyoxylate Oxalate is an end product of metabolism with no known useful bio-
metabolism. The excess oxalate is eliminated from the body by logical function in humans, indeed oxalate can be distinctly det-
the kidneys. High concentrations of oxalate in the urine increase rimental to complex life forms because of the low solubility of its
the risk of calcium oxalate deposition in the kidney (resulting calcium salt. The solubility product of calcium oxalate is readily ex-
in nephrocalcinosis) and in the urinary tract (leading to urinary ceeded in urine, resulting in its crystallization and aggregation into
stones). calculi. Under physiological conditions oxalate, especially calcium
Primary hyperoxaluria is characterized by recurring calcium oxalate, is only poorly absorbed from the gut, so a limited amount
oxalate stones, presenting from early childhood to late adult of the body’s oxalate is supplied directly by the diet. Most is de-
life. Over time, deposition of calcium oxalate crystals in kidney rived by endogenous synthesis from dietary precursors, or collagen
tissue leads to kidney damage with progressive loss of kidney turnover.
function. Primary hyperoxaluria type 1 (PH1; alanine–​glyoxylate Most oxalate in the body is removed by urinary excretion. Little
aminotransferase deficiency) is the most severe form with a me- appears to be excreted into the gut, but the physiological importance
dian age at end-​stage renal failure reached during young adult- of intestinal elimination, especially in the presence of normal renal
hood. Patients with PH type 2 (PH2; glyoxylate/​hydroxypyruvate function, is unclear. The predominant role of the kidney in oxalate
reductase deficiency) and PH type 3 (PH3; 4-​hydroxy-​2-​oxo-​ removal makes it the prime target for calcium oxalate deposition
glutarate aldolase deficiency) may show preservation of kidney (see ‘Renal and urinary manifestations’).
function well into adulthood. Systemic deposition of calcium ox- The reference range for plasma oxalate in health adults is 1 to
alate (oxalosis) can follow kidney failure and increased plasma 3 µmol/​litre and urinary excretion is less than 450 µmol/​24 h. In
oxalate levels. healthy children, the 24-​h oxalate excretion and random urine
Diagnosis is made by DNA analysis of peripheral blood samples, oxalate/​creatinine ratios vary according to age. However, when
or more rarely by enzyme assay of liver biopsy tissue. Prenatal diag- normalized for body surface area, urinary excretion rates for chil-
nosis can be accomplished in the first trimester by DNA analysis of dren 2 years or older are similar to those of adults (i.e. <450 µmol/​
chorionic villus samples. 1.73 m2 per 24 h).
Treatment relies on high fluid intake, inhibitors of calcium ox- Genetic causes of hyperoxaluria are rare, but can be severe.
alate crystallization, and, when required, urological procedures The number of different genetic causes of hyperoxaluria is un-
for stone removal. Some patients with PH1 respond to vitamin known. Three monogenic causes of hyperoxaluria have been well-​
B6 treatment. Management of end-​stage renal failure is difficult characterized. These are primary hyperoxaluria (PH) types 1, 2, and
as dialysis, whether haemo-​or peritoneal, cannot match oxalate 3 (PH1, PH2, and PH3).
production. Isolated kidney transplantation places patients at risk Historical perspectives
of recurring oxalate deposition in the graft in PH1 patients not re-
sponsive to vitamin B6. Liver transplantation, usually combined The condition now recognized as PH was first identified by
with kidney transplantation, is a curative treatment for PH1 but car- Lepoutre in 1925. However, it was another quarter of a century be-
ries significant risks. fore it was described in detail, and it was not until 1957 that it was
recognized as a metabolic disorder. The next great leap forward
 12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias 2175

came in 1968 when Williams and Smith realized that PH was at distributed cytosolic and mitochondrial enzyme glyoxylate/​
least two disorders, now known as PH1 and PH2. The enzyme hydroxypyruvate reductase (GRHPR, EC 1.1.1.26/​ 79). PH3 is
­defect in PH2 was recognized at the time, but the defect in PH1 did caused by a deficiency of 4-​hydroxy-​2-​
oxoglutarate aldolase
not emerge until 1986. Since then, advances in understanding of (HOGA, EC 4.1.3.16), a mitochondrial enzyme, highly expressed
the PHs have been rapid, offending genes having been cloned, and in liver and kidney tissues.
numerous mutations identified. The gene defect associated with
PH3 was identified in 2010. Biochemical abnormalities
Treatments have evolved in parallel with our increased under- The outcome of AGT, GRHPR, or HOGA deficiency is increased
standing of the aetiology and pathophysiology of the condition. Until synthesis and urinary excretion of oxalate. In common with all
20 years ago, the outlook for patients with PH was bleak. However, in aminotransferases, AGT requires a metabolite of vitamin B6, pyri-
the past two decades, life expectancy for most patients has improved doxal phosphate, as cofactor. GRHPR is dependent on reduced
markedly following the introduction of more rational medical and nicotinamide-​adenine dinucleotide phosphate (NADH) but HOGA
surgical treatments, of which enzyme replacement therapy by liver does not require a cofactor. AGT normally catalyses the conver-
transplantation stands out. Many PH patients are alive today who sion of the intermediary metabolite glyoxylate to glycine, but its
would not be were it not for liver transplantation. Our increased absence in PH1 allows glyoxylate to be oxidized to oxalate and re-
understanding, especially of enzyme genotype–​phenotype relation- duced to glycolate instead (Fig. 12.10.1). GRHPR normally catalyses
ships, has led to the exciting prospect of new, possibly mutation-​ the reduction of glyoxylate to glycolate as well as the reduction of
specific, pharmacological treatments in the not too distant future. hydroxypyruvate to d-​glycerate. However, its deficiency in PH2 al-
lows glyoxylate to be oxidized to oxalate and hydroxypyruvate to be
reduced to l-​glycerate (Fig. 12.10.1). HOGA catalyses the conver-
Aetiology and pathogenesis sion of 4-​hydroxy-​2-​oxoglutarate (HOG) to glyoxylate and pyruvate.
The deficiency of HOGA results in accumulation of HOG. The exact
The primary hyperoxalurias are a group of rare hereditary disorders mechanism by which this leads to increased oxalate production is
of which only three, PH1 (OMIM 259900), PH2 (OMIM 260000), still unclear and may involve inhibition of GRHPR by HOG and/​
and PH3 (OMIM 613616) are well characterized. The three types or conversion of HOG to glyoxylate or oxalate by as yet unknown
are simple autosomal recessive disorders of glyoxylate metabolism enzyme(s).
that result in marked increases in the metabolic production of ox- Oxalate cannot be further metabolized and can only be removed
alate and the resulting deposition of insoluble calcium oxalate in the from the body by renal and, to a lesser degree, gastrointestinal excre-
kidney and urinary tract. tion. Although glycolate, l-​glycerate, and HOG can be further me-
Despite these apparent similarities, the molecular bases of tabolized, their increased rate of synthesis in the PHs exceeds their
these disorders are completely different. PH1 is caused by a de- ability to be removed metabolically; hence, large amounts of these
ficiency of the liver-​ specific peroxisomal enzyme alanine–​ metabolites are also removed by renal excretion.
glyoxylate aminotransferase (AGT, Enzyme Commission (EC) In most, but not all, patients, hyperoxaluria is accompanied
number 2.6.1.44). PH2 is caused by a deficiency of the more widely by hyperglycolicaciduria (in PH1), hyper-​l-​glyceric aciduria (in

Hepatocyte Urine

GRHPR LDH
D-glycerate X hydroxypyruvate L-glycerate elevated in PH2
n
io
dr
on

glycoladehyde
h

e glycolate elevated in PH1

om
oc

xis
mit

ro
pe

X GRHPR
glycolate
pyruvate alanine glyoxylate + pyruvate
glycolate
AGT X GRHPR
X X HOGA
GO DHG
HOG elevated in PH3
glycine glyoxylate glyoxylate

DAO LDH hydroxyproline

elevated in
oxalate
cytosol PH1, 2, 3

Fig. 12.10.1 Main pathways of glyoxylate metabolism in human liver cells. The ‘X’ indicates the
location of the enzyme defects in primary hyperoxaluria type 1, 2, or 3. The membranes are likely
to be permeable to most or all of the metabolites shown (dotted lines). AGT, alanine–​glyoxylate
aminotransferase; DAO, d-​amino acid oxidase; DHG, dihydroxyglutarate; GO, glycolate oxidase;
GRHPR, glyoxylate/​hydroxypyruvate reductase; HOG, 4-​hydroxy-​2-​oxoglutarate; HOGA, 4-​
hydroxy-​2-​oxoglutarate aldolase; LDH, lactate dehydrogenase; PH1, primary hyperoxaluria type 1;
PH2, primary hyperoxaluria type 2, PH3, primary hyperoxaluria type 3.
2176 section 12 Metabolic disorders

PH2), or elevated concentrations of HOG and dihydroxyglutarate function (i.e. glyoxylate transamination) properly when located in
(DHG) in PH3. Concomitant hyperoxaluria and hyperglycolic the mitochondria.
aciduria used to be considered pathognomonic of PH1, and AGT is encoded by the AGXT gene, which contains 11 exons,
concomitant hyperoxaluria and hyper-​l-​glyceric aciduria path- spanning approximately 10 kb on chromosome 2q37.3. More than
ognomonic of PH2. However, up to one-​quarter of PH1 pa- 200 mutations and polymorphisms have been identified at the AGXT
tients do not exhibit hyperglycolicaciduria, and some PH2 locus, the three most common of which are described in Table
patients do not have hyper-​l-​glyceric aciduria. In PH3 elevated 12.10.1. Many mutations in AGXT, including some of the most
concentrations of HOG and DHG, a metabolite of HOG, are common, segregate and functionally interact with a very common
found in the urine. polymorphism that results in a Pro11Leu amino acid replacement.
Although glycolate and l-​glycerate are useful in the differential GRHPR is encoded by the GRHPR gene, which contains nine
diagnosis of PH1 and PH2, they themselves appear to cause no ill exons and spans approximately 9 kb in the pericentromeric re-
effects. All the pathological sequelae of the PHs are associated with gion of chromosome 9. HOGA is encoded by the HOGA1 gene, lo-
the increased synthesis and excretion of oxalate. cated on chromosome 10q24.2, containing seven exons, spanning
27 kb. Rather fewer mutations have been found at the GRHPR and
Molecular genetics HOGA1 loci.
The phenotype of PH1 is heterogeneous both at a clinical and at a
molecular level. Three major enzymic categories are recognized: (1) Structural biology
absence of both AGT catalytic activity and AGT immunoreactive The X-​ray crystal structures of AGT (Fig. 12.10.2), GRHPR, and
protein, (2) absence of AGT catalytic activity but the presence HOGA have been determined, enabling the effects of many of the
of AGT immunoreactive protein, and (3) presence of both AGT missense mutations and, in the case of AGT, their interactions with the
catalytic activity and AGT immunoreactive protein. Surprisingly Pro11Leu polymorphism to be rationalized. The most common muta-
for a recessive disease, many patients in the last category can have tion found in PH1, with an allelic frequency of 30 to 40% in Europeans,
AGT activity similar to that found in asymptomatic heterozygotes. leads to a Gly170Arg amino acid replacement. This mutation, to-
In most of the latter patients, disease is caused by a protein traf- gether with the common Pro11Leu polymorphism, is responsible
ficking defect in which AGT is mistargeted from its normal loca- for most cases of AGT peroxisome-​to-​mitochondrion mistargeting.
tion in the peroxisomes to the mitochondria. Although mistargeted The Pro11Leu polymorphism generates a functionally weak N-​
AGT is still enzymically active, it is unable to fulfil its metabolic terminal mitochondrial targeting sequence, the efficiency of which

Table 12.10.1 The most common mutations and polymorphisms found in alanine–​glyoxylate aminotransferase, glyoxylate reductase, and
4-​hydroxy-​2-​oxo glutarate aldolase in European and North American populations

Polymorphism/​ mutation Description Allelic frequencya

PH1 patients (%) Normal populationa (%)
AGXT polymorphisms
Pro11Leub, c Substitution of proline by leucine at residue 11 c.50 15–​20
Intron 1 duplicationc A 74-​bp partial duplication of intron 1 c.50 15–​20
c
Ile340Met Substitution of isoleucine by methionine at residue 340 c.50 15–​20
AGXT mutations
Gly170Argb, d Substitution of glycine by arginine at residue 170 30–​50
33–​34dupC Insertion of a single base (C) leading to a frameshift c.12
Ile244Thrd, e Substitution of isoleucine by threonine at residue 244 6–​9
PH2 patients (%)
GRHPR mutations
c.103delG Frameshift, premature stop codon c. 35
c.403_​404+2del Mis-​splicing 18
PH3 patients (%)
HOGA1 mutations
Glu315del In frame deletion of glutamine residue 31
c.700+5G>T Mis-​splicing 49

PH1, primary hyperoxaluria type 1; PH2, primary hyperoxaluria type 2; PH3, primary hyperoxaluria type 3.
a
In European and North American populations.
b
Pro11Leu and Gly170Arg synergistically interact to misdirect AGT from its normal location in hepatocyte peroxisomes to mitochondria.
c
These three polymorphic variations together define the minor AGXT allele.
d
Mutation segregates with the minor allele of AGXT.
e
Ile244Thr has a much higher frequency in some North African and Spanish populations.
 12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias 2177

Clinical features

Renal and urinary manifestations

PH presents with symptoms related to urolithiasis, usually in child-
hood but sometimes in adult life. Recurring stone formation is
characteristic, as is progressive kidney damage, especially in PH1
patients who advance to end-​stage kidney failure at a median of 25
to 35 years of age in European and North American populations.
There is better preservation of kidney function overall in PH2 and
PH3. With progressive loss of kidney function, a rising plasma ox-
alate concentration leads to deposition of calcium oxalate in many
organs (systemic oxalosis) (see ‘Systemic oxalosis’). Variability of
clinical expression is marked, with some patients reaching end-​stage
renal failure in early childhood, while others retain renal function
Fig. 12.10.2 Crystal structure of human alanine–​glyoxylate
aminotransferase. PLP, pyridoxal phosphate in orange. Proline residues into late adulthood.
in position 11 are shown on the N-​terminal arms. Residues with known High concentrations of oxalate in the urine result in the forma-
pathological mutations in red (G41R, F152I, G170R, I244T). tion of calcium oxalate crystals that attach to the renal tubule epi-
thelium. The crystals are then endocytosed by renal tubule epithelial
cells and migrate to the renal interstitium. There, the crystals incite
is enhanced by the additional presence of the p.Gly170Arg muta- an inflammatory, giant-​cell reaction that results in renal injury, ul-
tion. Interestingly, the Gly170Arg mutation on its own is predicted to timately leading to interstitial fibrosis. Widespread calcium oxalate
be without any untoward consequences, at least in vitro. Other AGT deposition in the renal parenchyma is termed nephrocalcinosis
mutations have been shown to be able to result in mitochondrial and is usually visible on renal imaging studies. Aggregation of cal-
mistargeting in in vitro systems, although only the p.Phe152Ile muta- cium oxalate crystals in the urinary space leads to stone formation
tion is known to do so in PH1. (nephrolithiasis or urolithiasis). For reasons that remain poorly
understood, infants and young children appear more likely to de-
Other forms of primary hyperoxaluria velop nephrocalcinosis, although it can occur at any age. Stones in
There are other forms of PH in addition to PH1, PH2, and PH3. the absence of nephrocalcinosis are more characteristic in older
These are indeterminate in number and poorly characterized. children and adults.
Case studies have been published of individuals with elevated Although marked hyperoxaluria is present from early infancy, the
urinary oxalate of presumed metabolic origin, but who have age at which symptoms develop is highly variable, ranging from a
normal AGT and GRHPR activities, or absence of mutation in few months to late adulthood. In most patients, symptoms or find-
any the genes responsible for PH1, PH2, and PH3. Potential ex- ings related to urolithiasis (pain, haematuria, stone passage) are evi-
planations of the basic defects in these non-​PH1, non-​PH2, or dent in early childhood. Recurring stone formation is characteristic,
non-​PH3 patients have included dysfunction of other metabolic often requiring multiple stone removal procedures. Over time, the
enzymes involved indirectly in oxalate synthesis, abnormalities damaging effects of calcium oxalate deposition in the kidney, epi-
in enteric oxalate absorption, and defects in renal oxalate excre- sodes of transient obstruction due to stones, and injury related to
tion, but no conclusive proof has been forthcoming for any of stone-​removal procedures or infection result in irreversible loss of
these possibilities. renal function. End-​stage kidney failure can occur at any age, from
infancy to the sixth decade of life, with a median of approximately
30 years in PH1 (Fig. 12.10.3). End-​stage kidney failure is also pos-
Epidemiology sible in patients with PH2 or PH3, despite being considered milder
forms of PH.
The PHs are rare disorders which account for 1 to 10% of cases In a few patients, the first clinical manifestation of PH is kidney
of paediatric end-​stage renal disease depending on the country. failure, with symptoms of uraemia prompting medical attention. On
In Europe, PH1 has an estimated prevalence of 1.0 to 2.9 per mil- evaluation, nephrocalcinosis and/​or bilateral renal stones are usually
lion people and an incidence of 0.12 to 0.15 per million per year. found. Occasionally, the diagnosis is made on renal biopsy in a pa-
However, both prevalence and incidence are likely to be greater in tient in whom PH was not considered on clinical grounds. A severe
populations with a high frequency of consanguinity. infantile form of PH1 results in irreversible kidney failure during the
There are limited data available regarding the prevalence or inci- first year or two of life, presenting as failure to thrive.
dence of PH2 or PH3. However, within the population of patients
with PH, PH1 represents 70 to 80% of patients, with PH2 and PH3 Systemic oxalosis
representing approximately 10% each. A recent analysis of carrier When kidney function falls below a GFR of about 30 to 35 ml/​
frequency in the general population suggests that PH is under-​ min per 1.73 m2, the kidney is unable to excrete the excess oxalate
diagnosed and/​ or incompletely penetrant, especially for PH3. ­produced by the liver and the plasma oxalate concentration begins
Specific mutations frequencies vary between ethnic groups in all to rise abruptly. When the calcium oxalate product in plasma ex-
three PH types. ceeds saturation, calcium oxalate crystals are deposited in many
2178 section 12 Metabolic disorders

100
NMD intravenous ascorbic acid in patients receiving parenteral nutri-
PH3 tion, or accidental ingestion of ethylene glycol, is occasionally
80 responsible. Enhanced gut absorption of oxalate is often encoun-
tered in patients with gastrointestinal disease or after small bowel
Renal Survival (%)

60 PH2 resection. Malabsorptive gastric bypass procedures, performed for

management of obesity, are emerging as an increasingly frequent
40
cause of enteric hyperoxaluria. Hyperoxaluria is also encountered
20
in patients receiving medications that alter fat absorption, such as
p<0.0001 PH1
tetrahydrolipstatin (orlistat).
0 20 40 60
Age (y)
PH1 76% (129) 43% (49) 12% (7) Clinical investigations
PH2 100% (18) 82% (11) 66% (4)
PH should be considered in any child with urinary tract stones
PH3 96% (12) 96% (8) 96% (4)
or nephrocalcinosis and in adults with recurrent calcium oxalate
NMD 100% (14) 100% (12) 100% (7) stones, especially if the clinical history extends back into childhood.
Fig. 12.10.3 Renal survival in primary hyperoxaluria. Kaplan–​Meier renal Impaired renal function in a patient with calcium urolithiasis or
survival plot of patients with PH1 (blue), PH2 (red), PH3 (green), and PH nephrocalcinosis, or in a sibling, should also suggest the diagnosis.
patients with no mutation detected (NMD, black). The lower table shows A presumptive diagnosis of PH can often be made on the basis
renal survival estimates with number of patients at risk in parentheses. of urinary oxalate, glycolate, l-​glycerate, and HOG/​DHG excre-
Source data from Hopp K, et al. (2015) Phenotype-​genotype correlations and
estimated carrier frequencies of primary hyperoxaluria. JASN. 2015 Oct;26(10):
tion. Due to highly age-​dependent normal ranges in young children,
2559–70. Copyright © 2018 American Society of Nephrology. random urine oxalate/​creatinine ratios are best regarded as an initial
screen. If the ratio appears elevated, a timed (12–​24-​h) urine collec-
tion should be obtained for more reliable diagnostic information.
organs and tissues (systemic oxalosis), resulting in progressively Repeating the measure on at least three occasions can be useful to
severe multisystem disease. Painful, nonhealing ulcers of the skin, help with false positives (as in the case of small children) and false
fracturing osteodystrophy, refractory anaemia, complete heart negatives. It should be kept in mind that urinary oxalate excretion
block, and heart failure due to oxalate cardiomyopathy are features can be misleadingly low in patients with advanced renal failure, and
of systemic oxalosis. Without prompt and definitive management, concomitant hyperglycolic aciduria (in PH1) or hyper-​l-​glyceric
death ensues. aciduria (in PH2) is not always present. Urinary HOG and DHG
are elevated in patients with PH3, though their diagnostic sensitivity
Differential features and specificity remain to be established. Plasma levels of oxalate,
There are no clinical features that can reliably differentiate among glycolate, and glycerate are rarely of diagnostic benefit in patients
the three PH types in an individual patient, but PH2 is characterized whose renal function is well maintained, though they can be valu-
by slightly lower oxalate excretion rates, fewer stone episodes, and able in those with renal failure. Plasma oxalate concentrations are
better preservation of renal function than PH1. PH3 patients have often increased in patients with end-​stage renal disease from causes
an earlier onset of symptoms but lower oxalate excretion rates and unrelated to PH, although the degree of elevation in this setting is
slower progression of disease. Though symptomatic stones are not typically modest.
infrequently encountered in infants and young children with PH3, Definitive diagnosis requires confirmation of homozygosity or
the frequency of stone events may improve during follow-​up. There compound heterozygosity for known mutations of AGT, GRHPR or
are rare reports of kidney failure in PH3, which may be ­related to HOGA, or the determination of either AGT (PH1) or GRHPR (PH2)
complications of urolithiasis. enzyme activity on a percutaneous needle biopsy of the liver. The
identification of more than 200 mutations in PH1 allows the possi-
bility of diagnosis by DNA analysis in suitable families. It has been
Differential diagnosis estimated that, even in the absence of family history, screening pos-
sible European or North American PH1 patients for the three most
Hyperoxaluria is a well-​recognized risk factor in the common common mutations (Table 12.10.1) would be able to diagnose PH1
condition of idiopathic calcium oxalate kidney stone disease. with an efficiency of 34%. When coupled with family and linkage
Although its causes in such patients remain unclear, they are analysis studies the success rate is greatly improved. Increasingly,
almost certainly multifactorial in nature, with both environ- more comprehensive gene sequencing is being used, leading to im-
mental and genetic components (see Chapter 21.14). Anything proved diagnostic efficiency, with mutations in AGXT, GRHPR, or
that increases the body’s burden of oxalate, or elevates the con- HOGA1 found in approximately 90% of patients with PH symptoms.
centration of oxalate in the urine, increases the risk of calcium The urinary profile of PH-​related metabolites (glycolate, l-​glycerate,
oxalate deposition in the kidney and/​or urinary tract resulting in HOG, DHG) can be used to target the initial genetic testing. In
nephrocalcinosis and/​or urinary stones. Environmental causes pedigrees with a known mutation, screening of family members is
of hyperoxaluria include excessive dietary intake of oxalate (par- straightforward.
ticularly when combined with low calcium intake) and extended The determination of AGT (for PH1) or GRHPR (for PH2) activity
periods of dehydration. Intake of oxalate precursors, such as on liver biopsy, is now mostly reserved for diagnosis confirmation
 12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias 2179

or exclusion in the absence of mutations of any of the three genes most adults. In infants and young children, placement of a feeding
involved. or gastrostomy tube may be needed to assure sufficient intake and in
Prenatal diagnosis relies on DNA (mutation or linkage) ana- situations of high fluid loss or limited oral intake, intravenous fluids
lysis of material obtained from chorionic villus samples in the first may be required to maintain hydration in PH patients.
trimester.
Pharmacological treatments
Reduction in calcium oxalate crystal formation can be accomplished
Treatment by lowering the urine oxalate concentration and by the use of medi-
cation. Urine alkalinization with citrates, either as sodium citrate
There are no international guidelines for the specific treatment of (0.1–​0.15 g/​kg per day) or equivalent doses of either sodium or po-
PH and recommendations are based on expert opinions. The man- tassium citrate, reduce the degree of calcium oxalate saturation in
agement initially involves maintenance of high fluid intake; medi- the urine. Other inhibitors of crystallization may be used such as
cations to inhibit calcium oxalate crystallization and decrease neutral phosphates (providing 20–​30 mg/​kg per day of elemental
oxalate production, with use of pharmacological doses of pyridoxine phosphorus in divided doses) to increase the excretion of pyrophos-
(vitamin B6) for some PH1 patients; and urological procedures and phate ions, which inhibit heterogeneous calcium oxalate crystal
support for end-​stage renal failure as required. nucleation, seeded growth, and aggregation. Magnesium supple-
Treatments that target reduction of calcium oxalate crystal or ments (e.g. magnesium oxide 200 mg/​day in adult patients) may also
stone formation, either in the urine or in the blood and body tis- inhibit crystal growth and aggregation. The doses used should be
sues (in patients with end-​stage kidney disease) are suitable for all sufficient to produce a material increase in the urinary excretion of
types of PH, whereas those addressing enzyme dysfunction are more either phosphate or magnesium. Phosphate and magnesium should
likely to be disease specific (Fig. 12.10.4). be avoided if there is renal insufficiency.
In about one-​third of PH1 patients, pharmacological doses (5–​
Diet and fluids 8 mg/​kg per day, <20 mg/​kg per day) of pyridoxine (vitamin B6)
Decreasing dietary oxalate in PH is of limited use since the main cause a significant (>30%) reduction in urinary oxalate levels and
source of oxalate is endogenous. Calcium intake should remain improvement in clinical condition. Pyridoxal phosphate, a metab-
normal as it binds intestinal oxalate. Excessive vitamin C intake olite of pyridoxine, is the cofactor for AGT, and acts both to in-
should be avoided, especially in end-​stage renal disease, as ascorbic crease the enzymatic activity of AGT and as a chaperone to help
acid can be broken down to oxalate. AGT folding and targeting. Patients carrying the p.Gly170Arg or
Patients with PH who have adequate renal function should main- p.Phe152Ile mutations have been shown to be able to respond to
tain a high oral fluid intake in order to keep oxalate in the urine as pyridoxine treatment, although to varying degrees. Some who are
dilute as possible. A suitable target level is 2 to 3 litres/​m2 body sur- homozygous for p.Gly170ARg demonstrate normalization or near
face area, distributed throughout the day, using the lower range for normalization of urine oxalate excretion while receiving pyridoxine.

Protein folding Enzyme

Gene mutation
targeting functional
deficiency

(Vit B6)
PH1 AGXT AGT

PH2 GRHPR GR
Increased Elevated
Increased Ca Ox Ca Ox Renal
oxalate oxalate
glyoxylate crystals stones failure
synthesized excretion
PH3 HOGA1 HOGA
Hydration Dialysis
Crystallization Lithotripsy
Kidney
inhibitors Surgery
Gene therapy Chemical Enzyme Substrate Reducing transplantation
chaperones replacement depletion Oxalate synthesis
therapy: (GO, HypDH) (LDH)
liver Oxalate
transplantation degradation

Treatments aimed at causes of PH Symptomatic treatments

Fig. 12.10.4 Current and future approaches to the treatment of primary hyperoxaluria types 1 (PH1), 2 (PH2), and 3 (PH3). Current and potential
treatments are indicated below the respective molecular and pathophysiological step targeted for PH1, PH2, and PH3. Treatments aimed at the
pathways on the left tend to be directed at the causes of disease and are usually specific for each type of primary hyperoxaluria (vitamin B6 is
specific to PH1). The treatments for the pathway on the right are aimed at the clinically observable symptoms and are likely to be common to
all three types. AGT, alanine–​glyoxylate aminotransferase; CaOx, calcium oxalate; GO, glycolate oxidase; GRHPR, glyoxylate/​hydroxypyruvate
reductase; HOGA, 4-​hydroxy-​2-​oxoglutarate aldolase, HypDH, hydroxyproline dehydrogenase. HOGA is expressed in both liver and kidney so that
liver transplantation would not necessarily be the only enzyme replacement strategy.
2180 section 12 Metabolic disorders

There are indications that other mutations may also benefit from haemodialysis, during which time the corporeal load of calcium ox-
pyridoxine treatment. A formal testing of pyridoxine responsiveness alate has built up, particularly in the bones.
during a 3-​month trial with urinary oxalate measurements before Pre-​emptive liver transplantation before the GFR has decreased to
and after initiation of pyridoxine is recommended for all PH1 pa- 30 ml/​min per 1.73 m2 is an option to be considered if PH1 is diag-
tients. Pyridoxal phosphate is not required for the activity of GRHPR nosed early and is following an aggressive course. The risks of the
or HOGA, hence pyridoxine is ineffective in PH2 and PH3 patients. transplant procedure, the added years of immunosuppression, and
the difficulty in accurate prediction of rate of loss of renal function
Radiological and surgical interventions must be balanced against the benefit. Heterotopic auxiliary liver
Obstructive uropathy requires prompt stent placement or per- transplantation is theoretically unsound since the remaining native
cutaneous nephrostomy to relieve the obstruction. For PH pa- liver continues to make large amounts of oxalate. Liver transplant-
tients, minimally invasive methods are preferred in dealing with ation has been shown to reduce oxalate excretion to normal in a
stones. Endoscopic procedures methods including semi-​ rigid single PH2 patient who had progressed to end stage kidney disease
ureterorenoscopy (URS), flexible ureterorenoscopy (RIRS), and per- (Dhondup et al. 2018). Further experience will be needed to evaluate
cutaneous nephrolithotomy (PCNL) are techniques used with suc- its role in management of PH2.
cess, with endoscopic lithotripsy using ultrasonic, electrohydraulic,
and laser techniques. Extracorporeal shock wave lithotripsy Timing of renal replacement therapy/​transplantation
(ESWL) is also used. Open lithotomy for large calculi has become Initiation of maintenance dialysis or transplantation should be ac-
exceptional. Stone debris may require either external drainage via complished as soon as the plasma oxalate concentration begins to
a nephrostomy or internal drainage via a stent, although stents and exceed the solubility threshold for calcium oxalate. This occurs in
other foreign bodies in the urinary tract may rapidly become en- most patients at a GFR of 20 to 25 ml/​min per 1.73 m2, though can
crusted with calcium oxalate deposits. Close follow-​up is essential occur earlier in some cases. The purpose of early initiation of renal
with regular radiological and/​or ultrasonographic assessment, the replacement therapy is to minimize systemic oxalosis and reduce the
aim being to keep the kidneys as free from stones as possible while risk of calcium oxalate deposits in any subsequently grafted kidney.
minimizing repeated ESWL or invasive procedures. Indeed, it has been suggested that PH1 patients who are either un-
responsive or only partially responsive to pyridoxine should be
Renal replacement therapy managed with pre-​emptive (before dialysis is required) combined
In most patients, haemodialysis and peritoneal dialysis are not cap- liver and kidney transplantation. By contrast, PH1 patients who re-
able of preventing progression of systemic oxalosis. Combined liver spond fully to pyridoxine, with normalization or near normalization
and kidney transplantation—​the treatment of choice in patients with of urine oxalate while on treatment, and patients with PH2, can do
PH1 who do not respond well to pyridoxine and are approaching well with kidney transplantation alone. Any time from initiation of
end-​stage renal failure—​entails its own significant risks. dialysis to transplantation should be kept as short as possible to min-
Management of end-​stage renal failure is difficult. The high rate of imize systemic oxalate accumulation. Vigorous dialysis, required
oxalate synthesis most often exceeds achievable rates of its removal, daily in most patients, is needed.
even with intensive haemodialysis regimens or combined haemo-​ The plasma oxalate concentration and urine oxalate excretion
and peritoneal dialysis. The condition of patients with renal failure rate should be followed sequentially before and after transplantation
progressively worsens as calcium oxalate is deposited throughout until normal. Elimination of tissue oxalate stores can take up to
the body (systemic oxalosis). 3 years or more following successful transplantation. Careful man-
Kidney transplantation can resolve the uraemic consequences of agement of hyperoxaluria throughout this time is essential to avoid
kidney failure and reduce plasma oxalate concentrations to levels damage to the renal allograft.
that fall below the supersaturation threshold for calcium oxalate.
However, kidney transplantation alone is problematic in PH1: pa-
tients who respond fully to pyridoxine (with normalization or near Future developments
normalization of urine oxalate) can do well, as can those with PH2,
but otherwise the new kidney is at significant risk from oxalate A recent avenue of research is based on substrate reduction, which has
deposition and rapid failure, particularly if there is delayed graft the potential to be applicable to more PH types and mutations. The
function. aims are either to reduce the amount of glyoxylate produced, since it
is the precursor to oxalate, or decrease its oxidation to oxalate. The
Liver transplantation inhibition of the enzyme glycolate oxidase is targeting the peroxi-
The rationale for liver transplantation relies on the fact that AGT is somal source of glyoxylate. Inhibition of the enzyme hydroxyproline
more or less liver specific and, although GRHPR is more widely dis- oxidase targets the mitochondrial source of glyoxylate. Inhibition of
tributed, its activity in the liver greatly exceeds that in other tissues. the enzyme lactate dehydrogenase targets the oxidation of glyoxylate
Liver replacement thus has the potential to replace all, or almost all, to oxalate, the last step, common to all PH types. These new thera-
the body’s requirement for AGT and, to a lesser extent, GRHPR. peutic strategies rely on small interfering RNA (siRNA) administra-
Several hundred liver transplantations, often combined with kidney tion or use the CRISPR/Cas9 technology. Other more conventional
transplantation, have been carried out worldwide for PH1 resulting strategies aim at identifying drugs capable of such enzyme inhib-
in a metabolic cure, although it may take many years for the urinary itions. Recent work on calcium oxalate mediated kidney inflamma-
excretion of oxalate to be normalized. This is especially the case tion suggest a potential adjunct role for targeting the inflammatory
if patients have spent many years with poor renal function or on reaction to preserve renal function. Following promising work in
 12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias 2181

animal models of PH1, clinical trials of siRNA therapeutics are cur-

Dhondup T, et al. (2018). Combined liver-kidney transplantation for
rently underway (phase II/III) and show great promise. Just as the primary hyperoxaluria type 2: A case report. American Journal of
discovery of AGT deficiency in PH1 heralded the introduction of Transplantation, 18(1), 253–7.
enzyme replacement therapy by liver transplantation 30 years ago, Dutta C, et al. (2016). Inhibition of glycolate oxidase with dicer-​
so recent discoveries on the functional relationships between mu- substrate siRNA reduces calcium oxalate deposition in a mouse
tations and enzyme dysfunction will lead to the design of pharma- model of primary hyperoxaluria type 1. Mol Ther, 24, 770–​8.
cological countermeasures. Mutation-​specific chemical chaperones Hopp K, et al. (2015). Phenotype-​genotype correlations and estimated
have potential as future treatments for patients with PH1 or PH2 carrier frequencies of primary hyperoxaluria. JASN, 26, 2559–​70.
who have missense mutations in AGT or GRHPR. Several screening Hoppe B, et al. (2009). The primary hyperoxalurias. Kidney Int, 75,
procedures have been developed to identify chemical chaperones in 1264–​71.
panels of repurposed pharmaceutical drugs. Liebow A, et al. (2017). An investigational RNAi therapeutic targeting
Gene therapy for PH was forecast more than 15 years ago. glycolate oxidase reduces oxalate production in models of primary
Hepatocyte transplantation in an AGT knockout mouse model hyperoxaluria. J Am Soc Nephrol, 28(2), 494–503.
Mandrile G, et al. (2014). Outcome of primary hyperoxaluria type 1
has been attempted, but this technique requires suppression of the
correlates with AGXT mutation type: data from a large European
host hepatocytes. Adeno-​associated virus gene transfer has also
study. Kidney Int, 86, 1197–​204.
been attempted in mice but requires further improvements. A re- Martin-​Higueras C, Luis-​Lima S, Salido E (2016). Glycolate oxidase is
cent study has identified a drug that can decrease the mitochon- a safe and efficient target for substrate reduction therapy in a mouse
drial mistargeting of AGT seen with certain mutations. Continued model of primary hyperoxaluria type I. Mol Ther, 24, 719–​25.
research in that direction may yield more candidates. Monico CG, Milliner DS (2001). Combined liver-​kidney and kidney-​
Probiotics such as the oxalate-​degrading bacteria Oxalobacter for- alone transplantation in primary hyperoxaluria. Liver Transpl, 7,
migenes have been the subject of interest for a few years, but have not 954–​63.
proven their efficacy in human clinical studies for PH so far, despite Monico CG, et al. (2005). Pyridoxine effect in type I primary
their potential to increase oxalate gut secretion. hyperoxaluria is associated with the most common mutant allele.
Multiple novel avenues for treatment of PH are explored and Kidney Int, 67, 1704–​9.
offer new hope for patients with this rare disease. National Center for Biotechnology Information. Online Mendelian
Inheritance in Man (OMIM): http://​www.ncbi.nlm.nih.gov/​entrez/​
query.fcgi?d6MIM; Primary hyperoxaluria type 1: http://​ omim.
org/​entry/​259900; Primary hyperoxaluria type 2: http://​ omim.
FURTHER READING org/​entry/​260000; Primary hyperoxaluria type 3: http://​omim.org/​
Anders HJ, et al. (2018). The macrophage phenotype and inflammasome entry/​613616.
component NLRP3 contributes to nephrocalcinosis-related chronic Purdue PE, et al. (1990). Identification of mutations associated with
kidney disease independent from IL-1-mediated tissue injury. peroxisome-​ to-​mitochondrion mistargeting of alanine:glyoxylate
Kidney Int, 93(3), 656–69. aminotransferase in PH1. J Cell Biol, 111, 2341–​51.
Belostotsky R, et al. (2010). Mutations in DHDPSL are responsible for Rumsby G (2015). Molecular basis of primary hyperoxaluria and strat-
primary hyperoxaluria type III. Am J Hum Genet, 87, 392–​9. egies for diagnosis. Expert Opin Orphan Drugs, 3, 663–​73.
Cochat P, et al. (2012). Primary hyperoxaluria type 1: indications for Salido EC, et al. (2006). Alanine-​glyoxylate aminotransferase-​deficient
screening and guidance for diagnosis and treatment. Nephrol Dial mice, a model for primary hyperoxaluria that responds to adeno-
Transplant, 27, 1729–​36. viral gene transfer. Proc Natl Acad Sci USA, 103, 18249–​54.
Cramer SD, et al. (1999). The gene encoding hydroxypyruvate reduc- Watts RW, et al. (1987). Successful treatment of primary hyperoxaluria
tase (GRHPR) is mutated in patients with primary hyperoxaluria type 1 by combined hepatic and renal transplantation. Lancet,
type II. Hum Mol Genet, 8, 2063–​9. 2, 474–​5.
Danpure CJ, Jennings PR (1986). Peroxisomal alanine:glyoxylate Zabaleta N, et al. (2018). CRISPR/Cas9-mediated glycolate oxi-
aminotransferase deficiency in primary hyperoxaluria type I. FEBS dase disruption is an efficacious and safe treatment for primary
Lett, 201, 20–​4. hyperoxaluria type I. Nat Commun, 9(1), 5454.
12.11
A physiological approach to acid–​base
disorders: The roles of ion transport and
body fluid compartments
Julian Seifter

ESSENTIALS Introduction
The normal pH of human extracellular fluid is maintained within the The normal pH of human extracellular fluid (ECF) is maintained
range of 7.35 to 7.45. The four main types of acid–​base disorders can within the range of 7.35 to 7.45. Though intracellular pH regula-
be defined by the relationship between the three variables, pH, Pco2, tion may be more critical to processes such as protein synthesis, cell
and HCO3–​. growth, and reproduction, it is generally assumed that cell pH, which
Respiratory disturbances begin with an increase or decrease is more difficult to measure, is reflected in the readily accessible ECF.
in pulmonary carbon dioxide clearance which—​through a shift The usual approach taken to understand how acid–​base disturb-
in the equilibrium between CO2, H2O, and HCO3–​—​favours a ances are generated starts with the principle of LeChâtellier: the
decreased hydrogen ion concentration (respiratory alkalosis) or tendency for chemical reactions thrown out of equilibrium to move
an increased hydrogen ion concentration (respiratory acidosis) in the direction that restores the equilibrium state. This is apparent
respectively. in the overall equation relating concentrations of carbon dioxide to
Metabolic acidosis may result when hydrogen ions are added hydrogen ion and bicarbonate ion in the following expression
with a nonbicarbonate anion, A−, in the form of HA, in which case
bicarbonate is consumed, or when bicarbonate is removed as the
CO2 +H2O ↔ H2 CO3 ↔ H+ +HCO3−
sodium or potassium salt, increasing hydrogen ion concentration.
Metabolic alkalosis is caused by removal of hydrogen ions or add-
PCO2 ←↑ (Equation 1)
ition of bicarbonate.
Laboratory tests usually performed in pursuit of diagnosis, aside The four main types of acid–​base disorders can be defined by
from arterial blood gas analysis, include a basic metabolic profile the relationship between the three variables, pH, Pco2, and HCO3–​
with electrolytes (sodium, potassium, chloride, bicarbonate), blood (Table 12.11.1).
urea nitrogen, and creatinine. Calculation of the serum anion gap, Respiratory disturbances begin with an increase or decrease
which is determined by subtracting the sum of chloride and bicar- in pulmonary carbon dioxide clearance which through a shift in
bonate from the serum sodium concentration, is useful. The normal the equilibrium favours a decreased hydrogen ion concentration
value is 10 to 12 mEq/​litre. An elevated value is diagnostic of meta- (respiratory alkalosis) or an increased hydrogen ion concentration
bolic acidosis, helpful in the differential diagnosis of the specific
metabolic acidosis, and useful in determining the presence of a
mixed metabolic disturbance. Table 12.11.1 Features of the four main types of primary acid–​base
Acid–​base disorders can be associated with (1) transport pro- disorder
cesses across epithelial cells lining transcellular spaces in the kidney
pH Pco2/​HCO 3− Primary disorder
(e.g. renal tubular acidosis), gastrointestinal tract (e.g. vomiting), and
−
skin (e.g. cystic fibrosis); (2) transport of acid anions from intracel- Acidaemia Low HCO 3 Metabolic acidosis
lular to extracellular spaces—​anion gap acidosis (e.g. diabetic keto- High Pco2 Respiratory acidosis
acidosis, lactic acidosis); and (3) intake (e.g. infusions with high Alkalaemia High HCO3 −
Metabolic alkalosis
chloride content). Low Pco2 Respiratory alkalosis
 12.11 A physiological approach to acid–base disorders 2183

(respiratory acidosis) respectively. Metabolic acidosis may result Characterization of the type of acid–​base disturbance
when hydrogen ions are added with a nonbicarbonate anion, A−, in A low bicarbonate is consistent with either metabolic acidosis or re-
the form of HA, in which case bicarbonate is consumed as the re- spiratory alkalosis. If blood gases reveal low pH (acidaemia) and low
action shifts left. Alternatively, bicarbonate may be removed as the bicarbonate (metabolic acidaemia), the dominant process is a meta-
sodium or potassium salt, shifting the reaction to the right, bolic acidosis. The response to metabolic acidosis is through stimu-
increasing hydrogen ion concentration. Metabolic alkalosis lation of carotid body and central nervous system chemosensors,
is caused by the removal of hydrogen ion or the addition of which stimulate an increase in alveolar ventilation, so the Pco2 is
bicarbonate. expected to drop. Normal compensation for metabolic acidosis is
In the case of adding acids such as HCl, acid phosphates, and predicted based on an expected range of Pco2 established by ob-
sulphates, or organic acids such as lactic or ketoacids, there would servation of subjects with simple metabolic acidosis. Should the
be a decrease in bicarbonate proportional to the increase in A−. The actual Pco2 be lower than the predicted value, the diagnosis of re-
bicarbonate lost due to HA appearance is renewed by net renal ex- spiratory alkalosis as a second primary disturbance can be made.
cretion of hydrogen and the anion in order to restore acid–​base If the actual Pco2 is higher than predicted, then a simultaneous re-
balance. Since the kidney initially filters large quantities of bicar- spiratory acidosis is present. It is apparent that metabolic acidosis
bonate from the ECF, all of the filtered bicarbonate must first be and its hyperventilatory compensation cause HCO3− and Pco2 to
reabsorbed just to stay even. Once that process is accomplished, fall. The ratio of HCO3−/​Pco2 is proportional to the pH, as dem-
nonbicarbonate buffers, usually ammonium and acid phosphate, onstrated in the Henderson–​Hasselbalch relationship expressing
remove hydrogen in the urine accompanied by A− and in the pro- equation 1 in logarithmic terms, where the pK is 6.1 and the con-
cess generate ‘new’ bicarbonate. The metabolic acids that require centration of carbon dioxide in water is 0.03 mmol/​litre per mmHg
urinary excretion are usually in the range of 1 to 2 mEq of H+ per kg of equilibrated gas.
of body weight. By comparison, the volatile carbon dioxide produc-
tion per day is about 20 moles. pH = pK + log[ HCO3− ]/[0.03 × PCO2 ] (Equation 2)

The finding of a metabolic acidosis does not rule out multiple

The diagnostic approach to identifying processes simultaneously present. There are many findings that
acid–​base disorders help diagnose mixed disturbances. In each of the primary disturb-
ances, once the dominant process is identified, it is necessary to
The key questions to ask when attempting to diagnose the cause of an infer the degree of compensation by looking at empirical data (see
acid–​base disorder are shown in Box 12.11.1. The usual diagnostic Box 12.11.2 for a range of normal compensations).
approach to an acid–​base disorder begins with a complete history Determining whether the respiratory response to a metabolic
and physical examination. When taking a history, it is important to acidosis is as expected for a mixed disorder allows the recognition
understand the quantity, contents, and source of fluid losses or gains or exclusion of an additional primary respiratory disorder, but a
from the body; ingested substances; and certain diseases known to mixed metabolic disturbance is still possible. For example, Winters’
be associated with acid–​base disorders. Examples include vomiting equation—​which gives the expected value for the patient’s Pco2 if
(metabolic alkalosis), diarrhoea (metabolic acidosis), chronic ob- there is adequate respiratory compensation for a metabolic acidosis
structive lung disease (respiratory acidosis), pneumonia (respira- (Box 12.11.2)—​is still valid when metabolic acidosis and alkalosis
tory alkalosis), and so on. coexist if the predominant process is acidosis. In the case where a
Laboratory tests usually performed, aside from arterial blood high-​chloride acidosis and a low-​chloride alkalosis coexist, it is not
gas analysis, include a basic metabolic profile with electrolytes (so- possible to differentiate this double disturbance from a simple meta-
dium, potassium, chloride, bicarbonate), blood urea nitrogen, and bolic acidosis.
creatinine. Disturbance of the bicarbonate concentration alone
does not prove a metabolic disturbance because there are two other
variables in equilibrium with bicarbonate: carbon dioxide and the
hydrogen ion concentration.

Box 12.11.2 Compensations for acid–​base disturbances

Pco2 is measured in mmHg and HCO 3− in mEq/​litre. The direction
Box 12.11.1 The key questions for diagnosis of the cause of an of compensatory response in Pco2 or HCO3− is the same as the ini-
acid–​base disorder tial change in HCO 3− or Pco2, but compensation is almost never
complete
Approach to acid–​base disorders
Expected values if simple disturbance
1 Is there acidaemia (pH <7.35) or alkalaemia (pH >7.45)? Metabolic acidosis (Winters’ formula): Pco2 = (1.5 × HCO3−) + 8 ± 2
2 What is the primary process (metabolic or respiratory, acidosis or Metabolic alkalosis: Pco2 = 0.7[HCO3−] + 20 ± 5
alkalosis)? Acute respiratory acidosis: [HCO3−] = 24 + [(Pco2 − 40)/​10]
3 Is there an appropriate compensatory response? Chronic respiratory acidosis: [HCO3−] = 24 + 4[(Pco2 − 40)/​10]
4 If this is an anion gap acidosis, are there other clues to a second pri- Acute respiratory alkalosis: [HCO3−] = 24 –​ 2[(Pco2 − 40)/​10]
mary process? Chronic respiratory alkalosis: [HCO3−] = 24 − 5[(Pco2 − 40)/​10]
2184 section 12 Metabolic disorders

The serum anion gap Box 12.11.4 Causes of hyperchloraemic acidosis and
It is useful to calculate the serum anion gap, which is determined their diagnosis
by subtracting the sum of chloride and bicarbonate from the serum
Chloride poor losses
sodium concentration (the measured ions). The normal value is Renal losses
approximately 10 to 12 mEq per litre, the amount of charge asso- • Diuretics with high cation content:
ciated with a normal albumin concentration. The relationship is —​ Acetazolamide
as follows: —​ Potassium-​sparing
• Renal tubular acidosis:
Na + − (Cl − + HCO3 − ) = (albumin − ) + unmeasured A − —​ Early only in proximal
= anion gap (Equation 3) —​ Chronic in distal
• Nonbicarbonate anion:
An elevated anion gap is diagnostic for a metabolic acidosis. —​ Ketoacidosis
Not only is the presence of an anion gap helpful in the differential —​ Hippurate anion
diagnosis of the specific metabolic acidosis (Box 12.11.3), but it Gastrointestinal losses
is also useful in determining the presence of a mixed metabolic • Small bowel losses
disturbance. A calculation of the increment in anion gap (ob- • Most diarrhoea
served anion gap minus normal anion gap of 10 mEq per litre)
Chloride rich gains
can be compared to a calculation of the decrease in bicarbonate
• 0.9%, 0.45% saline
concentration (normal bicarbonate of 25 mEq per litre minus the • Ringer’s lactate
observed bicarbonate concentration). If this relationship is ap-
proximately 1:1, then it is likely that the acidotic disorder is due Urinary electrolytes
to an unmeasured acid anion. However, if the rise in anion gap is • Suggest renal cause of acidosis:
—​ UNa + UK –​ UCl is positive
greater than the fall in bicarbonate, a process raising the bicar-
—​ Low urinary NH4Cl
bonate concentration such as a metabolic alkalosis coexists. This
• Suggest nonrenal cause of acidosis:
combination might be seen in a patient who is vomiting and has
—​ UNa + UK –​ UCl is negative
diabetic ketoacidosis. If the fall in bicarbonate concentration ex-
—​ High urinary NH4Cl
ceeds the rise in anion gap, then the second process is most likely
a hyperchloraemic acidosis.
Metabolic acidosis
In diagnosing the cause of metabolic acidosis, calculation of
Box 12.11.3 Causes of high anion gap metabolic acidosis the serum anion gap can distinguish hyperchloraemic acidosis
• Lactic acidosis: (Box 12.11.4) from common organic anion acidosis (Box 12.11.3),
—​ Severe illness some overproduced in the body, others caused by ingestion of toxic
—​ Sepsis substances. These conditions are discussed later in this chapter.
—​ Shock
—​ Seizures Metabolic alkalosis
—​ Malignancy Metabolic alkalosis is generally divided into two categories based on
—​ Drugs its responsiveness to chloride. Chloride-​responsive metabolic alkal-
—​ Metformin osis is associated with ECF and chloride depletion and is seen in cases
—​ Nucleoside reverse transcriptase inhibitors of gastric fluid loss and diuretic use. As is the case of hyperchloraemia
• Uraemia
versus anion gap acidosis, a diagnostic clue in metabolic alkalosis
• Rhabdomyolysis
comes from the serum electrolytes. Bicarbonate is increased with
• Ketoacidosis:
a corresponding fall in serum chloride (hypochloraemic alkalosis,
—​ Diabetes
—​ Ethanol (alcohol) Box 12.11.5). Chloride-​unresponsive metabolic alkalosis is seen in
—​ Starvation patients with ECF expansion in conditions such as primary aldos-
• Poisoning: teronism and hypokalaemia. These conditions are discussed later in
—​ Methanol this chapter.
—​ Ethylene glycol
—​ Propylene glycol
—​ Toluene (glue sniffer) hippurates Acid–​base disorders as disturbances of chemistry
• Drugs: of the extracellular fluid
—​ Salicylates
—​ Iron That the normal H+ concentration is in the range of 40 nM, while the
—​ Isoniazid bicarbonate concentration is in the 25 mM range, is an indication that
•​ Pyroglutamic acid (5-​oxoprolinuria) protons are involved in many reactions within the body, including
—​ Acetaminophen (paracetamol)
with water and many buffers such as phosphate, haemoglobin, and
•​ d-​Lactic acid
the amino groups on many proteins (carbamino compounds). Use
 12.11 A physiological approach to acid–base disorders 2185

Box 12.11.5 Causes of hypochloraemic alkalosis and

their diagnosis Components of total body water
Renal causes of hypochloraemia
Extracellular fluid
Diuretics and renal channelopathies
• NKCC:
—​ Furosemide, bumetanide
—​ Bartter’s syndrome
Interstitial fluid
• NaCl: P
Intracellular fluid
l
—​ Thiazides a
—​ Gitelman’s syndrome s
m
Nonrenal causes of hypochloraemia a
• Gastrointestinal:
—​ Gastric
—​ Congenital chloridorrhoea Transcellular fluids
—​ Infection
• Skin:
—​ Cystic fibrosis
Urinary electrolytes Fig. 12.11.1 Body fluid compartments.
• Suggest renal cause of alkalosis:
—​ Urinary electrolytes reveal Cl− loss
external world. Other transcellular spaces are the pleural and peri-
—​ UNa + UK –​ UCl is low or negative
toneal space and cerebrospinal fluid. These spaces reflect systemic
• Suggest nonrenal cause of alkalosis:
acid–​base conditions through equilibration rather than cause them
—​ Urinary electrolytes reveal low Cl−
because they are not in continuity with the external environment.
—​ UNa + UK –​ UCl is high
A second mechanism for introduction of acids or bases into or
out of the ECF involves movement of ions between cells and the
extracellular space. Organic acid anions (HA) such as ketoacids
of the standard bicarbonate approach relying on the HCO3−/​Pco2 and lactic acids produced in the liver, muscle, or other tissues,
system to describe acid–​base phenomena depends on the isohydric and metabolites of toxins absorbed from the gastrointestinal
principle: that a single H+ concentration is in equilibrium with mul- tract, undergo such internal transfers across cell plasma membranes
tiple other buffer pairs. Alternative approaches involve consider- as they enter the ECF. These examples constitute the anion gap
ation of electrostatic forces requiring electroneutrality between all acidoses because the anion (A−) entering the ECF is not chloride.
cations and anions in the ECF giving dependency of HCO3− and H+ When the same anions, such as lactate and citrate, are ingested
to concentrations of strong electrolytes such as sodium, potassium, as the sodium or potassium salt, taken up by liver cells, and oxi-
and chloride. Pertinent to the approach taken in this chapter, one dized, it is bicarbonate that is transported to the ECF, which may
could apply either theory because all that is required is disturbance cause metabolic alkalosis if production exceeds clearance.
of ionic species within the ECF. It should be noted that respiratory disorders also involve trans-
Since clinical acid–​base disorders are defined in terms of blood port of carbon dioxide into or out of the ECF. Carbon dioxide
chemistry, and because plasma volume is part of the total ECF generated by cell respiration diffuses into venous plasma before
volume, the approach taken here is to describe the ways by which entering red blood cells en route to the lungs, where the process
electrolytes including hydrogen and bicarbonate ions can be intro- is reversed as carbon dioxide diffuses from red cell to plasma to
duced into or removed from the ECF. As shown in Fig. 12.11.1, lung interstitium to cells lining the airspaces prior to alveolar
the boundaries of the ECF are cell membranes at the interface of ventilation.
intracellular water and the interstitial fluid compartment of the
ECF or specialized epithelial cells that line compartments known as
transcellular spaces. The transcellular spaces are outside cell water, Acid–​base disorders associated with transport
so fall into a special category of ECF, and their contents reflect solute across epithelial cells lining transcellular spaces
exchanges with the interstitial space. This chapter will approach
acid–​base disorders through understanding these cell membrane The following discussion emphasizes ion transport processes of
boundaries and their transport functions. the plasma membranes of epithelia in various organs. The first
We start with mechanisms by which acid–​base disturbances ori- to be examined are renal tubular epithelial cells. The reason be-
ginate through transfer of electrolytes such as sodium, potassium, hind starting with the kidney is that the same cell transporters that
chloride, hydrogen, and bicarbonate across epithelial cell mem- regulate acid–​base in normal physiology may initiate acid–​base
branes that line transcellular spaces within the ECF. Transcellular disturbances and compensate for disturbances that are generated
fluids include the lumina of the entire gastrointestinal tract, the elsewhere in the body. Primary renal disorders as well as the com-
kidney tubules, and sweat gland ducts. These particular epithe- pensations for respiratory and metabolic disturbances can be con-
lial lined spaces have a common feature in having an outlet to the sidered together.
2186 section 12 Metabolic disorders

Acid–​base disorders and the kidney can combine with a filtered bicarbonate ion, forming carbonic acid.
Glomerular filtration utilizes mechanical energy of the cardiac-​ The dehydration of carbonic acid to water and carbon dioxide is
generated blood pressure to form a glomerular ultrafiltrate that kinetically favoured by carbonic anhydrase IV in the brush-​border
requires modification by the renal tubules before being excreted membrane. Carbon dioxide can then re-​enter the cell where it com-
as urine. The role of the tubules is primarily to reclaim necessary bines with hydroxyl ions left in excess in the cell with the secretion
fluids, electrolytes, and solutes while allowing the elimination of ap- of hydrogen into the lumen. This reaction of hydroxyl and carbon
propriate quantities of waste substances. The process accounts for as dioxide to form bicarbonate is catalysed by intracellular carbonic
much as 15% of the body’s energy expenditure in the form of high-​ anhydrase II. The bicarbonate thus formed, representing filtered
energy phosphates. Oxygen consumption is high, particularly in the bicarbonate, can then pass across the basolateral membrane to the
renal cortex, and is related to these transport functions. extracellular space via a sodium bicarbonate cotransporter (NBC)
In normal circumstances, glomerular filtration rate (GFR) is in with a 1:3 stoichiometry. This electrogenic ratio of sodium to bicar-
the order of 180 litres/​day and the amount of freely filtered solutes bonate provides enough driving force for completing proximal bi-
can be calculated as the product of GFR and the concentration of carbonate reabsorption. Another way of viewing NBC function is
the solute in the arterial plasma. For bicarbonate, the quantity might that it protects against cellular alkalinization. Bicarbonate reabsorp-
be more than 4500 mEq/​day. The uncontrolled excretion of even a tion would be decreased as interstitial fluid bicarbonate concentra-
small quantity of this filtrate could prove fatal. tion is elevated when bicarbonate is ingested and the gradient for
bicarbonate to exit the cell diminished. This is one mechanism by
The proximal tubule which bicarbonaturia is achieved when serum bicarbonate levels go
up, even minimally.
The first tubular segment to confront this large filtrate is the prox-
The net result of proximal bicarbonate reabsorption is a luminal
imal tubule (Fig. 12.11.2). The early proximal tubule has abundant
pH decrease by the end of the proximal tubule to approximately 6.5.
brush-​border membranes on the apical surface allowing for a large
The reduced delivery of bicarbonate to the more distal segments of
surface area for reabsorption. As shown in Fig. 12.11.2a, the luminal
the tubule, which have lower capacity for bicarbonate absorption, al-
fluid remains isosmotic to plasma and accounts for approximately
lows completion of the process of reabsorption in regulated fashion.
50% of sodium and water reabsorption, but 85% of filtered bicar-
Proximal tubular reabsorption of sodium and HCO3− is regulated
bonate is reclaimed by the proximal tubule.
by hormones such as angiotensin II and catecholamines (which in-
The normal process of fluid resorption involves many steps, as
crease) and by parathyroid hormone (which decreases) the exchange
shown in Fig. 12.11.2b. There must be adequate ATP production by
of sodium and hydrogen. Other factors that regulate the activity of
proximal tubule mitochondria to fuel the sodium potassium ATPase
sodium–​hydrogen exchange and sodium bicarbonate cotransport
which pumps sodium into the extracellular space in exchange for
include hypokalaemia and hypercapnia, which increase the process.
potassium. The consequence is a low intracellular sodium con-
Hypocapnia has the opposite effect, decreasing proximal sodium bi-
centration and a cell-​negative electrical potential difference across
carbonate reabsorption.
the plasma membranes. A sodium electrochemical gradient thus
Another important function of the proximal tubule in acid–​base
formed favours entry of sodium from the lumen into the cell.
balance is the mitochondrial production of ammonia from glu-
Many transporters utilize the energy of the sodium gradient to
tamine and glutamate. The ammonia formed can get into the urine
cotransport important solutes such as glucose and amino acids back
by diffusion into the lumen or by counter-​transport with sodium
into the cell. The luminal secretion of protons from the cell occurs
via the sodium–​hydrogen exchanger. Basolateral glutamine uptake
by exchange with sodium entering the cell (sodium–​hydrogen ex-
and ammonia production by glutaminase activity is increased in
change). Once the proton is in the lumen of the proximal tubule it
both respiratory and metabolic acidosis and will increase urinary
net acid excretion as ammonium chloride. While ammonia is pro-
duced in the proximal tubule, regulation of how much is ‘trapped’
and excreted as ammonium is a function of the distal nephron where
urine pH falls to a value as low as 5. Hypokalaemia also increases
ammonia production.

Role of the proximal tubule in metabolic acidosis

Considering the many steps involved in proximal HCO3− reabsorp-
tion, it is understandable that an abnormality at any one of the steps
could result in delivering an amount of bicarbonate exceeding the
capacity for distal nephron reabsorption. Bicarbonaturia and an
alkaline urine would then result and metabolic acidosis develop.
Because the excretion of bicarbonate is with sodium and potassium
and less chloride, the ECF will express hyperchloraemic metabolic
acidosis. These syndromes are known collectively as proximal renal
tubular acidoses.

Fig. 12.11.2 The early proximal tubule: (a) luminal content; (b) cellular Proximal renal tubular acidosis (type 2) Proximal renal tubular
transport mechanism. CA, carbonic anhydrase. acidosis (type 2) is characterized by a decreased threshold for
 12.11 A physiological approach to acid–base disorders 2187

bicarbonate reabsorption. HCO3–​ wasting and concomitant urinary sodium bicarbonate reabsorption earlier. Chloride may then enter
losses of potassium occur until a lower level of serum bicarbonate re- the proximal tubule cell in exchange for base, or chloride—​favoured
duces the filtered HCO3–​ to a level at which the combined remaining by its high luminal to interstitial fluid concentration gradient—​
function of the abnormal proximal tubule and low capacity distal may pass through the paracellular route creating a positive luminal
nephron can completely reabsorb filtered bicarbonate. At that point, voltage that would increase paracellular sodium absorption. When
the urine becomes acid (pH <5.3) and net acid production equals filtered chloride is high at the outset (filtrate of plasma and ECF),
net acid excretion, with a steady-​state low plasma HCO3−. Attempts and bicarbonate low, no such chloride gradient develops. A clinical
to raise the plasma bicarbonate to normal may be difficult because corollary is that carbonic anhydrase inhibitors and hyperchloraemic
the added bicarbonate will promptly enter the urine (high fractional acidoses per se decrease the lumen to interstitial fluid chloride gra-
excretion of bicarbonate), unnecessary because once the low bicar- dient and therefore result in diuresis of sodium chloride.
bonate is achieved, a balance of acid produced and excreted occurs, The metabolic acidosis that develops in chronic kidney disease
and risky because the more bicarbonate excreted in the urine, the is related to the failure to produce ammonia, thereby limiting the
greater is potassium loss. However, correcting acidosis with bicar- amount of net acid that can be excreted in the urine. If that amount
bonate replacement is especially necessary in growing children. is smaller than acid production within the body, then metabolic
Isolated proximal renal tubular acidosis may result from muta- acidosis will develop. Many organic and inorganic anions, such as
tions of specific transporters of the proximal tubule, such as the phosphate and sulphates, are retained at GFRs of less than 25 ml/​
sodium–​hydrogen exchanger 3 (NHE3) or NBC, or from hereditary min and constitute an increased anion gap in association with the
deficiency of carbonic anhydrase isoforms or carbonic anhydrase metabolic acidosis. Patients with chronic kidney disease will not
inhibitors. More commonly, proximal renal tubular acidosis is as- normally compensate for respiratory acidosis or nonrenal metabolic
sociated with Fanconi’s syndrome or generalized proximal tubule acidosis because they do not have the ability to further increase am-
dysfunction. Causes include genetic diseases such as glucose-​6-​ monia production.
phosphatase deficiency, cystinosis, hereditary fructose intolerance,
and Wilson’s disease. Acquired conditions such as multiple myeloma Role of the proximal tubule in metabolic alkalosis
and Sjögren’s syndrome should be considered in an adult patient. An increase in proximal sodium bicarbonate reabsorption allows
For further discussion see Chapter 21.15. less bicarbonate to flow distally and will maintain the existing level of
Primary hyperparathyroidism results in proximal renal tubular plasma bicarbonate. In the case of volume (sodium) depletion with
acidosis and hypophosphataemia secondary to inhibition of Na/​H increased angiotensin II, or during hypokalaemia, it becomes diffi-
exchange (NHE3) and sodium phosphate cotransport in the prox- cult to excrete an increased bicarbonate load. In order to eliminate
imal tubule by parathyroid hormone through cyclic AMP. The Cl−/​ any excess of filtered bicarbonate, there must be normal sodium and
phosphate ratio in plasma may be elevated. Hyperparathyroidism potassium balance. Metabolic alkalosis, if present, is therefore main-
is one of the few causes of metabolic acidosis and hypercalcaemia. tained until replacement of potassium and extracellular volume is
Drug toxicity with aminoglycosides, cisplatin, and ifosfamide achieved (discussed later in this chapter).
may cause proximal tubule dysfunction. The antiretroviral drug
tenofovir, a nucleotide analogue reverse transcriptase inhibitor used Role of the proximal tubule in compensation
in the treatment of human immunodeficiency virus-​1 (HIV-​1) and for respiratory disorders
hepatitis B, is a cause of Fanconi’s syndrome. The syndrome also may In respiratory acidosis, increased ammonium excretion allows for
be seen after kidney transplantation. a rise in plasma bicarbonate because elimination of hydrogen ions
As shown in Fig. 12.11.3, the late proximal tubule receives fluid that does not result in bicarbonate reabsorption instead results in
that is low in bicarbonate and high in chloride due to preferential ‘new’ bicarbonate. Though the final formation of ‘new’ bicarbonate
is a distal function involving hydrogen secretion, the ammonia ne-
cessary for the process is made in the proximal tubule and stimu-
lated by hypercapnia. The role of a high Pco2 in respiratory acidosis
Late proximal tubule to increase sodium bicarbonate reabsorption in the proximal tubule
is the basis of the maintenance of high bicarbonate concentrations
in compensated respiratory acidosis. In patients with compensated
chronic respiratory acidosis who are acutely ventilated to normal
Pco2, high bicarbonate levels remain until chloride is replaced
(posthypercapnic alkalosis).
Taken together the compensation for respiratory acidosis re-
quires the generation of new bicarbonate and increased proximal
reabsorption of filtered sodium bicarbonate. By contrast, the renal
compensatory mechanism in respiratory alkalosis is decreased so-
dium bicarbonate reabsorption in the proximal tubule causing alka-
line urine and a low plasma bicarbonate concentration.

Thick ascending limb of Henle’s loop

Fig. 12.11.3 Late proximal tubule. (a) Luminal content; (b) cellular As the tubular fluid leaves the proximal tubule and enters the loop
transport mechanism. of Henle, the process of bicarbonate reabsorption continues in the
2188 section 12 Metabolic disorders

Thick ascending limb of Henle Distal convoluted tubule

Fig. 12.11.4 Thick ascending limb of Henle. (a) Luminal content; Fig. 12.11.5 Distal tubule. (a) Luminal content; (b) cellular transport
(b) cellular transport mechanism. CaR, calcium receptor mechanism.

thick ascending limb. Luminal sodium hydrogen exchangers and (NCC) is inhibited. NCC is often referred to as the thiazide-​sensitive
basolateral sodium bicarbonate cotransporters reabsorb approxi- sodium chloride transporter because of its inhibition by thiazide
mately 5% of the bicarbonate filtered. As shown in Fig. 12.11.4, the diuretics.
thick ascending limb has a major role in sodium chloride reabsorp-
tion for maintenance of extracellular volume, osmoregulation (both Role of the distal tubule in hypochloraemic alkalosis
concentrating and diluting mechanisms), and divalent cation re- Like furosemide, thiazide diuretics cause hypochloraemic alkal-
absorption (calcium and magnesium). osis due to urinary chloride loss. Gitelman’s syndrome is an auto-
somal recessive cause of extracellular volume depletion, urinary
Role of the thick ascending limb in hypochloraemic alkalosis chloride wasting, and hypokalaemic metabolic alkalosis. It is due to
The sodium, potassium, two-​chloride cotransporter, NKCC, can inactivating mutations in the SLC12A3 gene encoding the thiazide-​
be inhibited by drugs such as furosemide and bumetanide and by sensitive NCC cotransporter of the renal distal tubule. Urinary con-
hypercalcaemia through a unique mechanism of the basolateral centrating ability is preserved because the cortical distal tubule has
calcium receptor. Patients with hypercalcaemia lose salt in the no effect on the interstitial concentrating gradient of the medulla,
urine. The effect of hypercalcaemia is to inhibit the NKCC trans- and patients are hypocalciuric because decreased sodium chloride
porter, much like furosemide. This provides a mechanism for the reabsorption in the distal tubule is associated with a decrease in
frequently observed association between hypercalcaemia and al- calcium excretion (hence its usefulness in hypercalciuric states).
kalosis. Inhibition of chloride reabsorption in this segment leads to Hypomagnesaemia may also be severe.
hypochloraemic metabolic alkalosis. Patients who present with hypokalaemic metabolic alkalosis with
Bartter’s syndrome is an autosomal recessive disorder associated normal or low blood pressure and have urinary chloride concen-
with extracellular volume depletion and excessive urinary chloride trations greater than 25 mEq/​litre may be taking diuretics such as
loss that results in hypokalaemia and hypochloraemic metabolic furosemide or thiazides surreptitiously; a diuretic screen can docu-
alkalosis. Secondary increases of plasma renin and aldosterone ment the presence of the drug. If the screen is negative, Bartter’s or
occur, as does renal juxtaglomerular cell hyperplasia. The syndrome Gitelman’s syndrome should be considered. Bartter’s syndrome is
resembles the effects of furosemide on the thick ascending limb less common, usually more severe, and presents in young patients.
of Henle. Gene mutations in the NKCC cotransporter, the renal The presence of hypercalciuria favours Bartter’s syndrome, whereas
outer medullary K+ channel (ROMK), and Cl–​ channels (Bartin) hypocalciuria and hypomagnesaemia suggest Gitelman’s syndrome.
have been described. Because calcium reabsorption occurs in the The hypokalaemia in both syndromes is due to increased sodium
thick ascending limb of Henle, Bartter’s syndrome, like furosemide, delivery to more distal collecting tubule segments where K+ se-
causes hypercalciuria and nephrocalcinosis, as well as polyuria due cretion occurs and depends on delivered sodium, and secondary
to decreased urinary concentrating ability. For further discussion hyperaldosteronism. For further discussion, see Chapter 21.2.2.
see Chapters 21.2.2 and 21.16.
Role of the distal tubule in hyperchloraemic acidosis
Distal tubule In Gordon’s syndrome (pseudohypoaldosteronism type 1), in-
As shown in Fig. 12.11.5, the distal tubule receives input from the creases in Na+ and Cl–​ reabsorption through increased activity of
loop of Henle and plays an important role in continued salt re- the distal thiazide-​sensitive NCC transporter leads to hypertension
absorption to maintain extracellular volume and in urinary dilution and hyperkalaemic, hyperchloraemic acidosis, volume expansion,
by separating salt from water in the absence of antidiuretic hormone. and (consequently) low renin and aldosterone. The hyperkalaemia
Furthermore, the segment is responsive to parathyroid hormone is due to decreased sodium delivery to more distal collecting tubule
which increases calcium absorption in the distal tubule. Calcium segments where K+ secretion occurs and depends on delivered so-
reabsorption is increased when the sodium chloride cotransporter dium, and aldosterone. For further discussion see Chapter 21.15.
 12.11 A physiological approach to acid–base disorders 2189

The secreted protons can combine with the small amount of re-
Cortical collecting duct maining filtered bicarbonate delivered from proximal sites to re-
form luminal carbon dioxide which then enters the intercalated cell
where—​in the presence of intracellular carbonic anhydrase—​it re-
forms bicarbonate for return to the ECF by a chloride–​bicarbonate
exchanger. To the extent that the secreted proton combines instead
with ammonia or phosphate in the lumen, the hydroxyl left over
within the cell (as the proton is secreted), combines with ambient
carbon dioxide to recreate bicarbonate which returns to the ECF as
‘new’ bicarbonate to replace the extracellular bicarbonate initially
lost by acid produced within the body.
In other circumstances, particularly on an alkaline ash diet (con-
sisting mainly of fruit, vegetables, and milk) where bicarbonate
needs to be eliminated, the β-​intercalated cell (with reversed polarity
of proton pump and chloride–​bicarbonate exchange) predominates,
Fig. 12.11.6 Collecting duct principal cell. (a) Luminal content;
(b) cellular transport mechanism. 11β OHSD, 11β hydroxysteroid
allowing for bicarbonate secretion into the lumen in exchange for
dehydrogenase; AldoR, aldosterone receptor; ENaC, epithelial chloride (Fig. 12.11.8).
sodium channel. Coordinated function of the principal and intercalated cells
involves sodium reabsorption by ENaC, lumen negativity, and
Collecting duct increased distal acidification of the urine. ENaC is regulated
by aldosterone through the intracellular mineralocorticoid re-
The final 10% of filtered bicarbonate reabsorption occurs in the
ceptor (MR) in the principal cell. That receptor can be activated
renal collecting duct. The mechanism by which this occurs involves
by either aldosterone or cortisol. Cortisol is prevented from nor-
the coordinated effort of two types of cells: the principal cell and the
mally activating the MR by virtue of 11 β-​hydroxysteroid de-
intercalated cell (Figs. 12.11.6 and 12.11.7). As in other nephron
hydrogenase type 2, which degrades cortisol to inactive cortisone.
segments, principal cell basolateral sodium–​ potassium ATPase
Aldosterone production is increased independently by adrenal se-
lowers intracellular sodium and provides a gradient for inwardly
cretion due to angiotensin II and hyperkalaemia. The dual mech-
directed sodium movement. In this cell type, sodium enters through
anism for aldosterone production allows for potassium secretion
the epithelial sodium channel known as ENaC. The process of so-
in volume expanded states and potassium conservation in hypo-
dium reabsorption renders the lumen of the collecting duct elec-
volaemia. The so-​called aldosterone paradox, which refers to the
tronegative. If no other ion transport occurred, the lumen-​negative
ability of the kidney to retain sodium and chloride with minimal
charge would increase to a degree that would shut down further so-
potassium secretion in the presence of volume depletion and yet
dium reabsorption. However, if either a cation enters the lumen or
to maximize potassium excretion without sodium retention in
an anion leaves the lumen, the negative charge would be neutralized
hyperkalaemia, may be mediated by decreased activity of potas-
or ‘compensated’ allowing more sodium to be reabsorbed. Charge
sium channels in the collecting duct when angiotensin II is pre-
compensation for the negative lumen occurs by potassium secretion
sent and increased activity when angiotensin II is low. When AII
through luminal potassium channels or by selective anion reabsorp-
is high, more sodium is reabsorbed upstream from the potassium-​
tion. Another mechanism for charge compensation is proton secre-
secreting principal cells, decreasing net sodium for potassium
tion by the electrogenic proton ATPase of adjacent α-​intercalated
exchange.
cells shown in Fig. 12.11.7.

Cortical collecting duct: β-intercalated

Cortical and medullary collecting duct:
cell
α-intercalated cell

Fig. 12.11.7 Collecting duct α-​intercalated cell. (a) Luminal content; Fig. 12.11.8 Collecting duct β-​intercalated cell. (a) Luminal content;
(b) cellular transport mechanism. CA, carbonic anhydrase. (b) cellular transport mechanism. CA, carbonic anhydrase.
2190 section 12 Metabolic disorders

From this analysis, it is apparent that renal acidification can be- is maintained by a decrease in the serum HCO3–​ concentration,
come abnormal at many different steps within either the principal and a hyperchloraemic acidosis ensues. Renal production of
or intercalated cells of the collecting duct. If the disease results NH3 increases in an attempt to improve HCl (NH4 Cl) excretion.
in decreased hydrogen excretion, the abnormalities are collect- Hyperkalaemia can occur because the acidaemia favours the exit of
ively known as distal renal tubular acidoses. If the disease instead K+ from cells within the body. Acidaemia also inhibits K+ secretion
leads to increased acid excretion, then metabolic alkalosis ensues. in the renal collecting duct.
Disorders of the principal cell typically cause hyperkalaemia with
acidosis or hypokalaemia with alkalosis because of the similar Role of the collecting duct principal cell in hypokalaemic,
direction of potassium and hydrogen ion secretion. However, in- hypochloraemic alkalosis with extracellular volume
creased ENaC activity syndromes can cause extracellular volume expansion (hypertension)
expansion or be the appropriate response to extracellular volume The renal conditions that cause metabolic alkalosis and volume
depletion. Similarly, decreased ENaC activity can be the cause of expansion are due to a proportionately greater increase in Na+ re-
extracellular volume depletion or the appropriate response to extra- absorption above that required to maintain a steady state of Na+
cellular volume expansion. balance, rather than primary loss of the Cl–​ anion. As Na+ is reab-
sorbed, electroneutrality is maintained by an increase in plasma
Role of the collecting duct principal cell in hyperkalaemic, HCO3–​. The extracellular volume and plasma Na+ concentration
hyperchloraemic acidosis (distal/​type 4 renal tubular acidosis) may be increased, Cl–​ appears in urine, and hypochloraemia is not
This combination of abnormalities suggests dysfunction of the cor- present. In the kidney, the loss of net acid as NH4Cl in excess of
tical collecting duct, where acidification of urine and disorders in the acid produced generates a metabolic alkalosis in which the ‘new’
potassium secretion may occur. Some patients with high blood po- bicarbonate is due to proton secretion by the distal nephron H+-​
tassium and hyperchloraemic acidosis can lower urinary pH below ATPases. The H+ combines with NH3 to form NH4+ in urine.
5.3, whereas others appear to have defects in both potassium balance The increased plasma HCO3–​ will be filtered, but in the absence
and urinary acidification. Hyperkalaemia itself may worsen meta- of a stimulus to increase proximal HCO3–​ reabsorption, the HCO3–​
bolic acidosis since the high potassium outcompetes ammonia will flow distally to be reabsorbed by the increased H+ secretion of
reabsorption at the K-​site of NKCC in the thick limb, thereby the collecting duct. At first, the alkalosis is mild, but increased cor-
decreasing NH3 accumulation by countercurrent multiplication in tical collecting duct Na+ reabsorption leads to increased K+ secretion
the medullary interstitium. and hypokalaemia. Hypokalaemia increases the capacity for prox-
Causes include hyporeninaemic hypoaldosteronism, as seen in imal HCO3–​ reabsorption, thereby opposing the effect of volume
diabetic renal disease; other tubulointerstitial diseases, usually with expansion, so that distal delivery of HCO3–​ decreases. The higher
some renal impairment; sickle cell anaemia; or the use of drugs such than normal distal H+ secretion titrates urinary buffers so further
as renin inhibitors, β-​blockers, and nonsteroidal anti-​inflammatory ‘new’ HCO3–​ is formed and the alkalosis worsens. Metabolic alkal-
drugs, where cyclooxygenase-​2 inhibition of the cells of the macula oses of this type are sustained by hypokalaemia and the alkalosis can
densa result in decreased renin secretion. Low renin and aldosterone be treated by potassium replacement.
levels can be found in cases of volume expansion with hypertension. Specific causes of renal alkalosis with hypokalaemia, volume ex-
Ciclosporin and tacrolimus may lead to decreased electrical driving pansion, and hypertension can be classified according to levels of
forces for K+ and H+ secretion. renin and aldosterone. Primary increases in renin with secondary
Hyperkalaemic acidosis with elevated renin and low aldosterone increases in aldosterone can be seen in patients with unilateral renal
is found in adrenal insufficiency, isolated hypoaldosteronism, and artery stenosis, renin-​secreting tumours of the kidney, and malig-
the use of angiotensin-​converting enzyme inhibitors, and angio- nant hypertension.
tensin II receptor blockers. High renin and aldosterone levels are Low renin and elevated aldosterone levels are characteristic of
anticipated when the renal collecting duct cell is insensitive to aldos- primary hyperaldosteronism from adrenal adenoma or hyperplasia.
terone, as with urinary tract obstruction, sickle cell anaemia, amyl- If the aldosterone secretion is autonomous, a high salt intake will
oidosis, and systemic lupus erythematosus. worsen the hypokalaemia and the alkalosis because more sodium
Inhibition of aldosterone action with spironolactone, eplerenone, or will be delivered distally because of the volume expansion, and al-
new nonsteroidal MR receptor antagonists may cause hyperkalaemic dosterone, usually shut off in such circumstances, remains active
acidosis, as does ENaC inhibition by amiloride, triamterene, tri- causing increased potassium secretion.
methoprim, and lithium. Pseudohypoaldosteronism type 1 is due Low renin and low aldosterone are seen when volume expan-
to autosomal recessive, inactivating mutations of the Na+ channel sion is due to a high cortisol level in Cushing’s syndrome and the
ENaC, whereas autosomal dominant pseudohypoaldosteronism hypercortisolism of adrenocorticotropic hormone-​ secreting tu-
type 1 is due to mutations of the MR. Both cause hypovolaemia, mours. Inhibition of the intracellular enzyme 11β-​hydroxysteroid
metabolic acidosis, and hyperkalaemia with secondary increases in dehydrogenase, which normally inactivates cortisol to form cor-
renin and aldosterone. tisone in the principal cell, will also result in low renin levels
Hyperchloraemic metabolic acidoses with a normal or ele- and low aldosterone levels, as endogenous cortisol generates
vated potassium concentration can develop as a result of the the hypokalaemic alkalosis. Both genetic mutations (the ap-
addition of chloride salts such as NaCl, KCl, CaCl2, NH4Cl, ar- parent mineralocorticoid excess syndrome) and an excess con-
ginine and lysine hydrochlorides, or HCl itself. If the quantity sumption of glycyrrhizic acid (found in liquorice or anisette)
of Cl–​ introduced exceeds the ability of the kidney to eliminate are causes of this enzyme block. Another cause of hypertension
NH4Cl in urine, hyperchloraemia will develop. Electroneutrality with hypokalaemic alkalosis but with low renin and aldosterone
 12.11 A physiological approach to acid–base disorders 2191

levels is Liddle’s syndrome, in which an activating mutation in the be manifested as severe acidaemia and other tubular dysfunction,
cortical collecting duct Na+ channel (ENaC) leads to increased including nephrogenic diabetes insipidus. Chronic tubulointerstitial
Na+ reabsorption. diseases of the kidney, including reflux nephropathy and urinary ob-
Hypokalaemic metabolic alkalosis may also develop without struction, may result in renal tubular acidosis with hypokalaemia
volume expansion when a nonreabsorbable anion is presented to the or hyperkalaemia. Acute tubulointerstitial nephritis may also result
cortical collecting duct lumen. Nitrates, sulphates, and certain anti- in renal tubular acidosis. Drugs such as amphotericin B can cause
biotics such as nafcillin, carbenicillin, and ticarcillin may obligate hypokalaemic distal renal tubular acidosis. Topiramax, used for
K+ and H+ secretion as Na+ is reabsorbed. Topical administration of migraines, is a carbonic anhydrase inhibitor that may cause mixed
silver nitrate to burn victims may result in alkalosis. proximal and distal renal tubular acidosis.
Secondary hyperaldosteronism associated with high levels of
Distinguishing proximal and distal renal tubular acidosis In
renin contributes to the hypochloraemic alkalosis associated with
contrast to proximal renal tubular acidosis, distal renal tubular
chloride losses from diuretics or other states of chloride and extra-
acidosis (type 1) is generally a more severe metabolic disorder that
cellular volume depletion. When the secondary hyperaldosteronism
may be accompanied by hypercalciuria, nephrocalcinosis, calcium
is due to volume depletion in a setting of metabolic acidosis (such as
phosphate kidney stones, and bone disease that includes rickets in
proximal tubular acidosis), hypokalaemia but not metabolic alkal-
children and osteomalacia in adults. It is necessary to treat distal
osis is observed.
acidosis because of relentless acid retention, and—​compared to
proximal renal tubular acidosis—​easier to treat with enough bicar-
Role of the collecting duct intercalated cell in hypokalaemic, bonate to cover the usual production rate of acids, and safer to treat
hyperchloraemic acidosis (distal/​type 1 renal tubular acidosis) because potassium improves with return to normal pH.
In distal renal tubular acidosis (type 1), failure to excrete NH4Cl Proximal and distal renal tubular acidoses usually can be dis-
leads to an inability to excrete adequate net acid, thereby leading to tinguished by clinical evaluation (Table 12.11.2). Helpful find-
continuous retention of acid in the body. The degree of acidaemia is ings include the presence of a urine pH greater than 5.3 in distal
often severe, with pH reaching values as low as 7.2, whereas urine but not proximal renal tubular acidosis during acidaemia; a frac-
pH usually exceeds 5.3. tional excretion of bicarbonate as high as 10 to 15% during bicar-
Kindreds have been described in which mutations in genes for the bonate loading in proximal renal tubular acidosis; and the lowering
distal vacuolar H+-​ATPase cause an autosomal recessive distal renal of serum potassium upon correction of proximal but not distal
tubular acidosis with deafness. Mutations resulting in defective Cl/​ tubular acidosis.
HCO3 exchange protein (AE1) have been linked to an autosomal In order to know what the kidney is doing with respect to elec-
dominant form of distal renal tubular acidosis. trolyte excretion, it is necessary to evaluate the urine chemistry.
Distal renal tubular acidosis is also associated with autoimmune Considering sodium, potassium, and chloride in the urine, sodium
disorders, including systemic lupus erythematosus and Sjögren’s and potassium concentrations relative to chloride that are dispro-
syndrome, and genetic diseases, including sickle cell anaemia, portionate to that which exists in the ECF can predict whether the
Wilson’s disease, Fabry’s disease, cystic kidney diseases, and her- loss of that urine will have an acidifying or alkalizing effect on the
editary elliptocytosis. Hypercalciuria and hyperoxaluria may cause ECF. For example, if the sum of the sodium and potassium concen-
distal renal tubular acidosis; nephrocalcinosis and nephrolithiasis trations greatly exceeds the chloride concentration in urine, there
may be present. Increased proximal tubular citrate reabsorption will be a tendency to acidify the body fluids. If there is a meta-
as a consequence of the chronic acidosis leads to hypocitraturia, a bolic acidosis in the blood, then such an excretion pattern by the
risk factor for calcium nephrolithiasis. A chronically alkaline urine kidney suggests that the kidney is the culprit in the generation
is a risk for pure CaHPO4 stones, and when the latter are found of the acidosis. The diagnosis would then be called renal tubular
distal renal tubular acidosis should be suspected. Amyloidosis may acidosis and the unmeasured anion accompanying sodium and

Table 12.11.2 Comparison of renal tubular acidoses

Proximal (type 2) Classic distal (type 1) Hyporeninaemic

hypoaldosteronism
(type 4)
Common causes Ifosfamide Sjögren’s syndrome CKD plus:
NRTI (tenofovir, adefovir, cidofovir) SLE • DM, amyloid
Myeloma Amphotericin • obstruction
• sickle cell
• SLE
NSAIDs
Treatment Bicarbonate Bicarbonate K+-​lowering treatment:
(large dose) (1 mEq/​kg per day) • Diuretics
• Kayexalate
• Low K diet
• Mineralocorticoid
CKD, chronic kidney disease; DM, diabetes mellitus; SLE, systemic lupus erythematosus; NSAIDs, nonsteroidal anti-​inflammatory drugs; NRTI,
nucleoside reverse transcriptase inhibitors.
2192 section 12 Metabolic disorders

potassium might be bicarbonate. If, by contrast, chloride was ex-

creted in concentrations disproportionately high to the sum of so- Stomach
dium and potassium concentrations, then an alkalinizing effect on
plasma would be predicted. If a systemic acidaemia were present,
then this urinary pattern would be considered appropriate and
compensatory, favouring a search for an extrarenal cause of meta-
bolic acidosis such as diarrhoea or respiratory acidaemia. From the
urinary point of view, the extra chloride in the urine would need
be accompanied by an unmeasured cation, which we know would
be ammonium.
Role of the collecting duct in compensation for nonrenal
metabolic and respiratory disorders
Although the proximal tubule plays a major role in compensation
for these disorders, intracellular acidification of intercalated cells
by both metabolic and respiratory acidosis leads to increased exo- Fig. 12.11.9 Stomach and gastric parietal cell. (a) Luminal content;
cytotic expression of proton ATPase on the luminal membrane, (b) cellular transport mechanism. CA, carbonic anhydrase.
increasing urinary acidification. A maximally acid urine will trap
more ammonia in the form of ammonium. Alkalinization of cells in extracellular space would result in hypochloraemia and metabolic
metabolic and respiratory alkalosis has the opposite effect. alkalosis. With vomiting, the initiating or generating event is loss of
Renal compensations for respiratory disturbances can also be in- HCl. As shown in Fig. 12.11.9b, secretion of HCl into the stomach
ferred from urinary chemistry. For example, the renal compensation lumen by the parietal cell is coupled to the absorption of HCO3–​ in
for respiratory acidosis should be the loss of urinary electrolytes in exchange for chloride at the basolateral membrane.
the pattern that would alkalinize the extracellular space, that is, loss of With vomiting, initial increases in serum HCO3–​ are filtered by
high chloride concentration relative to sodium and potassium. As pre- the renal glomeruli and excreted in urine accompanied by Na+ and
viously discussed, the cation accompanying chloride is ammonium. K+; volume depletion begins to develop as sodium is lost in the urine
and chloride in the vomitus. Thus, extracellular volume depletion is
Acid–​base disorders and the gastrointestinal tract not accompanied by low sodium excretion in metabolic alkalosis. As
The organs of the gastrointestinal tract produce secretions that en- vomiting continues, extracellular volume depletion worsens, glom-
able the absorption of fluid, electrolytes, and organic solutes derived erular filtration falls, and HCO3–​ filtration is limited. The volume
from the metabolism of protein, carbohydrate, and fat. Excessive depletion activates the renin–​angiotensin II–​aldosterone system
production or loss of these secretions will disturb the economy of and proximal tubule fluid and NaHCO3 reabsorption increase as a
electrolytes and acid–​base equivalents in the ECF because the source consequence. Distal nephron Na+ reabsorption increases under the
of these secretions is the ECF. influence of aldosterone, and that results in greater H+ secretion,
Acid–​base disturbances also develop when ingested quantities of thereby enhancing HCO3–​ reabsorption. These effects reduce renal
chloride or bicarbonate salts exceed the ability of the kidney or in Na+ loss but at the expense of maintaining the metabolic alkalosis.
some cases liver to clear them from the circulation. Significant K+ losses, which occur as a result of the bicarbonaturia
and hyperaldosteronism, lead to hypokalaemia, which is due to
Stomach renal, not gastrointestinal, losses as a consequence of attempts to
In Fig. 12.11.9a, the gastric lumen is shown to contain HCl as well as maintain extracellular volume. Similar to initiating events in prox-
sodium and potassium. The volume of gastric fluid produced per day imal renal tubular acidosis, the hypokalaemia during generation of
is usually about 2 litres, but in disease states, particularly with bowel gastric alkalosis is of distal nephron aetiology as bicarbonate leaves
obstruction, the volume can increase markedly. Normally the fluid the proximal tubule in a volume-​depleted state of high aldoster-
flows distally into the upper small intestine where hydrogen and pan- onism, thereby enhancing potassium secretion.
creatic bicarbonate combine to form carbon dioxide and water, while The hypokalaemia further increases proximal NaHCO3 reabsorp-
the sodium and chloride are absorbed along the small intestine. In tion, distal H+ secretion, and K+ reabsorption via the proton-​potassium
that way, there is internal balance of acid–​base. However, a transient ATPase of the intercalated cell of the collecting duct, all at the ex-
postprandial sequestration of HCl in the gastrointestinal tract leads to pense of further reabsorption of HCO3–​. At the new steady state after
a phenomenon known as the alkaline tide, a transient alkalinization vomiting or nasogastric suctioning ceases, the paradoxical aciduria of
of the body fluids and the urine. Shown in Fig. 12.11.7b, the acid-​ metabolic alkalosis develops as HCO3–​ reabsorption is complete and
secreting parietal cell of the stomach has potassium-​hydrogen ATPase the urine contains low levels of Na+, K+, and Cl–​. The patient may be
on the apical side, which is responsible for the secretion of hydrogen hypovolaemic, hypokalaemic, and alkalaemic, but because Na+, K+,
ion into the stomach against its chemical gradient. Stomach pH may and acid–​base balance are intrinsically linked, life-​threatening volume
reach values as low as 1 to 2. Chloride is secreted by chloride channels. depletion, K+ depletion, and alkalaemia are usually avoided.

Role of the stomach in hypochloraemic metabolic alkalosis Small intestine

If gastric fluid is removed by a nasogastric tube or by vomiting, As shown in Fig. 12.11.10a, the fluid delivered from the upper small
then the loss of chloride and the gain of bicarbonate within the bowel is alkaline and contains iso-​osmotic sodium, chloride, and
 12.11 A physiological approach to acid–base disorders 2193

chloride–​bicarbonate exchange without accompanying sodium–​

Duodenum and proximal jejunum hydrogen exchange is the mechanism for chloride absorption and
bicarbonate secretion.

Role of the small intestine in hyperchloraemic acidosis

In patients who have small bowel malabsorption, as in inflamma-
tory bowel disease, pancreatitis, or with an infectious gastroenteritis,
large volumes of small intestinal losses result in high bicarbonate-​
containing diarrhoea. Patients with an ileostomy can lose large
quantities of pancreatic secretions rich in bicarbonate resulting in
hyperchloraemic metabolic acidosis because the large amounts of bi-
carbonate present in the lumen being delivered from upstream seg-
ments are greater than the chloride anion in a relative comparison to
Fig. 12.11.10 Upper small intestine. (a) Luminal content; (b) cellular ECF sodium and chloride. In some situations where bowel motility
transport mechanism. is poor, large quantities of pancreatic secretions accumulate in the
intestine creating a hyperchloraemic metabolic acidosis. On occa-
sion, acidaemia will result from vomiting small bowel contents or by
bicarbonate. Most ingested nutrients such as glucose and amino duodenal or jejunal drainage.
acids and much of the bicarbonate are absorbed in more proximal Ileal segments are used as urinary diversion conduits to replace
bowel, such as duodenum and jejunum, and water is absorbed os- bladder function. In such a situation, particularly when there
motically. The bicarbonate comes predominately from pancreatic is obstruction to flow, the ileal segment maintaining its ‘double
secretions, with some contribution of biliary secretion, while the exchange’ properties can lead to the reabsorption of excessive
chloride is primarily dietary and that remaining from gastric acid quantities of chloride by the loop, resulting in hyperchloraemic
secretion. acidosis.
In Fig. 12.11.11a, the luminal contents of fluid in the ileum and Diabetic patients receiving pancreas and renal transplantation
proximal colon are shown. An important role of these late small in- in which the exocrine pancreas drains into the urinary bladder
testinal and early colonic segments is to absorb sodium, chloride, can develop severe metabolic acidosis with hyperchloraemia,
bicarbonate, and water. In Fig. 12.11.11b, a cell is shown dem- and this is one of the reasons why bowel drainage of the exocrine
onstrating the mechanism by which this absorption takes place. pancreas is now the preferred surgical technique in pancreatic
The luminal membrane contains both sodium–​hydrogen exchan- transplantation.
gers and chloride–​bicarbonate exchangers oriented in such a way Secretagogues such as vasoactive intestinal peptide (VIP), which
to allow entry of sodium and chloride into the cell in exchange is associated with neoplasms of the pancreas or sympathetic chain,
for secreted hydrogen and bicarbonate: thus the mechanism for cause large losses of HCO3–​ in stool, with a resulting hypokalaemic,
sodium chloride absorption is by ‘double exchange’. In jejunal hyperchloraemic acidosis.
cells that favour sodium bicarbonate absorption, the sodium–​
hydrogen exchanger functions without a chloride–​bicarbonate Role of the small intestine in hypochloraemic alkalosis
antiporter, while in some villous cells of ileum and large intestine, From the previous discussion, one could predict the following: if
double exchange is dysfunctional as would be the case in a mutation
of the chloride–​bicarbonate exchanger, then the luminal fluid would
contain large quantities of chloride. If that chloride was unable to
Ileum and proximal colon be absorbed by the downstream large intestine, then stool chloride
would be increased.
In Zollinger–​Ellison syndrome, excessive gastrin-​induced gastric
acid secretion may result in large volumes of acidic stool with high
chloride content resulting in hypochloraemic alkalosis. Congenital
chloridorrhoea (chloride-​losing diarrhoea) is an autosomal reces-
sive disorder of defective intestinal, apical Cl/​HCO3 exchange asso-
ciated with the downregulated adenoma (DRA) gene, so-​named for
Lumen its decreased expression in some patients with villous adenomas or
adenocarcinomas.
Intestinal crypt cells secrete chloride across the apical mem-
brane in association with the cystic fibrosis transmembrane con-
ductance regulator (CFTR) and this process may be activated by
secretogogues including neurohumoral substances, cyclic AMP,
and certain toxins in infectious diarrhoea. Most diarrhoeal illnesses,
Fig. 12.11.11 Lower small intestine and early colon. (a) Luminal
including the secretory diarrhoeas, result in metabolic acidosis ra-
content; (b) cellular transport mechanism. CA, carbonic anhydrase; ClC, ther than alkalosis, but the acid–​base disorder is determined by the
chloride channel. electrolyte content of the stool. Diarrhoea does not cause metabolic
2194 section 12 Metabolic disorders

Distal colon Sweat gland duct

Fig. 12.11.12 Distal colon. (a) Luminal content; (b) cellular transport
mechanism. AldoR, aldosterone receptor; ENaC, epithelial sodium
channel. Fig. 12.11.13 Sweat gland duct. (a) Luminal content; (b) cellular
transport mechanism. AldoR, aldosterone receptor; CFTR, cystic fibrosis
transmembrane conductance regulator.
alkalosis unless the stool electrolyte relationship [Na+ + K+− Cl–​] is
less than plasma HCO3−.
Acid–​base disorders and the skin
Colon
Sweat gland ducts
Fig. 12.11.12a represents the diminishing amounts of water and
electrolytes in the distal colon. In Fig. 12.11.12b a colonic cell is The sweat gland ducts (Fig. 12.11.13), like the principal cells in
shown in which, as in the renal collecting duct, aldosterone increases the kidney and the cells of the colon, contain aldosterone-​sensitive
sodium absorption via the epithelial sodium channel and potassium ENaC. Na+ absorption from the glandular duct renders the lumen
is secreted into the lumen. electronegative. Normally the negative lumen drives chloride
absorption through the CFTR, leading to limited volumes of
Role of colonic diarrhoea and hyperchloraemic acidosis hypotonic sweat.
Diarrhoeal disorders affecting these areas usually cause hyper­
Cystic fibrosis and metabolic alkalosis
chloraemic acidosis as unabsorbed sodium and potassium are lost
with organic anions of bacterial origin. Chloride and bicarbonate Patients with cystic fibrosis may develop hypochloraemic alkalosis
concentrations may be low. Hypokalaemic, hyperchloraemic acid- as a consequence of excessive sweat chloride content related to their
osis results from loss of body fluids low in Cl–​ relative to Na+ and K+ CFTR gene mutation. When Cl− absorption is decreased in cystic
when compared with the ratio of Cl–​ to Na+ in ECF. It is not always fibrosis, the lumen becomes more negative, decreasing Na+, Cl−, and
the case that metabolic acidosis caused by diarrhoea is due to bicar- fluid absorption, leading to ‘salty’ sweat; the proportionally large Cl−
bonate loss. Stool losses of Na+, K+, and HCO3–​ characterize most loss may generate hypochloraemic metabolic alkalosis.
small bowel diarrhoea, while organic acid anions such as butyrate
and acetate of bacterial origin are often the lost anions in colonic
diarrhoea. Acid–​base disorders associated with transport
of acid anions from intracellular to extracellular
Role of colonic diarrhoea in hypochloraemic alkalosis spaces: anion gap acidosis
Rarely, villous adenomas or adenocarcinomas of the rectosigmoid
secrete excessive quantities of sodium, potassium, and chloride, re- Several organic acid anions are produced metabolically in one cell
sulting in severe hypokalaemic, hypochloraemic metabolic alkal- type and carried by the blood to another cell type where they can be
osis. Some infectious diarrhoeas may result in alkalosis. used as a fuel for further metabolism. For example, the Cori cycle
From this discussion of the gastrointestinal tract, it should be involves the production of lactate in skeletal muscle, where it en-
noted that functions of the early small intestine, where bicarbonate ters the interstitial fluid through monocarboxylic acid transporters
from pancreatic and biliary secretions is absorbed along with glu- (MCTs) on the plasma membrane, driven by solute gradients
cose, amino acids, and water of dietary source, are analogous with (Fig. 12.11.14). The lactate is then transported by similar MCTs
the situation in the proximal tubule, where bicarbonate, glucose, into hepatic cells where it enters gluconeogenic pathways to form
amino acids, and water are reabsorbed from a filtrate of plasma. glucose. Thus, when considering the plasma as part of the ECF, the
Likewise, the large intestine absorbs sodium and water and se- steady-​state lactate concentration is equal to the ratio of production
cretes potassium in an aldosterone regulated fashion, much like to clearance. Excessive levels may occur with overproduction or de-
the collecting duct of the kidney. As emphasized in this discus- creased clearance.
sion, the abnormal function of intestinal epithelial cells can result The reason that plasma does not accumulate pyruvate in the same
in volume depletion in association with either acidosis or alkal- way is that the MCT has greater specificity for lactate. Pyruvate
osis, depending on the balance of losses of sodium and potassium ­remains in the cell as a potential energy source through acetyl co-
compared to chloride. The term contraction alkalosis is therefore enzyme A. The ketoacids acetoacetate and β-​hydroxy butyrate are
misleading. made in liver mitochondria and transported out of the liver cells by
 12.11 A physiological approach to acid–base disorders 2195

Monocarboxylic acid Monocarboxylate transporters (MCTs)

transporters (MCTs)
Liver Skeletal muscle
Glycolysis Hepatocyte Interstitial fluid
Ketoacids
Lactate

Glucose
Lactate Lactate
Acetoacetate
β-hydroxybutyrate
Fat Heart, brain
Lipogenesis

Lactate Ketoacids (SLC)16 solute

carrier family
Oxidation
Fig. 12.11.15 An example of an MCT transporter in a hepatic cell
shows coupling to hydrogen ion as well as the substrates that are
Fig. 12.11.14 Monocarboxylic acid transporters (MCTs) in lactate and
transported through the (SLC) solute carrier family.
ketoacid transport. During exercise glucose is broken down to lactate in
skeletal muscle. Outwardly directed lactate gradients drive lactate into the
extracellular fluid via an MCT. The liver takes up that lactate, also via an MCT,
and converts it to glucose, which is available for export to the muscle cells The urinary dipstick nitroprusside test for ketones may
for completion of the Cori cycle. Ketoacids are produced in the liver from underestimate the degree of ketosis because it does not detect
fatty acids. They are then transported via an MCT, particularly in diabetes and β-​hydroxybutyrate, and the ketone test may become more positive
hypoglycemic conditions, and the ketoacids are then transported via MCTS as treatment helps metabolize β-​hydroxybutyrate to acetoacetate.
into brain and heart muscle cells as a source of energy through oxidation. This problem can be addressed by direct measurement of serum
β-​hydroxybutyrate.
MCTs, circulate, and are then cleared by brain and heart tissue (via Treatment of diabetic ketoacidosis consists of volume repletion,
MCTs) to be used as fuel when glucose is low, as in starvation. As with insulin administration (with dextrose if necessary to avoid hypogly-
lactate, the plasma level of ketoacids represents the production to caemia), and potassium replacement. Bicarbonate administration
clearance ratio. Because these anions are filtered by the kidney, they should be considered only if ketoacidosis is accompanied by shock
can enter the urine (by renal clearance), obligating cations sodium in conjunction with arterial pH of less than 7.0.
and potassium for electroneutrality. The urinary excretion of sodium
with a nonchloride anion leaves behind a relatively greater amount Alcoholic ketoacidosis
of extracellular chloride than sodium (hyperchloraemic acidosis). Alcoholic ketosis occurs in a patient who has been drinking very
Thus, with lactic acidosis and ketoacidosis there are two mechanisms heavily without eating. The pathophysiology is based on the over-
for acidosis; one an anion gap due to anion production greater than production of β-​hydroxybutyrate and (to a lesser extent) acetoacetate
total clearance, and a hyperchloraemic component that involves the because of an increased production of free fatty acids from adipose
production of HA entering plasma and loss of NaA in the urine. In tissue. Alcohol inhibits the conversion of lactate to glucose in the liver,
such a case, the decrease in HCO3–​ will exceed the increased anion favouring hypoglycaemia with fasting. The oxidation of ethanol in-
gap, especially if the GFR and the filtered load of the anion are high. creases the ratio of NADH to NAD+ and favours the production of
Box 12.11.3 lists causes of high anion gap metabolic acidosis, β-​hydroxybutyrate from acetoacetate. Damage to mitochondria by al-
some of which are now discussed further. cohol can further elevate the ratio of β-​hydroxybutyrate to acetoacetate
by preventing reoxidation of NADH to NAD. The oxidative metab-
Diabetic ketoacidosis olism of ethanol favours the reaction of dehydrogenase enzymes to
Diabetic ketoacidosis is defined as hyperglycaemia with meta- form β-​hydroxybutyrate and lactate (opposing glucose production).
bolic acidosis resulting from generation of the acid anions Alcoholic ketoacidosis usually follows binge drinking and
β-​hydroxybutyrate and acetoacetate in response to insulin defi- may be associated with withdrawal symptoms and the associ-
ciency and elevated counter-​regulatory hormones such as epineph- ated hyperadrenergic state. It is associated with abdominal pain,
rine and glucagon. Most commonly seen in cases of type 1 diabetes vomiting, starvation, and volume depletion. In contrast to diabetic
mellitus, severe stress can occasionally bring on ketoacidosis in type ketoacidosis, coma is rare. The blood glucose level is generally low
2 diabetes mellitus diabetics. or normal, and the insulin level is frequently low. The blood alcohol
The lack of insulin increases lipolysis in adipose tissue; free fatty level may be unrecordable (absent) or elevated on initial evaluation.
acids are transported to the liver, where hepatic mitochondria pro- The osmolar gap, if secondary to ethanol, should be equal to the
duce ketone bodies, including acetoacetate, from acetyl coenzyme ethanol concentration in milligrams per decilitre divided by 4.6. If
A. In the presence of a high NADH/​NAD ratio, the more reduced this calculation does not yield the expected gap based on the ethanol
form of β-​hydroxybutyrate is produced. Ketoacids produced within concentration, ingestion of another alcohol such as methanol, iso-
hepatocytes are secreted into the ECF by the monocarboxylate-​ propanol, or ethylene glycol should be suspected. Acetone, the
proton cotransporter, thereby causing acidaemia (Fig. 12.11.15). product of acetoacetate metabolism, is seen during recovery and
Ketoacidosis is also seen in cases of starvation, in which it is gen- may register as an unmeasured osmol. By contrast, isopropanol me-
erally mild and not associated with hyperglycaemia. tabolizes directly to acetone and causes ketosis without acidosis.
2196 section 12 Metabolic disorders

Treatment of alcoholic acidosis consists of volume repletion with Intoxication is characterized by profound central nervous
0.9% saline, administration of thiamine (50 to 100 mg intravenously), system symptoms, including diplopia, seizures and coma, severe
and enough glucose to treat hypoglycaemia, and the correction of metabolic acidosis, and cardiac, pulmonary, and renal failure.
any hypophosphataemia, hypokalaemia, and hypomagnesaemia Patients are often dehydrated and hypernatraemic because of os-
that may be present. The acid–​base disturbance usually resolves after motic diuresis from the renal clearance of the alcohol. Calcium
several hours. Both hypophosphataemia and thiamine deficiency, oxalate crystals in the urine may cause intratubular obstruction
which may not be apparent until 12 to 24 h after the initiation of and acute kidney injury.
treatment in an undernourished patient, are exacerbated by glucose Patients typically have a high osmolal gap, initially defined as
administration and may contribute to an associated lactic acidosis. the difference between the measured and the calculated serum
osmolality:
Lactic acidosis
Lactate, the final product in the anaerobic pathway of glucose me- Sosm − 2(Na + ) + glucose [mg/dl] ÷ 18
tabolism, is produced from pyruvate by the following reaction cata- + blood urea nitrogen [mg/dl] ÷ 2.8   (Equation 5)
lysed by lactate dehydrogenase:
Table 12.11.3 shows the differential diagnosis of patients with
NADH +pyruvate +H+ → lactate +NAD (Equation 4) anion gap metabolic acidosis and high osmolar gaps.
The serum osmolality should be measured by a freezing point
Lactic acidosis is caused by an imbalance in the rates of lactate pro- depression technique and compared with the calculated osmo-
duction and clearance, primarily in the liver. Lactic acidosis, which lality. If possible, ethanol, ethylene glycol, propylene glycol, and
increases the anion gap, is most often due to impaired lactate clear- methanol levels should be measured directly; each is associated
ance due to circulatory failure, hypoxia, and mitochondrial dysfunc- with a metabolic acidosis.
tion that increase anaerobic glycolysis and the rate of reduction of An increased anion gap is attributable to ethylene glycol metab-
pyruvate to lactate. Lactate, once formed, results in acidaemia after olites. A high osmolar gap will also be present because of the un-
transport into the ECF by the organic acid anion transporter, MCT1. charged alcohol, but an osmolar gap may not be present if all of the
Other causes of lactic acidosis are thiamine deficiency, hypo­ alcohol has been converted to the toxic anionic forms.
phosphataemia, isoniazid toxicity, and hypoglycaemic states. Treatment is aimed at rehydration with 0.9% saline and correc-
Metformin may cause lactic acidosis, particularly in elderly patients tion of acidosis with NaHCO3 based on an estimate of the bicar-
with cardiac, hepatic, or renal dysfunction. Nucleoside antivirals, bonate deficit. When there is an osmolal gap, competitive inhibition
including zidovudine, may cause lactic acidosis and abnormal liver of alcohol dehydrogenase should be initiated with fomepizole at a
function as a result of toxic mitochondrial effects. Abnormal mito- loading dose of 15 to 20 mg/​kg intravenously in 100 ml 0.9% sa-
chondrial function is also a feature of aspirin overdose. The anti- line over 30 min to 1 h, followed by a maintenance dose of 10 mg/​
biotic linezolid is another cause of lactic acidosis. Many tumours kg every 12 h. An alternative is to use ethanol itself, in which case
utilize glycolysis for energy and produce large quantities of lactate. a solution of 10% ethanol in 5% dextrose can be given as a loading
Treatment of lactic acidosis is aimed at correcting the underlying dose of 0.6 g/​kg intravenously, followed by a maintenance dose of
cause. Tissue perfusion and ventilation need to be restored. If the 150 mg/​kg per h in alcoholic patients, or 65 mg/​kg per h in non-
arterial pH is 7.0 or less, or when shock or cardiac failure has de- alcoholic patients. The blood ethanol level should be maintained at
veloped, sodium bicarbonate therapy should be considered. This is 100 to 200 mg/​dl. The goal of therapy is to prevent metabolism of
usually given as an isotonic infusion (1.26% sodium bicarbonate, or the uncharged glycol to acidic products. Haemodialysis is required
5% dextrose with added bicarbonate). Treatment carries risks of pul- in severe cases.
monary oedema and hypernatraemia. Some automotive fluids now contain the less toxic propylene
In patients with intestinal bacterial overgrowth, disorientation, glycol.
and ataxia, an anion gap metabolic acidosis may develop after a Propylene glycol, a 3-​carbon glycol, is used as a diluent in some
carbohydrate meal because of lactobacilli production of d-​lactate. intravenous medications such as lorazepam. It metabolizes to lac-
This isomer of the mammalian l-​lactate can be measured only by a tate. Treatment consists of early recognition, fluid replacement (es-
specific d-​lactate assay. The condition is treated with oral antibiotics pecially if associated with an osmotic diuresis), and withdrawal of
and appropriate diet. the offending agent.

Ethylene glycol
Ethylene glycol is a constituent of antifreeze and also used as an in-
dustrial solvent. It has a sweet taste and patients occasionally ingest it Table 12.11.3 Anion and osmolal gap in diagnosis of intoxications
as a substitute for ethanol. Although ethylene glycol itself is not par-
ticularly damaging, its highly toxic metabolites include glyoxylate, Anion gap acidosis Osmolal gap Diagnosis
glycolate, oxalic acid, and ketoaldehydes. These acidic products are + Normal Salicylates
formed by metabolism within cells catalysed by alcohol and alde- + High Ethanol
hyde dehydrogenase and then transported into the ECF by MCTs. Ethylene glycol
Oxalate is transported across cells by anion exchangers in the SLC26 Propylene glycol
Methanol
gene family. Glycolic acid appears to be primarily responsible for the
− High Isopropanol
metabolic acidosis observed.
 12.11 A physiological approach to acid–base disorders 2197

Methanol Respiratory alkalosis is the result of a direct stimulatory effect of

Methanol (wood alcohol) is a component of shellac and windshield salicylate on the medullary respiratory control centre. Salicylate in-
wiper fluid and is highly toxic to the central nervous system after toxication also increases the metabolic rate.
metabolism by alcohol and aldehyde dehydrogenase to formalde- Diagnosis is suspected by the clinical presentation and confirmed
hyde and formic acid. Optic papillitis may cause blindness. by the salicylate level. Treatment is aimed at correcting the meta-
Treatment consists of competitive inhibitors for alcohol dehydro- bolic acidosis and removing salicylate. Bicarbonate as a sodium salt
genase, including ethanol or fomepizole, in similar amounts as for should be administered according to an estimated calculation of the
ethylene glycol poisoning, to reduce the formation of acid anions deficit if metabolic acidosis predominates. Salicylates are removed
and the anion gap while maintaining a higher level of methanol in by alkaline diuresis because the less reabsorbable salicylate anion
the blood. Haemodialysis may be necessary to increase elimination. will predominate when the urine pH increases. In severe poisoning,
or when renal failure is present, dialysis may be required.
5-​Oxoprolinuria
5-​Oxoprolinuria is detected in debilitated patients with depleted
intracellular glutathione (GSH) who are taking paracetamol (acet- Acid–​base disorders associated with intake
aminophen). The accumulation of 5-​ oxoproline (pyroglutamic
acid) is caused by further drug-​induced depletion of GSH through The ECF contains approximately 140 mM sodium and 100 mM
interference with the γ-​glutamyl transpeptidase pathway respon- chloride. Sodium concentration is critically important in osmotic
sible for creating GSH for shuttling amino acids into the cytosol. regulation, hence if sodium salts are ingested, then water will be
Normal glutathione levels are necessary for feedback inhibition taken in and conserved in order to maintain a constant plasma so-
of γ-​glutamylcysteine synthase, which regulates the activity of the dium concentration. By contrast, plasma chloride concentration is
cycle and is metabolized to 5-​oxoproline. As shown in Fig. 12.11.16, determined by fluid balance and acid–​base requirements. The in-
5-​oxoproline leaves cells through plasma membrane H+-​coupled take of sodium and chloride in equivalent concentrations therefore
SLC16A1/​MCT1 transporter. requires a greater clearance of the chloride ion than of the sodium
ion, and this clearance is primarily urinary. In order to eliminate
Salicylate intoxication chloride without sodium, and without necessitating potassium ex-
Salicylate intoxication can be caused by accidental overdose, thera- cretion, there must be a cation to accompany chloride to achieve
peutic overdose, or in a parasuicide or suicide attempt. Salicylates electroneutrality. Ammonium serves that purpose, and yet we think
may cross cell membranes through nonionic diffusion, anion ex- of ammonium excretion as a mechanism for acid elimination in the
change, and organic anion transporters (OAT1). Salicylate functions urine. That the intake of sodium chloride requires the loss of ammo-
as an uncoupler of oxidative phosphorylation and consequently nium chloride (having an alkalinizing effect on the ECF) suggests
results in increased oxygen consumption and CO2 production. that sodium chloride is an acidifying salt. If the intake of sodium
However, the increase in alveolar ventilation resulting from stimu- chloride required the production of ammonium that exceeded the
lation of central chemoreceptors overcomes this increase in CO2. maximal ability of the kidney to do so, then the amount of acid ex-
The most common clinical manifestation is a combined anion gap creted would be limited and hyperchloraemic metabolic acidosis
metabolic acidosis and respiratory alkalosis, although the condition should follow.
also can be manifested as either one or the other only. Children are Intravenous fluids may cause metabolic disorders by direct access
often seen with metabolic acidosis, whereas adults often have pre- to the ECF. Acidosis may be caused by infusions of high chloride
dominant respiratory alkalosis. Hypoglycaemia, ketoacidosis, and salts including saline. Alkalosis may result from the addition of
lactic acidosis may result. intravenous alkali salts of metabolizable organic anions. The normal
Other manifestations of intoxication include haemorrhage, fever, response to NaHCO3 is rapid urinary alkalinization because of an
nausea and vomiting, hyperventilation, diaphoresis, tinnitus, and unaltered threshold for HCO3–​reabsorption. However, a marked ex-
occasionally polyuria followed by oliguria. Severe cases may lead cess of HCO3–​, as may be administered in an attempt to alkalinize a
to seizures, respiratory depression, and coma. Noncardiogenic pul- patient’s urine, expands volume and causes an alkalaemia, especially
monary oedema is sometimes seen in adults. in the presence of volume depletion or low glomerular filtration.
Milk-​alkali syndrome, usually seen when patients in chronic
kidney disease ingest milk or calcium antacids, is associated with
hypercalcaemia, alkalaemia, and normal Cl–​. Other situations in
which intake of alkali salts results in metabolic alkalosis include
MCT1 transports 5-oxoproline, as does SLC5A8 infusion of large quantities of sodium salts of acetate, citrate, lac-
tate, or bicarbonate; hyperalimentation with acetate salts; peritoneal
dialysis with acetate or lactate dialysate; or excessive transfusions or
plasmapheresis in which large quantities of citrate, used as an anti-
H+ coagulant, are delivered.
5-Oxoproline
Entry of hydrogen ions into cells can also lead to metabolic al-
kalosis in patients with hypokalaemia. If an alkalotic patient is not
hypochloraemic, electroneutrality must be maintained either by
depletion of an alternative anion or by an excessive concentration
Fig. 12.11.16 MCT1 transport of 5-​oxoproline (pyroglutamate). of a cation. An example of a metabolic alkalosis associated with
2198 section 12 Metabolic disorders

depletion of a nonchloride anion is hypoproteinaemic alkalosis, is indicated, but can be complicated by worsening of hypokalaemia
with hypoalbuminaemia and a small anion gap. Chloride balance is if the bicarbonate is promptly excreted, mandating simultaneous
normal and chloride appears in urine. treatment with potassium chloride. Expansion in patients with
hypovolaemic hyponatraemia may correct the low sodium concen-
tration faster than a safe rate, in which case the clinician must be
Symptoms of acid–​base disorders prepared to replace with hypotonic fluids or add an antidiuretic hor-
mone analogue to control water loss.
Mild metabolic alkalosis up to a pH of 7.50 is usually asymptomatic. The derivation of equation 6 is important in that it suggests the
When the pH exceeds 7.55, however, the alkalosis itself and the com- volume of distribution of bicarbonate to be 50% body weight. In fact,
pensatory hypoventilation are frequently associated with metabolic the bicarbonate volume of distribution is closer to 20% body weight,
encephalopathy. Symptoms include confusion, obtundation, de- or the ECF volume. At pH 7.40, the fraction of total body buffer
lirium, and coma. The seizure threshold is lowered, and tetany, par- capacity for the bicarbonate system approximates 0.4, thus 0.2/​0.4 is
aesthesias, muscular cramping, and other symptoms of low ionized the derivation of 0.5 × body weight. Due to the isohydric relation-
calcium are seen. In patients with hypocalcaemia, these signs may ship being nonlinear, at acid pH the denominator of 0.2 decreases,
be seen at pH values above 7.45, hence extreme caution should be meaning that bicarbonate becomes a less important buffer and con-
taken if a decision is made to alkalinize a hypocalcaemic patient with sequently the bicarbonate amount calculated as replacement using
acidaemia and this should only be done if there is a very pressing equation 6 will be an underestimate. Further, in an acidaemic con-
need for rapid correction of acidosis. Other findings include cardiac dition the change in chloride added to the ECF may differ from the
tachyarrhythmias and hypotension. Lactate production increases as amount of bicarbonate leaving the ECF, the latter being more. That
a result of increased anaerobic glycolysis. the change in chloride equals the change in bicarbonate concentra-
Healthy, trained athletes may develop severe acidaemia (pH <7.0), tion is evidence that the bicarbonate concentration is dependent on
but in acutely ill patients, blood pH as low as 7.2 may cause shock, the balance of strong ions like sodium and chloride.
and cardiac arrhythmia. Symptoms of chronic metabolic acidosis
include nausea, vomiting, anorexia, and dyspnoea on exertion.
Acutely, patients often exhibit Kussmaul respirations and volume FURTHER READING
depletion. Neurological symptoms include fatigue and lethargy with
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Batlle DC, et al. (1988). The use of the urinary anion gap in the diagnosis
of hyperchloremic metabolic acidosis. N Engl J Med, 318, 594–​9.
Treatment of acid–​base disorders Chadha V, Alon US (2009). Hereditary renal tubular disorders. Semin
Nephrol, 29, 399–​411.
Metabolic acidosis De Backer D (2003). Lactic acidosis. Intensive Care Med, 29, 699–​702
Aside from treatment of the underlying condition, patients whose Emmett M, Narins RG (1977). Clinical use of the anion gap. Medicine
pH is less than 7.2 are typically treated with infusions of sodium (Baltimore), 56, 38–​54.
bicarbonate, guided by the estimated bicarbonate deficit, calculated Fordtran JS (1971). Organic anions in fecal contents. N Engl J Med,
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Gennari FJ, Weise WJ (2008). Acid-​base disturbances in gastrointes-
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Amount of HCO3 − = (25 − [HCO3 − ]) × wt(kg)/2 (Equation 6) Gennari FJ (2011). Pathophysiology of metabolic alkalosis: a new clas-
sification based on the centrality of stimulated collecting duct ion
In general, the correction of metabolic acidaemia should be based transport. Am J Kidney Dis, 58, 626–​36.
on a calculated amount, with not more than 50% of the estimate Halestrap AP, Wilson MC (2012). The monocarboxylate transporter
given before re-​measurement of electrolyte and bicarbonate concen- family—​role and regulation. IUBMB Life, 64, 109–​19.
trations and recalculation. It should be noted that this equation is Koeppen BM (2009). The kidney and acid-​base regulation. Adv Physiol
used for deficit correction only; the ongoing losses of 1 to 2 mEq/​ Educ, 33, 275–​81.
kg per day, equivalent to the daily acid load, should be replaced in Kraut JA, Madias NE (2007). Serum anion gap: its uses and limitations
distal renal tubular acidosis with NaHCO3, KHCO3, or citrate salts in clinical medicine. Clin J Am Soc Nephrol, 2, 162.
Luke RG, Galla JH (2012). It is chloride depletion alkalosis, not con-
in divided doses. Citrate should be avoided as an alkalinizing salt in
traction alkalosis. J Am Soc Nephrol, 23, 204–​7.
patients with low GFR.
Oh MS, Carroll HJ (1977). The anion gap. N Engl J Med, 297, 814–​17.
Metabolic alkalosis Seldin DW, Rector FC Jr (1972). Symposium on acid-​basis homeo-
stasis: the generation and maintenance of metabolic alkalosis.
The treatment of metabolic alkalosis rarely depends on giving back Kidney Int, 1, 306–​21.
HCl. In chloride responsive alkalosis, replacement with 0.9% saline
12.12
The acute phase response, hereditary
periodic fever syndromes, and amyloidosis

CONTENTS protein (CRP) and serum amyloid A protein (an apolipoprotein of

12.12.1 The acute phase response and C-​reactive protein 2199 high-​density lipoprotein particles) are unique in that their concen-
Mark B. Pepys trations can change by more than 1000-​fold.
C-​reactive protein—​this consists of five identical, nonglycosylated,
12.12.2 Hereditary periodic fever syndromes 2207 noncovalently associated polypeptide subunits. It binds to au-
Helen J. Lachmann, Stefan Berg, and Philip N. Hawkins
tologous and extrinsic materials which contain phosphocholine,
12.12.3 Amyloidosis 2218 including bacteria and their products. Ligand-​bound CRP activates
Mark B. Pepys and Philip N. Hawkins the classical complement pathway and triggers the inflammatory
and opsonizing activities of the complement system, thereby con-
tributing to innate host resistance to pneumococci and probably to
recognition and safe ‘scavenging’ of cellular debris.
Clinical features—​(1) determination of CRP in serum or plasma is
the most useful marker of the acute phase response in most inflam-
matory and tissue damaging conditions. It is a stable analyte, easy to
12.12.1 The acute phase response measure, and has proven value in monitoring therapeutic responses.
and C-​reactive protein (2) Acute phase proteins may be harmful in some circumstances.
Sustained increased production of serum amyloid A protein can lead
Mark B. Pepys to the deposition of AA-​type, reactive systemic amyloid, a serious
and if untreated, usually fatal condition that can complicate chronic
infective and inflammatory diseases. CRP, through its capacity to acti-
ESSENTIALS vate complement, can exacerbate ischaemic (and possibly also other
forms) of tissue damage.
The acute phase response—​trauma, tissue necrosis, infection, inflam-
mation, and malignant neoplasia induce a complex series of non-
specific systemic, physiological, and metabolic responses including
fever, leucocytosis, catabolism of muscle proteins, greatly increased
Introduction
de novo synthesis and secretion of a number of ‘acute phase’ plasma
proteins, and decreased synthesis of albumin, transthyretin, and
The principal plasma proteins that change in concentration in the
high-​and low-​density lipoproteins. The altered plasma protein
acute phase response are listed in Table 12.12.1.1. C-​reactive protein
concentration profile is called the acute phase response. All endo-
(CRP) has particular clinical utility as a robust and easily measured
thermic animals mount a similar response, suggesting that it may
systemic marker for monitoring the extent, activity, and response
have survival value, and increased availability of proteinase inhibi-
to therapy in many inflammatory, infective, and tissue-​damaging
tors, complement, clotting, and transport proteins presumably
conditions.
enhances host resistance, minimizes tissue injury, and promotes re-
generation and repair.
Acute phase proteins—​these are mostly synthesized by hepato-
cytes, in which transcription is controlled by cytokines including C-​reactive protein
interleukin 1, interleukin 6, and tumour necrosis factor. The circu-
lating concentrations of complement proteins and clotting factors CRP was the first protein to be discovered that behaves as an acute
increase by up to 50 to 100%; some of the proteinase inhibitors and phase reactant, and was named for its calcium-​dependent inter-
α1-​acid glycoprotein can increase three-​to fivefold; but C-​reactive action with the somatic C-​polysaccharide of pneumococci, in which
CRP recognizes phosphocholine residues. CRP also binds to other
2200 section 12 Metabolic disorders

Table 12.12.1.1 Plasma protein concentrations in the acute phase complement activation by CRP binding to damaged tissue exacer-
response bates ischaemic and possibly other forms of tissue injury. However,
in healthy subjects, infusion of pure CRP has no proinflammatory,
Protein Increased Decreased
proatherogenic, or any other adverse effects.
Proteinase α1-​antitrypsin Inter α-​antitrypsin
inhibitors Serum concentration of CRP
α1-​antichymotrypsin
Coagulation Fibrinogen Circulating CRP is synthesized by the hepatocytes under tran-
proteins scriptional regulation by the proinflammatory cytokines, especially
Prothrombin
Factor VIII
IL-​6. CRP is a trace protein in apparently normal healthy individ-
uals, the median value in adults being 0.8 mg/​litre, with an inter-
Plasminogen
quartile range of 0.3 to 1.7 mg/​litre. Among apparently healthy
Complement Cls Properdin subjects, 90% of CRP values are less than 3 mg/​litre and 99% less
proteins
C2, B than 10 mg/​litre. Serum CRP concentrations are lower in healthy
C3, C4, C5 newborns, but reach adult values within a few days. Normal values
C56 in the indigenous Japanese population are substantially lower
C1INH
than in white Caucasians. Serial studies of normal subjects and of
monozygotic and dizygotic twins show that each individual’s base-
Transport Haptoglobin
proteins line CRP value is rather constant and is substantially genetically
Haemopexin determined. Baseline CRP is strongly correlated with body mass
Caeruloplasmin index, especially abdominal obesity, and is also higher in smokers,
Miscellaneous C-​reactive protein Albumin hypertensive subjects, diabetics, those who take little or no exercise,
Serum amyloid A protein Transthyretin (prealbumin) and individuals from the lower socioeconomic classes. Occasional
higher values of CRP seen in ostensibly healthy people almost cer-
Fibronectin High-​density lipoprotein
tainly reflect intercurrent subclinical pathology. In large surveys of
α1-​acid glycoprotein Low-​density lipoprotein
the unscreened general population, there is a trend towards higher
Gc globulin values with increasing age, with the median value rising to about
2 mg/​litre, and this likely reflects the higher incidence of many dif-
ferent pathological processes with age.
substances that contain phosphocholine, including phospho- Serum CRP concentration rises rapidly in the acute phase re-
lipids, some plasma lipoproteins, and the plasma membranes of sponse and can exceed 300 mg/​litre by 48 h after a severe stimulus
damaged cells. In addition, CRP binds specifically to small nu- such as acute systemic bacterial infection, major trauma or surgery,
clear ribonucleoprotein particles when these are exposed in dead or acute myocardial infarction. With uncomplicated resolution of
or damaged cells. The CRP molecule consists of five identical, injury or effective treatment of infection, the circulating CRP con-
nonglycosylated, noncovalently associated polypeptide subunits, centration generally falls equally rapidly.
each of mass 23027 Da and containing 206 amino acid residues. The speed of change and incremental range of CRP concentra-
The subunits have a flattened β-​sheet jellyroll fold with a single tions are exceptional among all the acute phase proteins, apart
intrachain disulphide bond, and are arranged in an annular config- from serum amyloid A protein, which behaves in a similar fashion.
uration with cyclic pentameric symmetry. There is a single calcium-​ The half-​life of CRP in the circulation is 19 h and is constant in
dependent ligand-​binding site on the medial aspect of each subunit, all conditions, regardless of the presence of an acute phase re-
all located on the same planar face of the molecule. A distinct but sponse or its cause. In contrast to other acute phase proteins, such
closely related plasma protein, serum amyloid P component, which as clotting factors, complement proteins, transport proteins, and
is not an acute phase protein in humans, has a very similar molecular proteinase inhibitors, CRP does not undergo major local seques-
structure with the same fold, characteristic of the lectin-​fold super- tration or consumption, fragmentation, or complex formation.
family. CRP and serum amyloid P component belong to the phylo- This means that, unlike most of the other acute phase reactants,
genetically conserved pentraxin family. Although many properties the single major determinant of the circulating concentration of
of human CRP have been reported in experimental systems, no CRP is its rate of synthesis. Since this in turn is dependent on the
structural polymorphism of human CRP has been observed nor has intensity of the acute phase stimulus, the serum CRP level usually
any human CRP deficiency been described, so the actual functions closely reflects the extent and activity of disease. These properties
of human CRP in humans are not yet known. underlie the value in clinical practice of precise measurement of
Ligand-​bound CRP activates the classical complement pathway the serum CRP concentration. Drug or other treatments do not
via C1, and can trigger the inflammatory and opsonizing activ- affect CRP production unless they also affect the disease process
ities of the complement system. A significant biological function that is responsible for the induction of CRP synthesis. The only ex-
of CRP may thus be to recognize and scavenge cellular debris, ception is combined ciclosporin and steroid treatment given after
promoting its safe clearance and helping to maintain tolerance to renal transplantation. This suppresses the CRP response to renal
potential autoantigens. CRP may also contribute to innate resist- allograft rejection, though not that provoked by infection. The only
ance against infection with bacteria that express phosphocholine, physical condition that seriously interferes with the capacity to in-
and experiments in CRP knockout mice show that CRP is essential terpret CRP levels is severe hepatocellular impairment, since CRP
for innate host defence against pneumococci. On the other hand, is made exclusively in the liver.
 12.12.1 The acute phase response and C-reactive protein 2201

Conditions associated with marked increases in serum concentration in a proportion of individuals, though this may reflect
CRP concentration secondary bacterial infection. However, severe influenza virus, sys-
Most tissue-​damaging processes, infections, inflammatory diseases temic cytomegalovirus or herpes simplex infections of immunosup-
of unknown aetiology, and malignant neoplasms are associated with pressed patients cause a major CRP response. Little is known about
a major acute phase response of CRP. CRP production is exquisitely the CRP response to metazoan parasitic infestation in otherwise
sensitive to all these pathologies and is thus a nonspecific response healthy subjects but malaria, especially Plasmodium falciparum in-
to disease. It can never, on its own, be used as a diagnostic test. fection, is associated with high CRP values, as are Pneumocystis spp.
However, if the CRP result is interpreted in the light of full clinical and Toxoplasma spp. infections in immunodeficient patients.
information about the patient, it can provide exceptionally useful in- Minor or localized low-​grade infection may not stimulate CRP
formation for clinical management. Thus in nearly all the conditions production greatly, but the major CRP response in acute, serious
listed in Box 12.12.1.1 the CRP concentration reflects quite precisely bacterial infection is almost invariable and is present at all ages from
the extent and activity of disease. With deterioration, the CRP value premature neonates to older people. It also occurs in patients who
rises, whereas with spontaneous or therapeutically induced remis- are immunosuppressed or immunocompromised, whether by a pri-
sion, the CRP value falls, and it thereby supplies an objective index mary disease such as leukaemia, lymphoma, or other malignancy, by
of progress that is rarely available in any other way. AIDS, or by treatment with cytotoxic drugs, corticosteroids, or ir-
radiation. This is of particular importance in the very young, in older
Infection people, in compromised hosts, and in any other patient in whom the
Most forms of systemic microbial infection are associated with high usual clinical signs and symptoms of infection, including fever and
serum CRP concentrations and, although the peak values attained neutrophil leucocytosis, may be masked or lacking (Figs. 12.12.1.1
in different patients cover a wide range, serial assays in individual and 12.12.1.2). Furthermore, at the onset of bacterial infection, es-
subjects usually show an excellent correlation between the CRP value pecially in patients who are otherwise well following elective surgery
and the severity of disease and its response to treatment. Acute sys- or myocardial infarction, the CRP response frequently precedes
temic Gram-​positive and Gram-​negative bacterial infections are clinical symptoms, including fever, by up to 24 to 48 h.
among the most potent stimuli for CRP production. Systemic fungal Once infection is diagnosed or suspected and antimicrobial
infections occurring in immunodeficient hosts are also associated treatment has been commenced, frequent monitoring of the serum
with high CRP values, whereas the concentrations in chronic bac- CRP concentration provides an objective means of assessing the
terial infections such as tuberculosis and leprosy are usually rather
lower, though nevertheless still markedly raised. Uncomplicated viral
infections, particularly meningitis, may induce only a very modest
response or none at all. Clinical rhinovirus infection (common
cold) and influenza are associated with minor increases in CRP

Box 12.12.1.1 Conditions associated with major increases

in serum CRP concentration
• Infection and immunological complications of infection
• Inflammatory disease:
—​ Rheumatoid arthritis
—​ Juvenile chronic (rheumatoid) arthritis
—​ Ankylosing spondylitis
—​ Psoriatic arthritis
—​ Systemic vasculitis
—​ Polymyalgia rheumatica
—​ Reiter’s disease
—​ Crohn’s disease
—​ Familial Mediterranean fever, CAPS
• Necrosis:
—​ Myocardial infarction
—​ Tumour embolization
—​ Acute pancreatitis
• Trauma:
Fig. 12.12.1.1 A 69-​year-​old diabetic man was admitted with a 3-​day
—​ Surgery
history of confusion, cough, and incontinence of urine. There was clinical
—​ Burns and radiological evidence of a left-​sided pneumonia and although
—​ Fractures both the temperature and white cell count remained normal, the CRP
• Malignant neoplasia: value was high (119 mg/​litre), confirming the suspicion of infection.
—​ Lymphoma Following treatment with amoxicillin, 250 mg three times daily, the CRP
—​ Hodgkin’s disease concentration fell rapidly, in a characteristic exponential manner, and
—​ Carcinoma, sarcoma he made a speedy recovery with return of continence and improved
mental state.
2202 section 12 Metabolic disorders

Box 12.12.1.2 Applications of serum CRP measurement

in infectious disease
• Pyogenic bacterial infections, including:
—​ bacteraemia and septicaemia in children and adults
—​ bacteraemia and septicaemia in neonates
—​ bacterial and other infections in immunosuppressed patients
—​ bacterial infections after major elective surgery or other invasive
procedures
—​ infective relapse after abdominal surgery for sepsis
—​ peritonitis in patients on chronic ambulatory peritoneal dialysis
—​ acute appendicitis (differential diagnosis)
—​ evaluation of antibiotic therapy for female pelvic infection
—​ laryngotracheitis/​pharyngitis/​epiglottitis in children
—​ chorioamnionitis after premature rupture of membranes
—​ disseminated versus localized gonococcal infection
—​ infection precipitating sickle cell crisis
• Meningitis (viral < tuberculosis < bacterial)
• Deep fungal infection

and/​or other serious pathology likely to cause death. However, with

alteration in the antimicrobial drug regimen or the evacuation of
pus or elimination of other pathology, the rapid fall in CRP that
may then be observed is an encouraging objective sign of clinical
Fig. 12.12.1.2 An 86-​year-​old woman had been refusing food and improvement.
drink for 6 weeks. She was dehydrated, but rehydration in hospital failed These considerations apply at all ages and regardless of intercur-
to improve her mental state. She was paranoid and refused nursing and rent pathology, with the exception of severe hepatocellular impair-
medical care. Paraphrenia was diagnosed and deterioration continued. ment. In view of the very small amount of serum required for the
A CRP concentration of 130 mg/​litre and a white cell count of 13.5 ×
assay and the speed and precision of automated CRP immunoassays,
109/​litre were then found. Chest radiography, normal on admission, now
showed a cavitating lesion from which 150 ml of pus were aspirated. it is apparent that routine monitoring of serum CRP makes a valu-
Intravenous ampicillin reduced neither the CRP nor the white cell count, able contribution to the recognition and management of infectious
prompting a change of therapy to gentamicin and metronidazole. diseases. Situations in which these applications have been well docu-
Streptococcus equinus was finally identified in the pus and treatment was mented are listed in Box 12.12.1.2.
changed to benzyl penicillin alone. The CRP value then fell exponentially Meningitis is of particular interest in view of its potential severity
but rather slowly. The patient’s clinical and mental state gradually
improved and she was eventually discharged.
and the importance of rapid diagnosis and appropriate treatment.
Bacterial meningitis is associated with much higher serum CRP
levels at presentation than cases of aseptic or proven viral meningitis.
response, which is often not otherwise available. Effective therapy The latter frequently have CRP concentrations within the normal
is associated with a rapid, exponential fall in CRP value, with a half-​ range or which are only very slightly raised, unless they develop sec-
life of about 24 h, and occurrence of this pattern is an encouraging ondary bacterial infective complications; patients with tuberculous
prognostic sign (Fig. 12.12.1.2). Normalization of the CRP usually meningitis have intermediate values. Appropriate therapy for either
corresponds to clinical cure of the infection and may thus be used bacterial or tuberculous meningitis causes the CRP c­ oncentration
to determine the necessary duration of antimicrobial therapy. On to fall, and this can be used to monitor objectively the response to
the other hand, especially in neutropenic or immunodeficient pa- treatment.
tients, persistent elevation of CRP at the end of a course of anti- Baseline CRP values are much lower at birth and for the first few
biotics often presages relapse or recurrence of infection. days than in older children or adults. Also, neonatal infections pro-
When bacterial infection is complicated by abscess formation or gress much more rapidly and can have a fatal outcome before the
for any other reason is less readily eradicated by antimicrobial drugs, CRP response has produced concentrations detectable in routine
the serum CRP concentration may remain elevated or may fall lin- assays. It is therefore essential to use highly sensitive methods cap-
early rather than exponentially during treatment. Such a pattern able of detecting and precisely measuring CRP in the range 0.05 to
should raise questions regarding the dosage of the drugs, the sen- 5.0 mg/​litre, otherwise the critical initial acute phase response to in-
sitivity of the organism, and/​or stimulate a diagnostic search both fection will be missed.
for localized pus and for other underlying, noninfective pathologies
such as malignancy. Indeed, in the absence of one of the chronic idio- Inflammatory disease
pathic inflammatory conditions which are known to be associated Most of the chronic inflammatory diseases of unknown aetiology
with high CRP concentrations (see later subsections), the persist- (Box 12.12.1.1), with some notable exceptions described later in
ence of a raised serum CRP concentration is usually a grave prog- this chapter, are associated with high CRP values when they are ac-
nostic sign indicating the presence of either uncontrolled infection tive. Serial measurements of CRP in individuals with any of these
 12.12.1 The acute phase response and C-reactive protein 2203

diseases generally reflect the extent and activity of their condition This can be very important when treatments include steroids and
as determined by clinical examination and by other laboratory tests. other powerful and potentially hazardous immunosuppressive, anti-​
Rheumatoid arthritis is the most common and important disease inflammatory, and cytotoxic drugs. It permits precise titration of
in this group and the correlation between CRP values in individual dosages and may help to avoid excessive or unnecessary use.
patients and the extent and activity of arthritis is very well estab- Induction of clinical remission and control of the underlying dis-
lished. Importantly, there are appreciable differences between the ease process is associated with prompt normalization of the CRP.
CRP concentrations attained in different subjects with apparently However, CRP also becomes abnormal with intercurrent infection,
similar severity of arthritis, but in each case the CRP value always a common complication of some of these disorders and their treat-
reflects current disease activity. Furthermore, CRP values precisely ments, and this serves to focus diagnostic attention often before
predict future progression of bone erosion and joint damage. Left the infection has become too severe or even before it is clinically
unchecked, high CRP values are inevitably followed by progressive evident. Monitoring the CRP response to antimicrobial therapy
erosive disease, whereas treatments that reduce the CRP concentra- can then help to confirm the diagnosis and the efficacy of therapy.
tion retard or arrest this process. Persistent elevation of the CRP after eradication of infection may
In some of the inflammatory disorders, for example, systemic vas- indicate relapse of the underlying inflammatory disease, requiring
culitis or Crohn’s disease (Fig. 12.12.1.3), unlike rheumatoid arth- additional anti-​inflammatory treatment.
ritis, the pathology is relatively inaccessible to direct examination,
and serum CRP measurement provides the best available, objective Necrosis
index of disease activity. Furthermore, the presence or absence of a Untreated acute myocardial infarction is invariably associated with a
CRP response can distinguish between symptoms or organ dysfunc- major CRP response, as is elective embolization leading to necrosis of
tion that are due to currently active inflammation and those that tumours in the liver and elsewhere. The peak concentration of CRP
are the consequence of fibrosis and scarring from previous episodes. occurs about 50 h after the onset of pain in acute myocardial infarc-
tion patients who do not undergo revascularization, and is earlier
and smaller following effective early revascularization. CRP produc-
Improving Improving
tion usually correlates in magnitude, though not in timing, with the
peak serum concentration of the specific myocardial markers, cre-
Severe atine kinase MB and troponin. In patients who recover uneventfully,
Moderate
Mild the CRP value falls rapidly towards normal in the usual exponential
40 fashion. However, complications such as persistent cardiac dysfunc-
(mg/
day)

Prednisolone
0 tion, further infarction, aneurysm formation, intercurrent infection,
(183)
thromboembolism, or postinfarction syndrome are associated with
protein (mg/l)

100
either persistently raised CRP values or a secondary increase after the
C-reactive

ESR (mm

initial decrease. Myocardial rupture is seen only in patients with high

in 1h)

peak CRP values (>200 mg/​litre) and the peak CRP concentration
0
67 after acute myocardial infarction strongly predicts overall outcome,
including survival, in the short, medium, and long term.
66
Stable angina and coronary arteriography investigations do not
Body weight (kg)

16 65 stimulate CRP production, whereas other relevant causes of chest

pain, including pulmonary embolism, pleurisy, or pericarditis, pro-
Stool frequency

12 61 64
duce raised CRP values. Routine assays of CRP after infarction or
8
60
63 in patients with chest pain may thus assist in diagnosis and in the
4
59 recognition and management of complications, including iatrogenic
0 62
6 8 10 12 14 16 8 10 12 2 infection associated with invasive cardiovascular monitoring.
July 1979 (days) 1979 (months) 1980 Serum CRP concentrations closely reflect the severity and progress
Hospital admission of acute pancreatitis, providing a better guide to intra-​abdominal
events than other markers such as leucocyte counts, erythrocyte
Fig. 12.12.1.3 A 26-​year-​old man with pancolonic Crohn’s disease.
He was admitted with severe exacerbation; temperature 38°C; pulse sedimentation rate (ESR), temperature, and the plasma concentra-
110 beats/​min; 16 stools per day; haematocrit 41.5%, leucocytes tions of antiproteinases. A CRP concentration greater than 100 mg/​
13.8 × 109/​litre. Rectal mucosa severely inflamed with histiocytic litre at the end of the first week of illness is associated with a more
granulomas on biopsy. Rapid improvement occurred with oral and rectal prolonged subsequent course and a higher risk of the development
prednisolone, ampicillin, and metronidazole, with complete clinical and of a pancreatic collection. Serial CRP measurements can therefore
histological remission on day 11. A relapse 5 months later responded
promptly to a short course of oral and rectal prednisolone. CRP and ESR guide the use of appropriate imaging techniques and help to confirm
values were both high during the initial exacerbation. The rapid response resolution before discharge from hospital.
to treatment was paralleled by a prompt fall in CRP concentration,
whereas the ESR responded more slowly. Despite clinical remission and Trauma and surgery
a normal ESR, the CRP remained slightly elevated, suggesting persistent The CRP concentration always rises after significant trauma, sur-
low-​grade inflammatory activity, and it rose further during a subsequent
gery, or burns, peaking after about 2 days and then falling towards
relapse when the ESR did not change.
Reproduced from Fagan A, et al. (1982). Serum levels of C-​reactive protein in Crohn’s
normal with recovery and healing. Infections or other tissue-​
disease and ulcerative colitis. Eur J Clin Invest, 12, 351–​9, with permission. damaging complications alter this normal pattern of CRP response
2204 section 12 Metabolic disorders

and the failure of the CRP to continue falling, or the appearance of a pathways that mediate the acute phase response to autologous in-
second peak, may precede clinical evidence of intercurrent infection flammation and tissue damage.
by 1 to 2 days. Serial prospective CRP measurement is therefore ad- Pyrexia is common in SLE and may be caused by microbial in-
visable in such patients. fection or by activity of the lupus itself. Both SLE and its treatment
predispose to infection, and steroids and immunosuppressive drugs
Malignancy can mask the usual symptoms and signs of infection. Furthermore,
Most malignant tumours, especially when they are extensive and infection can trigger exacerbations of SLE. This is a serious clinical
metastatic, induce an acute phase response. This is particularly so situation and infection remains one of the most common causes of
with those neoplasms that cause systemic symptoms such as fever death in patients with SLE. CRP values of 60 mg/​litre or more are
and weight loss, for example, Hodgkin’s disease (stage B) and renal very rare in SLE in the absence of infection, whereas values below
carcinoma, but raised CRP values are seen with many others. In 60 mg/​litre are seen in patients with documented infection only
some studies, notably of prostatic carcinoma and bladder car- when it is rather mild and often localized (e.g. to the skin or lower
cinoma, the CRP concentration at presentation has been found to urinary tract). Differential diagnosis and management of fever in
correlate with the overall tumour load and also with the prognosis, SLE are thus considerably improved by the measurement of serum
being higher for a given mass of tumour in those patients who sub- CRP concentration (Fig. 12.12.1.4).
sequently fare worse. The CRP value may also correlate better with
progress and regression of tumour than other, more specific tumour Cefuroxime Pulse doses
Gentamicin methylprednisolone
markers. However, given the nonspecific nature of the acute phase
Prednisolone 30 mg/day
response and the limited number of adequate studies performed a
Abdominal
definite role for CRP measurement in the management of cancer pain
patients, other than in cases of intercurrent infection, has not been Fever Diarrhoea
Rash E. coli
established. Arthritis septicaemia
41
Allograft rejection
°C
In the era before routine immunosuppression with combined 37
ciclosporin and steroid treatment, rejection episodes following renal
allografting were generally associated with increased production of
150
ESR (mm in first hour) (mg/l)

CRP. However, this treatment almost completely suppresses the CRP

ESR
response to allograft rejection. In contrast, the acute phase response
of serum amyloid A protein is unaffected and, importantly, intercur- 100
rent infection still stimulates greatly increased production of both
CRP and serum amyloid A protein.
50 C-reactive protein

Conditions associated with minor increase in serum

CRP concentration 0
Mar Jun Sept 4 10 16 22 28 Dec Jan
Despite unequivocal evidence of active inflammation and/​or tissue
November
damage, the conditions listed in Box 12.12.1.3 are usually associ-
ated with only minor increases in the serum CRP concentration, Fig. 12.12.1.4 A 12-​year-​old girl with a 3-​year history of SLE; recurrent
and in many cases it may even remain normal in the face of severe febrile episodes, polyarthritis, cutaneous vasculitis, and episodes of
asymptomatic bacteriuria. Intermittent treatment was with prednisolone,
disease. The contrasts of systemic lupus erythematosus (SLE) with
azathioprine, and plasma exchange. Serum CRP concentration was only
rheumatoid and other arthritic conditions shown in Box 12.12.1.1, marginally increased throughout but erythrocyte sedimentation rate was
and between ulcerative colitis and Crohn’s disease, are very striking. persistently high. Fever recurred with diarrhoea and abdominal pain.
However, intercurrent microbial infection provokes a major CRP All microbial cultures were negative except for growth of Escherichia coli
response in all the conditions shown in Box 12.12.1.3, and this is from the urine. Despite oral cefalexin and prednisolone her condition
of great value in diagnosis and management, especially in SLE and deteriorated, with severe neutropenia, probably due to azathioprine. The
CRP value rose from 36 to 101 mg/​litre and then 137 mg/​litre, and at
leukaemia. The basis of the apparently selective failure of the acute this stage her blood culture grew Escherichia coli. Intravenous antibiotics
phase response of CRP (which is also shown by serum amyloid were given and the serum CRP concentration fell rapidly, but there was
A protein) is not known, but presumably involves defect(s) in the little clinical improvement. Active SLE appeared then to be the sole cause
of the fever and this was confirmed by the development of a diffuse
vasculitic rash and polyarthritis. Three pulse doses of methylprednisolone
Box 12.12.1.3 Conditions associated with minor increases were given intravenously on successive days and produced a dramatic
in serum CRP concentration improvement in her clinical state with resolution of the fever. This case
illustrates (1) the differential response of CRP to fever resulting from
• Systemic lupus erythematosus activity of SLE alone and fever due to bacterial infection; (2) the rapid
• Scleroderma response of CRP both to the onset and to the effective treatment of
• Dermatomyositis serious bacterial infection; and (3) the failure of ESR measurements to
• Ulcerative colitis provide any useful information in this complex and rapidly evolving
• Leukaemia clinical situation.
• Graft-​versus-​host disease Reproduced from Pepys MB, Langham JG, de Beer FC (1982). C-​reactive protein in
systemic lupus erythematosus. Clin Rheum Dis, 8, 91–​103, with permission.
 12.12.1 The acute phase response and C-reactive protein 2205

The reason why leukaemia patients fail to mount more than a decision as to whether infection is present or not must depend on
modest CRP response, even during induction therapy when there is clinical examination and other laboratory tests; the role of CRP
massive death of leukaemia cells, is not known. However, the CRP testing is then to demonstrate rapidly and objectively whether there
response to infection is normal. Since all febrile episodes in leu- is a response to whatever treatment is used. Effective antimicrobial
kaemia must initially be treated as infective, the main value of CRP therapy of infection is always associated with a prompt fall in the
monitoring is to determine the response to therapy and assist in de- CRP, whereas persistent CRP production indicates continuing infec-
cisions about its duration. Acute or chronic graft-​vs-​host disease tion and/​or activity of the underlying disease. There is no other ob-
after bone marrow transplantation is usually associated with only jective test that yields this sort of information so accurately. Changes
a modest CRP response, if any. However, the immunosuppressive in the results of clinical examinations and tests of organ function
treatments used to prevent bone marrow rejection and to control usually lag hours or days behind the CRP response.
graft-​vs-​host disease render the patients susceptible to intercurrent
infections, often with unusual microorganisms, and these are always Other considerations
associated with high CRP values. CRP monitoring is therefore very CRP and body temperature
useful in post-​transplant management.
The acute phase response, which is best measured clinically by quan-
Interpretation of clinical serum CRP measurements tification of the serum CRP concentration, is part of the systemic re-
sponse to disease. Monitoring of this same response by measurement
The CRP response is not specific and CRP measurements on their
of body temperature is an integral part of routine clinical manage-
own can therefore never be diagnostic of any particular condition,
ment. CRP production is triggered by the same cytokines that cause
nor should they be used in isolation for any other clinical purpose.
fever, and the serum CRP concentration is therefore in part a bio-
The CRP value can only be interpreted in the light of all other avail-
chemical surrogate for the body temperature. However, the CRP re-
able clinical and laboratory information. Provided this is done, it can
sponse is not susceptible to the many vagaries of thermoregulation
make a most useful contribution to overall assessment of the patient
and of routine clinical measurement of body temperature. The precise
and determination of the best management.
numerical value of the CRP concentration and its changes over time
The applications fall into three main categories:
reflect much more accurately than the temperature the intensity of
• Screening for organic disease the underlying stimulus. Furthermore, there is often a CRP response
• Monitoring of extent and activity of disease—​infection, inflam- in the absence of fever, especially in neonates and older people, and
mation, malignancy, and necrosis also in many chronic inflammatory conditions at any age. There is
• Detection and management of intercurrent infection thus a good case for charting serial serum CRP concentrations along-
side the standard temperature chart in appropriate patients.
Screening for organic disease
CRP production is a very sensitive response to organic disease. CRP or ESR?
A normal CRP value therefore eliminates many possible types of path- The only other comparable nonspecific index of disease that is rou-
ology and is a reassuring finding. Those serious conditions that stimu- tinely measured is the ESR. The ESR reflects, in part, the intensity
late CRP production only weakly, if at all, for example, SLE, ulcerative of the acute phase response, especially that of fibrinogen and the
colitis, and leukaemia, are all readily recognized by clinical examin- α-​globulins, but is also largely determined by the concentration of
ation and simple routine investigations. The presence of a raised CRP immunoglobulins, which are not acute phase reactants. These pro-
value is unequivocal evidence of active pathology, though this may teins all have half-​lives of days to weeks. ESR thus changes very
not necessarily be the cause of the complaint for which the patient pre- much more slowly than the CRP concentration, and it rarely reflects
sented. Such a finding, in the absence of other obvious abnormality, precisely the clinical status of the patient at the time of testing. ESR
warrants a repeat CRP assay after a few days when a trivial cause such is also dependent on the number and morphology of the red cells,
as an upper respiratory tract infection will have resolved. Further in- which bear no relationship to the acute phase response. In addition,
vestigation of a persistently raised CRP concentration will then de- there is a significant diurnal variation in ESR, depending on food
pend on the severity of the complaint and other clinical findings. intake, which is not seen in the CRP concentration. Finally, the dy-
namic range of the ESR is much less than that of CRP concentration
Monitoring extent and activity of disease and the precision and reproducibility of ESR measurement is poor
Once the diagnosis is established, in those diseases which cause compared to the robust clinical chemistry immunoassays available
major CRP production, serial measurements reflect activity and re- for CRP. The ESR is therefore of limited use as an objective index of
sponse to treatment and can be used for monitoring. However, they disease activity on which management decisions can be based.
can only be interpreted provided other possible intercurrent causes In all clinical situations that have been carefully evaluated, ran-
of an acute phase response, particularly infections, are excluded. ging from acute bacterial infections to the chronic remittent in-
flammatory diseases, such as Crohn’s disease, rheumatoid arthritis,
Detection and management of intercurrent infection and other inflammatory arthropathies, and systemic vasculitis in its
Production of CRP is a very sensitive response to most forms of various forms, frequent prospective measurements of CRP reflect
infection and a raised concentration is thus a useful guide to the disease activity very much more closely than measurements of the
possible presence of infection in otherwise normal subjects or in- ESR. However, the ESR remains a useful screening test for the detec-
dividuals with a primary condition that predisposes to infection. tion of paraproteinaemias, especially multiple myeloma, in which an
In disorders that themselves increase the CRP concentration, the acute phase response is often absent.
2206 section 12 Metabolic disorders

CRP and cardiovascular disease The unfortunate conflation of association with causality triggered
The 1994 report of a prognostic association between increased CRP much speculation about whether CRP is a pathogenetic factor for
and serum amyloid A protein values and outcome in severe un- cardiovascular disease events. However, Mendelian randomization
stable angina, and the discovery of a significant predictive associ- genetic epidemiological studies looking at hereditary polymorphisms
ation between baseline CRP values in the general population and associated with higher or lower baseline CRP values all show no
future coronary events, triggered an avalanche of work in this field. ­association with cardiovascular disease risk. This negative outcome
These observations became increasingly controversial, but the re- is entirely consistent with the negative in vivo animal studies of CRP
cent publications of very large-​ scale observational and genetic and atherogenesis. In contrast, experimental animal studies robustly
epidemiological studies have eventually resolved the major issues. show that human CRP can exacerbate pre-​existing ischaemic injury
The key questions are whether the measurement of baseline CRP via a complement dependent mechanism and that this can be blocked
concentration provides information useful for the assessment and by experimental drugs that inhibit CRP function. Preliminary clinical
management of cardiovascular disease risk, and whether CRP itself studies of extra-corporeal absorption of CRP, to lower the circulating
contributes to the pathogenesis of atherosclerosis, atherothrombosis, CRP concentration, are in progress in patients with acute myocardial
and/​or ischaemic tissue injury. infarction. Future testing of more effective novel CRP blocking drugs
The possible involvement of CRP in atherogenesis was first sug- should demonstrate whether this mechanism is clinically relevant.
gested by the binding of CRP to low-​density lipoprotein and the pres-
ence of CRP in atherosclerotic lesions. In recent years, a wide range Serum amyloid A protein
of proinflammatory and cell-​activating effects have been claimed for
CRP, based on in vitro studies with various cell types. Unfortunately, Serum amyloid A protein, an apolipoprotein of high-​density lipo-
nearly all this work was done with commercial CRP preparations protein particles, is a marked acute phase reactant, its concentration
produced in recombinant bacteria, and none of the positive obser- rising from normal levels of about 2 mg/​litre by as much as 1000-​
vations have been reproducible with authentic pure human CRP fold. It is essential to monitor and control serum amyloid A protein
isolated from human source material. The amazing range of potent levels in patients with reactive systemic, AA type amyloidosis (see
proinflammatory and cell-​activating properties ascribed to CRP is Chapter 12.12.3). It is a critical marker of disease control in patients
not consistent with the fact that neither the administration of large with hereditary periodic fever syndromes, to ensure that they do not
amounts of pure human CRP in normal healthy animals nor the develop systemic AA amyloidosis. Serum amyloid A protein concen-
1000-​fold natural acute phase response of CRP in patients are as- tration is also the most sensitive marker of rejection episodes in renal
sociated with any such effects. Furthermore, intravenous infusion allograft recipients and is useful in routine monitoring of these patients.
of authentic, pure, pharmaceutical grade human CRP into healthy
adult human volunteers had no proinflammatory, proatherogenic, FURTHER READING
or any other adverse effects. In experimental animal models of ath- Boralessa H, et al. (1986). C-​reactive protein in patients undergoing
erosclerosis, CRP either has no effect on atherogenesis in vivo or is cardiac surgery. Anaesthesia, 41, 11–​15.
atheroprotective. Human epidemiological studies of atherosclerosis Casas JP, et al. (2008). C-​reactive protein and coronary heart disease: a
burden have had varying results, but overall provide no compelling critical review. J Intern Med, 264, 295–​314.
evidence for an association with CRP values. C-​reactive Protein Coronary Heart Disease Genetics Collaboration
Baseline CRP values are significantly associated with all the (CCGC) (2011). Association between C reactive protein and cor-
known risk factors and pathogenetic mechanisms for coronary onary heart disease: mendelian randomisation analysis based on in-
heart disease events, and about 70% of the variance in baseline CRP dividual participant data. BMJ, 342, d548.
is ascribable to these factors. Although CRP concentration is thus Elliott P (2009). Genetic loci associated with C-​reactive protein levels
not independently associated with cardiovascular disease risk, a and risk of coronary heart disease. JAMA, 302, 37–​48.
Emerging Risk Factors Collaboration (2009). C-​ reactive protein
statistically significant association remains even after maximal ad-
concentration and risk of coronary heart disease, stroke and mor-
justment. However, the level of association is markedly less than
tality: an individual participant meta analysis. Lancet, 375, 132–​40.
was originally reported and is comparable with the association with Emerging Risk Factors Collaboration (2009). C-​reactive protein, fi-
cardiovascular disease risk of other nonspecific systemic markers of brinogen and cardiovascular disease prediction. N Engl J Med, 367,
inflammation, such as low plasma albumin, raised white cell count, 1310–​20.
ESR, and serum amyloid A protein. The Emerging Risk Factors Fagan EA, et al. (1982). Serum levels of C-​reactive protein in Crohn’s
Collaboration meta-​analysis of 52 major epidemiological studies of disease and ulcerative colitis. Eur J Clin Invest, 12, 351–​60.
baseline CRP values and cardiovascular disease prediction, showed Griselli M, et al. (1999). C-​reactive protein and complement are im-
that CRP measurement adds almost no useful information to risk portant mediators of tissue damage in acute myocardial infarction. J
assessment, potentially helping to prevent only one additional Exp Med, 190, 1733–​9.
event over a period of 10 years for every 400–​500 people screened. Hartmann A, et al. (1997). Serum amyloid A protein is a clinically
Also, since statins lower risk when administered at any level of useful indicator of acute renal allograft rejection. Nephrol Dial
low-​density cholesterol and in all subgroups of the population, re- Transplant, 12, 161–​6.
gardless of intercurrent disease or additional risk factors, there is Kushner I, Rzewnicki D, Samols D (2006). What does minor elevation
of C-​reactive protein signify? Am J Med, 119, 166.e117–​28.
no justification for the use of CRP measurement to select patients
Lane T, et al. (2014). Infusion of pharmaceutical-​grade natural human
for statin treatment. Indeed, measuring the exquisitely nonspecific
C-​reactive protein is not pro-​inflammatory in healthy adult human
CRP in this context, without comprehensive review of a patient volunteers. Circ Res, 114, 672–​6.
with a raised value, risks missing other important pathologies.
 12.12.2 Hereditary periodic fever syndromes 2207

Liuzzo G, et al. (1994). The prognostic value of C-​reactive protein and and (4) the cryopyrin-​associated periodic syndromes (CAPS), which
serum amyloid A protein in severe unstable angina. N Engl J Med, include (a) familial cold urticarial syndrome, (b) Muckle–​Wells syn-
331, 417–​24. drome, and (c) chronic infantile neurological, cutaneous, and ar-
Lowe GDO, Pepys MB (2006). C-​reactive protein and cardiovascular ticular syndrome. With advances in genetics, further syndromes are
disease: weighing the evidence. Curr Atheroscler Rep, 8, 421–​8. continually being recognized. These are all extremely rare and in the
Pepys MB (2005). CRP or not CRP? That is the question. Arterioscler majority are only known to affect a handful of kindred or individuals.
Thromb Vasc Biol, 25, 1091–​4.
Understanding of the molecular pathogenesis of these disorders
Pepys MB, Hirschfield GM (2003). C-​reactive protein: a critical up-
provides unique insights into the regulation of innate immunity and
date. J Clin Invest, 111, 1805–​12.
Pepys MB, Lanham JG, de Beer FC (1982). C-​reactive protein in sys-
inflammation.
temic lupus erythematosus. Clin Rheum Dis, 8, 91–​103. Diagnosis relies on recognition of suggestive clinical features (e.g.
Pepys MB, et al. (2005). Proinflammatory effects of bacterial recombinant fever with peritonitis and/​or pleurisy, arthralgia/​arthritis) that are al-
human C-​reactive protein are caused by contamination with bacterial most always accompanied by a substantial acute phase response,
products, not by C-​reactive protein itself. Circ Res, 97, e97–​103. and is supported by genetic testing. With the exception of FMF,
Pepys MB, et al. (2006). Targeting C-​reactive protein for the treatment which is a common disease in certain geographic areas, hereditary
of cardiovascular disease. Nature, 440, 1217–​21. periodic fever syndromes are rare and easily overlooked in the differ-
Pepys MB (2018).The Pentraxins 1975–2018: Serendipity, Diagnostics ential diagnosis of recurrent fevers.
and Drugs. Front Immunol, 9, 2382. Clinical features and management—​attacks can be mild to debili-
Ridker PM, et al. (1997). Inflammation, aspirin, and the risk of cardio- tating and short to prolonged, while their most feared complication is
vascular disease in apparently healthy men. N Engl J Med, 336, 973–​9. AA amyloidosis. Effective therapies are available for some syndromes,
Riess W, et al. (2018). First in man: case report of selective C-reactive pro-
for example: (1) FMF—​daily prophylactic colchicine prevents clinical
tein apheresis in a patient with acute ST segment elevation myocardial
attacks and susceptibility to AA amyloidosis, (2) CAPS—​treatment
infarction. https://www.hindawi.com/journals/cric/2018/4767105/
with anti-​IL-​1 agents produces rapid and often complete clinical and
Simons JP, et al. (2014). C-​reactive protein is essential for innate resist-
ance to pneumococcal infection. Immunology, 142, 414–​20. serological remission, and (3) TRAPS—​anti-​IL therapies are extremely
Starke ID, et al. (1984). Serum C-​reactive protein levels in the man- effective.
agement of infection in acute leukaemia. Eur J Cancer, 20, 319–​25.
van Leeuwen MA, et al. (1997). Individual relationship between pro-
gression of radiological damage and the acute phase response in Introduction
early rheumatoid arthritis. Towards development of a decision sup-
port system. J Rheumatol, 24, 20–​7.
The hereditary periodic fever syndromes are a group of multisystem
Wasunna A, et al. (1990). C-​reactive protein and bacterial infection in
disorders characterized by fluctuating or irregularly recurring epi-
preterm infants. Eur J Pediatr, 149, 424–​7.
sodes of fever and systemic inflammation, notably affecting the
joints, eyes, skin, and serosal surfaces. More than 30 syndromes
are now recognized; many of these are extremely rare and only af-
fect a handful of individuals. Diseases affecting more than 1 per
million, and therefore likely to be encountered in specialist prac-
tice, include familial Mediterranean fever (FMF), tumour necrosis
12.12.2 Hereditary periodic factor (TNF) receptor-​ associated periodic syndrome (TRAPS),
mevalonate kinase deficiency (MKD, previously known as the
fever syndromes hyperimmunoglobulin D and periodic fever syndrome (HIDS)),
and the cryopyrin-​associated periodic syndromes (CAPS). The
Helen J. Lachmann, Stefan Berg, latter are a spectrum of three hitherto apparently distinct dis-
and Philip N. Hawkins orders of increasing severity: familial cold urticarial syndrome
(now known as familial cold autoinflammatory syndrome; FCAS),
Muckle–​Wells syndrome (MWS), and chronic infantile neuro-
ESSENTIALS logical, cutaneous, and articular syndrome (CINCA). The latter
The hereditary periodic fever syndromes or hereditary auto­ is also known in the United States of America as neonatal-​onset
inflammatory diseases are disorders of innate immunity that mostly multisystem inflammatory disorder (NOMID).
present in childhood and are characterized by recurrent, self-​ Although many symptoms of these disorders are shared, there
limiting, seemingly unprovoked episodes of fever and systemic in- are clear distinctions in the pattern of their inheritance, the dur-
flammation that occur in the absence of autoantibody production ation and frequency of attacks, and their overall clinical picture
or identifiable infection. (Table 12.12.2.1). With a few exceptions, these diseases are usu-
Disorders include (1) familial Mediterranean fever (FMF), due to ally compatible with normal life expectancy, though with the
mutations in the gene encoding pyrin; (2) tumour necrosis factor ever-​looming grave threat of AA amyloidosis. Recent insights
(TNF) receptor-​associated periodic syndrome (TRAPS), due to mu- into their molecular pathogenesis have led to enhanced diagnosis
tations in a gene for a TNF receptor; (3) mevalonate kinase defi- through DNA analysis, the development of rational therapies,
ciency (MKD), caused by mutations in the mevalonate kinase gene; and have shed important new light on regulation of the innate
­immune system.
 2208

Table 12.12.2.1 Features of inherited periodic fever syndromes

Periodic Gene, OMIM Mode of Predominant Usual age Potential Distinctive clinical Typical Typical Characteristic Treatment
fever chromosome inheritance population at onset precipitants features duration of frequency of laboratory
syndrome of attacks attacks attacks abnormalities
FMF MEFV, 249100 Autosomal Eastern Childhood/​ Usually none Short severe attacks 1–​3 days Variable Marked acute Colchicine
chromosome 16 608107 recessive Mediterranean early Occasionally of peritonitic phase response
(dominant in adulthood menstruation, and/​or pleuritic during attacks
rare families) fasting, stress, pain, colchicine-​
or trauma responsive,
erysipelas-​like
section 12 Metabolic disorders

erythema
TRAPS TNFRSF1A, 142680 Autosomal Northern Childhood/​ Usually none Prolonged More than a Variable (may Marked acute Anti-​IL-​
chromosome 12 191190 dominant European, but early symptoms week (may be continuous) phase response 1therapies
(can be de reported in adulthood be very during attacks High-​dose
novo) many ethnic prolonged) Low levels of corticosteroids
groups soluble TNFR1
when well
MKD MVK, 260920 Autosomal Northern Infancy Immunizations Diarrhoea and 3–​7 days 1–​2 monthly Acute phase Anti-​IL-​1
chromosome 12 251170 recessive European, but lymphadenopathy. response, and therapies, anti-​
reported in mevalonate TNF therapies,
many ethnic aciduria during anti-​IL-​6
groups attacks, elevated therapies
IgD and IgA
FCAS NLRP3, 120100 Autosomal Northern Neonatal/​ Exposure Cold-​induced fever, 24–​48 h Depends on Acute phase Cold avoidance,
chromosome 1 606416 dominant but reported infancy to cold arthralgia, rash, and environmental response during anti-​IL-​1
in many environment red eye factors attacks; to a therapies
ethnic groups lesser extent
European, when well
MWS NLRP3, 191900 Autosomal Northern Neonatal/​ Marked Urticarial rash, red Continuous Often daily Varying but Anti-​IL-​1
chromosome 1 606416 dominant, European, but infancy diurnal eye, sensorineural (often marked acute therapies
reported in variation deafness worse in the phase response
many ethnic Cold evenings) most of the time
groups environment,
but less
marked than
in FCAS
CINCA/​ NLRP3, 607115 Sporadic Northern Neonatal/​ None Urticarial rash, Continuous Continuous Varying but Anti-​IL-​1
NOMID chromosome 1 606416 European, but infancy aseptic meningitis, marked acute therapies
reported in deforming phase response
many ethnic arthropathy, most of the time
groups sensorineural
deafness,
developmental
damage
PAPA PSTPIP1 604416 Autosomal Northern Childhood None Pyogenic arthritis, Intermittent Variable (may Acute phase Anti-​TNF
(CD2BP1), 606347 dominant European, but pyoderma attacks with be continuous) response during therapies
chromosome 15 reported in gangrenosum, and migratory attacks
many ethnic cystic acne arthritis
groups
Blau’s NOD2 (CARD15), 605956 Autosomal None Age <5 years None Granulomatous Continuous Continuous Sustained Corticosteroids,
syndrome chromosome 16 186580 dominant polyarthritis, iritis, modest acute some reports
and dermatitis phase response of benefit from
anti-​TNF agents
FCAS2 NLRP12, 611762 Autosomal South/​Central Neonatal Sometimes Urticarial rash, Intermittent Variable Acute phase None know
chromosome 19 609648 dominant American, but exposure to fever, arthralgia response during
reported in cold attacks
other ethnic
groups
DIRA IL1RN, 612852 Autosomal Northern Infancy None Pustular rash, sterile Continuous Continuous Sustained acute Anakinra
chromosome 2 147679 recessive Europe and osteomyelitis of phase response (recombinant
Central long bones IL-​1 receptor
America antagonist)
Majeed’s LIPN2, 609628 Autosomal Middle East Infancy None Recurrent 2-​7 days Variable Acute phase NSAIDs and
syndrome chromosome 18 605519 recessive multifocal response during corticosteroids.
osteomyelitis, attacks Possible benefit
congenital from IL-​1
dyserythropoietic blocking agents
anaemia,
neutrophilic
dermatosis
DITRA IL36RN, 614204 Autosomal None Variable—​ Drug initiation Recurrent fever, Intermittent Variable Acute phase Possible benefit
chromosome 2 605507 recessive from infancy or withdrawal, generalized rash, response during from IL-​1
onwards menstrual and disseminated attacks, typical blocking agents
cycle, pustules often but spongiform
pregnancy not always on a pustules on skin
background of biopsy
psoriasis
CANDLE/​JMP PSMB8, 256040 Autosomal None Infancy None Lipodystrophy, Continuous Continuous Acute phase None
chromosome 6 177046 recessive characteristic response, typical established? JAK
rash, swollen lips, appearances on inhibitors
violaceous eyelids skin biopsy
Early-​onset IL10RA, 613148 Autosomal None Infancy None Very early-​ Continuous Continuous Acute phase Stem cell
inflammatory chromosome 612567 recessive onset severe response, colitis transplantation
bowel 11, IL10RB, 612381 inflammatory with granulomas
disease/​IL-​10R chromosome bowel disease with
deficiency 21, or IL-​10, perianal fistulae
chromosome1
APLAID PLCG2, 614878 Autosomal Single family Infancy Rash worse Recurrent blistering Continuous Continuous Acute phase Partial response
chromosome 16 600220 dominant with heat or rash and mild response, dense to IL-​1
sun exposure humoral immune inflammatory blockade and
deficiency with infiltrate in skin, corticosteroids
sinopulmonary decreased IgM
infections and IgA, no
autoantibodies

(continued)
12.12.2 Hereditary periodic fever syndromes
2209
 2210

Table 12.12.2.1 Continued

Periodic Gene, OMIM Mode of Predominant Usual age Potential Distinctive clinical Typical Typical Characteristic Treatment
section 12 Metabolic disorders

fever chromosome inheritance population at onset precipitants features duration of frequency of laboratory
syndrome of attacks attacks attacks abnormalities
HOIL-​1 RBCK1, 615895 Autosomal Two European Infancy None Polyglucosan Intermittent Intermittent Acute phase All 4 cases died
deficiency chromosome 20 recessive families myopathy and response, in childhood—​
cardiomyopathy intracellular symptomatic
with glycogen improvement
immunodeficiency inclusions, on with
and bacterial muscle biopsy corticosteroids,
infection and allogenic
autoinflammation stem cell
transplantation
attempted
DADA2 CECR1, 615688 Autosomal None Childhood None Systemic and Intermittent Intermittent Acute phase Anti-​TNF
chromosome 22 recessive local polyarteritis response during
nodosa, livedo attacks
racemose, and
early-​onset stroke
SAVI TMEM173, 615934 Autosomal None Infancy None Rash on cheeks, Continuous Continuous Capillary None
chromosome 5 dominant ears, nose, and inflammation, established? JAK
digits with cartilage acute phase inhibitors
damage, failure to response
thrive, interstitial
lung disease

APLAID, autoinflammation and PLCγ2-​assocaited antibody deficiency and immune dysregulation, CINCA/​NOMID, chronic infantile neurological, cutaneous, and articular syndrome/​neonatal-​onset multisystem inflammatory disorder;
DADA2, deficiency of adenosine deaminase 2; DIRA, deficiency of the IL-​1 receptor antagonist; DITRA, deficiency of the IL-​36 receptor antagonist; FCAS, familial cold autoinflammatory syndrome; FMF, familial Mediterranean fever;
HOIL-​1, haem-​oxidized IRP2 ubiquitin ligase 1; IL-​1, interleukin 1; MKD, mevalonate kinase deficiency; MWS, Muckle–​Wells syndrome; PAPA, pyogenic arthritis, pyoderma gangrenosum, and acne syndrome; SAVI, STING-​associated
vasculopathy with onset in infancy; TNF, tumour necrosis factor; TNFR1, tumour necrosis factor receptor 1; TRAPS, tumour necrosis factor receptor-​associated periodic syndrome.
 12.12.2 Hereditary periodic fever syndromes 2211

or damage-​associated molecular patterns. Recent work suggests

Historical perspective
that pyrin is an indirect sensor of a wide variety of bacterial toxins;
pyrin interacts, via its N-​terminal death domain, with cytoskeleton
Although the hereditary periodic fever syndromes have only been
microtubules and appears to detect pathological perturbation of
identified as such during the last few decades, there are various
actin polymerization dynamics caused by bacterial modification or
ancient references to them, particularly FMF. Perhaps the earliest
inactivation of Rho GTPases.
extant clinical description is found in William Heberden’s 1802
More than 20 other proteins that have homology with pyrin’s
Commentaries on History and Care of Disease: ‘Pains which are regu-
N-​terminal sequence are now classified generically to have a pyrin
larly intermittent, the fits of which return periodically as those of
domain and are members of the death domain superfamily. They
an ague; such as I have known in the bowels, stomach, breast, loins,
play important roles in the assembly and activation of apoptotic and
arms and hips, though it be but seldom that such parts suffer in such
inflammatory complexes through homotypic protein–​protein inter-
a manner.’
actions. Proteins with pyrin domains are involved in inflammation,
apoptosis, and nuclear factor (NF)-​κB signalling and have been im-
plicated in pathways in CAPS as well.
Familial Mediterranean fever
Epidemiology
Genetics FMF occurs worldwide, though predominantly in populations
FMF is predominantly inherited in a recessive manner. The gene as- arising from the eastern Mediterranean basin, particularly non-​
sociated with FMF, MEFV, which encodes a protein called pyrin, Ashkenazi Jews, Armenians, Turks, and Levantine Arabs. The
was identified through positional cloning in 1997. MEFV is ex- prevalence of FMF has been estimated to be 1 in 250 to 1 in 500
pressed in neutrophils, monocytes, dendritic cells, and fibroblasts. among non-​Ashkenazi Jews and 1 in 1000 in the Turkish popula-
Expression is up-​regulated in response to inflammatory activators tion. The carrier frequency is as high as one in five among Armenian,
such as interferon-​γ and TNFα. The more than 40 MEFV mutations Turkish, and North African Jewish populations, fuelling speculation
that are associated with FMF encode either single amino acid substi- that the FMF trait may have conferred survival benefit, most likely
tutions or small deletions. The mutations that cause FMF are mostly through enhanced resistance to microbial infection mediated by up-​
in exon 10, but also occur elsewhere, particularly in exons 1, 3, 5, and regulation of the innate inflammatory response. Males and females
9. Mutations in each of the two MEFV alleles can be identified in most are equally affected. FMF usually presents in childhood, in 60% be-
patients with FMF. Most individuals with a single mutated allele re- fore the age of 10 years and in 90% by 20 years.
main healthy carriers but heterozygote FMF is well recognized and
may account for up to 20% of cases. While it is inherently likely that Clinical features
different mutations will affect the function of a protein to differing Attacks of FMF occur irregularly at variable frequencies and may
extents, several findings suggest that the methionine residue at pos- be precipitated by physical and emotional stress, menstruation, and
ition 694 is especially important. Five different pathogenic exon 10 diet. The onset is rapid and symptoms resolve spontaneously within
mutations involving Met694 have been identified, and individuals 6 to 72 h. Fever with peritonitis and/​or pleurisy are the hallmark
homozygous for Met694Val have particularly severe disease. Simple features, but occur with widely varying intensity from very mild
heterozygous deletion of this residue is associated with autosomal to severely incapacitating. The clinical picture may mimic an acute
dominant FMF of variable penetrance in the British population. surgical abdomen with ileus and vomiting, and 40% of patients
More extensive disruption of a single MEFV allele by one or more undergo laparoscopy before the diagnosis is made. Pleuritic attacks
mutations may account for other rare reports of dominant FMF. occur in 40% of patients, characteristically unilaterally, either alone
Much more commonly, FMF affecting more than one generation of or in association with peritonitis. Pericarditis is rare and cardiac
a family is pseudodominantly inherited, reflecting consanguinity or tamponade extremely rare. Headache with meningism is reported,
a high local prevalence of the heterozygous carrier state. but generally the nervous system is not involved in attacks. Orchitis
One particular pyrin variant, E148Q encoded in exon 2, is ex- occurs in less than 5% of males, most commonly in early childhood,
tremely frequent in Asian populations, with an allele frequency of when it can be confused with torsion of the testis. Transient arth-
10 to 20%, and occurs in other populations at a much lower fre- ralgia in lower-​limb joints is not infrequent in acute attacks, and
quency. Although pyrin E148Q can cause typical FMF when usually subsides within 2 to 4 days; dramatic acute oligoarthritis of
coupled with various exon 10 mutations, homozygosity for E148Q the large joints of the lower limb can occur but chronic destructive
alone is thought not to be associated with disease in the vast majority inflammation is rare. There is a rare but genuine association be-
of cases. There is, however, a suggestion that the presence of pyrin tween FMF associated with MEFV M694V and chronic sacroiliitis.
E148Q might intensify non-​FMF types of inflammation. A characteristic erysipelas-​like erythematous rash occurs in 20% of
patients (Fig. 12.12.2.1), usually on the lower extremities. Myalgia
Pathology can be part of the constitutional upset during acute attacks, but up
Unusually, given the recessive inheritance, the mutations underlying to one-​fifth of patients complain of persistent muscle pain on exer-
FMF appear to result in gain of function. Pyrin is a key component tion, usually affecting the calves. The rare but distinct syndrome of
of an inflammasome which activates caspase-​1 by autoproteolysis. protracted febrile myalgia presents as severe pain, mainly affecting
Maturation of interleukin (IL)-​1β and IL-​18 requires cleavage by the lower limbs or abdominal musculature; symptoms may persist
caspase 1 which also induces macrophage pyroptosis. Assembly of for weeks and be accompanied by a vasculitic rash, but usually re-
inflammasomes is triggered by recognition of intracellular pathogen spond to corticosteroids.
2212 section 12 Metabolic disorders

Tumour necrosis factor receptor-​associated

periodic syndrome

Genetics
TRAPS is an autosomal dominant disease associated with mutations
in the 10-​exon TNF receptor superfamily 1A gene (TNFRSF1A) on
chromosome 12p13. A disproportionate number of the 50 or so as-
sociated mutations disrupt the coding of cysteine residues in the first
and second extracellular domains.

Pathology
TNF is a key mediator in the inflammatory response, with several
activities including increased expression of adhesion molecules,
induction of cytokine secretion, and activation of leucocytes. TNF
Fig. 12.12.2.1 Typical erythematous erysipelas-​like rash in a man with receptor 1 (TNFR1) is a member of the death domain superfamily
familial Mediterranean fever. and comprises an extracellular region containing four cysteine-​rich
domains, a transmembrane domain, and an intracellular death do-
Clinical investigation main. Binding of TNF results in trimerization of the receptor and
Acute attacks are accompanied by a number of laboratory abnor- activation of NF-​κB, with downstream induction of inflammation
malities including neutrophilia, raised ESR, and a dramatic acute or apoptosis. Under normal circumstances, TNF signalling is ter-
phase response. Investigations may be required to exclude other minated by cleavage of the extracellular domain; this results in the
potential causes of symptoms but, in general, imaging by radiog- release of soluble TNFR1 into the plasma, competitively inhibiting
raphy, ultrasonography, or echocardiography during acute attacks the binding of circulating TNF to cell surface receptors.
is unrewarding. The mechanisms by which heterozygous TRFRSF1A mutations
The results of genetic testing must be interpreted with care, since cause TRAPS are still unclear, and may well vary according to the
some individuals with paired pathogenic MEFV mutations remain specific mutation. Postulated explanations have included defective
completely healthy, and others with apparent carrier status develop TNFR1 shedding from the cell surface, TNF-​induced apoptosis, NF-​
classical FMF. Furthermore, MEFV spans 10 exons, and most diag- κB activation, aberrant activation of c-​Jun N-​terminal kinase (JNK)
nostic laboratories offer only limited screening. However, in classical and p38 mitogen-​activated protein kinases (MAPK), and mitochon-
populations, the absence of a mutation in exon 10 makes a diagnosis drial reactive oxygen species inducing proinflammatory cytokine
of FMF unlikely. production. Recent work has focused on aberrant trafficking of the
variant protein inducing an unfolded protein response and endo-
Treatment plasmic reticulum stress with production of reactive oxygen species.
Supportive treatment, including analgesia, may be required in acute These intracellular stress responses appear to be mediated by inositol-​
attacks, but the mainstay of therapy in FMF is prophylaxis with requiring enzyme 1α (IRE1α), protein kinase-​like endoplasmic re-
colchicine, a serendipitous discovery made by Goldfinger in 1972. ticulum kinase (PERK), and activating transcription factor 6 (ATF6).
Continuous treatment with colchicine 1 to 2 mg daily prevents or
substantially reduces the symptoms of FMF in at least 95% of cases. Epidemiology
Recent data also suggest that colchicine acts by a number of mech- TRAPS was first described in 1982, somewhat tongue-​in-​cheek,
anisms including competition with pyrin for cleavage by caspase 1 as ‘familial Hibernian fever’, reflecting a preponderance of pa-
thereby reducing the effect of N-​terminal cleavage pyrin in enhan- tients from Ireland and Scotland in early reports. It is now clear
cing NF-​κB activation in FMF. that TRAPS occurs in diverse populations, including white, Jewish,
Long-​term use of colchicine is advisable in every patient with FMF Arab, and Central American populations, but the disease is rare with
and mandatory in those with AA amyloidosis. Although colchicine an estimated prevalence of 1 to 2 per million. Males and females are
is extremely toxic in large overdose, the small regular doses required affected equally and the median age at presentation is 4 years. Most
for the treatment of FMF are very well tolerated. Particularly at dose mutations are associated with high penetrance, but one variant that
initiation colchicine may cause diarrhoea which often responds to a can be associated with TRAPS (R92Q) is present in approximately
lactose-​free diet. Despite theoretical concerns about antimitotic po- 2% of healthy chromosomes, and is thus variously regarded as a low-​
tential, large cohort studies are very reassuring about the use of col- penetrance mutation or polymorphism.
chicine throughout conception and pregnancy. The concentration of
colchicine in breast milk is sufficiently low to permit breastfeeding. Clinical features
Acute initiation or increase of the dose of colchicine does not usually Attacks of TRAPS are far less distinct than in FMF, sometimes lasting
ameliorate acute attacks. many weeks, and almost one-​third of patients have fairly continuous
In the few patients who are genuinely resistant to colchicine, symptoms. Approximately one-​third of patients with pathogenic
there have been reports of benefit in such patients following treat- mutations report no family history. This is the case in more than
ment with IL-​1 blocking agents and a number of small trials have 80% of patients carrying R92Q which tends to be associated with
confirmed this. milder disease and older age at presentation. Symptoms are rather
 12.12.2 Hereditary periodic fever syndromes 2213

variable: more than 95% of patients experience fever and 80% com- minor trauma, surgery, or stress. Fever, cervical lymphadenopathy,
plain of arthralgia or myalgia; abdominal pain occurs in 75%, and and abdominal pain with vomiting and diarrhoea are typical. Other
a rash (often overlying areas of myalgia) occurs in 50%. Other fea- common symptoms include headache, arthralgia, large joint arth-
tures include pleuritic pain, lymphadenopathy, conjunctivitis, and ritis, erythematous macules and papules, and aphthous ulcers. Rare
periorbital oedema. There are also reports of central nervous system complications include intellectual impairment, epilepsy, and retin-
manifestations resembling multiple sclerosis and TNFRSF1A R92Q itis pigmentosa. The disease sometimes ameliorates in early adult life
confers a weak but significant genetic predisposition to multiple and older patients may remain free of symptoms for years.
sclerosis.
Clinical investigation
Clinical investigation Diagnosis is supported by the presence of mevalonic acid in the
Symptoms are almost universally accompanied by a very marked urine during clinical attacks when there is an elevated acute phase
acute phase response. Genetic testing is pivotal in establishing the response. Serum immunoglobulin (Ig)-​D and IgA concentration
diagnosis. Interpretation of the significance of R92Q remains diffi- are persistently elevated in 80% of patients although, particularly
cult and depends heavily on the clinical picture. in the very young, this is nondiscriminative with respect to other
autoinflammatory diseases. A mutation in both alleles of MVK can
Treatment be identified in most patients, more than 80% of whom have the
Despite high hopes for anti-​TNF biological agents, their effect in most common V337I variant.
the treatment of TRAPS has proved disappointing in many patients.
Acute attacks can be suppressed with corticosteroids, but pro- Treatment
longed treatment may be required at potentially harmful doses. IL-​1 Treatment for milder disease remains largely supportive, including
blockade is the most effective current option in severe TRAPS and in nonsteroidal anti-​inflammatory drugs (NSAIDs) and on-​demand
the majority of cases induces a complete disease response. corticosteroids. Colchicine and thalidomide have no convin-
cing benefit. There is no evidence of benefit from treatment with
simvastatin, an inhibitor of 3-​hydroxy-​3-​methylglutaryl coenzyme
Mevalonate kinase deficiency A (HMG-​CoA) reductase (the enzyme before MKD in the chol-
esterol biosynthetic pathway). There are reports of responses to
Genetics etanercept, tocilizumab, and anti-​IL-​1 agents; the latter are currently
MKD is an autosomal recessive disease caused by mutations in the the most widely used biologics. In severe early-​onset disease, bone
mevalonate kinase gene (MVK) on the long arm of chromosome marrow transplantation can be curative.
12. To date, 160 MKD-​associated mutations have been described,
spanning exons 2 to 11, the most common of which encode MVK
variants V377I and I268T. The carriage frequency in the population Cryopyrin-​associated periodic syndromes
of the Netherlands, in which MKD is most prevalent, is estimated
to be 1 in 65. Genetics
CAPS comprises a spectrum of disease associated with mutations
Pathology in the gene NLRP3/​CIAS1 on chromosome 1q44 that encodes
The MVK mutations associated with MKD result in 85 to 95% de- the death domain protein variously known as NLRP3 (previously
ficiency in mevalonate kinase activity. This enzyme is involved in NALP3) and cryopyrin. Dominant inheritance is evident in about
cholesterol, farnesyl, and isoprenoid biosynthesis. It is not yet known 75% of patients with MWS and FCAS, whereas CINCA, the most
how mevalonate kinase deficiency causes recurrent inflammation, severe phenotype, is usually due to a de novo mutation. More than
although there is speculation that reduced protein isoprenylation 140 single amino acid substitutions have been reported; the majority
causes defective lymphocyte apoptosis. Other mutations in MVK in exon 3. Somatic mosaicism is increasing recognized in both early-​
result in even greater reduction in enzyme activity, and cause the and later-​onset disease. The relationship between mutation and clin-
much more severe disease known as mevalonic aciduria. ical phenotype can differ between individuals, even within a family,
although some mutations are associated with a greater risk of neuro-
Epidemiology logical damage.
MKD is most prevalent in the Netherlands, where it was first de-
scribed as HIDS in 1984. It has subsequently been reported in other Pathology
populations, including Arabs and South-​East Asians, though is NLRP3 is expressed in peripheral blood leucocytes and chondro-
least rare among northern European white populations. The disease cytes, and encodes a death domain protein that contains a pyrin do-
usually presents in the first year of life and occurs equally in both main, a nucleotide-​binding site domain, and a leucine-​rich repeat
sexes. There are about 200 patients with MKD on the Dutch disease motif. Following recognition and binding, via its leucine-​rich repeat,
registry, and only some dozens recognized in the United Kingdom. of an intracellular pathogen-​associated molecular pattern, NLRP3
associates with other members of the death domain superfamily to
Clinical features form a multimeric cytosolic assembly, the inflammasome. This re-
Symptoms are episodic and are often well circumscribed. Attacks are sults in activation of caspase 1, which processes pro-​IL-​1 to produce
irregular, usually last 4 to 6 days, and can be provoked by vaccination, the active cytokine; it also up-​regulates NF-​κB expression, resulting
2214 section 12 Metabolic disorders

in increased IL-​1 gene expression. IL-​1 is a major proinflammatory

cytokine involved in mediating local and systemic responses to in-
fection and tissue injury. The remarkable response to IL-​1 receptor
blockade in CAPS confirms that the clinical features are substan-
tially mediated by IL-​1.

Epidemiology
So far, most reported patients have European ancestry, but CAPS
occurs worldwide. Onset of disease is in early infancy, and there is
no sex bias.

Clinical features
FCAS was first described in 1940 as recurrent episodes of cold-​
induced fever, arthralgia, red eye (with inflammation at multiple
levels), and rash. MWS was described in 1962 as a much more per-
sistent urticaria-​like rash, conjunctivitis, arthralgia, and fever, com-
plicated by progressive sensorineural deafness and a high risk of AA
amyloidosis (Fig. 12.12.2.2). CINCA was described as a sporadic se-
vere inflammatory disorder that presents in the neonatal period with
involvement of many organs including the skin, skeletal system, and
central nervous system. Bony overgrowth and premature ossification
may occur, particularly in the skull and knees, and chronic aseptic
meningitis can result in severe developmental delay, optic atrophy,
and deafness. It is now evident that FCAS, MWS (Fig. 12.12.2.3), and
CINCA represent a spectrum of a single disease entity. Fig. 12.12.2.3 Urticarial rash of Muckle–​Wells syndrome. These lesions,
accompanied by conjunctivitis, arthralgia, and fever, appeared daily in
Clinical investigation the early evenings.

There is usually an acute phase response, and often leucocytosis and

thrombocytosis that can vary substantially between measurements,
and may not at times be present in some patients at the milder end of
Other hereditary periodic fever syndromes
the disease spectrum (i.e. with FCAS and mild MWS). Audiometric
evidence of sensorineural hearing loss should be sought, and charac- Pyogenic arthritis, pyoderma gangrenosum,
teristic bony abnormalities may be radiologically evident in CINCA. and acne (PAPA) syndrome
Features consistent with chronic meningitis may be evident on This autosomal dominant disease is caused by mutations in
lumbar puncture, fundoscopy, and MRI. A mutation in NLRP3 can CD2BP1/​PTSTPIP1, the gene encoding CD2 binding protein 1. The
be readily identified in most patients with FCAS and MWS, though underlying pathogenesis remains poorly understood, although
about half of those with CINCA are somatic mosaics. there is evidence that CD2 binding protein 1 interacts with the pyrin
pathway. It is characterized by early-​onset recurrent sterile arthritis
Treatment typically occurring after minor trauma, severe cystic acne, and pyo-
Treatment with anti-​IL-​1 agents produces rapid and often complete derma gangrenosum. Penetrance seems variable and asymptomatic
clinical and serological remission of CAPS. Three IL-​1 inhibitors, gene carriage is recognized. There is no proven treatment, responses
anakinra, canakinumab and rilonacept, are licensed for the treat- to steroids are usually partial, and early reports suggest variable re-
ment of CAPS. There is hope that early treatment may prevent sponses to anti-​TNF or anti-​IL-​1 agents. In general, skin disease is
neurological and skeletal abnormalities. more treatment refractory than the arthritis.

Blau’s syndrome
This was first described in 1985 as an autosomal dominant syn-
drome of sarcoid-​like granulomatous infiltration causing a triad of
arthritis, dermatitis, and uveitis. Sporadic disease in the absence
of a family history is sometimes called early-​onset sarcoidosis. The
joint involvement is usually synovitis or tenosynovitis, sometimes
causing camptodactyly (fixed flexion deformity of the proximal
interphalangeal joint, usually most marked in the little finger).
The rash is characteristically tan coloured and can be ichthyotic.
Approximately a third of patients develop visual impairment from
panuveitis and its complications. Other recognized features in-
Fig. 12.12.2.2 Typical rash of mevalonate kinase deficiency. These clude fever, erythema nodosum, granulomatous hepatitis, and large
lesions appear during febrile attacks. vessel vasculitis.
 12.12.2 Hereditary periodic fever syndromes 2215

swelling. Long-​ term complications of growth retardation and

flexion contractures are well recognized. The disease was found to
be due to mutations in LPIN2, a widely expressed gene thought to
play a role in lipid metabolism, in 2005. NSAIDs and corticoster-
oids can provide symptomatic relief. Recent case reports suggest
IL-​1 blockade may be effective although the long-​term effect on
dyserythropoiesis is not yet known

Deficiency of interleukin-​36 receptor

antagonist (DITRA)
This rare disease is a recessively inherited autoinflammatory disease
due to mutations in IL36RN resulting in unregulated signalling of
IL-​36α, -​β, and -​γ. It is characterized by recurrent episodes of a gen-
eralized sterile pustular psoriasis accompanied with neutrophilia, a
Fig. 12.12.2.4 Camptodactyly due to Blau’s syndrome. marked acute phase response, and fever. Age at onset varies from
childhood to the sixth decade. Episodes may be precipitated by
stress, pregnancy, or initiation or withdrawal of drugs and can be
life-​threatening. There is no established treatment but case reports
Presentation is usually before the age of 5 years and is caused suggest anakinra has been beneficial.
by missense mutations in NOD2/​CARD15, another member of the
death domain superfamily. NOD2 mutations have also been im- Chronic atypical neutrophilic dermatosis
plicated in familial Crohn’s disease but the gain-​of-​function mu- with lipodystrophy and elevated temperature
tations in Blau’s syndrome occur in the NACTH domain whereas (CANDLE syndrome) or proteasome-​associated
in Crohn’s disease, there are loss-​of-​function mutations in the autoinflammatory syndrome (PRAAS), or joint
LRR region. The NOD2 mutations associated with Blau’s syn- contractures, muscular atrophy, microcytic anaemia,
drome have not been found in adults with sarcoidosis. Most cases and panniculitis-​induced lipodystrophy (JMP)
are steroid responsive but steroid-​sparing agents and increas- This recessive disease is characterized by a neonatal onset of inter-
ingly anti-​TNF therapy may be required in more severe disease mittent fevers, swollen violaceous eyelids, thicken lips, erythema-
(Fig. 12.12.2.4). tous rash with a mixed myeloid, neutrophilic, and histiocytic
infiltrate on skin biopsy, arthralgia/​ arthritis, and progressive
NALP12-​associated periodic fever syndrome lipodystrophy with later-​onset joint contractures and raised acute
This autosomal dominant syndrome was described in 2008 in fam- phase response. Patients have been found to carry PSM8 mutations.
ilies from the Caribbean. Patients presented in infancy or the neo- This encodes an inducible subunit of the immune proteosome and
natal period with a syndrome with some features of cold induction, deficiency is postulated to result in failure of proteolysis resulting
fever, arthralgia and myalgia, urticarial rash, and sensorineural deaf- in accumulation of damaged protein and intracellular stress. This
ness. The nonsense and splice site mutations identified in NALP12 appears to result in dysregulation of the interferon signalling
appear to reduce its inhibitory effect on NF-​κB signalling. There is pathway and early reports suggest treatment with Janus kinase in-
no established treatment. hibitors may be useful.

Deficiency of the IL-​1 receptor antagonist (DIRA) IL-​10 receptor deficiency

This autosomal recessive disease was first described in 2009. It is due This is also known as early-​onset inflammatory bowel disease and
to mutations in the IL1RN gene that result in total deficiency of IL-​1 presents with enterocolitis with perianal fistulae, recurrent fever,
receptor antagonist. The disease has been reported in only a handful arthritis, and folliculitis in the first 3 months of life. It is a reces-
of families of various ethnicities including Northern Europe and sive disease caused by mutations in IL10RA, IL10RB, or IL10 re-
Central America. The disease presents in the immediate neonatal sulting in decreased IL-​10 signalling and macrophage activation.
period with a pustular rash, joint swelling, multifocal osteitis of the Conventional treatment of inflammatory bowel disease is ineffective
ribs and long bones, heterotopic ossification, and periarticular soft and bone marrow transplantation has been curative.
tissue swelling. Treatment is replacement of the missing protein with
recombinant IL-​1Ra (anakinra), and good responses have been re- Autoinflammation and PLCγ2-​associated antibody
ported in all patients treated so far. deficiency and immune dysregulation (APLAID)
Only a single kindred is known with this autosomal dominant
Majeed’s syndrome disease caused by gain-​of-​function mutations in PLCG2 which
This autosomal recessive syndrome characterized by chronic encodes phospholipase Cγ2 (PLCγ2). This enzyme is involved
recurrent multifocal osteomyelitis (CRMO), congenital in several immunological pathways and in APLAID it may acti-
dyserythropoietic anaemia, and inflammatory dermatosis was first vate the NLRP3 inflammasome. Patients have low IgA and IgM
described in 1989 in consanguineous Arab kindred. Onset is usu- and immunodeficiency with recurrent sinopulmonary infections.
ally in the neonatal period and attacks consist of several days of Autoinflammatory features include blistering rash, interstitial
fever, severe pain, and the appearance of periarticular soft tissue pneumonitis, ocular inflammation, and arthralgia. Deletions in
2216 section 12 Metabolic disorders

PLCG2 are known to cause a different syndrome, PLCγ2-​associated 2.5 years and 83% of children presented before their fifth birthday
antibody deficiency and immune dysregulation (PLAID) with an with a slight male preponderance of 62%. The ‘acronym symptoms’
autoimmune phenotype. of aphthous oral ulcers, pharyngitis, and cervical lymphadenopathy
are frequently not all present during a single attack. During attacks,
Haem-​oxidized IRP2 ubiquitin ligase 1 deficiency the acute phase response is often strikingly elevated. In general the
(HOIL-​1 deficiency) prognosis is good and most children will outgrow their symptoms
This fatal autosomal recessive disease has been reported in two fam- within a decade.
ilies and is due to loss-​of-​function mutations in HOIL1 also known For many clinicians, the strongest diagnostic pointers are the
as RBCK. This encodes a component of the linear ubiquitin chain extreme regularity of attacks (although attacks may be missed
assembly complex, which adds polyubiquitin chains to substrate particularly in the summer) and the response to a small dose of cor-
proteins and plays a role in NF-​κB induction. The phenotype is a ticosteroids. Before diagnosis, recurrent infections and cyclic neu-
combination of severe immunodeficiency and autoimmunity with tropenia must be excluded.
recurrent fever, systemic inflammation, hepatosplenomegaly, and The first-​line treatment of PFAPA is a single dose of corticosteroid
lymphadenopathy. The patients also developed amylopectinosis given at the start of the attack. Padeh et al. suggested that the dra-
resulting in skeletal and cardiac myopathy. All four affected indi- matic response to a single oral dose of corticosteroids is sufficiently
viduals died in childhood, cortisteroids were reported to be symp- unique to PFAPA syndrome that it could be used as a diagnostic
tomatically helpful. criterion. The H2 receptor antagonist cimetidine and colchicine have
been tried in PFAPA with variable reports of success. Tonsillectomy
Deficiency of ADA2 (DADA2) is the only treatment for which there is supportive evidence from
This was first described in 2014 as a monogenetic form of polyarteritis clinical studies. Tonsillectomy can be curative in PFAPA; in gen-
nodosa (PAN). It is a recessive disease caused by loss-​of-​function eral, more than 50% of children appear to have excellent long-​term
mutations in CECR1 encoding adenosine deaminase 2 (ADA2). results. However, these data may be biased since many centres se-
ADA2 is thought to be a growth factor for endothelial cells as well lectively refer children with persistently enlarged tonsils for surgery,
as leucocytes and deficiency appears to induce an inflammatory and it is possible that responses may occur preferentially in this
vasculopathy. Clinical manifestations include childhood systemic subgroup.
and local PAN, recurrent fever, mild immunodeficiency, livedo ra-
cemose, and early-​onset stroke. Treatment with anti-​TNF agents has Schnitzler’s syndrome
been reported to be effective and bone marrow transplantation has This was first reported in 1974 and is characterized by a chronic
been reported to induce clinical benefit and improve ADA2 levels. urticarial-​
like rash, a monoclonal IgM (IgM kappa in 85%)
A small study of fresh frozen plasma as a source of replacement gammopathy, and systemic inflammation usually presenting as
ADA2 in acute attacks was not supportive. fever. The median age at onset is 51 years and there is a slight
male preponderance. The monoclonal protein appears central
STING-​associated vasculopathy with onset to the pathogenesis although the mechanism remains unclear.
in infancy (SAVI) About a fifth of patients eventually progress to overt plasma cell
This autosomal dominant disease due to gain-​of-​function muta- malignancy. Chemotherapy has been used in the past but does
tions in TMEM173 (encoding the stimulator of interferon genes not appear to relieve the syndrome and should only be used
(STING)) was first described in 2014 and results in increased inter- for conventional haematological indications. The treatment of
feron 1 signalling. Fewer than 20 patients are known and the dis- choice for Schnitzler’s syndrome is IL-​1 blockade which is highly
ease is characterized by very early-​onset facial and digital rash with effective.
scarring, cartilage destruction, and capillaritis on biopsy. Other fea-
tures include failure to thrive, lymphadenopathy, fever, and intersti-
tial lung disease. There is no proven treatment but treatment with Differential diagnosis of the hereditary periodic
Janus kinase inhibitors seems rational based on the apparent role of fever syndromes
upregulated interferon signalling.
These diseases have a broad differential diagnosis, particularly
at first presentation, which is influenced by age and encompasses
Autoinflammatory diseases of unknown aetiology a vast spectrum of infectious, immune, and neoplastic disorders
(Table 12.12.2.2). Conversely, symptoms such as fever, arthralgia,
Periodic fever, aphthous stomatitis, pharyngitis, and and rashes in a patient known to have a hereditary periodic fever
adenitis (PFAPA) syndrome may also result from an alternative intercurrent disorder.
First described in 1987, the diagnosis is suggested by a recurrent fever
of early onset and one of the following associated symptoms: oral
aphthous ulcers, cervical lymphadenopathy, or pharyngitis, in the Prognosis and complications
absence of recurrent upper respiratory tract infections or cyclic
neutropenia. Characteristically the children are entirely well be- Although CINCA/​NOMID can be sufficiently severe to cause death
tween attacks. In a large case series, median age at presentation was within the first few decades, life expectancy among most patients
 12.12.2 Hereditary periodic fever syndromes 2217

Table 12.12.2.2 Differential diagnosis of inherited periodic fever syndromes

Abdominal pain and fever Thoracic pain and fever Arthritis and fever Fever, rash, and myalgia Nonhereditary periodic
fever syndromes
Acute surgical abdomen Myocardial infarction Septic arthritis Viral illness PFAPA (periodic fever,
aphthous stomatitis,
pharyngitis, and adenopathy)
Acute cholecystitis Pneumonia/​pleurisy Juvenile idiopathic arthritis Systemic lupus erythematosus Schnitzler’s syndrome
Pyelonephritis Pericarditis Rheumatic fever Cellulitis/​erysipelas
Pelvic inflammatory disease Pulmonary embolism Lyme disease Behçet’s disease
Endometriosis Palindromic arthritis Cyclic neutropenia
Mesenteric adenitis Crystalline arthritis (gout) and Malignancy
calcium pyrophosphate dihydrate
crystal deposition disease
Systemic vasculitis Adult-​onset Stills disease Dermatomyositis
and systemic-​onset juvenile
idiopathic arthritis
Hereditary or acquired Adult-​onset Stills disease
angio-​oedema (not and systemic-​onset juvenile
associated with fever) idiopathic arthritis

with hereditary recurrent fever syndromes is relatively good, and ex-

Likely future developments
cellent in those for whom there is now effective therapy. The most
serious and life-​threatening complication of these diseases generally
The recent elucidation of the pathogenesis of these diseases has led to
is AA amyloidosis.
major advances in their treatment, most notably in CAPS. It is likely
AA amyloidosis that continued studies will shed further light on aspects of the innate
immune system and inflammation generally, and on strategies for the
This usually presents with proteinuric kidney dysfunction. AA
treatment of TRAPS and MKD in particular. The clinical significance
amyloid fibrils are derived from the circulating acute phase protein
of low-​penetrance mutations and polymorphisms in the genes asso-
serum amyloid A protein (SAA), which is synthesized by hepato-
ciated with inherited periodic fever syndromes will be sought. CAPS
cytes under the transcriptional regulation of IL-​1, IL-​6, and TNFα.
provides a powerful model of IL-​1-​driven disease, and a uniquely in-
The terminology is either serum amyloid A protein or SAA. The
formative test bed for the early-​phase development of novel IL-​1 in-
circulating concentration of SAA in health is less than approxi-
hibitors that may have applications in many common inflammatory
mately 3 mg/​litre, but this can rise by up to 1000-​fold in the pres-
disorders, ranging from gout and rheumatoid arthritis to sepsis.
ence of inflammation. In chronic inflammatory diseases generally,
AA amyloidosis occurs in up to 5% of patients after a median dur-
ation of about 20 years, but is much more frequent among patients
with untreated inherited periodic fever syndromes. This may reflect FURTHER READING
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plasma concentrations of SAA, even when they seem clinically qui- Mediterranean fever: an overview. Ann Rheum Dis, 62, 916–​19.
escent. Before the widespread introduction of colchicine prophy- Canna SW, Goldbach-​ Mansky R (2015). New monogenic auto­
laxis, up to 60% of patients with FMF died of amyloidosis, and even inflammatory diseases—​a clinical overview. Semin Immunol, 37, 387–​94.
recently it was reported in 13% of a large Turkish series. The inci- Cowen EW, Goldbach-​Mansky R (2012). DIRA, DITRA, and new in-
dence of AA amyloidosis in TRAPS and MWS is approximately 25%, sights into pathways of skin inflammation: what’s in a name? Arch
Dermatol, 148, 381–​4.
but is less than 5% in MDK, perhaps because the disease often ameli-
Goldbach-​Mansky R, et al. (2006). Neonatal-​onset multisystem in-
orates in early adulthood.
flammatory disease responsive to interleukin-​ 1beta inhibition.
The natural course of AA amyloidosis is renal failure and early
N Engl J Med, 355, 581–​92.
death, but this can be prevented by treatment of the underlying Holzinger D, et al. (2015). From bench to bedside and back again: trans-
inflammatory disorder that substantially suppresses the produc- lational research in autoinflammation. Nat Rev Rheumatol, 10, 573–​85.
tion of serum amyloid A. Indeed, treatment such as colchicine Lachmann HJ, et al. (2007). Natural history and outcome in systemic
in FMF and anakinra in CAPS can halt further deposition of AA AA amyloidosis. N Engl J Med, 356, 2361–​71.
amyloid, facilitate gradual regression of existing deposits, and lead Lachmann HJ, et al. (2014). The phenotype of TNF receptor-​associated
to preservation or even improvement in renal function. Regular autoinflammatory syndrome (TRAPS) at presentation: a series of
long-​term measurement of serum amyloid A is vital in patients 158 cases from the Eurofever/​EUROTRAPS international registry.
with AA amyloidosis. Arthritis Rheum, 73, 2160–​7.
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Levy R, et al. (2015). Phenotypic and genotypic characteristics of cross-​polarized light, and the protein type can be identified by
cryopyrin-​associated periodic syndrome: a series of 136 patients immunostaining or proteomic analysis. Amyloid deposits always
from the Eurofever Registry. Ann Rheum Dis, 7411, 2043–​9. contain a nonfibrillar plasma glycoprotein, serum amyloid P com-
Liu Y, et al. (2012). Mutations in proteasome subunit β type 8 cause ponent, the universal presence of which is the basis for use of radio-
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Sönmez HE, et al. (2016). Familial Mediterranean fever: current per- prevalent type of systemic amyloidosis currently diagnosed. The fi-
spectives. J Inflamm Res, 17, 13–​20. brils consists of all or part of the variable (VL) domain of monoclonal
Twig G, et al. (2014). Mortality risk factors associated with familial immunoglobulin light chains. May complicate any B-cell dyscrasia
Mediterranean fever among a cohort of 1.25 million adolescents. but most cases are associated with otherwise ‘benign’ ‘monoclonal
Ann Rheum Dis, 73, 704–​9. gammopathy of undetermined significance’ (MGUS). Highly variable
Zhao Y, Shao F (2016). Diverse mechanisms for inflammasome sensing idiotypic disease but characteristic presentations include involve-
of cytosolic bacteria and bacterial virulence. Curr Opin Microbiol, ment of the heart (restrictive cardiomyopathy), kidneys (protein-
29, 37–​42.
uria, renal failure), gut (motility disorders, malabsorption), tongue
(macroglossia), and nerves (painful sensory polyneuropathy; auto-
nomic neuropathy). Treatment is with cytotoxic chemotherapy,
similar to that used in myeloma, aimed at suppression of the causa-
tive B-cell clone.
Transthyretin (ATTR) amyloidosis—caused by wild type trans­thyretin
(TTR) forming amyloid predominantly in the heart, mostly in eld-
12.12.3 Amyloidosis erly men. Previously diagnosed extremely rarely but shown by new
Mark B. Pepys and Philip N. Hawkins imaging methods to be much more common with prevalence lately
approaching that of AL amyloidosis, and potentially exceeding it in
future.
ESSENTIALS Hereditary systemic amyloidoses—include hereditary ATTR amyl-
oidosis caused by mutations in the TTR gene. Presents as progres-
Amyloidosis is the clinical condition caused by extracellular de- sive peripheral and autonomic neuropathy and varying degrees of
position of amyloid in the tissues. Amyloid deposits are composed visceral involvement (formerly known as familial amyloidotic poly-
of amyloid fibrils, abnormal insoluble protein fibres formed by neuropathy), and sometimes with predominant cardiomyopathy.
misfolding of their normally soluble precursors. About 30 different Reactive systemic (AA) amyloidosis—fibrils composed of AA pro-
proteins can form clinically or pathologically significant amyloid fi- tein derived from the acute phase protein, serum amyloid A protein
brils in vivo as a result of either acquired or hereditary abnormalities. (SAA). It can be a complication of any chronic inflammatory disorder
Small, focal, clinically silent amyloid deposits in the brain, heart, sem- (e.g. rheumatoid arthritis, Crohn’s disease) or chronic infections in
inal vesicles, and joints are a universal accompaniment of ageing. which SAA concentrations are persistently increased. Has become
Clinically important amyloid deposits usually accumulate progres- very rare in recent years due to improved management of chronic
sively, disrupting the structure and function of affected tissues and inflammation and infection. Usually presents with proteinuria and/or
lead inexorably to organ failure and death. There is no licensed treat- organomegaly (e.g. hepatosplenomegaly); nephrotic syndrome may
ment which can specifically clear amyloid deposits, but intervention develop before progression to end-stage renal failure.
which reduces the availability of the amyloid fibril precursor proteins
can arrest amyloid accumulation and may lead to amyloid regression
with clinical benefit.
Pathology—​amyloid fibrils of all types are similar: straight, rigid, and Introduction
nonbranching; of indeterminate length and 10–​15 nm in diameter;
and with their subunit proteins arranged in a stack of twisted anti-
Amyloidosis and amyloid deposits
parallel β-​pleated sheets. The fibrils bind Congo red dye producing
pathognomonic green birefringence when viewed in high-​intensity Amyloid deposits can be systemic, that is present anywhere in
the body. The predominant locations and most damaging clinical
 12.12.3 Amyloidosis 2219

effects can vary widely in different types of amyloidosis and in dif- Clinicopathological correlation
ferent individuals. In systemic amyloidosis the deposits can be in Although there are some correlations between fibril protein type
the extracellular space of any tissue and any organ except the brain, and clinical manifestations, there are also many forms of acquired
because the amyloid fibrils are derived from circulating, normally and hereditary amyloidosis in which there is little or no concord-
soluble, globular plasma proteins. There are also localised forms of ance between the fibril protein, or the genotype of its precursor,
amyloidosis in which the deposits are confined to a single tissue or and the clinical phenotype (Tables 12.12.3.1 and 12.12.3.2). There
organ system, such as the cerebral blood vessels walls in cerebral are evidently genetic and/​or environmental factors, distinct from
amyloid angiopathy or localised amyloid of the respiratory system the amyloid fibril protein itself, that determine whether, when,
or urogenital tract. Crucially, in all forms of amyloidosis, tissue and where clinically significant amyloid deposits form. The nature
damage and thus disease are directly caused by the amyloid de- of these important determinants of amyloidogenesis is obscure.
posits that disrupt normal tissue architecture and thus function. In Furthermore, the mechanisms by which amyloid deposition causes
contrast, the histopathology in some other diseases includes local disease are poorly understood. While a heavy amyloid load is in-
amyloid deposits, for example, the Aβ amyloid plaques in the brain variably a bad sign, there may be a poor correlation between the
in Alzheimer’s disease and islet amyloid in the islets of Langerhans local amount of amyloid and the level of organ dysfunction. Active
in the pancreas of patients with type 2 diabetes, but there is no direct deposition of new amyloid is often associated with accelerated de-
evidence that these deposits cause disease. They should therefore not terioration compared with stable, long-​standing deposits. Nascent
be included as types of amyloidosis. Similarly, microscopic amyloid or newly formed amyloid fibrils generated in vitro may also be cyto-
deposits are frequently present in the elderly, in the seminal vesicles toxic to cultured cells, whereas aged or ex vivo fibrils are generally
and the walls of large arteries, without evidence that they necessarily inert, but it is not known if or how this relates to effects in vivo.
cause disease. In most forms of systemic amyloidosis there is overwhelming evi-
Systemic amyloidosis causes about 1 in 1500 of all deaths in dence that tissue damage and resultant disease are caused by the
developed countries but this figure will likely rise as the true physical presence and accumulation of amyloid deposits, and not
prevalence of wild type ATTR amyloidosis is recognized and is a by cytotoxicity of the amyloidogenic proteins or their prefibrillar
serious and important disease because it is often difficult to diag- aggregates.
nose, it is usually fatal, and its management is complex and costly.
Most systemic amyloidosis is a complication of other underlying
primary conditions, which include monoclonal gammopathies of Clinical types of amyloidosis
all types, chronic inflammatory disorders, and dialysis for end-​
stage renal failure. Hereditary amyloidosis is very rare, except in Reactive systemic (AA) amyloidosis
a few geographic foci, but its diversity is remarkable. It is im-
portant because of its poor prognosis, the complexity of clinical Associated conditions
management, the difficult genetic issues involved, and its con- AA amyloidosis occurs in association with chronic inflammatory
siderable value as a model for understanding the pathogenesis of disorders, chronic local or systemic microbial infections, and, oc-
amyloid deposition. casionally, malignant neoplasms. In western Europe and the United

Table 12.12.3.1 Acquired amyloidosis syndromes

Clinical syndrome Fibril protein

Systemic AL amyloidosis, associated with immunocyte dyscrasia, myeloma, AL derived from monoclonal immunoglobulin light chains
monoclonal gammopathy, occult dyscrasia
Local nodular AL amyloidosis (skin, respiratory tract, urogenital tract, etc.) AL derived from monoclonal immunoglobulin light chains
associated with focal immunocyte dyscrasia
Reactive systemic AA amyloidosis, associated with chronic active diseases AA derived from SAA
Non-hereditary wild-type transthyretin amyloidosis Transthyretin derived from plasma transthyretin
Sporadic cerebral amyloid angiopathy Aβ derived from APP
Haemodialysis-​associated amyloidosis; localized to osteoarticular tissues β2-​microglobulin derived from high plasma levels
or systemic
Primary localized cutaneous amyloid (macular, papular) ? Keratin-​derived
Primary localized cutaneous amyloid (macular, papular) ? Keratin-​derived
Systemic ALECT2 amyloidosis causing renal dysfunction Leucocyte chemotactic factor 2
Ocular amyloid (cornea, conjunctiva) Not known
Orbital amyloid AL or AH derived from monoclonal Ig

AA, amyloid A; AH, monoclonal immunoglobulin heavy chain fragment; AL, monoclonal immunoglobulin light chain; ALECT2, leucocyte chemotactic factor 2
amyloid; APP, amyloid precursor protein; Ig, immunoglobulin; SAA, serum amyloid A protein.
2220 section 12 Metabolic disorders

Table 12.12.3.2 Hereditary amyloidosis syndromes

Clinical syndrome Fibril protein

Predominant peripheral nerve involvement, hereditary transthyretin amyloidosis Transthyretin variants (commonly Met30, >120 others
associated polyneuropathy (familial amyloid polyneuropathy). Autosomal dominant described)
Apolipoprotein A-​I N-​terminal fragment of Arg26 variant
Predominant cranial nerve involvement with lattice corneal dystrophy. Gelsolin, fragment of variants Asn187 or Tyr187
Autosomal dominant
Oculoleptomeningeal amyloidosis. Autosomal dominant Transthyretin variants
Non-​neuropathic, prominent visceral involvement. Autosomal dominant Apolipoprotein A-​I N-​terminal fragment of variants
Lysozyme variants
Fibrinogen α-​chain variants
β2-​microglobulin variant Asn76
Predominant cardiac involvement, no clinical neuropathy, hereditary Transthyretin variants
transthyretin amyloidosis associated cardiomyopathy. Autosomal dominant
Hereditary cerebral haemorrhage with amyloidosis (cerebral amyloid Cystatin C, fragment of variant Glu68
angiopathy). Autosomal dominant:
Icelandic type (major asymptomatic systemic amyloid also present)
Dutch type Aβ derived from APP variant Gln693
Cutaneous deposits (bullous, papular, pustulodermal) Not known

Amino acids: Arg, arginine; Asn, asparagine; Gln, glutamine; Glu, glutamic acid; Met, methionine; Tyr, tyrosine.
Aβ, amyloid β; APP, amyloid precursor protein; SAA, serum amyloid A protein.

States of America, the most frequent predisposing conditions are related connective tissue diseases, and in ulcerative colitis in which
idiopathic rheumatic diseases, notably including rheumatoid arth- there is a blunted acute phase response of serum amyloid A protein,
ritis and juvenile idiopathic arthritis (Box 12.12.3.1). AA amyloid- the precursor of AA amyloid fibrils. Tuberculosis and leprosy are
osis has become increasingly rare, reflecting improved treatment of important causes of AA amyloidosis where these infections remain
chronic inflammatory disorders, and for reasons that are not clear, the endemic. Chronic osteomyelitis, bronchiectasis, chronically infected
incidence is lower in the United States of America than in Europe. burns, and decubitus ulcers, as well as the chronic pyelonephritis
Amyloidosis is exceptionally rare in systemic lupus erythematosus, of paraplegic patients, are other well-​recognized associations (Box
12.12.3.1). Hodgkin’s disease and renal carcinoma, which often cause
Box 12.12.3.1 Conditions associated with reactive systemic fever, other systemic symptoms, and a major acute phase response,
amyloid A amyloidosis are the malignancies most commonly associated with systemic AA
amyloidosis. Intriguingly, about 10% of patients with AA amyloidosis
Chronic inflammatory disorders do not have a clinically obvious chronic inflammatory disease, and
• Rheumatoid arthritis may erroneously be assumed to have AL amyloidosis. The commonest
• Juvenile idiopathic arthritis
identifiable pathologies in such cases in our own experience have been
• Ankylosing spondylitis
previously undiagnosed inherited periodic fever syndromes and cyto-
• Psoriasis and psoriatic arthropathy
• Reiter’s syndrome
kine-​secreting Castleman’s disease tumours of the solitary plasma cell
• Adult Still’s disease type, located in either the mediastinum or the gut mesentery.
• Behçet’s syndrome
Clinical features
• Crohn’s disease
• Hereditary periodic fever syndromes AA amyloid involves the viscera, but may be widely distributed
without causing clinical symptoms. More than 90% of patients present
Chronic microbial infections
with nonselective proteinuria resulting from glomerular deposition,
• Leprosy
• Tuberculosis and nephrotic syndrome may develop before progression to end-​
• Bronchiectasis stage renal failure. Haematuria, isolated tubular defects, nephrogenic
• Decubitus ulcers diabetes insipidus, and diffuse renal calcification rarely occur. Kidney
• Chronic pyelonephritis in paraplegics size is usually normal, but may be enlarged, or, in advanced cases,
• Osteomyelitis reduced. End-​stage chronic renal failure is the cause of death in 40
• Whipple’s disease to 60% of cases, but acute kidney injury may be precipitated by hypo-
Neoplasms
tension and/​or salt and water depletion following surgery, excessive
• Castleman’s disease use of diuretics, or intercurrent infection. The second most common
• Hodgkin’s disease presentation is with organ enlargement, such as hepatosplenomegaly
• Renal carcinoma or thyroid goitre, with or without overt renal abnormality, but in any
• Carcinomas of gut, lung, and urogenital tract case, amyloid deposits are almost always widespread at the time of
• Basal cell carcinoma presentation. Involvement of the heart and gastrointestinal tract is
• Hairy cell leukaemia frequent, although the former rarely causes functional impairment.
 12.12.3 Amyloidosis 2221

AA amyloidosis may become clinically evident early in the course and in up to 50% of these patients it is fatal. Other cardiac presenta-
of associated disease, but the incidence increases with the duration tions include arrhythmias and angina. Measurement of circulating
of the primary condition. The mean duration of chronic rheumatic brain natriuretic peptide (BNP) or its precursor N-​ terminal-​
diseases, such as rheumatoid arthritis, ankylosing spondylitis, or proBNP provide a sensitive index of cardiac dysfunction in cardiac
juvenile rheumatoid arthritis, before amyloid is diagnosed is 12 to AL amyloidosis, and often show rapid improvement when produc-
14 years, although they can present much sooner. For most patients, tion of the aberrant clonal light chain is substantially suppressed
the prognosis is closely related to the degree of renal involvement and by cytotoxic chemotherapy. This suggests that amyloidogenic light
the effectiveness of treatment for the underlying inflammatory con- chains, perhaps in an aggregated prefibrillary form, may them-
dition. In the presence of persistent uncontrolled inflammation, 50% selves have intrinsic cardiotoxicity, in addition to their deposition
of patients with AA amyloidosis die within 5 years of diagnosis; how- as amyloid fibrils. Renal AL amyloidosis has the same manifest-
ever, if the acute phase response can be consistently suppressed, pro- ations as renal AA amyloidosis, but the prognosis is worse. Gut in-
teinuria can cease, renal function can be retained, and the prognosis volvement may cause disturbances of motility (often secondary to
is much better. The availability of chronic haemodialysis and trans- autonomic neuropathy), malabsorption, perforation, haemorrhage,
plantation prevents early death from uraemia per se, but amyloid de- or obstruction. Macroglossia occurs rarely, but is almost pathogno-
position in extrarenal tissues may be responsible for a less favourable monic. Hyposplenism sometimes occurs in both AA and AL amyl-
prognosis than for some other causes of end-​stage renal failure. oidosis. Painful sensory polyneuropathy, with early loss of pain and
temperature sensation, followed later by motor deficits, is seen in
Amyloidosis associated with immunocyte 10 to 20% of cases, and carpal tunnel syndrome in 20%. Autonomic
dyscrasia: monoclonal immunoglobulin neuropathy leading to orthostatic hypotension, impotence, and
light chain (AL) amyloidosis gastrointestinal disturbances may occur alone or together with the
Associated conditions peripheral neuropathy, and has a very poor prognosis. Skin involve-
ment takes the form of papules, nodules, and plaques, usually on
AL amyloidosis may complicate almost any dyscrasia of cells of the face and upper trunk, and involvement of dermal blood vessels
the B-​lymphocyte lineage, including multiple myeloma, malignant results in purpura, occurring either spontaneously or after minimal
lymphomas, and macroglobulinaemia, but most cases develop on a trauma, and is very common. Articular amyloid is rare, but may
background of monoclonal gammopathy of undetermined signifi- mimic acute polyarticular rheumatoid arthritis, or it may present
cance. Amyloidosis occurs in up to 10% of cases of myeloma, in a as asymmetrical arthritis affecting the hip or shoulder. Infiltration
lower proportion of other malignant B-​cell disorders, and about 2% of the glenohumeral joint and surrounding soft tissues occasionally
of patients with monoclonal gammopathy of undetermined signifi- produces the characteristic ‘shoulder pad’ sign. A rare but serious
cance, which are, of course, much more common than myeloma. manifestation of AL amyloidosis is an acquired bleeding diathesis
A monoclonal paraprotein or abnormal serum free light chain that may be associated with deficiency of factor X, and sometimes
concentration can be detected in the serum of most patients with also factor IX, or with increased fibrinolysis. It does not occur in
AL amyloidosis, confirming a monoclonal gammopathy. Subnormal AA amyloidosis, although in both AL and AA disease there may be
levels of some or all serum immunoglobulins, or increased numbers serious bleeding in the absence of any identifiable coagulation factor
of marrow plasma cells may provide less direct clues to the under- deficiency due to widespread vascular amyloid deposits.
lying aetiology. Until recently it has been the practice to diagnose ap-
parently primary cases of amyloidosis, with no previous predisposing Senile amyloidosis
inflammatory condition or family history of amyloidosis, as AL type Some amyloid is seen in all autopsies on individuals over 80 years
by exclusion. However, it has now been recognized that autosomal of age, but it is not known whether this contributes to the ageing
dominant, hereditary non-​neuropathic amyloidosis, particularly that process or whether it is an epiphenomenon that becomes clinically
caused by variant fibrinogen α-​chain, may be poorly penetrant and important only when it is extensive.
of late onset, so there may be no family history. The coincident oc-
currence of a monoclonal gammopathy, which occurs in more than Wild-​type transthyretin (cardiac) amyloidosis
10% of the healthy older population, may then be gravely misleading, Up to 25% of older people have systemic deposits of wild-​type
and it is essential to exclude by genotyping all known amyloidogenic transthyretin amyloid involving the walls of the heart and blood ves-
mutations, and to seek positive immunohistochemical or proteomic sels, smooth and striated muscle, fat tissue, renal papillae, and al-
identification of the amyloid fibril protein in all cases. veolar walls. In contrast to most other forms of systemic amyloidosis
(including hereditary transthyretin amyloid caused by point mu-
Clinical features tations in the transthyretin gene), clinical manifestations are usu-
AL amyloidosis occurs equally in men and women, usually over the ally restricted to the heart and carpal tunnel syndrome. The brain
age of 50 years, but occasionally in young adults. It has a lifetime is not involved. The typical clinical picture of progressive restrictive
incidence (and is the cause of death) of between 0.5 and 1 in 1000 cardiomyopathy is usually fatal within 5 years. The isoleucine 122
individuals in the United Kingdom. The clinical manifestations are variant of transthyretin, which occurs in about 4% of black individ-
protean, as virtually any tissue other than the brain may be directly uals of African ethnicity, is associated with a greatly increased risk
involved. Uraemia, heart failure, or other effects of amyloidosis usu- of cardiac transthyretin amyloidosis, the phenotype of which is in-
ally cause death within 2 years of diagnosis, unless the underlying distinguishable from the wild-​type form. It is likely that senile car-
B-​cell clone is effectively suppressed. diac amyloidosis is substantially underdiagnosed and may account
The heart is affected in 90% of patients with AL amyloidosis. In for many cases of cardiac failure associated with preserved ejection
30% of these, restrictive cardiomyopathy is the presenting feature fraction in the elderly.
2222 section 12 Metabolic disorders

Senile focal amyloidosis States of America and a corresponding proportion of other Western
Microscopic and clinically silent amyloid deposits of different fibril populations. It is generally a disease of older people, and its prevalence
types, localized to particular tissues, are very commonly found in older is therefore increasing. The clinical differential diagnosis of senile de-
people. Deposits of β-​protein (Aβ, see ‘Alzheimer’s disease’) as amyloid mentia and the positive identification of Alzheimer’s disease are diffi-
in cerebral blood vessels and intracerebral plaques seen in normal older cult and often of limited precision in life. However, intracerebral and
brains may or may not have been the harbinger of Alzheimer’s disease cerebrovascular amyloid deposits are hallmarks of the neuropatho-
had the patient survived long enough. Amyloid deposits composed of logical diagnosis and are detectable by PET imaging with radionuclide-​
apolipoprotein A-​I are present in most osteoarthritic joints at surgery labelled ligands specific for amyloid fibrils composed of β-​protein (Aβ).
or autopsy, usually in close association with calcium pyrophosphate The Alzheimer’s disease Aβ protein is a 39-​to 43-​residue cleavage
deposits, and affect the articular cartilage and joint capsule. However, product of the large amyloid precursor protein. The vast majority of
the significance of this age-​associated articular amyloid, the amount cases of Alzheimer’s disease are sporadic, but there are also families
of which is correlated with neither the presence nor clinical severity of with an autosomal dominant pattern of inheritance and usually early
osteoarthritis, is not known. The corpora amylacea of the prostate are onset. In about 20 families there are causative mutations in the APP
composed of β2-​microglobulin amyloid fibrils. Amyloid in the seminal gene for amyloid precursor protein on chromosome 21, and most
vesicles is derived from semenogelin I, an exocrine secretory product other kindreds have mutations in the genes for presenilin 1 (chromo-
of the vesicle cells. Isolated deposits of cardiac atrial amyloid consist of some 14) and presenilin 2 (chromosome 1). All these mutations are
atrial natriuretic peptide. The focal amyloid deposits commonly pre- associated with increased production from amyloid precursor pro-
sent in atheromatous plaques of older subjects are of two types: con- tein of Aβ1–​42, the most amyloidogenic form of Aβ. Since all in-
taining fibrils either composed of medin, a fragment of lactadherin, or dividuals with Down’s syndrome (trisomy 21) develop Alzheimer’s
the N-​terminal fragment of apolipoprotein A-​I. disease if they survive into their 40s, there is evidently a close link
between amyloid precursor protein, Aβ overproduction, Aβ amyl-
Cerebral amyloid oidosis, and the pathogenesis of Alzheimer’s disease. However, it re-
The brain is a very common and important site of amyloid depos- mains unclear whether or how Aβ per se, or the amyloid fibrils that
ition (Box 12.12.3.2), although, possibly because of the blood–​brain it forms, contribute to the neuronal loss that underlies the dementia.
barrier, there are never any deposits in the cerebral parenchyma it- Synthetic Aβ fibrils formed in vitro are markedly cytotoxic, and
self in any form of acquired systemic visceral amyloidosis. However, cause the death of cultured cells by apoptosis and necrosis. Although
cerebrovascular transthyretin amyloid may occur in familial it is not clear to what extent these findings reflect phenomena that
amyloid polyneuropathy, although the serious clinical entity of may be responsible for neurodegeneration in vivo, there is increasing
oculoleptomeningeal amyloidosis is very rare and associated with evidence, from both transgenic mouse models of Alzheimer’s dis-
certain uncommon transthyretin variants. The major forms of brain ease and in vivo intracerebral injection of different molecular con-
amyloid are confined to the brain and cerebral blood vessels, with formations of Aβ, that small oligomeric prefibrillar aggregates of
the single exception of cystatin C amyloid in hereditary cerebral Aβ are associated with and cause cognitive dysfunction. There is
haemorrhage with amyloidosis, Icelandic type, in which there are controversy about the correlation between the severity of dementia
major, though clinically silent, systemic deposits. in Alzheimer’s disease and the extent of amyloid angiopathy and
plaques. Nevertheless, the fact that patients with Alzheimer’s dis-
Alzheimer’s disease ease caused by amyloid precursor protein and presenilin mutations
By far the most frequent and important type of amyloid in the brain is have exactly the same neuropathology as sporadic cases, including
that related to Alzheimer’s disease, which is the most common cause tangles, argues strongly that the amyloid precursor protein and Aβ
of dementia and affects more than 3 million individuals in the United pathway can be of primary pathogenetic significance.
In addition to the Aβ deposits in the brains of patients with
Alzheimer’s disease and Down’s syndrome, there are also exten-
Box 12.12.3.2 Cerebral amyloidosis sive ‘amorphous’ deposits throughout the brain. These do not stain
with Congo red, and are detectable only by immunohistochemical
• Age-​related amyloid angiopathy with or without intracerebral deposits
staining. Their significance is unknown. They apparently precede
(cerebral amyloid angiopathy)
• Hereditary amyloid angiopathy of meningeal and cortical vessels asso- the appearance of histochemically identifiable amyloid, but are
ciated with cerebral haemorrhage: not necessarily the precursor of it because they are present in areas
—​ Icelandic type (variant cystatin C) such as the cerebellum in which Aβ is never seen. The nonfibrillar,
—​ Dutch type (variant Aβ) nonamyloid protein apolipoprotein E is demonstrable in many
• Hereditary amyloid angiopathy affecting the entire central nervous amyloid deposits, including those of Alzheimer’s disease. The
system APOE4 gene (chromosome 19), encoding one of the three isoforms
• Alzheimer’s disease: sporadic, familial, or associated with Down’s of this apolipoprotein, is strongly associated with a predisposition to
syndrome
develop Alzheimer’s disease and with increased amounts of amyloid
• Cerebral amyloid associated with prion disease:
in the brain, but the underlying mechanisms are unknown.
—​ Sporadic spongiform encephalopathy, Creutzfeldt–​Jacob disease,
variant Creutzfeldt–​Jakob disease Another neuropathological feature of Alzheimer’s disease, and
—​ Familial prion disease, familial Creutzfeldt–​ Jacob disease, some other neurodegenerative conditions, is the neurofibrillary
Gerstmann–​Sträussler–​Scheinker syndrome atypical familial prion tangle located intracellularly within neuronal cell bodies and pro-
disease cesses. These tangles have a characteristic ultrastructural morph-
• Familial oculoleptomeningeal amyloidosis ology of paired helical filaments, and are composed of an abnormally
 12.12.3 Amyloidosis 2223

phosphorylated form of the normal neurofilament protein, tau. They plaques, without congophilic amyloid cores. Multi-​infarct dementia
bind Congo red and then give the pathognomonic green birefrin- occurs in survivors, but some patients become demented in the ab-
gence of amyloid when viewed in polarized light. Although their sence of stroke. Amyloid outside the brain has not been reported.
electron microscopic ultrastructure is distinctly different from that
of amyloid fibrils, the most recent review of amyloid nomenclature Cerebral amyloid associated with prion disease
includes them as amyloid. All extracellular and most intracellular The neuropathology of a group of progressive, invariably fatal
tangles are coated with serum amyloid P component. spongiform encephalopathies sometimes, but certainly not always,
includes intracerebral amyloid plaques. These diseases are trans-
Sporadic cerebral Aβ amyloidosis and cerebral missible and in some cases hereditary. The sporadic and familial
amyloid angiopathy Creutzfeldt–​ Jacob disease, the familial Gerstmann–​ Sträussler–​
At autopsy, up to 60% of the brains of nondemented older individuals Scheinker syndrome, and kuru are caused by prions (PrPSc), con-
contain Aβ amyloid in the cerebral blood vessels, and there may also formational isoforms of the normal physiological cellular prion
be focal intracerebral Aβ plaques. These deposits may or may not protein (PrPC). The human diseases are closely related to the animal
have been harbingers of Alzheimer’s disease, had the patients sur- diseases scrapie of sheep and goats, transmissible encephalopathy of
vived long enough, but are increasingly recognized as an important mink, elk, and male deer, and bovine spongiform encephalopathy.
cause of cerebral haemorrhage and stroke, to be distinguished from Variant Creutzfeldt–​Jacob disease is apparently the result of trans-
atherosclerotic cerebrovascular disease. Progressive deposition of mission of bovine spongiform encephalopathy to humans.
Aβ amyloid occurs in the walls of arteries of up to about 2 mm in The significance of amyloid per se in these disorders is not clear
diameter, arterioles, and capillaries in the cerebral cortex and lepto- because it is not always histologically detectable, and in some dis-
meninges. Deposits may less commonly occur in the cerebellum orders is not seen, for example, fatal familial insomnia and bovine
and brainstem. Cerebral amyloid angiopathy is a common cause of spongiform encephalopathy (which is apparently a result of the
intracerebral haemorrhage beyond the age of 60 years, which has a transmission of ovine scrapie to cattle). When scrapie or its human
very high mortality approaching 50%. Recognized consequences of counterparts are transmitted to experimental animals by inoculation
the deposits also include progressive cognitive impairment, which of affected brain tissue, the development of intracerebral amyloid
may be rapid, and transient neurological symptoms. depends on the strain of infectious agent and the genetic back-
Aβ amyloid deposition interferes with vascular structure resulting ground of the recipient. Even when amyloid is present in the brain it
in loss of smooth muscle cells, thickening of vessel walls, and lu- is not seen elsewhere (e.g. in the spleen), although the latter is a rich
minal narrowing, endothelial dysfunction and fragility that the ren- source of the infective agent. However, when the infective agent is
ders vessels susceptible to microaneurysm formation and bleeding. exhaustively and highly purified from brain or spleen it forms typ-
Advancing age and APOE genotype are the only known risk fac- ical congophilic amyloid fibrils composed of the proteinase-​resistant
tors for sporadic cerebral amyloid angiopathy. Polymorphisms in subunit PrPSc, and when amyloid deposits are present in affected
the APOE gene encoding the ε2 and ε4 isoforms are associated with brains they immunostain with antiprion antibodies.
greater risk of developing the disease and its severity, and individ- The amyloid fibril protein is thus directly related to the cause of
uals with both these alleles have the earliest onset of disease and the encephalopathy, but histologically demonstrable amyloid de-
greatest probability of recurrent stroke. The mechanism by which position is evidently not necessary for the expression of disease.
apolipoprotein E contributes to disease are not clear, but may in- Indeed, recent work in transgenic and knockout mouse strains
clude promoting Aβ amyloid deposition and inducing structural clearly demonstrates both that prion amyloid deposition is not a
changes in involved vessels. necessary condition for the development of transmissible spongi-
form encephalopathy, and that expression of the normal cellular
Hereditary cerebral haemorrhage with amyloidosis:
isoform, PrPC, is absolutely required. Neuronal damage may per-
hereditary cerebral amyloid angiopathy haps be caused by a cytotoxic interaction between prefibrillar PrPSc
Icelandic type (OMIM 604312) aggregates and the normal PrPC, or indeed by other mechanisms
Cerebrovascular amyloid deposits composed of a fragment of a gen- entirely. This is a different situation from the extracerebral amyl-
etic variant of cystatin C are responsible for recurrent major cere- oidosis, and from cystatin C and nonhereditary cerebral amyloid
bral haemorrhages starting in early adult life in members of families angiopathies, in which amyloid deposition is invariably present
originating in western Iceland. There is autosomal dominant in- when there is clinical disease, and is unequivocally the cause of
heritance and appreciable, but clinically silent, amyloid deposits tissue damage.
are present in the spleen, lymph nodes, and skin. There is no extra- Hereditary systemic amyloidosis
vascular amyloid in the brain, and the neurological deficits, often
including dementia, of surviving patients are compatible with their Hereditary transthyretin amyloidosis (OMIM 176300)
cerebrovascular pathology. Hereditary transthyretin amyloidosis is an autosomal dominant
­syndrome with onset at any time from the second decade onwards.
Dutch type (OMIM 605714)
It is characterized by progressive peripheral and autonomic neur-
In families originating from a small region on the coast of the opathy and varying degrees of visceral involvement especially af-
Netherlands the autosomal dominant inheritance of a genetic variant fecting the heart, the h vitreous of the eye, kidneys, thyroid, and
of Aβ, which is deposited as cerebrovascular amyloid, results in re- adrenals. There are usually amyloid deposits throughout the body
current normotensive cerebral haemorrhages starting in middle age. involving the walls of blood vessels and the connective tissue matrix;
There are also amorphous Aβ deposits in the brain and early senile the pathology is due to these deposits. Major foci exist in Portugal,
2224 section 12 Metabolic disorders

Japan, and Sweden but familial amyloid polyneuropathy has been far the most common variant is transthyretin isoleucine 122, which
reported in most populations throughout the world. There is con- occurs in 4% of African Americans and causes cardiac amyloidosis
siderable variation in the age of onset, rate of progression, and in- from the sixth decade onwards.
volvement of different systems, although within families the pattern
tends to be more consistent. There is remorseless progression over Familial Mediterranean fever (OMIM 249100)
5 to 15 years and the disorder is invariably fatal. Death results from Familial Mediterranean fever is an autosomal recessive
the effects and complications of peripheral and/​or autonomic neur- autoinflammatory disorder caused by mutations in the gene MEFV
opathy, or from cardiac or renal failure. on chromosome 16 that encodes a neutrophil-​specific protein of
Hereditary transthyretin amyloidosis is caused by mutations in unknown function called pyrin (see Chapter 12.12.2). The disease
the gene for the plasma protein transthyretin (formerly known as is characterized by recurrent episodes of fever, abdominal pain,
prealbumin). The most frequent of these worldwide causes a me- pleurisy, or arthritis, and predominantly occurs in non-​Ashkenazi
thionine for valine substitution at position 30 in the mature protein, Jews, Armenians, Anatolian Turks, and Levantine Arabs. Among
but more than 100 amyloidogenic mutations have been described; Sephardi Jews of North African origin, and in the other populations
substitution of alanine for threonine at position 60 is the most fre- (except Armenians and, to a lesser extent, Ashkenazi Jews), untreated
quent cause in the United Kingdom. There is often little correlation familial Mediterranean fever is eventually complicated in a high pro-
between the underlying mutation and the clinical phenotype, which portion of cases by typical systemic AA amyloidosis. Furthermore,
is evidently determined by other genetic and possibly also environ- some patients with familial Mediterranean fever present with AA
mental factors, although in a few cases certain mutations are uniquely amyloidosis before they have experienced any symptoms, and this
associated with particularly aggressive or relatively organ-​limited dis- is consistent with the recent finding that a substantial acute phase
ease. The amyloidogenic transthyretin mutations are not always pene- plasma protein response is frequently present, even in asymptom-
trant, and asymptomatic methionine-​30 homozygotes over the age of atic individuals. The variable incidence of amyloidosis in patients
60 years have been reported. Rare kindreds with the apolipoprotein A-​ with familial Mediterranean fever from different populations is not
I arginine 26 variant, which usually causes non-​neuropathic amyloid- wholly explained by their specific pyrin gene mutations, and is an-
osis, may present with prominent peripheral neuropathy resembling other illustration of the unknown genetic determinants of clinical
transthyretin familial amyloid polyneuropathy (OMIM 107680). amyloidosis. Heterozygosity for deletion of methionine at position
694 of pyrin is associated with dominantly inherited but otherwise
Familial amyloid polyneuropathy with predominant cranial typical familial Mediterranean fever in the British population.
neuropathy (OMIM 137350)
Originally described in Finland, but now reported in other popula- Haemodialysis-​associated amyloidosis
tions, this very rare, autosomal dominant, hereditary amyloidosis In the past, almost all patients with end-​stage renal failure who
presents in adult life with cranial neuropathy, lattice corneal dys- were maintained on haemodialysis for more than 5 years developed
trophy, and distal peripheral neuropathy. There may be skin, renal, amyloid deposits composed of β2-​microglobulin. These deposits
and cardiac manifestations and microscopic amyloid deposits are were predominantly osteoarticular and were associated with carpal
widely distributed in connective tissue and blood vessel walls; life tunnel syndrome, large-​joint pain and stiffness, soft tissue masses,
expectancy approaches normal. The amyloid fibrils are derived from bone cysts, and pathological fractures. Renal tubular amyloid con-
variants of the actin-​modulating protein gelsolin, encoded by point cretions could also form. The serious clinical problems associated
mutations. with such amyloidosis were a major cause of morbidity in patients
on long-​term dialysis. Furthermore, in some patients more exten-
Non-​neuropathic systemic amyloidosis (OMIM 105200) sive deposition occurred, most commonly in the spleen but also in
In this rare autosomal dominant syndrome of major systemic amyl- other organs, and a few cases of death associated with systemic β2-​
oidosis without clinical evidence of neuropathy, the patterns of microglobulin amyloid were reported.
organ involvement and overall clinical phenotype vary between The β2-​microglobulin was derived from the high plasma con-
families. The kidneys are often the most severely affected organ, centration that developed in renal insufficiency, which was not
leading to hypertension and renal failure, but the heart, spleen, liver, adequately cleared by dialysis. This condition also occurred (with
bowel, connective tissue, and exocrine glands may all be involved. lower incidence) in patients on continuous ambulatory peritoneal
Following clinical presentation there is inexorable progression to dialysis and has rarely been reported in patients with chronic kidney
death or organ failure requiring transplantation. Clinical presen- disease who have never been dialysed. Improved clearance of β2-​
tation is typically around the sixth decade, but can occur in early microglobulin by current dialysis membranes and procedures has
adulthood. The amyloid proteins so far identified are genetic vari- much reduced the incidence and severity of this form of amyloidosis.
ants of apolipoprotein A-​I and A-​II, lysozyme, and least rarely the
fibrinogen α-​chain. A single kindred has lately been identified with Leucocyte chemotactic factor 2 amyloidosis
a genetic variant of β2-​microglobulin. A recently identified and still obscure form of systemic amyloidosis is
associated with amyloid deposits derived from leucocyte chemotactic
Familial amyloid cardiomyopathy factor 2 (LECT2). The aetiology of this apparently sporadic disease
Cardiac amyloidosis without overt involvement of other viscera or is unknown. Most patients present in their sixth to seventh decades
neuropathy, progressing inexorably to death, is associated with cer- with slowly progressive renal impairment; proteinuria tends to be
tain transthyretin gene mutations and is inherited in an autosomal low grade and hypertension is a frequent accompaniment. Although
dominant manner with variable penetrance (Table 12.12.3.2). By splenic and adrenal amyloid deposits are frequently evident on serum
 12.12.3 Amyloidosis 2225

amyloid P component scintigraphy, the clinical manifestations are

Amyloid fibrils
predominantly renal. The disease is apparently most prevalent in
Mexican Americans and South Asians, and renal biopsy data from
Regardless of their very diverse protein subunits, amyloid fibrils of
the United States of America suggests that ALECT2 amyloidosis may
different types are remarkably similar: straight, rigid, nonbranching,
account for up to 2.5% of amyloidotic renal biopsy specimens.
of indeterminate length, and 10 to 15 nm in diameter. They are insol-
The LECT2 gene, located on chromosome 5q31.1–​q32, consists of
uble in physiological solutions, relatively resistant to proteolysis, and
four exons that encode 151 amino acids, of which 133 are present in
bind Congo red dye, producing pathognomonic green birefringence
the secreted product. In addition to having chemotactic activity for
when viewed in intense cross-​polarized light. Electron microscopy
neutrophils, LECT2 may have other physiological functions related
reveals that each fibril consists of two or more protofilaments, the
to cell growth and repair after damage. Although synthesized pre-
precise number varying with the fibril type. The X-​ray diffraction
dominately in the liver, it also is expressed in other tissues, including
patterns of all the different ex vivo amyloid fibrils, and of synthetic
testis, vascular and endothelial smooth muscle cells, and kidney.
fibrils formed in vitro, that have been studied demonstrate the pres-
The pathogenesis underlying ALECT2 amyloid formation is un-
ence of a common core structure within the filaments: the subunit
known, but the fibrils have been demonstrated to be derived from
proteins are arranged in a stack of twisted antiparallel β-​pleated
full-​length, 133-​residue LECT2 protein.
sheets lying with their long axes perpendicular to the long axis of
Endocrine amyloid the fibril.
Many different proteins, including molecules totally unrelated to
Many tumours of APUD (amine precursor uptake and decarboxyl-
amyloidosis in vivo, can be refolded after denaturation in vitro to
ation) cells that produce peptide hormones have amyloid deposits in
form typical, stable, congophilic cross-​β fibrils. Although it is not
their stroma. These are probably composed of the hormone peptides;
clear why only the 26 known amyloidogenic proteins adopt the
in the case of medullary carcinoma of the thyroid, the fibril sub-
amyloid fold and persist as fibrils in vivo, a major unifying theme
units are derived from procalcitonin. In insulinomas, the amyloid
is that, in all cases studied, the precursors are relatively destabilized.
fibril protein is a novel peptide first identified in that site and subse-
Even under physiological or other conditions they may encounter
quently shown to be the fibril protein in the amyloid of the islets of
in vivo, they adopt partly unfolded states that involve the loss of
Langerhans seen in type 2 (maturity-​onset) diabetes. This peptide is
tertiary or higher-​order structure. These misfolded intermediates
called islet amyloid polypeptide, or amylin, and shows appreciable
readily aggregate, with retention of β-​sheet secondary structure, into
homology with calcitonin gene-​related peptide. Amyloid of this
protofilaments and fibrils. Once the process has started, seeding may
type is an almost universal feature of the pancreatic islets in type
also play an important facilitating role, so that amyloid deposition
2 diabetes, and becomes more extensive with increasing duration
may progress exponentially as expansion of the amyloid template
and severity of the disease. Although the amyloid itself is probably
captures further precursor molecules.
not initially responsible for the metabolic defect in this form of dia-
betes, it is likely that progressive amyloid deposition, leading to islet Amyloid fibril proteins and their precursors
destruction, subsequently does contribute to the pathogenesis. The
possible hormonal or other role of islet amyloid polypeptide itself, Immunoglobulin light chain
which is produced by the islet β-​cells, is also not yet clear. AL proteins are derived from the N-​terminal region of monoclonal
immunoglobulin light chains and consist of all or part of the vari-
Rare localized amyloidosis syndromes able domain. Intact light chains may occasionally be found, and the
Amyloid deposits localized to the skin occur in both acquired and molecular weight therefore varies between about 8 and 30 kDa. The
hereditary forms of amyloidosis. Primary localized cutaneous amyl- light chain of the monoclonal paraprotein is either identical to, or
oidosis presents in adult life as macular or papular lesions, the fibrils clearly the precursor of, AL isolated from the amyloid deposits.
of which may be derived from keratin. Hereditary cutaneous amyloid AL fibrils are more commonly derived from λ chains than
lesions are rare, of unknown fibril type, and are sometimes associated from κ chains, despite the fact that κ chains predominate among
with other, nonamyloid, multisystem disorders. Amyloid deposits in both normal immunoglobulins and the paraprotein products of
the eye cause local problems in the cornea (corneal lattice dystrophy) immunocyte dyscrasias. A particular λ-​chain subgroup, λVI, was
or conjunctiva, while orbital amyloid presents as mass lesions that can initially identified as an AL protein in two cases of immunocyte
disrupt eye movement and the structure of the orbit. In one such case, dyscrasia-​associated amyloidosis, before it had been recognized in
the fibril protein has been identified as a fragment of IgG heavy chain. any other form, and it is present in many more cases of AL amyl-
Lactoferrin and keratoepithelin have been identified as the amyloid oidosis. Furthermore, sequence analysis of Bence Jones proteins of
fibril proteins in different cases of corneal amyloidosis. both κ and λ types from patients with AL amyloidosis, and of AL
Localized foci of AL amyloid can occur anywhere in the body in proteins themselves, shows that these polypeptides contain unique
the absence of systemic AL amyloidosis, the most common sites amino acid replacements or insertions compared with nonamyloid
being the skin, upper airways and respiratory tract, and the uro- monoclonal light chains. In some cases, the changes involve the re-
genital tract. They may be associated with a local plasmacytoma or B-​ placement of hydrophilic framework residues by hydrophobic res-
cell lymphoma producing a monoclonal immunoglobulin, but often idues, changes likely to promote aggregation and insolubilization; in
the cells, which must be present to produce the amyloidogenic pro- others, the monoclonal light chains from amyloid patients have been
tein, are scattered inconspicuously in the affected tissue. The clinical directly demonstrated to have decreased solubility and a greater
problems caused by these space-​occupying amyloidomas can often propensity for precipitation than control nonamyloid proteins. The
be ameliorated by surgical resection, but this is not always possible. inherent amyloidogenicity of particular monoclonal light chains
2226 section 12 Metabolic disorders

has been elegantly confirmed in an in vivo model in which isolated monitoring of SAA should be an integral part of the management
Bence Jones proteins were injected into mice. Animals receiving of all patients with AA amyloidosis or disorders predisposing to it,
light chains from AL amyloid patients developed typical amyloid de- as control of the primary inflammatory process in order to reduce
posits composed of the human protein, whereas animals receiving SAA production is essential if amyloidosis is to be halted, enabled
light chains from myeloma patients without amyloid did not. to regress, or prevented. Automated immunoassay systems for SAA
are available that are calibrated on the World Health Organization
Amyloid A (AA) international reference standard.
The AA protein is a single nonglycosylated polypeptide chain usually
of mass 8000 Da and containing 76 residues corresponding to the N-​ Transthyretin
terminal portion of the 104-​residue serum amyloid A protein (SAA). Transthyretin, formerly known as prealbumin, is a normal
Smaller and larger AA fragments, even some whole SAA molecules, nonglycosylated plasma protein with a relative molecular mass of
have also been reported in AA fibrils. SAA is an apolipoprotein of 55 044 Da. It is composed of four identical noncovalently associ-
high-​density lipoprotein particles, and is the polymorphic product of ated subunits, each of 127 amino acids. It is produced by hepatocytes
a set of genes located on the short arm of chromosome 11. It is highly and the choroid plexus, and is a significant negative acute phase
conserved in evolution and is a major acute phase reactant. Most of protein. Each tetrameric molecule is able to bind a single thyroxine
the SAA in plasma is produced by hepatocytes, in which the synthesis or triiodothyronine molecule and up to 15% of circulating thyroid
is under transcriptional regulation by cytokines (especially inter- hormone is transported in this way. Transthyretin also forms a 1:1
leukin 1, interleukin 6, and TNF) acting via NF-​κB-​like transcription molecular complex with the vitamin A transporter, retinol-​binding
factors, and possibly others. After secretion it rapidly associates with protein, and is essential for keeping it in the circulation.
high-​density lipoproteins, from which it displaces apolipoprotein Transthyretin is encoded by a single-​copy gene, but is appreciably
A-​I. The circulating concentration can rise from normal levels of polymorphic and more than 120 different point mutations encoding
up to 3 mg/​litre to over 1000 mg/​litre within 24 to 48 h of an acute single residue substitutions have been identified. Normal wild-​type
stimulus, and with ongoing chronic inflammation the level may re- transthyretin is an inherently amyloidogenic protein that forms the
main persistently high. Certain isoforms of SAA, the products of dif- fibrils in wild-​type transthyretin (also known as senile systemic)
ferent genes, are predominantly synthesized elsewhere in the body by amyloidosis. Almost all variant forms of transthyretin have been as-
macrophages, adipocytes, and certain other cells. Although they also sociated with hereditary amyloidosis, and show decreased stability
associate with high-​density lipoproteins, their acute phase synthesis in vitro compared with the wild type.
is stimulated differently and they presumably have different func- Individuals heterozygous for transthyretin mutations have a mixture
tions. There is also a closely related family of high-​density lipoprotein of wild-​type and variant transthyretin monomers in their circulating
trace apoproteins that are not acute phase reactants; they have been transthyretin, and if they develop amyloidosis both forms are often
designated constitutive SAAs, although they do not form amyloid. present, although the variant may predominate in the amyloid fibrils.
The precursor of amyloid fibril AA protein is circulating SAA, from In addition to intact protomers, ATTR amyloid fibrils also usually con-
which amyloid fibril AA protein is derived by proteolytic cleavage. tain the C-terminal fragment, residue 49-127, of transthyretin. This is
Such cleavage can be produced by macrophages and by a variety produced by a recently elucidated mechano-enzymatic mechanism,
of proteinases, but since further cleavage of AA is readily demon- in which physiological scale shear forces critically facilitate cleavage of
strable in vitro it is not clear why the AA peptide persists in amyloid. transthyretin at residue 48 by plasmin. This specific cleavage catalyses,
Furthermore, it is not known whether the process of AA fibril gen- and is necessary for, transthyretin amyloid fibril formation. Plasmin, the
eration involves cleavage of SAA before and/​or after aggregation of pivotal essential mediator of physiological fibrinolysis, is thus also a key
monomers. Persistent overproduction of SAA causing sustained pathogenic factor in transthyretin amyloidosis.
high circulating levels is a necessary condition for deposition of AA
amyloid, but it is not known why only some individuals in this state Amyloid beta (Aβ)
develop amyloidosis. In mice, only one of the three major isoforms of The fibril protein in the intracerebral and cerebrovascular amyloid
SAA is the precursor of AA in amyloid fibrils. Human SAA isoforms of Alzheimer’s disease, Down’s syndrome, and hereditary amyloid
are more complex, but homozygosity for particular types seems to fa- angiopathy of the Dutch type is a 39-​to 43-​residue sequence de-
vour amyloidogenesis, although there may also be ethnic differences. rived by proteolysis from a precursor protein of high molecular
The normal functions of SAA are not known, although modu- weight, the amyloid precursor protein (APP), encoded on the long
lating effects on reverse cholesterol transport and on lipid function arm of chromosome 21. Several isoforms of APP are generated by
in the microenvironment of inflammatory foci have been proposed. alternative splicing of transcripts from the 19-​exon gene, yielding
A protein, homologous with SAA, produced by rabbit fibroblasts has three major forms: APP695, APP751, and APP770. These are each
been reported to act as an autocrine stimulator of collagenase pro- single-​chain, multidomain glycoproteins with the 47 residues of the
duction in vitro. Other reports of potent cell-​regulatory functions C-​terminal lying within the cytoplasm, a 25-​residue membrane-​
of isolated denatured delipidated SAA have yet to be confirmed in spanning region, and the rest of the molecule lying extracellularly.
physiological preparations of SAA-​rich high-​density lipoproteins. APP751 and APP770 contain a 56-​residue Kunitz-​type serine pro-
Regardless of its physiological role, the behaviour of SAA as an ex- teinase inhibitor domain encoded by exon 7.
quisitely sensitive acute phase protein with an enormous dynamic Following glycosylation and membrane insertion, APPs are
range makes it an extremely valuable empirical clinical marker. It can cleaved extracellularly, close to the transmembrane sequence, by so-​
be used objectively to monitor the extent and activity of infective, in- called APP secretase activity. This releases, in the case of APP751
flammatory, necrotic, and neoplastic disease. Furthermore, routine and APP770, a molecule known as proteinase nexin II, which avidly
 12.12.3 Amyloidosis 2227

binds factor XIa, trypsin, and chymotrypsin, as well as epidermal Gelsolin

growth factor-​binding protein and the γ subunit of nerve growth Gelsolin is a widely distributed 90-​kDa cytoplasmic protein that
factor. The predominant species of mRNA found in the brain encodes binds actin monomers, nucleates actin filament growth, and severs
APP695, which lacks the proteinase inhibitor domain, while mRNA actin filaments. Alternative transcriptional initiation and message
for APP751 is the most abundant in other tissues. Despite this, 85% processing from a single gene on chromosome 9 are responsible for
of secreted APP in the brain is proteinase nexin II. Interestingly, APP the synthesis of a secreted form of gelsolin (93 kDa), which circu-
secreted by a glial cell line is substantially glycosylated with chon- lates in the plasma at a concentration of about 200 mg/​litre. Its func-
droitin sulphate glycosaminoglycan chains. APP also undergoes tion in the blood is not known, but may be related to the clearance of
high-​affinity interactions with heparan sulphate. These observations actin filaments released by dying cells. In the Finnish type of heredi-
suggest that APP may have important functions in cell adhesion, tary amyloidosis, the amyloid fibril protein is a 71-​residue fragment
cell migration, and modulation of growth-​factor activities. APP pro- of variant gelsolin, with asparagine substituted for aspartic acid at
teinase nexin II is present in and released by platelets, and probably position 15 (corresponding to residue 187 of the mature molecule),
functions in the clotting cascade. and the same mutation has been discovered in affected kindreds
The amyloidogenic peptide Aβ, encoded by parts of exons 16 and from different ethnic backgrounds. In one Danish family with the
17, corresponds to the part of the APP sequence that extends from same phenotype there is a different mutation at the same nucleo-
within the cell membrane into the extracellular space. Secretase tide, predicting a tyrosine for aspartic acid substitution at residue
cleavage of APP to release the soluble form cannot therefore gen- 187. Synthetic and recombinant peptides that include the asparagine
erate intact Aβ itself, or larger fragments containing it. However, for aspartic acid substitution at residue 187 are less soluble than the
there is an alternative processing pathway for APP, in which it is wild-​type sequence and readily form amyloid fibrils in vitro.
taken up whole by lysosomes and cleaved to yield fragments that do
contain the whole Aβ sequence. Furthermore, APP cleaved at the N-​ Apolipoprotein A-​I and A-​II
terminus of Aβ, and soluble Aβ itself, are normally produced by cell Apolipoprotein A-​I is the most abundant apolipoprotein among the
lines and by mixed brain cells in culture, and are present in the cere- high-​density lipoprotein particles, and participates in their central
brospinal fluid. However, the source of the Aβ in the intracerebral function of reverse cholesterol transport from the periphery to the
amorphous deposits, and that which aggregates as amyloid fibrils liver. Apolipoprotein A-​I variants are extremely rare, and may be
in the brain and cerebral blood vessels, is still not known. The 42-​ phenotypically silent or may affect lipid metabolism. However, at
residue form of Aβ (Aβ1–​42) is markedly the most amyloidogenic, least 15 different variants of apolipoprotein A-​I, including single-​
and all the mutations in the APP and presenilin genes that are associ- and multiple-​residue substitutions and deletions, have been associ-
ated with hereditary Alzheimer’s disease result in increased produc- ated with amyloidosis. These are inherited in an autosomal dominant
tion of this fragment. Increased availability of the precursor is thus manner and are usually highly penetrant, but there are marked vari-
responsible for amyloidogenesis, but the pathogenesis of neuronal ations in the age and manner of presentation, even within the same
damage and dementia remain unclear. family and in different kindreds with the same mutation.
The amyloid fibril protein consists, in all cases studied, of the
Cystatin C first 90 or so N-​terminal residues, even when the causative variant
Cystatin C (formerly called γ-​trace) is an inhibitor of cysteine pro- residue(s) are more distal. Wild-​type apolipoprotein A-​I is also
teinases, including cathepsin B, H, and L. It is encoded by a gene on amyloidogenic, forming the deposits associated with atheromatous
chromosome 20 and consists of a single nonglycosylated polypep- plaques in older people. The various amyloidogenic mutations pre-
tide chain of 120 residues. It is present in all major human biological sumably encode sequence changes that render apolipoprotein A-​I
fluids at concentrations compatible with a significant physiological less stable and/​or more liable to cleavage that yields the fibrillogenic
role in proteinase inhibition. The normal concentration in cere- N-​terminal fragment.
brospinal fluid is 6.5 mg/​litre (range 2.7–​13.7), but is much lower Predominantly renal amyloidosis has also been described in a
(2.7 mg/​litre, range 1.0–​4.7) in patients with the Icelandic type of handful of families in association with several different mutations
hereditary cerebral amyloid angiopathy, in whom fragments of the in a normal stop codon in the gene for apolipoprotein A-​II, which
glutamine-​68 genetic variant of cystatin C form the amyloid fibrils. results in a peptide extension from residue 78.
This reduced concentration is diagnostically useful, and is evident
even in presymptomatic carriers of the cystatin C gene mutation. Lysozyme
The point mutation that causes the disease encodes a glutamine Lysozyme is the classic bacteriolytic enzyme of external secretions,
for leucine substitution in the mature protein, and the amyloid fibril discovered by Fleming in 1922. It is also present at high concentra-
protein consists of the C-​terminal 110 residues of the variant. This tion within articular cartilage and in the granules of polymorphs,
N-​terminally truncated form is not detectable in the cerebrospinal and is the major secreted product of macrophages. Lysozymes are
fluid of affected patients, suggesting that cleavage takes place either present in most organisms in which they have been sought, although
in close proximity to fibril deposition or after the fibrils have formed. their physiological role is not always clear. The complete structures
The variant cystatin C is less stable than the wild type and readily of hen egg-​white and human lysozymes are known to atomic reso-
forms fibrils in vitro. It is not known whether cerebral haemorrhage lution, and their catalytic mechanism, epitopes, folding, and other
in cystatin C amyloidosis is caused simply by the damaging effects aspects of their structure–​function relationship have been analysed
of vascular amyloid deposition, or whether deficiency in inhibitory exhaustively. Wild-​ type lysozyme, unlike transthyretin and β2-​
capacity for cysteine proteinases also plays a part. microglobulin, is not inherently amyloidogenic and, coupled with
2228 section 12 Metabolic disorders

the extensive knowledge of its structure and folding, it is therefore a to 2 mg/​litre and the protein is rapidly cleared by glomerular filtra-
valuable model for the investigation of amyloid fibrillogenesis. There tion and then catabolized in the proximal renal tubule. Impairment
is only one copy of the lysozyme gene in the human genome, and no of renal function is associated with retention of β2-​microglobulin
disease is associated with lysozyme other than amyloidosis. The first and increased circulating concentrations because there is no other
lysozyme mutations identified to cause amyloidosis were the sub- site for its catabolism. Daily production of β2-​microglobulin is about
stitution of threonine for isoleucine at residue 56 in one family, and 200 mg, and in patients in end-​stage renal failure on haemodialysis,
histidine for aspartic acid at residue 67 in another. These dramatic plasma β2-​microglobulin levels rise to and remain at levels of about
changes in residues that are extremely conserved throughout the 40 to 70 mg/​litre. Isolated unaltered β2-​microglobulin can form
lysozyme and related α-​lactalbumin protein families destabilize the amyloid-​like fibrils itself in vitro, and most studies of ex vivo β2-​
native fold, so that the variants readily adopt partly unfolded states, microglobulin fibrils show the whole intact molecule to be the major
even under physiological conditions, and spontaneously aggregate subunit, although fragments and altered forms of β2-​microglobulin
in vitro, and evidently also in vivo, into amyloid fibrils. Several fur- have also been reported.
ther amyloidogenic variants of lysozyme have subsequently been Intriguingly, a highly amyloidogenic variant of β2-​microglobulin
described. has been identified in a French kindred with hereditary systemic
amyloidosis manifesting with slowly progressive gastrointestinal
Islet amyloid polypeptide symptoms and autonomic neuropathy. Renal function and cir-
Islet amyloid polypeptide (IAPP; amylin) is a 37-​residue molecule culating concentration of β2-​ microglobulin were normal. The
encoded by a gene on chromosome 12 and with 46% sequence hom- Asp76Asn β2-​microglobulin variant was thermodynamically un-
ology to the neuropeptide calcitonin gene-​related peptide. Islet stable and uniquely fibrillogenic in vitro under physiological
amyloid polypeptide is produced in the β-​cells of the pancreatic is- conditions.
lets of Langerhans, and is stored in and released from their secretory
granules together with insulin. It has been reported to modulate in- Glycosaminoglycans
sulin release and to induce peripheral insulin resistance, vasodilata- Amyloidotic organs contain more glycosaminoglycans than normal
tion, and lowering of plasma calcium, but neither its physiological tissues, and at least some of this is a tightly bound integral part of
role nor its contribution to diabetes are known. the amyloid fibrils. These fibril-​associated glycosaminoglycans are
The amyloidogenicity of islet amyloid polypeptide depends on heparan sulphate and dermatan sulphate in all forms of amyloid
the amino acid sequence between residues 20 and 29, as shown by that have been investigated. Fibrils isolated by water extraction and
in vitro fibrillogenesis with synthetic peptides. The synthetic deca- separated from other tissue components contain 1 to 2% by weight
peptide IAPP20–​29, and even the hexapeptide IAPP25–​29, form glycosaminoglycan, none of which is covalently associated with
amyloid-​like fibrils in vitro, whereas other fragments do not. There the fibril protein. Interestingly, in systemic AA and AL amyloid-
is also a correlation between conservation of this sequence and de- osis, the only forms in which this has been studied so far, there is
position of the amyloid in the islets of diabetic animals of different markedly restricted heterogeneity of the glycosaminoglycan chains,
species. However, the role of the amyloid in diabetogenesis remains suggesting that particular subclasses of heparan and dermatan
to be established. In the degu, a South American rodent, spontan- sulphates are involved. Immunohistochemical studies demonstrate
eous diabetes is associated with islet amyloid composed of insulin, the presence of proteoglycan core proteins in all amyloid deposits,
and xenogeneic insulin can also form amyloid in humans at the site and that these are closely related to fibrils at the ultrastructural
of repeated therapeutic insulin injections. level. However, in isolated fibril preparations much of the glyco-
saminoglycan material is free carbohydrate chains, and it is not yet
β2-​microglobulin clear whether this represents aberrant glycosaminoglycan metab-
β2-​microglobulin is a nonglycosylated, nonpolymorphic, single-​ olism related to amyloidosis or is just an artefact of postmortem
chain protein of 99 residues, with a single intrachain disulphide degradation of core protein.
bridge and a relative molecular mass of 11 815, encoded by a single The significance of glycosaminoglycans in amyloid remains un-
gene on chromosome 15. It becomes noncovalently associated with clear, but their universal presence, intimate relationship with the
the heavy chain of major histocompatibility class I antigens, and is fibrils, and restricted heterogeneity all suggest that they may be im-
required for transport and expression of the major histocompati- portant. Glycosaminoglycans are known to participate in the organ-
bility complex (MHC) at the cell surface. Amino acid sequence ization of some normal structural proteins into fibrils and they may
homology places β2-​microglobulin in the superfamily that includes have comparable fibrillogenic effects on certain amyloid fibril pre-
immunoglobulins, T-​cell receptor α-​ and β-​chains, Thy-​1 (CD90), cursor proteins. Furthermore, the glycosaminoglycans on amyloid
MHC class I and II molecules, secretory component, etc. Its three-​ fibrils may be ligands to which serum amyloid P component, an-
dimensional structure is a typical β-​barrel with two antiparallel other universal constituent of amyloid deposits, binds.
pleated sheets comprising three and four strands, respectively, and
closely resembles an immunoglobulin domain. Amyloid P component and serum amyloid P component
β2-​microglobulin is produced by lymphoid and a variety of other Amyloid deposits in all different forms of the disease, both in hu-
cells, in which it stabilizes the structure and function of MHC mans and in animals, contain the nonfibrillar glycoprotein, amyloid
class I antigens at the cell surface. When these complexes are shed by P component. Amyloid P component is identical to and derived
cleavage of the heavy chain at the cell surface, free β2-​microglobulin from the normal circulating plasma protein, serum amyloid P com-
is released. The circulating concentration of β2-​microglobulin is 1 ponent, a member of the pentraxin protein family that includes
 12.12.3 Amyloidosis 2229

C-​reactive protein. Human serum amyloid P component is secreted immunohistochemically in some amyloid deposits. These in-
only by hepatocytes, is a trace constituent of plasma (women: mean clude α1-​ antichymotrypsin, some complement components,
24 mg/​litre, range 8–​55, men: mean 32 mg/​litre, range 12–​50), and apolipoprotein E, and various proteins of the extracellular matrix
is not an acute phase reactant. Nevertheless, apart from the fibrils and basement membrane. None of these is as universal, abundant, or
themselves, amyloid P component is always by far the most abun- selective as serum amyloid P component, and their role, if any, in the
dant protein in all amyloid deposits. pathogenesis or effects of amyloid deposition is not known.
Serum amyloid P component consists of five identical
noncovalently associated subunits, each with a molecular mass of
25 462 Da, arranged in a pentameric disc-​like ring. The tertiary Diagnosis and monitoring of amyloidosis
fold of the subunit is dominated by antiparallel β-​sheets, forming
a flattened β-​barrel with jellyroll topology and a core of hydro- The gold standard for diagnosis of amyloid is Congo red staining
phobic side chains. This is the lectin fold, shared with a variety of of histological sections under strictly defined conditions, followed
other animal, plant, and bacterial carbohydrate-​binding proteins by viewing under intense cross-​polarized light to detect the path-
(lectins). Serum amyloid P component is a calcium-​dependent ognomonic green birefringence. Although inherently not complex
ligand-​binding protein; its best-​defined specificity is for the 4,6-​ or challenging, the essential practical procedures are often not per-
cyclic pyruvate acetal of β-​d-​galactose, but it also binds avidly and formed adequately, leading to a substantial proportion of false-​
specifically to DNA, chromatin, glycosaminoglycans (particu- negative and false-​positive histopathological diagnoses which can
larly heparan and dermatan sulphates), and to all known types of be devastating for individual patients. The relative rarity of amyl-
amyloid fibrils. The latter interaction is responsible for the unique oidosis and its highly variable and protean clinical presentation also
specific accumulation of serum amyloid P component in amyloid mean that clinicians often do not think of it and thus do not request
deposits. Aggregated, but not native, serum amyloid P compo- its histological identification. The variable standard of histological
nent also binds specifically to C4-​binding protein and fibronectin assessment compounds the problem and together these factors ex-
from plasma, although serum amyloid P component is not com- plain why the diagnosis is very challenging in routine practice. The
plexed with any other protein in the circulation. In addition to result is that amyloidosis is frequently diagnosed very late and pa-
being a plasma protein, human serum amyloid P component is also tients already have advanced organ damage before they come to spe-
a normal constituent of certain extracellular matrix structures. It cialist attention. Even when properly stained and viewed, biopsies
is covalently associated with collagen and/​or other matrix compo- provide extremely small samples and therefore can never provide
nents in the lamina rara interna of the human glomerular basement information on the extent, localization, progression, or regression of
membrane, and is present on the microfibrillar mantle of elastin amyloid deposits, either locally or in the whole patient. The devel-
fibres throughout the body. opment of radiolabelled serum amyloid P component as a specific
Although no deficiency of serum amyloid P component has been tracer for amyloid was therefore a major advance in clinical amyl-
described, and it has been stably conserved in evolution, its physio- oidosis and provided a wealth of new information on the natural
logical function remains unclear. There is a single copy of its gene history of many different forms of amyloid and their response to
on chromosome 1, no polymorphism of the amino acid sequence, treatment.
and the single biantennary oligosaccharide chain attached to as-
Histochemical diagnosis of amyloidosis
paragine at residue 32 is the most invariant glycan of any known
glycoprotein. Studies of serum amyloid P component knockout Biopsy
mice have shown that serum amyloid P component is involved in In many patients with systemic amyloidosis, amyloid is an unex-
host resistance to some infections, and contributes to the pathogen- pected finding on biopsy of the kidneys, liver, heart, bowel, per-
esis of others, but these animals are otherwise healthy and have a ipheral nerves, lymph nodes, skin, thyroid, or bone marrow during
normal lifespan. investigation of undiagnosed clinical problems. When amyloidosis
The serum amyloid P component molecule is highly resistant to is suspected clinically, biopsy of the rectum or subcutaneous fat is
proteolysis and, although not itself a proteinase inhibitor, its binding the least invasive. Amyloid is present at these sites in 50 to 70% of
to amyloid fibrils in vitro protects them against proteolysis. Once cases of systemic AA or AL amyloidosis. Alternatively, a clinically
bound to amyloid fibrils in vivo, serum amyloid P component per- affected tissue may be biopsied directly.
sists for very prolonged periods and is not catabolized at all, by con-
trast with its rapid clearance from the plasma (half-​life 24 h) and Congo red and other histochemical stains
prompt catabolism in the liver. These observations suggest that Many cotton dyes, fluorochromes, and metachromatic stains
serum amyloid P component may contribute to the persistence of have been used to stain amyloid in tissue sections but Congo red
amyloid deposits in vivo; serum amyloid P component knockout staining, specifically using an alcoholic alkaline solution, and the re-
mice show retarded and reduced induction of experimental AA sultant green birefringence when viewed with high-​intensity cross-​
amyloidosis, confirming that serum amyloid P component is signifi- polarized light, is the pathognomonic histochemical test. The stain is
cantly involved in the pathogenesis of amyloidosis. unstable and must be freshly prepared every 2 months or less and it
is essential that the batch of Congo red has been validated. It is crit-
Other proteins in amyloid deposits
ical to have a section thickness of 5 to 10 µm and to include in every
A number of plasma proteins, other than the fibril proteins them- staining run a positive control tissue containing modest amounts
selves and the serum amyloid P component, have been detected of amyloid. Reliable reporting on the microscopic appearances
2230 section 12 Metabolic disorders

absolutely depends on the use of a microscope of suitable quality be difficult to detect, even by comprehensive Doppler echocardiog-
equipped to provide high-​intensity cross-​polarized light. It is impos- raphy and other functional studies. Myocardial strain imaging has
sible to rigorously recognize or exclude amyloid unless these condi- emerged as a useful additional echocardiographic technique in car-
tions are all fulfilled. diac amyloidosis, with the ‘relative apical sparing’ pattern of longitu-
dinal strain being a strong pointer to the diagnosis.
Immunohistochemistry Cardiac MRI provides functional and morphological informa-
Although many amyloid fibril proteins can be identified tion on cardiac amyloid, and yields more accurate measurements
immunohistochemically, the demonstration of amyloidogenic of volume, mass, and wall thickness than echocardiography, which
proteins in tissues does not, on its own, establish the presence of may be of particular benefit in sequential assessments. An advan-
amyloid. Congo red staining and green birefringence are always tage of cardiac MRI is myocardial tissue characterization, which
required, and immunostaining may then enable the amyloid to be provides information on the presence and extent of amyloid de-
classified. Antibodies to serum amyloid A protein are commer- posits. Characteristic patterns of global subendocardial and trans-
cially available and always stain AA deposits, similarly with anti-​β2-​ mural late gadolinium enhancement have very high diagnostic
microglobulin antisera and haemodialysis-​associated amyloid. In sensitivity for cardiac amyloidosis and correlate with prognosis.
AL amyloid, the deposits are stainable with standard antisera to κ T1 mapping studies performed after administration of gadolinium
or λ immunoglobulin light chains in only about one-​half of cases, contrast can quantify the extracellular amyloid load and myocar-
probably because the light-​chain fragment in the fibrils is usually the dial cell mass.
N-​terminal variable domain, which is largely unique for each mono-
clonal protein. Immunohistochemical staining of transthyretin, Aβ, Scintigraphy
and prion protein amyloid may require pretreatment of sections Scintigraphy following injection of technetium 99m-​labelled 3,3-​
with formic acid or alkaline guanidine, or deglycosylation. diphosphono-​1,2 propanodicarboxylic acid (99mTc-​DPD), which was
developed as a bone tracer, has lately been repurposed as a remarkably
Electron microscopy sensitive method for detecting the presence of cardiac transthyretin
Amyloid fibrils cannot always be convincingly identified ultra­ amyloid deposits. Localization of this tracer to the heart to a greater in-
structurally, and electron microscopy alone is not sufficient to con- tensity than to the bones in the absence of a monoclonal gammopathy
firm the diagnosis of amyloidosis. is pathognomonic for cardiac transthyretin amyloidosis. Cardiac
localization of this tracer can also occur in some patients with AL,
Problems of histological diagnosis apolipoprotein A-​I, and other types of amyloidosis, but usually to only
The tissue sample must be adequate (e.g. the inclusion of sub- a minor degree.
mucosal vessels in a rectal biopsy specimen), and failure to find
Genetic and biochemical tests
amyloid does not exclude the diagnosis. The unavoidable sampling
problem means that biopsy cannot reveal the extent or distribu- In cases of known or suspected hereditary amyloidosis, the gene
tion of amyloid. Experience with Congo red staining and viewing defect must be characterized. If amyloidotic tissue is available,
is required if clinically important false-​negative and false-​positive the fibril protein may be known and the corresponding gene can
results are to be avoided. Immunohistochemical staining requires then be studied, but if no tissue containing amyloid is available,
positive and negative controls, including demonstration of the spe- screening of the genes for known amyloidogenic proteins must be
cificity of staining by absorption of positive antisera with isolated undertaken.
pure antigens. There are biochemical and immunochemical tests for screening
the plasma for amyloidogenic variant protein products of mutant
Proteomic analysis genes (e.g. for transthyretin and apolipoprotein A-​I variants), but
Laser capture microdissection of amyloid deposits from histological molecular genetic analysis of DNA is easier to perform and is the
sections, followed by proteolytic digestion of the excised amyloid most direct approach. However, regardless of the DNA results, it is
material and mass spectrometric identification of the fragments desirable, if possible, to directly identify the respective protein in the
can also be used for typing. Suitable for use only in major centres amyloid.
of expertise, this highly specialized technique is an adjunct to Serum amyloid P component as a specific tracer
immunohistochemistry for identification of amyloid fibril proteins, in amyloidosis
especially in the case of previously unknown fibrils, but appropriate
interpretation of the results can be challenging. The universal presence in amyloid deposits of amyloid P com-
ponent, derived from circulating serum amyloid P component,
Nonhistological investigations is the basis for the use of radioisotope-​labelled serum amyloid P
component as a diagnostic tracer in amyloidosis. No localization
Structural imaging or retention of labelled serum amyloid P component occurs in
Two-​dimensional echocardiography showing small, concentrically healthy subjects or in patients with diseases other than amyloidosis
hypertrophied ventricles, generally impaired contraction, dilated (Fig. 12.12.3.1a). Radioiodinated serum amyloid P component has
atria, homogeneously echogenic valves, and ‘sparkling’ echodensity a short half-​life (24 h) in the plasma and is rapidly catabolized, with
of ventricular walls is strongly suggestive of cardiac amyloidosis. complete excretion of the iodinated breakdown products in the
However, clinically significant restrictive diastolic impairment may urine. However, in patients with systemic or localized extracerebral
 12.12.3 Amyloidosis 2231

(a) (b) (c)

Fig. 12.12.3.1 Whole-​body scintigraphs 24 h after intravenous

injection of 123I-​labelled human serum amyloid P component.
(a) Anterior view of a normal control subject showing the distribution of
residual tracer in the blood pool and radioactive breakdown products
in urine in the bladder; note the absence of localization or retention
of tracer anywhere in the body. (b) Posterior (left) and anterior (right)
views of a patient with juvenile chronic arthritis complicated by AA
amyloidosis. There is uptake of tracer in the spleen, kidneys, and adrenal
glands, a typical distribution of AA amyloid in which the spleen is
involved in 100% of cases, kidneys in 75%, and adrenals in 40%. Note Fig. 12.12.3.2 Serial posterior whole-​body 123I-​serum amyloid P
the reduced blood pool and bladder signal compared with (a). This component scintigraphs of a man with AL amyloidosis complicating
patient, whose amyloid was diagnosed by renal biopsy 15 years before benign monoclonal gammopathy. At presentation (scan 1) there was
when nephrotic syndrome developed, and who was then treated with uptake in the spleen, liver, and bone marrow, obscuring any possible
chlorambucil, had been in complete remission for 10 years during which renal signal. Chemotherapy was given before scan 2, which shows
there had been no acute phase response. At the time of this scan there increased spleen uptake, reduced liver uptake, and some renal uptake,
was no biochemical abnormality in blood or urine, despite the very but no change in total amyloid load determined by measurements of the
appreciable amyloid deposits, illustrating the discordance between the clearance and retention of the tracer (not shown). Subsequently, he had
presence of amyloid and clinical effects. (c) Posterior (left) and anterior recurrent splenic infarctions and splenectomy was performed. Thereafter
(right) views of a patient with monoclonal gammopathy complicated by (scan 3) there was increased tracer uptake in the liver, although a notably
extensive AL amyloidosis. There is uptake and retention of tracer in the lower total amyloid load. Six months later (scan 4) liver and kidney
liver, spleen, kidneys, bone marrow, and soft tissues around the shoulder. uptake, plasma clearance, and whole-​body retention of tracer were
This scintigraphic pattern of amyloid distribution is pathognomonic all reduced, indicating regression of amyloid. He was clinically much
for AL amyloidosis; bone-​marrow uptake has not been seen in any improved and remained well.
other type. Note the complete absence of blood pool or bladder signal
resulting from complete uptake of the tracer dose into the substantial
amyloid deposits.
123
I-​SAP to be determined when there is tracer uptake in unusual
anatomical sites.
amyloidosis, the tracer rapidly and specifically localizes to the de- Important observations regarding amyloid include the fol-
posits, in proportion to the quantity of amyloid present, and per- lowing: the different distribution of amyloid in different forms of
sists there without breakdown or modification (Figs. 12.12.3.1b the disease; amyloid in anatomical sites not available for biopsy
and 12.12.3c). Highly purified serum amyloid P component, iso- (adrenals, spleen); major systemic deposits of forms of amyloid
lated from donor plasma according to pharmaceutical current good previously thought to be organ-​limited; a poor correlation between
manufacturing practice, is oxidatively iodinated under conditions the quantity of amyloid present in a given organ and the level of
that preserve its function intact. The medium-​energy, short half-​ organ dysfunction; a nonhomogeneous distribution of amyloid
life, pure γ-​emitter 123I is used for scintigraphic imaging, and the within individual organs; and evidence for rapid progression and
long half-​life isotope 125I is used for metabolic studies. The dose of sometimes regression of amyloid deposits with different rates in
radioactivity administered (<4 mSv) is well within accepted safety different organs (Fig. 12.12.3.2). Examples of major regression
limits and more than 30 000 studies have been completed without of amyloidosis, when it has been possible to reduce or eliminate
any adverse effects. In addition to high-​resolution scintigraphs, the the supply of fibril precursor, are very encouraging. Studies with
uptake of tracer into various organs can be precisely quantified and, labelled serum amyloid P component thus make a valuable con-
together with highly reproducible metabolic data on the plasma tribution to the diagnosis and management of patients with sys-
clearance and whole-​body retention of activity, the progression or temic amyloidosis, and in the United Kingdom these are routinely
regression of amyloid can be monitored serially and quantitatively. available for all known or suspected cases of amyloidosis in the
Dual modality three-​dimensional single-​photon emission com- National Health Service National Amyloidosis Centre at the Royal
puted tomography coupled with CT enables precise localization of Free Hospital, London.
2232 section 12 Metabolic disorders

needs to be tailored to individual patients based on age, performance

Management of amyloidosis
status, organ involvement, cardiac staging, and the known toxicities
of individual drugs, balancing the ideal for complete remission of
There have been substantial recent advances in the management
the clonal disease with the need to minimize treatment-​related mor-
of systemic amyloidosis, in particular active measures to support
bidity and mortality.
failing organ function while attempts are made to reduce the supply
Quantitative measurements of serum free light chains using the
of the amyloid fibril precursor protein. Serial serum amyloid P com-
robust, sensitive, Freelite immunoassay are usually the most ef-
ponent scintigraphy in more than 8000 patients with various forms
fective means for evaluating the early effects of chemotherapy as well
of amyloidosis has shown that control of the primary disease pro-
as the requirement for ongoing treatment. Although partial haem-
cess, or removal of the source of the amyloidogenic precursor, often
atological responses, that is, greater than 50% reduction in aberrant
results in regression of existing deposits and recovery or preserva-
light chain concentration, can be beneficial, more complete clonal
tion of organ function. This strongly supports aggressive interven-
responses, that is, greater than 90% reduction, are strongly desir-
tion, and relatively toxic drug regimens or other radical approaches
able and are associated with the best clinical outcomes. Serial meas-
can be justified by the poor prognosis. Such an approach, leading to
urements of the cardiac biomarker serum NT-​proBNP are highly
reduced morbidity and improved survival, was the basis for the es-
informative with respect to the response of cardiac amyloidosis to
tablishment of the National Health Service National Amyloidosis
chemotherapy.
Centre. However, clinical improvement in amyloidosis is often
Many different chemotherapy regimens are in current use, re-
­delayed long after the underlying disorder has remitted, reflecting
flecting the paucity of clinical trials and international consensus,
the very gradual regression of the deposits that is now recognized
ranging from relatively low-​intensity oral melphalan and dexametha-
to occur in most patients. Continuing production of the amyloid
sone through various intermediate-​dose drug combinations to high-​
precursor protein should be monitored as closely as possible in
dose chemotherapy with autologous peripheral stem cell rescue in
the long term, to determine the requirement for and intensity of
younger and fitter patients. In our current practice, most patients
treatment for the underlying primary condition. In AA amyloid-
with AL amyloidosis receive a cyclic combination of the alkylating
osis this involves frequent estimation of the plasma SAA level, and
agent cyclophosphamide, the proteasome inhibitor bortezomib
in AL amyloidosis it requires monitoring of the serum free light-​
(Velcade) and dexamethasone, delivered 3-​to 4-​weekly over 3 to
chain concentration or other markers of the underlying monoclonal
6 months. More recently developed proteasome inhibitors including
plasma cell proliferation.
carfilzomib and ixazomib are undergoing evaluation in AL amyl-
Specific conventional therapies oidosis. The immunomodulatory drugs, thalidomide, lenalidomide,
and pomalidomide, are also widely used in combination with dexa-
AA amyloidosis methasone and sometimes with proteasome inhibitor in addition.
The treatment of AA amyloidosis ranges from potent anti-​ A multidisciplinary specialist approach is required to formulate and
inflammatory and immunosuppressive biological drugs in patients supervise optimal clinical management.
with rheumatoid arthritis, to lifelong prophylactic colchicine in fa-
Specific innovative therapies
milial Mediterranean fever, and surgery in conditions such as re-
fractory osteomyelitis and the tumours of Castleman’s disease. Most Transthyretin amyloidosis
patients with AA amyloidosis complicating inflammatory arthritis Several therapies have been undergoing advanced clinical testing in
can now be treated effectively with one or other of the many bio- transthyretin amyloidosis and three have been approved by regu-
logical agents now available (i.e. anticytokine (TNF, IL-​1, IL-​6) and latory agencies. While hepatic transplantation has been shown to
anti-​CD20 antibodies etc.); IL-​1 inhibition with biological agents reduce neurological disease progression in patients with early-​stage
has revolutionized the management and prognosis of most patients familial amyloid polyneuropathy associated with the methionine-​
with inherited periodic fever syndromes. 30 substitution, in whom cardiac amyloid deposits are absent, this
Median SAA concentration has been shown to be a strong pre- approach is limited by donor liver availability, associated morbidity
dictor of both survival and renal outcome; sustained remission of and mortality, and continued deposition of wild-​type transthyretin
inflammation in association with normal SAA values is associated amyloid in the heart when cardiac amyloid is present at the time of
with an almost 18-​fold lower risk of death than median SAA levels surgery.
of greater than 155 mg/​L. Median survival of 79 to 137 months has
been reported in a very large series. Approximately 40% of patients Small-​molecule drugs
will eventually require renal replacement therapy, with a median New pharmacological therapies include the small-​ molecule
time to dialysis from diagnosis of 78 months. drugs diflunisal and tafamidis, which are bound in the plasma
by transthyretin and postulated to inhibit its conversion into
AL amyloidosis amyloid fibrils. The pivotal trial of tafamidis involved 441 pa-
Treatment of AL amyloidosis is based on that for myeloma, although tients with wild-​type as well as the hereditary form of disease.
the plasma cell dyscrasias in AL amyloidosis are often very subtle In 264 patients who received the active drug, all-​cause mortality
and tolerance of chemotherapy is frequently limited by amyloidotic and cardiovascular-​related hospitalizations were reduced as com-
organ dysfunction. Chemotherapy for AL amyloidosis therefore pared with placebo (30% reduction in death over a period of 2½
 12.12.3 Amyloidosis 2233

years); decline in functional capacity and quality of life was also because they can reduce cardiac output substantially in the pa-
decreased. Tafamidis (dose 20 mg daily) is approved for familial tient with stiff ventricles. Dysrhythmias may respond to conven-
amyloid polyneuropathy by the European Medicines Agency and tional pharmacological therapy or to insertion of pacemakers and
authorized by NHS England for treatment of transthyretin familial implantable defibrillators. Replacement of vital organ function,
amyloid polyneuropathy in patients with stage 1 symptomatic notably by dialysis, may be necessary, and cardiac, renal, and liver
polyneuropathy to delay peripheral neurological impairment and transplantation procedures have a role in selected cases. Excellent
before liver transplantation. results of renal transplantation in end-​stage renal failure have
been obtained in patients with apolipoprotein A-​I amyloidosis,
RNA interference therapy and in selected patients with systemic AA and AL amyloidosis;
In 2018, two therapies—​independently developed by competing it probably also remains the treatment of choice for patients with
biopharmaceutical companies (Alnylam and Akcea)—​ received hereditary fibrinogen α-​chain amyloidosis, although recurrent
marketing approval. These respectively use either an intravenously amyloid deposition of this type usually affects the transplant
administered small interfering double-​stranded RNA or a sub- within 5 to 10 years.
cutaneous antisense oligonucleotide that complements the mes-
Future treatment possibilities
senger transthyretin RNA. By selectively blocking the cognate sense
mRNA transcript of the TTR gene, hepatic synthesis of the unstable As noted at the beginning of this chapter, most of the pathogen-
transthyretin protein, which misfolds to give rise to amyloid de- esis of disease in amyloidosis is caused by the accumulation of
posits, is markedly inhibited. The Food and Drug Administration in the extracellular amyloid deposits which physically disrupt tissue
the United States of America and the European Medicines Agency architecture and thus function. The deposition of more amyloid
have approved both patisiran (Onpattro) and inotersen (Tegsedi), is invariabl y associated with clinical deterioration but sufficient
respectively, for treatment of the neuropathy caused by hereditary reduction of fibril precursor protein abundance halts amyloid ac-
transthyretin amyloidosis. In the larger of the two phase III clinical cumulation with slow regression of amyloid deposits in some pa-
trials, involving 255 patients, patisiran was shown to reverse neur- tients, stabilization of clinical status and potential improvement.
opathy in most; it also had salutary effects on a composite measure However, therapeutic interventions to directly target amyloid
of life quality, reducing autonomic manifestations and improving deposits and promote their clearance from the tissues would be
activities of daily living. highly desirable. Proof of concept, with unprecedented, clinically
These studies are encouraging for patients with transthyretin beneficial, removal of visceral amyloid, has been demonstrated by
amyloidosis but also serve as a landmark in the field of diseases antibody targeting of the serum amyloid P component present in
caused by the proteins misfolding. Patisiran and inotersen need all human amyloid deposits.
to be repeatedly administered, and while this mandates an at-
tractive business model for companies developing high-​ cost
therapies for rare diseases, it is not clear that the high annual FURTHER READING
charges proposed and health gains achieved will be reimbursable Adams D, et al. (2018). Patisiran, an RNAi therapeutic, for hereditary
worldwide. Access to the drugs may thus be limited for many af- transthyretin amyloidosis. N Engl J Med, 379, 11–​21.
fected patients. Benson MD, et al. (2018). Inotersen treatment for patients with heredi-
tary transthyretin amyloidosis. N Engl J Med, 379, 22–​31.
General measures Booth DR, et al. (1997). Instability, unfolding and aggregation of
human lysozyme variants underlying amyloid fibrillogenesis.
The disabling arthralgia of β2-​microglobulin amyloidosis may
Nature, 385, 787–​93.
partially respond to nonsteroidal anti-​inflammatory drugs or cor-
Gatt ME, Palladini G (2013). Light chain amyloidosis 2012: a new era.
ticosteroids, but even the most severe symptoms usually rapidly Br J Haematol, 160, 582–​98.
vanish following renal transplantation. The basis for this remark- Hawkins PN (2002). Serum amyloid P component scintigraphy
able clinical response is unclear, since although transplantation for diagnosis and monitoring amyloidosis. Curr Opin Nephrol
rapidly restores normal β2-​microglobulin metabolism, regression Hypertens, 11, 649–​55.
of β2-​microglobulin amyloid may not be evident for many years. Hawkins PN, Lavender JP, Pepys MB (1990). Evaluation of systemic
Supportive therapy remains critical in systemic amyloidosis, amyloidosis by scintigraphy with 123I-​labeled serum amyloid P com-
with the potential for delaying target organ failure, maintaining ponent. N Engl J Med, 323, 508–​13.
quality of life, and prolonging survival while the underlying pro- Kumar S, et al. (2012). Revised prognostic staging system for light
cess can be treated. Rigorous control of hypertension is vital in chain amyloidosis incorporating cardiac biomarkers and serum free
renal amyloidosis. Surgical resection of amyloidotic tissue is oc- light chain measurements. J Clin Oncol, 30, 989–​95.
casionally beneficial but, in general, a conservative approach to Kyle RA, Gertz MA (1995). Primary systemic amyloidosis: clinical and
laboratory features in 474 cases. Semin Hematol, 32, 45–​9.
surgery, anaesthesia, and other invasive procedures is advisable.
Lachmann HJ, et al. (2002). Misdiagnosis of hereditary amyloidosis as
Should any such procedure be undertaken, meticulous attention
AL (primary) amyloidosis. N Engl J Med, 346, 1786–​91.
to blood pressure and fluid balance is essential. Amyloidotic tis-
Lachmann HJ, et al. (2007). Natural history and outcome in systemic
sues may heal poorly and are liable to bleed. Diuretics and vaso- AA amyloidosis. N Engl J Med, 356, 2361–​71.
active drugs should be used cautiously in cardiac amyloidosis
2234 section 12 Metabolic disorders

Larsen CP, et al. (2010). Prevalence and morphology of leukocyte Pepys MB (2006). Amyloidosis. Annu Rev Med, 57, 223–​41.
chemotactic factor 2-​associated amyloid in renal biopsies. Kidney Richards DB, et al. (2015). Therapeutic clearance of amyloid by
Int, 77, 816–​19. antibodies to serum amyloid P component. N Engl J Med, 373,
Mangione, PP, et al. (2018). Plasminogen activation triggers 1106–​14.
transthyretin amyloidogenesis in vitro. J Biol Chem, 293(37), 14192–​9. Richards DB, et al. (2018). Repeat doses of antibody to serum amyloid
Marcoux, J. et al. (2015). A novel mechano-enzymatic cleavage mech- P component clear amyloid deposits in patients with systemic amyl-
anism underlies transthyretin amyloidogenesis. EMBO Mol Med, oidosis. Sci Transl Med, 10(422), eaan3128.
7, 1337–49. Sipe JD, et al. (2014). Nomenclature 2014: amyloid fibril pro-
Maurer MS, et al. (2018). Tafamidis treatment for patients with teins and clinical classification of the amyloidosis. Amyloid, 21,
transthyretin amyloid cardiomyopathy. N Engl J Med, 379, 1007–​16. 221–​4.
Papa R, Lachmann HJ (2018). Secondary, AA, amyloidosis. Rheum Dis Valleix S, et al. (2013). Hereditary systemic amyloidosis due to
Clin North Am, 44, 585–​603. Asp76Asn variant β2-​microglobulin. N Engl J Med, 366, 2276–​83.
12.13
α1-​Antitrypsin deficiency and
the serpinopathies
David A. Lomas

electrophoresis. Three of the individuals had emphysema and one

ESSENTIALS had a family history of emphysema. α1-​Antitrypsin is a 394-​amino
α1-​Antitrypsin is an acute phase glycoprotein synthesized by the acid, 52-​kDa acute phase glycoprotein synthesized by the liver,
liver that functions as an inhibitor of a range of proteolytic en- the lung and gut epithelial cells, neutrophils, and alveolar macro-
zymes, most importantly neutrophil elastase in the lung. Ninety-​five phages. It is present in the plasma at a concentration of between 0.9
per cent of severe plasma deficiency of α1-​antitrypsin results from and 1.8 g/​litre and functions as an inhibitor of a range of proteolytic
homozygosity for the Z allele (Glu342Lys), which causes the protein enzymes of which the most important is neutrophil elastase. α1-​
to undergo a conformational transition and form ordered polymers Antitrypsin deficiency results from point mutations that cause the
that are retained within hepatocytes as periodic acid–​Schiff-​positive, protein to misfold and be retained within hepatocytes which in turn
diastase-​resistant inclusions. causes liver disease. The lack of circulating α1-​antitrypsin causes un-
controlled tissue digestion within the lung and hence emphysema.
Clinical features—​ all adults homozygous for the Z allele of
α1-​antitrypsin have a minor degree of portal fibrosis that is often sub-
clinical, but up to 50% have clinically evident cirrhosis and occasionally
hepatocellular carcinoma. They also develop panlobular emphysema Genetics and pathogenesis of disease
that typically affects the lung bases and is greatly exacerbated by
smoking. Cor pulmonale and polycythaemia are late features. Genetics
Diagnosis and management—​ severe genetic deficiency of α1-​ α1-​Antitrypsin is subject to genetic variation resulting from mu-
antitrypsin is readily diagnosed by low plasma levels and the virtual tations in the 12.2-​kb, 7-​exon SERPINA1 gene on the long arm of
absence of the α1-​band on protein electrophoresis. Patients should chromosome 14 (14q32.1) (OMIM 107400). Over 100 allelic vari-
abstain from smoking and avoid agents that cause hepatic injury, ants have been reported and classified using the PI (protease in-
such as excessive alcohol and obesity. Emphysema is treated along hibitor) nomenclature that assesses α1-​ antitrypsin mobility in
conventional lines. α1-​Antitrypsin replacement therapy is widely used isoelectric focusing analysis. Normal α1-​antitrypsin migrates
in North America to slow the progression of the lung disease and has in the middle (M) and variants are designated A (anodal) to L if
recently been licensed by the European Medicines Agency, but its they migrate faster than M, and N to Z if they migrate more slowly.
clinical efficacy remains contentious and it has no effect on liver dis- Many of these variants have been sequenced at the DNA level and
ease. Clinical trials are underway to ‘knock down’ the expression of shown to result from point mutations in the α1-​antitrypsin gene
mutant Z α1-​antitrypsin within hepatocytes to try to prevent cirrhosis. (Table 12.13.1). For example, the Z allele results from the substitu-
Other serpinopathies—​ the polymerization that underlies α1-​ tion of a positively charged lysine for a negative glutamic acid at pos-
antitrypsin deficiency is found in other members of the serine pro- ition 342. The S allele results from the substitution of a neutral valine
tease inhibitor (or serpin) superfamily to cause diseases as diverse for a glutamic acid at position 264. Point mutations are inherited as a
as thrombosis (antithrombin), angio-​oedema (C1 inhibitor), and de- simple Mendelian trait; the normal genotype is designated PI MM or
mentia (neuroserpin). PI M, a heterozygote for the Z gene is PI MZ, and a homozygote is PI
ZZ or PI Z. α1-​Antitrypsin alleles are codominantly expressed, with
each allele contributing to the plasma level of protein. Therefore each
Introduction of the deficiency alleles results in a characteristic decrease in the
plasma concentration of α1-​antitrypsin; the S variant forms 60% of
α1-​Antitrypsin deficiency was first described by Carl-​Bertil Laurell the normal M concentration and the Z variant 10 to 15%. Thus com-
and Sten Eriksson in 1963 when they reported five individuals binations of alleles have predictable effects: the MZ heterozygote has
in whom there was a deficiency of the α1 band on serum protein an α1-​antitrypsin plasma level of 60% (50% from the normal M allele
2236 section 12 Metabolic disorders

Table 12.13.1 Pathogenic alleles that cause α1-​antitrypsin deficiency. The letter represents the migration on isoelectric focusing and
the name is typically the origin of the first reported individual

Variant Mutation Molecular basis of disease Clinical features Epidemiology

Deficiency alleles
I Arg39Cys Protein misfolding; able to No clear disease association Disease only reported in compound
form heteropolymers with heterozygotes
Z α1-antitrypsin
Reduced serum protein
King’s Hisp334Asp Rapid polymerization in Neonatal jaundice. Presumed high Case report
hepatocyte endoplasmic risk of emphysema in homozygote/​
reticulum, delayed secretion compound heterozygote
Mheerlen Pro369Leu Retained in the endoplasmic High risk of emphysema in Case report
reticulum, none secreted homozygotes/​compound heterozygotes.
Unknown liver disease risk
Mmalton Δ52Phe (M2 variant) Intracellular degradation and Well-​established association with Most common rare deficiency allele
polymerization; low serum liver disease and emphysema in in Sardinia; seen sporadically in the
concentration homozygotes UK and Canada
Mmineral springs Gly67Glu Abnormal post-​translational Emphysema in homozygotes Unusual as described in a
biosynthesis but no Afro-​Caribbean individual in the
polymerization; low serum United States
concentration
Mnichinan Δ52Phe and Intracellular polymerization Risk of liver disease and emphysema Case report ( Japanese family with
Gly148Arg in hepatocytes and plasma consanguineous origin)
deficiency
Mpalermo Δ51Phe Serum deficiency High risk of emphysema in Case report
homozygotes
Mprocida Leu41Pro Unstable protein structure High risk of emphysema in Case report
leading to intracellular homozygotes
degradation; reduced inhibitory
activity of circulating protein
Mvall d’hebron Pro369Ser Retained in the endoplasmic Presumed risk of emphysema Case reports from Spain and
(=Mwurzburg) reticulum, none secreted in homozygotes/​compound Germany
heterozygotes; 50% normal serum
α1-​antitrypsin level in M/​vall d’hebron
(/​wurzburg) heterozygotes
Mvarallo Δ41–​51, replaced Unknown intracellular defect Presumed risk of emphysema Case report
with 22 bp sequence in homozygotes/​compound
creating stop codon heterozygotes; 50% normal serum
at 70–​71 α1-​antitrypsin level in M/​Mvarallo
heterozygote
Pittsburgh Met358 Arg Function altered to an Fatal bleeding disorder Case report
antithrombin
Plowell (=QO Asp256Val (M1 Intracellular degradation and Increased risk of emphysema in Z/​QO Case report
Cardiff) and Pduarte and M4 alleles plasma deficiency compound heterozygotes
respectively)
S Glu264Val Protein misfolding and Emphysema seen in SZ heterozygotes Most common deficiency variant.
reduced secretion; able to but less severe than in ZZ homozygotes. Carrier frequency: 1:5 Northern
form heteropolymers with Z Cirrhosis reported in SZ heterozygotes Europe 1:30 USA 1:23 Australian
α1-​antitrypsin Caucasian 1:26 New Zealand
Caucasian Rare/​non-​existent in Asia,
Africa and Australian Aboriginals
Siiyama Ser53Phe Intracellular degradation and Liver disease and emphysema in Rare, but most common deficiency
polymerization; low serum homozygotes allele in Japan
concentration
Wbethesda Ala336Thr Intracellular degradation, Risk of liver disease and emphysema in Case report
serum levels 50% normal compound heterozygotes
Ybarcelona Asp256Val and Unknown intracellular defect; Severe emphysema reported in Case report
Pro391His very low serum protein homozygote
Z Glu342 Lys Intracellular degradation and Homozygotes: well-​established Commonest severe deficiency
polymerization; low serum association with liver disease and variant. Carrier frequency: 1:27
concentration emphysema. MZ heterozygotes may be Northern Europe 1:83 USA 1:75
more susceptible to airflow obstruction Australian Caucasian 1:46 New
and chronic liver disease Zealand Caucasian Not seen in
China, Japan, Korea, Malaysia,
Northern and Western Africa
 12.13 α1-​Antitrypsin deficiency and the serpinopathies 2237

Table 12.13.1 Continued

Variant Mutation Molecular basis of disease Clinical features Epidemiology

Zausburg (=Ztun) Glu342 Lys (M2 Intracellular degradation and Liver disease and emphysema Case report
variant) polymerization; low serum in homozygotes/​compound
concentration heterozygotes
Zwrexham Ser−19Leu and Poor expression, low serum Emphysema reported in compound Z/​ Case report
Glu342 Lys (Z concentration Zwrexham compound heterozygotes.
mutation) Unclear whether Ser-​19 Leu would
cause disease in absence of Z mutation
Null (QO) alleles
QO Bellingham Lys217 stop codon No detectable α1-​antitrypsin High risk of emphysema in Case report
mRNA homozygotes/​compound
heterozygotes
QO Bolton Δ1bpPro362 causing Truncated protein; intracellular High risk of emphysema in Case report
stop codon at 373 degradation and no secreted homozygotes/​compound
protein heterozygotes
QO Cairo Lys259 stop codon Unknown intracellular defect High risk of emphysema in Case report
homozygotes/​compound
heterozygotes
QO Clayton Pro362 insC causing Truncated protein; intracellular High risk of emphysema in Case report
stop codon at 376 degradation and no secreted homozygotes/​compound
protein heterozygotes
QO Devon (=QO Gly115Ser and Intracellular degradation Risk of emphysema and liver disease Case report
Newport) Glu342 Lys (Z and polymerization; reduced in compound heterozygotes. Unclear
mutation) serum concentration whether Gly115Ser would cause disease
in absence of Z mutation
QO Granite Falls Δ1bpTyr160 causing No detectable α1-​antitrypsin Severe emphysema reported in Z Case report
stop codon mRNA compound heterozygote
QO Hong Kong Δ2bpLeu318 causing Truncated protein; High risk of emphysema in Case reports (individuals of Chinese
stop codon at 334 intracellular aggregation (no homozygotes/​compound descent)
polymerization), degradation heterozygotes
and no secreted protein
QO Isola di Procida Δ17 Kb inc. exons No detectable α1-​antitrypsin Emphysema reported in Mprocida Case report
II–​V mRNA compound heterozygote
QO Lisbon Thr68Ile Truncated protein; not High risk of emphysema in Case report
secreted homozygotes. 50% normal serum
α1-​antitrypsin in M/​QO Lisbon
heterozygotes
QO Ludwisghafen Ile92 Asn Disruption of tertiary structure; High risk of emphysema in Case report
intracellular degradation and homozygotes/​compound
no detectable serum protein heterozygotes
QO Mattawa Leu353Phe causing Truncated protein; misfolding Emphysema reported in homozygotes Case reports
(M1allele)/​QO stop codon at 376 and reduced serum levels
Ourém (M3 allele)
QO Riedenburg Whole gene deletion No gene expression High risk of emphysema in Case report
homozygotes/​compound
heterozygotes
QO Saarbueken 1158dupC causing Truncated protein; not High risk of emphysema in Case report
stop codon at 376 secreted homozygotes. 50% normal serum
α1-​antitrypsin in M/​QO Saarbueken
heterozygotes
QO Trastevere Try194 stop codon Reduced mRNA, degradation Emphysema reported in compound Case report
of truncated protein; not heterozygote
secreted
QO West ΔGly164 Lys191 Aberrant mRNA splicing, Emphysema reported in compound Case report
intracellular degradation and heterozygote
no detectable serum protein

Reproduced from Dickens, J.A. and Lomas D.A. (2011) Why has it been so difficult to prove the efficacy of alpha-​1-​antitrypsin replacement therapy? Insights from the study of disease
pathogenesis. Drug Des Devel Ther, 5, 391–​405 with permission.
2238 section 12 Metabolic disorders

M M* D P

Fig. 12.13.1 Mutant Z α1-​antitrypsin is retained within hepatocytes as polymers. The structure of α1-​antitrypsin is centred
on β-​sheet A (green) and the mobile reactive-​centre loop (red). Polymer formation results from the Z variant of α1-​antitrypsin
(Glu342Lys at P17; arrowed) or mutations in the shutter domain (blue circle) that open β-​sheet A to favour partial loop insertion
and the formation of an unstable intermediate (M*). The patent β-​sheet A can accept the loop of another molecule to form a
dimer (D) which then extends into polymers.
From Gooptu, B., Hazes, B., Chang, W.-​S.W., Dafforn, T.R., Carrell, R.W., Read, R. & Lomas, D.A. (2000). Inactive conformation of the serpin
a1-​antichymotrypsin indicates two stage insertion of the reactive loop; implications for inhibitory function and conformational disease.
Proc. Natl. Acad. Sci (USA), 97, 67–​72, with permission.

and 10% from the Z allele), the MS heterozygote 80%, and the SZ The conformational transition that ensues results in the formation
heterozygote 40%. Rarely, point mutations can result in null alleles of a stable complex that inhibits the enzyme and allows it to be elim-
that express no functional α1-​antitrypsin and there is a case report inated from sites of inflammation. The Z mutation (Glu342Lys)
of a dysfunctional α1-​antitrypsin that no longer inhibits neutrophil results in normal translation of the gene, but 85% of the Z α1-​
elastase but which can inhibit other serine proteases. The Pittsburgh antitrypsin is retained within the endoplasmic reticulum with only
mutant (Met358Arg) converted α1-​antitrypsin into an inhibitor of 10 to 15% entering the circulation. The Z mutation distorts the re-
thrombin, thereby causing a fatal bleeding diathesis. lationship between the loop and the A β-​pleated sheet that forms
the major feature of the molecule. The consequent perturbation in
The molecular basis of α1-​antitrypsin deficiency structure allows the reactive-​centre loop of one α1-​molecule to lock
into the A sheet of a second to form a dimer which then extends
Liver disease to form chains of loop-​sheet polymers (Fig. 12.13.1). The forma-
α1-​Antitrypsin functions by presenting its reactive-​centre methio- tion of these polymers is temperature and concentration dependent
nine residue on an exposed loop of the molecule such that it forms and is localized to the endoplasmic reticulum of the hepatocyte
an ideal substrate for the enzyme neutrophil elastase (Fig. 12.13.1). (Fig. 12.13.2). These chains of polymers become interwoven to

(a) (b) (c)

Fig. 12.13.2 Z α1-​antitrypsin is retained within hepatocytes as intracellular inclusions. These inclusions are PAS positive and diastase resistant
(a) and are associated with neonatal hepatitis and hepatocellular carcinoma. (b) Electron micrograph of a hepatocyte from the liver of a patient
with Z α1-​antitrypsin deficiency shows the accumulation of α1-​antitrypsin within the rough endoplasmic reticulum (arrow). These inclusions are
composed of chains of α1-​antitrypsin polymers (c).
(b) and (c) Reproduced from (i) Lomas, D.A., Evans, D.L., Finch, J.T. & Carrell, R.W. (1992). The mechanism of Z α1-​antitrypsin accumulation in the liver. Nature, 357, 605–​
607. Copyright © 1992, Springer Nature. (ii) Lomas, D.A., Finch, J.T., Seyama, K., Nukiwa, T. & Carrell, R.W. (1993). α1-​antitrypsin Siiyama (Ser53→Phe); further evidence for
intracellular loop-​sheet polymerisation. J. Biol. Chem., 268, 15333–​15335, with permission.
 12.13 α1-​Antitrypsin deficiency and the serpinopathies 2239

form the insoluble intracellular aggregates that are the hallmark populated mid/​ northern Europe and before their migration to
of α1-​antitrypsin liver disease. The process of intrahepatic poly- Scandinavia. It is likely that the Z allele of α1-​antitrypsin was then
merization also underlies the severe plasma deficiency of the rare distributed across northern Europe by the Viking raiders between
Siiyama (Ser53Phe), Mmalton (deletion of residue 52) and King’s 800 and 1100 ad, and then to the United States of America and the
(His334Asp) deficiency alleles and the mild plasma deficiency of rest of the world during migration over the past 200 years. The S al-
the S (Glu264Val) and I (Arg39Cys) variants (Table 12.13.1). There lele appears to have arisen in the north of the Iberian peninsula, but
is a strong genotype–​phenotype correlation that can be explained the date of origin is uncertain. This mutation was similarly intro-
by the molecular instability caused by the mutation and in par- duced into North America by mass migration.
ticular the rate at which the mutant forms polymers. Those mutants
that cause the most rapid polymerization cause the most retention
of α1-​antitrypsin within the liver. This in turn correlates with the Clinical features
greatest risk of liver damage and cirrhosis, and the most severe
plasma deficiency. Misfolded Z α1-​antitrypsin within hepatocytes α1-​Antitrypsin deficiency and liver disease
is cleared by the proteosome but the ordered polymers are not de- The accumulation of abnormal protein starts in utero and is char-
tected by the unfolded protein response and are handled by less well acterized by periodic acid–​Schiff (PAS)-​positive, diastase-​resistant
understood pathways including autophagy. inclusions of α1-​antitrypsin in the periportal cells (Fig. 12.13.2).
Seventy-​ three per cent of Z α1-​ antitrypsin homozygote infants
Lung disease have a raised serum alanine aminotransferase in the first year of
The development of emphysema associated with α1-​antitrypsin life but in only 15% of people is it still abnormal by 12 years of age.
deficiency is greatly accelerated by tobacco smoking. Emphysema Similarly serum bilirubin is raised in 11% of PI Z infants in the first
results from uncontrolled enzymatic activity within the lung with 2–​4 months but falls to normal by 6 months of age. One in ten in-
those individuals with plasma α1-​antitrypsin levels of less than 40% fants develops cholestatic jaundice and 6% develop clinical evidence
of normal being most at risk. This is compounded by a fivefold reduc- of liver disease without jaundice. These symptoms usually resolve
tion in association rate kinetics with neutrophil elastase caused by by the second year of life but approximately 15% of patients with
the Z mutation and the polymerization of secreted Z α1-​antitrypsin cholestatic jaundice progress to juvenile cirrhosis. The overall risk
within the airways and alveoli. The formation of polymers inacti- of death from liver disease in PI Z children during childhood is 2
vates α1-​antitrypsin (thereby further reducing the protein avail- to 3%, with boys being at more risk than girls. All adults with the Z
able to inhibit neutrophil elastase) and the polymers themselves are allele of α1-​antitrypsin have slowly progressive hepatic damage that
chemotactic for neutrophils and so may drive some of the excessive is often subclinical and only evident as a minor degree of portal fi-
inflammation that characterizes the lung disease associated with α1-​ brosis. However, up to 50% of Z α1-​antitrypsin homozygotes present
antitrypsin deficiency. with clinically evident cirrhosis and occasionally with hepatocellular
carcinoma.

Epidemiology α1-​Antitrypsin deficiency and emphysema

Patients with emphysema related to α1-​antitrypsin deficiency usu-
Two point mutations have been shown to explain the vast ma- ally present with increasing dyspnoea with cor pulmonale and poly-
jority of cases of α1-​antitrypsin deficiency. The Z allele causes the cythaemia occurring late in the course of the disease. Emphysema
most severe plasma deficiency and is most prevalent in southern associated with Z α1-​ antitrypsin deficiency differs from ‘usual
Scandinavia and the north-​western European seaboard where 4% chronic obstructive pulmonary disease (COPD)’ with normal
of the population are MZ heterozygotes and 1 in 1700 are PI Z levels of M α1-​antitrypsin in that it affects predominantly the bases
homozygotes. The gene frequency of the Z allele reduces towards rather than the apices of the lungs, it is associated with panlobular
the south and east of Europe. In contrast, the S allele causes only rather than centrilobular disease, and it results from the expression
mild plasma deficiency and is most common in southern Europe of different genes when assessed by microarray analysis. However,
where up to 28% of the population are MS heterozygotes. The S allele in many cases the distribution of disease is indistinguishable from
becomes less frequent as one moves north-​east. The frequencies of ‘usual COPD’. High-​resolution CT scans are the most accurate
the Z allele in the United States of America are similar to the lowest method of assessing the distribution of panlobular emphysema and
frequencies in Europe but the S allele is more common than in nor- for monitoring the progress of the pulmonary disease, although this
thern Europeans. α1-​Antitrypsin deficiency is infrequent in Asian, currently has little value outside clinical trials. Lung function tests
African, and Middle Eastern populations. It is also rare in Japan, but are typical for emphysema with a reduced FEV1/​FVC ratio (forced
when present it is usually due to the Siiyama mutation (Ser53Phe). expiratory volume in 1 s/​forced vital capacity) and FEV1, gas trap-
In the genetically isolated island of Sardinia, the commonest cause of ping (raised residual volume/​total lung capacity ratio), and a low
severe α1-​antitrypsin deficiency is the Mmalton mutation (deletion gas-​transfer factor. Partial reversibility of airflow obstruction (as
of residue 52). defined by an increase of 12% and 200 ml in FEV1) is common in
The Z allele is believed to have arisen from a single origin 66 individuals with COPD secondary to α1-​antitrypsin deficiency as
generations or 2000 years ago. The high frequency in southern it is in many individuals with COPD. The most important factor in
Scandinavia suggests that the mutation arose in the Viking popula- the development and progression of emphysema in α1-​antitrypsin
tion. The date of origin implies that the allele arose when the Vikings deficiency is tobacco smoking.
2240 section 12 Metabolic disorders

Other conditions associated Parents with a child with severe Z α1-​antitrypsin liver disease may
with α1-​antitrypsin deficiency require genetic counselling. The likelihood of similar severe liver
α1-​Antitrypsin deficiency is associated with an increased prevalence damage in a subsequent Z homozygote sibling is approximately 20%.
of asthma, panniculitis, granulomatosis with polyangiitis, and pos- The uncommon α1-​antitrypsin deficiency-​associated panniculitis
sibly pancreatitis, gallstones, bronchiectasis, and intracranial and usually responds to dapsone, 100 to 150 mg daily, for 2 to 4 weeks,
intra-​abdominal aneurysms. There appears to be a reduced risk of but occasionally it necessitates the administration of intravenous α1-​
cardiovascular disease. antitrypsin replacement therapy.

Clinical investigation Prognosis

The severe genetic deficiency of α1-​antitrypsin is readily diagnosed Estimates of the annual rate of decline in FEV1 range from 41 to 109
by low plasma levels and the virtual absence of the α1 band on protein ml in individuals with α1-​antitrypsin deficiency although one study
electrophoresis. As α1-​antitrypsin is an acute phase protein, most reported a rate of decline of 316 ml/​year in current smokers. The
laboratories will report levels with another acute phase reactant, fastest rate of decline is in current smokers (and, to a lesser extent,
such as α1-​antitchymotrypsin or C-​reactive protein, which allows ex-​smokers), men, individuals aged 30–​44 years, those with FEV1
an assessment of the likelihood of deficiency in the context of the values between 35 and 79% predicted, and those with a broncho-
inflammatory response. The acute phase response raises the plasma dilator response. Respiratory failure accounts for 50 to 72% of deaths
level of α1-​antitrypsin, but the plasma level of the PI Z homozygote in individuals with α1-​antitrypsin deficiency with the second most
can never reach the normal range. The deficiency variant is then as- common cause of death being liver cirrhosis (10–​13%). Most chil-
signed a PI phenotype according to the migration of the protein on dren avoid significant liver damage in childhood but are still at risk
an isoelectric focusing gel. The mutation underlying the deficiency of disease in adult life. The factors that predict progressive liver dis-
can be determined by sequencing the SERPINA1 gene. Commercial ease are unclear but males and the obese appear to be most at risk.
kits permit detection of the Z and S alleles but will not detect null or The only significant cohort study has followed 184 individuals with
other rare alleles. α1-​antitrypsin deficiency (127 PI Z, 2 PI Znull, 54 PI SZ, 1 PI Snull)
from birth to 34 years of age. One PI SZ and five PI Z children died
in early childhood (two of liver disease and two of other causes but
Treatment were found to have histological signs of cirrhosis or fibrosis at post-
mortem) and 12% and 6% of PI Z subjects had abnormal liver func-
The treatment of α1-​antitrypsin deficiency depends largely on the tion tests at 18 and 26 years respectively but no clinical evidence of
avoidance of stimuli causing repeated pulmonary inflammation—​ liver disease. All the 34-​year-​olds had normal liver and lung function
primarily smoking. Patients with α1-​antitrypsin deficiency-​related (including the 14% of individuals who were current or ex-​smokers)
emphysema should receive conventional therapy with trials of bron- but smoking frequency was significantly lower among individuals
chodilators and inhaled corticosteroids, pulmonary rehabilitation, with α1-​antitrypsin deficiency than in the controls.
and, where appropriate, assessment for long-​term oxygen therapy A logical follow-​on from the association of α1-​antitrypsin defi-
and lung transplantation. The role of lung volume-​reduction surgery ciency with emphysema is an assessment of the risk of COPD in
in this group is less clear as the disease is basal rather than apical and heterozygotes who carry an abnormal Z allele and a normal M allele.
resections of this region are technically more difficult. Any benefits These individuals have plasma α1-​antitrypsin levels that are approxi-
are shorter lasting than in individuals with COPD and normal levels mately 60% of normal. A population-​based study demonstrated that
of α1-​antitrypsin. PI MZ α1-​antitrypsin heterozygotes do not have a clearly increased
The lung disease results from a deficiency in the anti-​elastase risk of lung damage. However, if groups of patients are collected who
screen. This may be rectified biochemically by intravenous infu- already have COPD, then the prevalence of PI MZ individuals ap-
sions of α1-​antitrypsin. Registry data suggest that individuals with pears to be elevated. In addition, a longitudinal study has demon-
α1-​antitrypsin deficiency and an FEV1 of 35 to 49% predicted may strated that among COPD patients, the PI MZ heterozygotes have a
derive benefit from replacement therapy. One controlled trial has more rapid decline in lung function. These data suggest that either
shown reduced progression of CT markers of emphysema in in- all PI MZ α1-​antitrypsin individuals are at slightly increased risk
dividuals receiving intravenous α1-​antitrypsin, but none has been for the development of COPD, or that a subset of the PI MZ α1-​
powered to detect an effect on patient-​reported outcomes or mor- antitrypsin subjects are at substantially increased risk of pulmonary
tality. α1-​Antitrypsin replacement therapy is widely used in North damage if they smoke.
America and has recently been licensed by the European Medicines
Agency but its clinical efficacy remains contentious.
All Z homozygotes have some liver damage and, as such, would Other ‘serpinopathies’
be wise to avoid alcohol abuse and obesity. PI Z homozygotes should
be monitored for the persistence of hyperbilirubinaemia as this, α1-​Antitrypsin is the archetypal member of a superfamily of proteins
along with deteriorating results of coagulation studies, indicates the termed the serine protease inhibitors, or serpins, that have closely
need for liver transplantation. Clinical trials are underway to ‘knock related structures and functions. These inhibitors control various in-
down’ the expression of mutant Z α1-​antitrypsin within hepatocytes flammatory cascades, including coagulation (antithrombin), com-
to prevent the protein overload that causes cirrhosis. plement activation (C1-​inhibitor), and fibrinolysis (α2-​antiplasmin).
 12.13 α1-​Antitrypsin deficiency and the serpinopathies 2241

Pathological processes that underlie the deficiency of one member Clinical trials are underway to evaluate the efficacy of this agent in
may account for deficiency of others. Indeed, the process of α1-​antitrypsin deficiency-​related liver disease in humans. The long-​
polymer formation has also been reported in deficiency mutants of term aim is to exploit our understanding of the pathogenesis of
antithrombin, C1-​inhibitor, α1-​antichymotrypsin, and heparin co- α1-​antitrypsin deficiency to develop small molecules to block poly-
factor II. These polymers are inactive as proteinase inhibitors and so merization and so treat the associated liver and lung disease.
predispose the individual to thrombosis (antithrombin) and angio-​
oedema (C1-​inhibitor). The plasma deficiency that results from the
polymerization of mutants of α1-​antichymotrypsin has been asso- FURTHER READING
ciated with COPD in some (but not all) association studies, but the
Chapman KR, et al. (2015). Intravenous augmentation treatment and
plasma deficiency of heparin cofactor II has yet to be associated with
lung density in severe α1-​antitrypsin deficiency (RAPID): a ran-
a clinical phenotype. Perhaps the most striking serpinopathy results domised, double-​blind, placebo-​controlled trial. Lancet, 386, 360–​8.
from the polymerization of mutants of a neuron-​specific serpin, Davis RL, et al. (2002). Association between conformational muta-
neuroserpin, to cause the novel inclusion-​body dementia known as tions in neuroserpin and onset and severity of dementia. Lancet,
familial encephalopathy with neuroserpin inclusion bodies (FENIB; 359, 2242–​7.
OMIM 604218). This is inherited as an autosomal dominant trait Eriksson S, Carlson J, Velez R (1986). Risk of cirrhosis and primary liver
with the inclusions of neuroserpin in the brain being PAS positive cancer in alpha1-​antitrypsin deficiency. N Engl J Med, 314, 736–​9.
and diastase resistant, identical to those of Z α1-​antitrypsin in the Gooptu B, Lomas DA (2009). Conformational pathology of the
liver. The six mutations that have been described show a striking in- serpins—​themes, variations and therapeutic strategies. Ann Rev
verse correlation between the rate that the protein forms polymers Biochem, 78, 147–​76.
and the age of onset/​severity of the dementia. Hidvegi T, et al. (2010). An autophagy-​enhancing drug promotes
degradation of mutant alpha1-​antitrypsin Z and reduces hepatic fi-
brosis. Science, 329, 229–​32.
Laurell C-​B, Eriksson S (1963). The electrophoretic α1-​globulin pat-
New and emerging treatments tern of serum in α1-​antitrypsin deficiency. Scand J Clin Lab Invest,
15, 132–​40.
Other treatments at earlier stages of development include gene and Lomas DA (2006). The selective advantage of α1-​antitrypsin deficiency.
stem cell therapy and chemical chaperones. Vectors carrying the Am J Resp Crit Care Med, 173, 1072–​7.
α1-​antitrypsin gene have been targeted to liver, lung, and muscle in Mahadeva R, et al. (2005). Polymers of Z α1-​antitrypsin co-​localise
animals. There is good expression of α1-​antitrypsin but further data with neutrophils in emphysematous alveoli and are chemotactic in
are required to assess whether this can be achieved in humans. In vivo. Am J Pathol, 166, 377–​86.
particular, it is important to determine the length of time of protein Owen MC, et al. (1983). Mutation of antitrypsin to antithrombin.α1-​
expression and whether the levels of α1-​antitrypsin in the epithelial antitrypsin Pittsburgh (358 Met to Arg), a fatal bleeding disorder. N
lining fluid of the lung are sufficient to prevent ongoing proteolytic Engl J Med, 309, 694–​8.
damage. Genomic correction of fibroblast-​derived, induced pluri- Tanash HA, et al. (2015). The Swedish α1-​antitrypsin Screening
potent stem cells provides a novel strategy to generate ‘corrected Study: health status and lung and liver function at age 34. Ann Am
hepatocytes’ from individuals with α1-​antitrypsin deficiency, but Thorac Soc, 12, 807–​12.
Sveger T (1976). Liver disease in alpha1-​antitrypsin deficiency de-
further development is required before these can be used as ‘hep-
tected by screening of 200,000 infants. N Engl J Med, 294, 1316–​21.
atocyte replacement therapy’ in humans. The antiepileptic drug
Yusa K (2011). Targeted gene correction of α1-​antitrypsin deficiency in
carbamazepine increases autophagy and so promotes the degrad- induced pluripotent stem cells. Nature, 478, 391–​4.
ation of Z α1-​antitrypsin in cell lines and mouse models of disease.
SECTION 13
Endocrine disorders
Section editor: Mark Gurnell

13.1 Principles of hormone action 2245 13.6.3 Benign breast disease 2406
Rob Fowkes, V. Krishna Chatterjee, and Mark Gurnell Gael M. MacLean
13.6.4 Sexual dysfunction 2408
13.2 Pituitary disorders 2258 Ian Eardley
13.2.1 Disorders of the anterior pituitary gland 2258
Niki Karavitaki and John A.H. Wass 13.7 Disorders of growth and development 2416
13.2.2 Disorders of the posterior pituitary gland 2277 13.7.1 Normal growth and its disorders 2416
Niki Karavitaki, Shahzada K. Ahmed, Gary Butler
and John A.H. Wass 13.7.2 Normal puberty and its disorders 2428
Fiona Ryan and Sejal Patel
13.3 Thyroid disorders 2284
13.7.3 Normal and abnormal sexual
13.3.1 The thyroid gland and disorders of thyroid
differentiation 2435
function 2284 S. Faisal Ahmed and Angela K. Lucas-​Herald
Anthony P. Weetman and Kristien Boelaert
13.3.2 Thyroid cancer 2302 13.8 Pancreatic endocrine disorders and multiple
Kristien Boelaert and Anthony P. Weetman endocrine neoplasia 2449
B. Khoo, T.M. Tan, and S.R. Bloom
13.4 Parathyroid disorders and diseases altering
calcium metabolism 2313 13.9 Diabetes and hypoglycaemia 2464
R.V. Thakker 13.9.1 Diabetes 2464
Colin Dayan and Julia Platts
13.5 Adrenal disorders 2331
13.9.2 Hypoglycaemia 2531
13.5.1 Disorders of the adrenal cortex 2331 Mark Evans and Ben Challis
Mark Sherlock and Mark Gurnell
13.5.2 Congenital adrenal hyperplasia 2360 13.10 Hormonal manifestations of non​endocrine
Nils P. Krone and Ieuan A. Hughes disease 2541
Thomas M. Barber and John A.H. Wass
13.6 Reproductive disorders 2374
13.6.1 Ovarian disorders 2374 13.11 The pineal gland and melatonin 2553
Stephen Franks, Kate Hardy, and Lisa J. Webber J. Arendt and Timothy M. Cox
13.6.2 Disorders of male reproduction and male
hypogonadism 2386
P.-​M.G. Bouloux
13.1
Principles of hormone action
Rob Fowkes, V. Krishna Chatterjee, and Mark Gurnell

ESSENTIALS Definition
Hormones, produced by glands or cells, are messengers which act Endocrinology is the study of hormones secreted by glands or
locally or at a distance to coordinate the function of cells and organs. cells which, acting locally or at a distance, facilitate communica-
Types of hormone include (1) peptides (e.g. hypothalamic releasing tion between cells and different organs, thus coordinating their
factors) and proteins (e.g. insulin, growth hormone)—​these generally activities.
interact with membrane receptors located on the cell surface, causing Classically, the production of hormones has been associated
activation of downstream signalling pathways leading to alteration in with specialized glands or tissues including the hypothalamus,
gene transcription or modulation of biochemical pathways to effect pituitary, thyroid, parathyroids, gonads, pancreatic islet cells, ad-
a physiological response; (2) steroids (e.g. cortisol, progesterone, tes- renal glands, and placenta. It is now recognized that hormones
tosterone, oestradiol) and other lipophilic substances (e.g. vitamin are also produced by a range of other organs and tissues which
D, retinoic acid, thyroid hormone)—​these act by crossing the plasma are not considered to be classical endocrine glands. The heart is
membrane to interact with intracellular receptors, with hormone ac- the primary source of atrial natriuretic peptide factor which has
tion via nuclear receptors altering cellular gene expression directly. effects blood pressure and intravascular volume; endothelin and
Hormone synthesis, processing, and secretion—​production of hor- nitric oxide are derived from vascular endothelium and regulate
mones can be regulated at many levels, including (1) gene transcrip- vascular tone. Endocrine cells are distributed throughout the
tion; (2) mRNA processing; (3) post-​translational modification. Some gastrointestinal tract and are a rich source of hormones such as
hormones are not significantly concentrated within cells and are re- cholecystokinin, gastrin, secretin, and vasoactive intestinal pep-
leased via Golgi-​derived transport vesicles that fuse with the plasma tide; many of these gastrointestinal hormones are also produced
membrane (a ‘constitutive’ pathway of secretion). By contrast, many in the brain and central nervous system, where their role is less
endocrine cells contain an additional ‘regulated’ secretory pathway, well understood. Erythropoietin, a circulating factor that stimu-
which allows the export of high concentrations of hormone stored lates erythropoiesis, is derived from the kidney. Adipose tissue
in cytoplasmic vesicles. Many hormones are released in a rhythmic produces leptin, a circulating hormone which acts centrally to
or pulsatile manner. control appetite.
Control of hormone production—​the classical mechanism by which However, as understanding of intercellular communication
hormone-​producing glands are controlled is by negative feedback, has advanced, the lines of division that separate different physio-
e.g. triiodothyronine (T3) inhibits production of thyrotropin-​releasing logical systems have become blurred. For example, neuroendo-
hormone and thyroid-​stimulating hormone. crinology represents intimate connections between the nervous
Physiological roles of hormones—​these are enormously varied and and endocrine systems: peptide hormones produced in the brain
include (1) control of growth and differentiation; (2) maintenance of exert effects via the hypothalamus to control hormone secre-
homeostasis—​energy balance, metabolic pathways; fluid, electrolyte, tion from the pituitary gland; in the periphery, the sympathetic
and calcium balance; control of blood pressure; and (3) regulation nervous system modulates hormone production by the adrenal
of reproduction. medulla and pancreatic islets. Similarly, there are complex
Clinical features of endocrine disorders—​these comprise conditions interrelationships between the immune and endocrine systems
of either hormone excess or hormone deficiency or hormone resist- (e.g. glucocorticoid hormones exert powerful immunosuppres-
ance, caused by acquired endocrine cellular dysfunction or germline sive effects); conversely, cytokines (e.g. tumour necrosis factor α
or somatic defects in genes mediating hormone synthesis or action and interleukin (IL)-​6), produced by cells of the immune system,
causing inherited syndromes. markedly influence hormone secretion by glands such as the pi-
tuitary and adrenal.
2246 SECTION 13 Endocrine disorders

cortex developing from mesoderm, together with a catecholamine-​

Nature of hormones
producing medulla composed of chromaffin cells derived
from neural crest. Germ cells within indifferent gonadal prim-
In general, hormones can be classified into those that are based on
ordia differentiate to form the ovary or, in the presence of the Y
proteins or peptides and those that are chemically derived. Small
chromosome-​encoded sex-​determining gene (SRY), develop into
peptides include hypothalamic releasing factors produced by neuro-
testes. Endocrine cells of the pancreas are derived from endoderm
endocrine cells, which act locally on the pituitary; larger polypep-
and differentiate to form the islets of Langerhans. Various tran-
tides such as insulin or growth hormone (GH) are characteristically
scription factors which control the development of cells within
circulating hormones which act on more distant targets. Biogenic
endocrine glands and their differentiation to hormone biosynthesis
amines including catecholamines, dopamine, and serotonin are de-
are listed in Table 13.1.1.
rived from amino acids. Most protein and peptide hormones interact
with membrane receptors located on the cell surface. Binding to
membrane receptors activates downstream signalling pathways
leading to changes in cellular function which mediate responses to
Hormone synthesis, processing, and secretion
hormones.
The organization of endocrine genes is homologous to those
A second class of hormones includes steroids and other lipophilic
encoding many other proteins, although there are some character-
substances which act by crossing the plasma membrane to interact
istic features. Gene transcription is usually regulated by the pro-
with intracellular receptors. Steroid hormones are derived from
moter, which is located in the upstream 5′ flanking region of the gene
cholesterol and include cortisol, progesterone, testosterone, and
(Fig. 13.1.1). Typically, the promoter may contain three types of
oestradiol. Vitamin D and retinoic acid, which are synthesized from
regulatory DNA sequence which are recognized by specific tran-
dietary sources, and thyroid hormone produced by modification of
scription factors; a hormone response element is recognized by
tyrosines in thyroglobulin, are structurally dissimilar to steroids but
nuclear receptors; a tissue-​ specific element binds cell-​ specific
also act via nuclear receptors.

Development of endocrine glands Cell specific

transcription Jun
Nuclear factor
The hypothalamus develops from forebrain tissue adjacent to receptor
Fos
the third ventricle. Neurons secreting releasing factors send cel- Basal
CREB transcription
lular processes which terminate in portal capillaries that perfuse factors + +
the pituitary gland. The latter develops from ectoderm to form
the adenohypophysis or anterior pituitary; the posterior pituitary HRE TSE CRE AP-1
or neurohypophysis is formed directly from axonal terminals of Transcription
initiation site
hypothalamic neurons which grow downward. The thyroid gland
develops from endoderm in the floor of the oropharynx with mi-
mRNA
gration of cells caudally to its final position in the neck. During
its descent, parafollicular C cells derived from neural crest tissue Nucleus
within the ultimobranchial body and parathyroid glands from the Cytoplasm
third and fourth pharyngeal pouches, become incorporated into Signal
sequence
the thyroid gland. The adrenal glands comprise a steroid-​secreting Rough
Prepro-
hormone endoplasmic
reticulum

Table 13.1.1 Some transcription factors involved in endocrine

gland development Prohormone
Mature hormone
cleavage
Gland Transcription factor(s) Golgi
network
Pituitary HESX-​1, POU1F1, PROP-​1, TBX19
Post-translational
Thyroid TTF-​1, TTF-​2, PAX-​8 modification

Adrenal cortex SF-​1, DAX-​1

Intracellular
Pancreatic islet cells IPF-​1
Testis SRY, SF-​1 Secretory
granule Extracellular
Ovary SF-​1, DAX-​1
Mature
DAX-​1, dosage-​sensitive sex reversal adrenal hypoplasia critical region on the
X-​chromosome 1; HESX-​1, homeobox gene expressed in embryonic stem cells 1; IPF-​1,
Ca2+− polypeptide
insulin promoter factor 1; PAX-​8, paired box gene 8; POU1F1, POU homeodomain dependent
containing pituitary transcription factor 1 (previously known as Pit-​1); PROP-​1, prophet exocytosis
of Pit-​1; SF-​1, steroidogenic factor 1; SRY, sex-​determining region of the Y chromosome;
TBX-​19 (also known as TPIT), a T-​box containing transcription factor; TTF-​1, thyroid Fig. 13.1.1 Pathway of hormone synthesis, processing, and secretion.
transcription factor 1; TTF-​2, thyroid transcription factor 2. See text for explanation.
 13.1 Principles of hormone action 2247

transcription factors (see Table 13.1.1), which enhance the tran- translocation and docking with the plasma membrane (see Fig.
scription of the hormone gene in a tissue-​specific manner; a third 13.1.1). Cells secreting steroid hormones contain abundant mito-
class of response element mediates transcriptional activation in re- chondrial and smooth endoplasmic reticulum which contain en-
sponse to second-​messenger signalling pathways. A rise in intra- zymes that mediate steroid biosynthesis. Mitochondrial side-​chain
cellular cAMP leads to the activation of protein kinase A and cleavage enzyme converts cholesterol to pregnenolone and the latter
subsequent phosphorylation of cAMP response element binding is converted to glucocorticoid, mineralocorticoid, or sex steroids de-
proteins (CREBs) which interact with CREs; cell signalling path- pendent on the cell-​specific expression of steroidogenic enzymes.
ways which activate protein kinase C induce phosphorylation of the Steroid hormones are not stored to any extent and are secreted
Fos-​Jun (AP-​1) transcription factor complex which binds its cog- constitutively.
nate DNA regulatory sequence. Binding of transcription factors to
regulatory DNA response elements, activates and stabilizes basal
transcription factors, promoting gene transcription and mRNA Control of hormone production
synthesis (Fig. 13.1.1).
Transcription of the gene generates mRNA which undergoes The classic mechanism by which hormone-​producing glands com-
translation in ribosomes leading to polypeptide synthesis. In some municate is by endocrine pathways, whereby the products from one
endocrine genes, alternative exon splicing allows substitution or re- gland are secreted into the circulation (and exert effects on a dif-
moval of particular exons, such that peptides of differing sequence ferent, distant target gland). Such endocrine pathways integrate the
can be produced. For example, alternative splicing of the calcitonin hypothalamus, pituitary, and various end organs to control the pro-
gene in a tissue-​specific manner directs the production of calcitonin duction of major hormones (Fig. 13.1.2). Thus, peptide-​releasing
in the C cells of the thyroid, whereas calcitonin gene-​related peptide factors (e.g. GnRH, TRH, GHRH, CRH) from the hypothalamus,
is produced preferentially in the brain. stimulate production of tropic hormones from specific pituitary cell
Secreted polypeptide hormones incorporate a signal sequence at types; exceptions to this are somatostatin, which inhibits pituitary
the amino terminus of the protein which directs its translocation GH release, and dopamine, which is secreted continuously to in-
across the endoplasmic reticulum where this sequence is cleaved hibit prolactin secretion. The pituitary hormones act on end organs
(Fig. 13.1.1). Many hormones are synthesized as larger polypep- to generate products which, in turn, exert a negative feedback ef-
tides (prohormones) which undergo proteolytic cleavage to generate fect at both hypothalamic and pituitary levels to regulate their own
smaller functional peptides. Such proteolytic processing is mediated synthesis. Triiodothyronine (T3) inhibits TRH and TSH produc-
by specific proteases, such as prohormone convertase 1 and 2 (PC1, tion; gonadal steroids and inhibin negatively regulate hypothalamic
PC2), which are highly expressed in cells of neuroendocrine lineage. GnRH and pituitary gonadotropins; cortisol suppresses CRH and
Examples of hormone processing include the cleavage of proinsulin ACTH generation; circulating insulin-​like growth factor 1 (IGF-​1)
with removal of an internal C peptide to yield insulin, the active inhibits GHRH and GH secretion (Fig. 13.1.2). Osmoreceptors in
hormone. Processing of the polypeptide precursor can also yield the hypothalamus sense changes in serum osmolality to control the
multiple functioning products. For example, pro-​opiomelanocortin release of vasopressin from the posterior pituitary.
(POMC) is cleaved by endopeptidases to yield adrenocorticotropic In addition to these endocrine control mechanisms, other types
hormone (ACTH), melanocyte-​stimulating hormone (MSHα, β, γ), of local regulatory pathways are recognized. Paracrine regulation re-
β-​endorphin, and lipocortin. fers to factors that are released by one cell and act upon a nearby cell
Hormones may also undergo post-​translational modification in the same tissue. For example, somatostatin produced by δ cells
such as amidation of neuropeptides, acylation, or glycosylation. in pancreatic islets inhibits the local production of insulin from β
Modification of amino acids by addition of carbohydrate side cells; in the testis, testosterone produced from Leydig cells exerts an
chains is a particular characteristic of the glycoprotein hormones—​ effect on nearby Sertoli cells to enhance spermatogenesis. Autocrine
luteinizing hormone (LH), follicle-​stimulating hormone (FSH), control refers to a factor which acts upon the same cell in which it is
thyroid-​ stimulating hormone (TSH), and human chorionic produced. Examples include gonadotroph secretion of activin which
gonadotropin (hCG)—​and such glycosylation affects both their stimulates production of FSH from the same cell; similarly, T cells
biological activity as well as their half-​life in the circulation (see produce IL-​2 which acts to promote their own proliferation.
Fig. 13.1.1). In addition to discrete hormonal responses, endocrine systems
Hormones such as growth factors and cytokines are not concen- can respond to environmental stimuli by the integrated production
trated within cells significantly but released via small, clear, Golgi-​ of multiple hormones. For example, stress activates an array of path-
derived transport vesicles which fuse with the plasma membrane, ways, with sympathetic activation mediating catecholamine release
representing a ‘constitutive’ pathway of secretion. In contrast, many from the adrenals, and stimulation of the hypothalamus inducing
endocrine cells contain an additional ‘regulated’ secretory pathway, multiple axes, resulting in the production of cortisol, GH, prolactin,
which allows the export of high concentrations of hormone stored and vasopressin. The hormonal responses to starvation are also inte-
in cytoplasmic dense-​core vesicles. Chromogranin B, an acidic grated by the hypothalamus. Here, diminished production of leptin
protein, and polypeptide proteases are additional constituents from adipose tissue inhibits hypothalamic GnRH and TRH secre-
of secretory vesicles. Adrenal cells secreting catecholamine hor- tion with a consequent reduction in the production of both gonadal
mones contain chromaffin granules which include enzymes (e.g. steroids and thyroid hormone to limit reproduction and energy
dopamine β hydroxylase) that catalyse catecholamine biosynthesis. expenditure.
Dense-​core vesicle exocytosis is mediated by a rise in intracellular In addition to the feedback regulatory mechanisms just outlined,
calcium which activates cytoskeletal machinery, promoting vesicle many hormones are released in a rhythmic or pulsatile manner.
2248 SECTION 13 Endocrine disorders

Oestrogen
Progesterone
Testosterone ↑Plasma
Inhibin T3 IGF1 Cortisol osmolality
−
Hypothalamus GnRH TRH GHRH CRH Vasopressin Oxytocin
Somatostatin Dopamine

Anterior pituitary
− − Posterior
+ Pituitary LH/FSH TSH GH ACTH PRL
gland pituitary

+ Target Thyroid Adrenal Distal Uterus

Gonads Liver Breast
organ gland cortex nephron Breast

Hormone Effect(s)
+ −
Other
target
organs
Effect(s)

Fig. 13.1.2 Control of hormone production. Regulatory pathways integrating the

hypothalamus, pituitary, and various end organs. Hormones shown in italics exert inhibitory
effects. Negative feedback regulation occurs at both hypothalamic and pituitary levels. See
text for explanation.

Insulin is secreted in rapid (c. every 10 min) pulses in response to binding proteins is to provide a reservoir of circulating hormone.
changes in glucose concentration in the pancreatic β cell. GnRH is The interaction of hormones with binding proteins is relatively
secreted from the hypothalamus at a lower pulse frequency of every weak compared to their affinity for receptors, enabling them to dis-
1.5 to 3 h, stimulating similar pulses of pituitary LH and FSH release; sociate easily. Only free hormone interacts with receptor to elicit
differential release of LH and FSH is controlled by varying GnRH a biological response. Hormone-​binding proteins are produced by
pulse frequency, with low frequency pulses favouring FSH secre- the liver and their synthesis can be increased (e.g. by oestrogens
tion and high frequency pulses stimulating LH secretion. Another or in pregnancy) or decreased (e.g. in liver disease), affecting the
hypothalamic peptide (kisspeptin) can augment GnRH secretion circulating concentration of total hormones. Accordingly, wher-
in a paracrine manner. This hormonal rhythm controls ovarian ever possible, the concentration of free hormones in the circulation
folliculogenesis and steroid production to establish the female re- (e.g. T4, T3) or urine (cortisol) is measured. Some protein hor-
productive and menstrual cycle. Pituitary GH secretion is regulated mones also circulate associated with binding proteins, which
by pulses of stimulatory GHRH and inhibitory somatostatin from may modulate their action. A range of insulin-​like growth factor
the hypothalamus, which are out of phase with each other, corres- binding proteins bind to IGF-​1, with some inhibiting and others
ponding to peaks and troughs of circulating GH. facilitating the action of this peptide on target tissue receptors. GH
Many hormonal pathways are influenced by the light–​dark cycle, circulates bound to the extracellular domain of its receptor derived
with circadian variation in their circulating levels. For example, the by cleavage from the membrane, with the complex prolonging the
hypothalamic–​pituitary–​adrenal axis exhibits most activity in the circulating half-​life of the hormone.
early morning with peak cortisol production, followed by a nadir in
glucocorticoid levels in the evening. Sleep is another environmental
regulator: GH secretion is enhanced nocturnally and the release of Functions of hormones
vasopressin during sleep inhibits diuresis; puberty is associated with
nocturnal surges of LH. The physiological roles of the major hormones can be broadly clas-
sified into three areas: control of growth and differentiation; main-
tenance of homeostasis; and regulation of reproduction. Some
Hormone-​binding proteins hormones have multiple functions and play a role in more than one
area. In addition, some biological effects are mediated by the com-
Thyroid hormones and many steroids are transported in the circula- bined action of several different hormonal pathways. The principal
tion with serum binding proteins. Thus, thyroxine (T4) and triiodo- actions of major hormones are outlined in Table 13.1.2.
thyronine (T3) are bound to thyroxine-​binding globulin, albumin, Linear growth is dependent on a complex interplay of many hor-
and thyroxine binding prealbumin. Cortisol and progesterone are mones and growth factors. GH plays a key role and exerts many of
bound to cortisol binding globulin, while oestrogens and andro- its effects by stimulating the hepatic production of IGF-​1. Thyroid
gens are bound to sex hormone-​binding globulin. The role of serum hormone also stimulates the epiphyseal growth plate in childhood
 13.1 Principles of hormone action 2249

Table 13.1.2 Major actions of hormones

Hormone Action
Homeostasis
Energy balance
Leptin Reduces food intake
Ghrelin Increases hunger
Fluid and electrolyte balance
Aldosterone Renal Na+/​K+ exchange
Vasopressin ↓Renal free water clearance
Metabolism
Insulin ↑Cell glucose uptake; ↑glycogen synthesis; lipogenic; ↑protein synthesis
Glucagon Glycogenolysis; gluconeogenic
Cortisol Gluconeogenic; lipolysis; ↑protein breakdown
Growth hormone Lipolysis; ↑protein synthesis
Testosterone ↑Protein synthesis
Calcium
Parathyroid hormone ↑Ca2+ resorption from bone and kidney; ↑renal 1α hydroxylation of vitamin D
Vitamin D ↑Ca2+ absorption from gastrointestinal tract; ↑Ca2+ resorption from bone and kidney
Growth and development
Growth hormone Growth
Thyroid hormone Growth, regulation of basal metabolic rate, central nervous system development
Retinoic acid Embryonic development; morphogenesis
C-​type natriuretic peptide Bone growth, meiosis inhibition, axonal development
Reproduction
Testosterone Sexual differentiation, virilization, spermatogenesis
Dihydrotestosterone Male external genitalia
Oestradiol Female external genitalia; mammary gland development
Progesterone Uterotrophic
Prolactin Lactation
Oxytocin Uterine contraction; milk reflex

whereas, at puberty, production of sex steroids leads to epiphyseal insulin mediates lipogenesis; insulin and GH are also anabolic by
closure. Other important actions of thyroid hormone include en- promoting protein biosynthesis, whereas cortisol increases protein
hancement of myocardial contractility and differentiation of the breakdown. Adiponectin, another adipose tissue-​derived hormone,
central nervous system. enhances tissue insulin sensitivity.
The maintenance of homeostasis includes the control of en- Circulating concentrations of ions and water balance are also
ergy balance, metabolic pathways, fluid, electrolyte and calcium under hormonal control. Vasopressin promotes water reabsorption
balance, and regulation of blood pressure. Energy homeostasis in- via membrane channels (aquaporins) in the distal collecting ducts
volves regulation of food intake and energy expenditure. Leptin, of the kidney; aldosterone acts at the renal distal convoluted tubule
an adipose tissue-​derived hormone, acts via hypothalamic path- to stimulate sodium reabsorption and potassium excretion, effects
ways (e.g. melanocortin 4) to reduce food intake; conversely, which are antagonized by atrial natriuretic peptide (ANP). Both
rising gastrointestinal production of ghrelin preprandially stimu- parathyroid hormone and vitamin D increase serum calcium levels;
lates food intake. Thyroid hormone is an important determinant PTH mediates Ca2+ resorption from bone and kidney, whereas
of resting energy expenditure or basal metabolic rate. Metabolic vitamin D acts on the gastrointestinal tract as well as these sites.
effects are mediated by several hormones: insulin lowers blood Catecholamines and angiotensin II are potent vasoconstrictors and,
glucose by enhancing its cellular uptake and promotes glycogen together with cortisol, control blood pressure.
synthesis; conversely, GH, cortisol, glucagon, and adrenaline act Hormones involved in reproduction exert effects from early in de-
as counterregulatory hormones to raise blood glucose. Glucagon velopment. During embryogenesis, Müllerian inhibiting substance
and adrenaline stimulate glycogenolysis and, together with cortisol, (MIS) from the testis causes regression of female structures (uterus,
promote gluconeogenesis. Other metabolic pathways are also in- fallopian tube) and testosterone promotes the development of male
fluenced by these hormones: GH and cortisol are lipolytic whereas structures (vas deferens, epididymis, seminal vesicles) which are
2250 SECTION 13 Endocrine disorders

derived from the Wolffian duct. Dihydrotestosterone promotes de- Table 13.1.3 Membrane receptor families
velopment of the male external genitalia. In both sexes, the gonadal
G protein-​coupled
axes are quiescent in childhood and become reactivated at puberty.
Testosterone mediates virilization, secondary sexual characteristics, Glycoprotein hormones FSH, TSH, LH/​CG
and spermatogenesis in the male; in females, ovarian production of Biogenic amines Adrenaline, noradrenaline, serotonin,
oestrogen and progesterone induces secondary sexual features and histamine, dopamine
controls the menstrual cycle. In both sexes, gonadal steroids are re- Peptides Calcitonin, PTH/​PTHrP
quired for the attainment of peak bone density at the end of puberty Ghrelin, GHRH, CRH, GnRH, kisspeptin,
and its subsequent maintenance. During pregnancy, prolactin acts SRIF, TRH
in concert with oestrogen to promote lactation; oxytocin stimulates Vasopressin, oxytocin
uterine contraction at parturition and smooth muscle contraction in Angiotensin
the mammary gland during suckling. Glucagon, secretin, VIP, gastrin
Small molecules Calcium, GABA

Hormone action Tyrosine kinase Insulin, IGF-​1

Guanylyl cyclase Atrial natriuretic peptide, CNP, guanylin
Hormones induce biological responses by interacting with receptors Cytokine GH, PRL, EPO, leptin
located either on the membrane or intracellularly in the cytoplasm Serine/​threonine kinase Activin, inhibin, MIS
or nucleus. Hormones bind to receptors with high affinity, such that
CG, chorionic gonadotrophin; CRH, corticotropin releasing hormone; EPO,
low concentrations of free hormone associate and dissociate from erythropoietin; FSH, follicle-​stimulating hormone; GABA, γ-​aminobutyric acid; GH,
receptors rapidly in a dynamic equilibrium. The interaction of hor- growth hormone; GHRH, growth hormone releasing hormone; GnRH, gonadotropin
releasing hormone; IGF-​1, insulin-​like growth factor 1; LH, luteinizing hormone; MIS,
mones with receptors is usually highly specific, with individual Müllerian inhibiting substance; PRL, prolactin; PTH, parathyroid hormone; PTHrP,
receptors being highly selective for a single hormone even within parathyroid hormone-​related peptide; SRIF, somatostatin; TRH, thyrotropin-​releasing
hormone; TSH, thyroid-​stimulating hormone; VIP, vasoactive intestinal polypeptide.
a class of structurally related molecules (e.g. steroid hormones).
However, there are exceptions to this: parathyroid hormone (PTH)
and parathyroid hormone-​related peptide (PTHrP) or LH and hCG domain of variable size, enabling further subclassification of
share a common receptor, generating similar biological responses; these receptors: glycoprotein hormones or small molecule ligands
insulin and IGF-​1 exhibit some degree of cross-​reactivity with their (e.g. calcium, GABA) interact with large N-​terminal extracellular
respective receptors; the mineralocorticoid receptor binds cortisol domains; biogenic amines (e.g. catecholamines, serotonin) bind to
with equal or higher affinity than aldosterone. residues that lie within the transmembrane domain; other polypep-
Hormones that bind to membrane receptors act via effector pro- tide hormones interact with residues in both the extracellular and
teins to activate second-​messenger signalling pathways. In turn, transmembrane domains. The intracellular domains of the receptor
the second messengers stimulate a cascade of kinases, which then enable interaction with G proteins.
act upon target substrates in the cell membrane, the cytoplasm G proteins typically form a heterotrimeric complex of α, β, and
or nucleus, to alter gene transcription or modulate a biochemical γ subunits which bind the guanine nucleotides GTP and GDP. The
pathway, leading to a physiological response. Hormones that act complex transduces signals from the receptor to downstream ef-
through nuclear receptors are transported passively, or pumped ac- fectors such as adenylate cyclase, phospholipase C, or membrane
tively, across the plasma membrane to interact with their targets. The voltage-​dependent calcium channels. A family of different G pro-
hormone–​receptor complex interacts with DNA sequences in target teins (Gs, Gi, Gq, and others) exists with the ability to couple to dif-
genes to either stimulate or repress their expression. The cellular ac- ferent receptors and effectors, allowing a large array of potential
tions of nuclear receptors are mediated by changes in target gene receptor–​G protein–​effector complexes, leading to diversity of cel-
transcription, altering mRNA synthesis and, in turn, the levels of lular signalling.
protein product. Several hormones signal via the cAMP pathway (Table 13.1.4)
and this mechanism is considered in further detail (Fig. 13.1.4).
In the resting state, the G protein complex is inactive and bound
Signalling by membrane receptors to GDP (Fig. 13.1.4a). Following hormone binding to the receptor
(Fig. 13.1.4b), the Gα subunit binds GTP, becomes activated and
Membrane receptors can be divided into several groups (Table 13.1.3) dissociates from the βγ complex, to interact with adenylate cyclase
depending on the signalling pathways that they utilize. The largest (Fig. 13.1.4c). The latter converts ATP to the second messenger,
group consists of receptors with multiple transmembrane domains cAMP. This rise in intracellular cAMP activates protein kinase
which are coupled to G proteins; a second class of receptor contains an A (PKA), which can phosphorylate certain cellular targets: phos-
intracellular domain with tyrosine kinase activity; several hormones phorylation of a transcription factor, CREB, stimulates transcription
signal via membrane proteins that are homologous to cytokine recep- of genes containing CREs; other targets for PKA include enzymes in
tors; a fourth class of hormone receptor contains an intracellular do- biochemical pathways or membrane ion channels.
main with serine or threonine kinase activity. Several mechanisms serve to terminate signalling via a hormone–​
G protein-​ coupled receptors (GPCRs) are characterized by receptor complex: first, hydrolysis of GTP to GDP by the Gα subunit
seven separate hydrophobic domains that traverse the membrane promotes its reassociation with βγ subunits to reform an inactive
phospholipid bilayer (Fig. 13.1.3a). They possess an extracellular complex; second, the hormone–​receptor complex is internalized via
 13.1 Principles of hormone action 2251

(a) NH2

Extracellular
domain

Transmembrane
domain

Intracellular
domain

COOH

(b)

‘Zinc fingers’

C C C C

Zn D box Zn
P box A box
C C C C

N-terminal DNA-binding
N- Ligand-binding domain -C
domain domain

CoR CoA

Dimerization

Fig. 13.1.3 Schematic representations of (a) G protein-​coupled receptor and

(b) nuclear receptor, illustrating their functional domains. See text for explanation.

cell surface vesicles and targeted for lysosomal degradation; third, subunit activates membrane phospholipase C (PLC) (Fig. 13.1.5).
following hormone binding, the GPCRs undergo phosphorylation This enzyme catalyses the hydrolysis of phosphatidylinositol 4,5-​
of their intracellular domains by either PKA or other specific kinases bisphosphate (PIP2) to generate the second messengers, inositol
(GRKs). Such phosphorylation prevents further coupling to G pro- 1,4,5-​triphosphate (IP3) and 1,2-​diacylglycerol (DAG). IP3 inter-
teins and promotes receptor internalization desensitizing the cell to acts with a specific receptor located on smooth endoplasmic re-
hormone action, until further surface receptor is expressed. ticulum, inducing opening of intracellular channels leading to a
Activation of their receptors by hormones such as somatostatin rise in cytoplasmic calcium (Fig. 13.1.5). Interaction of calcium
or dopamine, is known to decrease intracellular cAMP. Here, the with calmodulin, a cytoplasmic calcium-​binding protein, activates
hormone–​receptor complex associates with a G protein (Gi), whose a specific kinase (CAM kinase), which regulates several processes
α subunit inhibits adenylate cyclase. Although many GPCRs signal including hormone secretion, gene transcription, and metabolic
via cAMP, some receptors (e.g. TRH, GnRH, Table 13.1.4) are linked enzymes. The rise in cellular calcium also facilitates DAG activa-
to different pathways. These receptors are coupled to Gq, whose α tion of protein kinase C (PKC), leading to phosphorylation of the
2252 SECTION 13 Endocrine disorders

Table 13.1.4 Signalling pathways of membrane receptors receptors promoting their dimerization (Fig. 13.1.7). The hormone–​
receptor complex recruits Janus kinases (JAKs) which phosphorylate
Signalling pathway Hormone/​receptor
STATs (signal transducers and activators of transcription). STATs
Gsα/​cAMP↑ β-​Adrenergic receptor translocate to the nucleus, interact with regulatory DNA elements,
CRH and promote target gene transcription.
GHRH Activin and inhibin belong to the transforming growth factor
ACTH class of peptides which signal via a heterodimeric transmembrane
receptor complex with intrinsic protein serine/​threonine kinase
Giα/​cAMP↓ Somatostatin
activity (Fig. 13.1.8). Here, hormone binding promotes the asso-
Dopamine
ciation of two surface receptors (type I and type II) with differing
α-​Adrenergic receptor properties. Subsequent transphosphorylation of the type I receptor
Gqα/​IP3 and DAG TRH by the intracellular kinase domain of the type II receptor leads to
GnRH phosphorylation and dimerization of cytoplasmic Smad proteins.
Gsα/​cAMP↑ and Gqα/​IP3 and DAG LH The Smad complex translocates to the nucleus to activate target gene
FSH expression (Fig. 13.1.8).
TSH The membrane guanylyl cyclases act as receptors for natriuretic
peptides. ANP and CNP bind their selective receptors (guanylyl
PTH
cyclase A and B, respectively), which exist as phosphorylated
Calcitonin
homodimers, leading to intrinsic guanylyl cyclase activity. This
JAK-​STAT GH leads to elevated cGMP generation, and subsequent activation of
PRL cGMP-​binding proteins such as phosphodiesterases (PDEs), cyclic
EPO nucleotide-​gated ion channels, and protein kinase G (Fig. 13.1.9).
Leptin As just described, GPCR signalling is usually coupled to responses
(e.g. hormone secretion) by Gα subunit activation of cAMP or
cGMP↑ ANP
phosphoinositide pathways. However, following receptor activation
CNP
in some cellular contexts, the dissociated Gβ/​γ dimer subunit com-
Tyrosine kinase/​MAP kinase Insulin plex is also capable of stimulating effectors (e.g. Ras, PI3-​kinase), to
IGF-​1 enhance MAP kinase activity and elicit a mitogenic response.
Ser/​Thr kinase/​SMAD Activin, inhibin, MIS

Abbreviations as for Table 13.1.3.

Nuclear receptor signalling

Fos-​Jun transcription factor complex, inducing target gene expres- The nuclear receptors are a family of transcription factors which
sion (Fig. 13.1.5). Hormones do not signal exclusively via a single mediate the action of steroid and other lipophilic hormones. The
pathway, with glycoprotein hormones and some peptides for ex- human genome encodes approximately 60 to 70 different recep-
ample (Table 13.1.4) activating both cAMP and phosphoinositide tors and it is clear that only a minority of these are targets for
signalling. the action of major hormones (Table 13.1.5). The remainder com-
The tyrosine kinase class of receptors is a diverse family that prise a large group classified as ‘orphan receptors’, reflecting the
transduces signalling by insulin and IGF-​1 but also epidermal, fact that either their ligands and/​or physiological roles remain to
nerve, fibroblast, and platelet-​derived growth factors. Growth factor be elucidated.
signalling differs from insulin and the latter pathway will be con- Based on homologies in their primary amino acid sequence, nu-
sidered (Fig. 13.1.6). Hormone interaction with receptor promotes clear receptors can be divided into distinct domains which mediate
autophosphorylation of tyrosine residues in their cytoplasmic do- specific functions (Fig. 13.1.3b). A central DNA binding domain
mains. In turn, this promotes phosphorylation of substrates, for contains cysteine-​rich peptide motifs which chelate zinc to form two
example, Shc and insulin receptor substrate 1 (IRS-​1), followed by ‘zinc fingers’. The latter mediate receptor binding to specific DNA
recruitment of adaptor proteins (Grb2/​SOS). The Grb2/​SOS com- sequences or hormone response elements, usually located in target
plex recruits Ras, a GTP-​binding protein. Ras activation induces gene promoters. The C-​terminal region of receptors encompasses
signalling via a series of kinases (Raf, Mek, MAP kinase), culmin- their hormone-​binding function as well as their ability to dimerize.
ating in the phosphorylation and activation of transcription factors Nuclear receptors can be divided into two major subclasses, the
which regulate target genes involved in mitogenesis or cellular dif- steroid receptors and heterodimeric receptors, which differ in their
ferentiation. On the other hand, IRS-​1 recruits phosphatidylinositol-​ mode of action.
3′-​
OH-​ kinase (PI3-​ kinase), which in turn activates the AKT Steroid receptors (e.g. GR, MR, ER, PR, AR) bind to hormone
cascade. The latter mediates several of the metabolic effects of in- response elements as homodimers (Fig. 13.1.10b). Some recep-
sulin, enhancing translocation of a glucose transporter to the mem- tors (e.g. GR, PR, AR) are bound to cytosolic heat shock proteins.
brane to promote cellular glucose uptake, and activating pathways Hormone binding to receptors promotes their dissociation from
involved in glycogen, lipid, or protein synthesis. these, enabling translocation to the nucleus, dimerization, and inter-
Hormones such as prolactin and GH interact uniquely with their action with DNA. In contrast, the thyroid, retinoid, and vitamin D
receptors; a single polypeptide interacts simultaneously with two receptors are constitutively nuclear and form heterodimers with a
 13.1 Principles of hormone action 2253

(a)
Hormone

Extracellular

Plasma
membrane Adenylate
Gsα β γ cyclase
Intracellular
GDP

(b)
Hormone

Adenylate
Gsα β γ cyclase

GTP
GDP

(c)
Hormone

Adenylate
β γ cyclase
Gsα

GTP ATP
cAMP

PKA

P
Cytoplasm
CREB
Nucleus

P +
++
CREB

CRE

Fig. 13.1.4 G protein-​coupled receptor signalling via the cAMP pathway. See text for explanation.

common partner (retinoid X receptor, RXR), to interact with DNA (Fig. 13.1.10a). For all nuclear receptors, hormone binding induces
even in the absence of hormone or ligand (Fig. 13.1.10a). In some a conformational change with dissociation of corepressors and re-
target gene contexts, RXR can also form homodimers to mediate cruitment of coactivator proteins (Fig. 13.1.10b). This latter com-
retinoid signalling. plex acts to relax the interaction between histone proteins and DNA
In contrast to other transcription factors whose activity is con- in chromatin, thereby facilitating the access of basal transcription
trolled by post-​translational modification (e.g. phosphorylation), factors and RNA polymerase, which induce gene transcription.
the hallmark of nuclear receptors is their ability to modulate gene A further mechanism which controls signalling via nuclear recep-
expression in a hormone-​dependent manner. Thus, in the absence of tors is regulation of the supply of their ligands to cells and tissues.
ligand, the thyroid and retinoic acid receptors actively silence target A specific membrane transporter (MCT8) mediates cellular entry
gene transcription by recruiting a corepressor complex of cofactors of thyroid hormone in the central nervous system. T3, the ligand
2254 SECTION 13 Endocrine disorders

Hormone
Extracellular
Plasma
membrane
PLC
Intracellular β γ
Gqα
PIP2
DAG + IP3

IP3R
P
Jun Ca2+
Cytoplasm PKC
Smooth
Fos endoplasmic
Nucleus reticulum

Calmodulin
P
Jun +
++
Fos
CAM kinase

Fig. 13.1.5 G protein-​coupled receptor signalling via the phosphoinositide pathway. See text for
explanation.

Insulin

Glucose
α α
Extracellular

Plasma membrane

Cbl P P P Intracellular
P
Shc
CAP β β
Ras
P P
Grb2 SOS
P IRS-1 P
AKT PI3 Kinase P IRS-2 P
‘cascade’ GTP
GLUT4 P IRS-3 P
vesicle P IRS-4 P GDP

GSK3 mTOR
Raf
Lipid
synthesis

MEK
Glycogen Protein
synthesis synthesis

MAPK

Mitogenesis Differentiation

Fig. 13.1.6 Insulin action via its tyrosine kinase receptor and signalling cascade. See text for explanation.
 13.1 Principles of hormone action 2255

Hormone Hormone

Extracellular
Extracellular RII RI
Plasma
membrane Plasma
P P membrane
Intracellular
P JAK JAK P GS P
P P Intracellular

P P

S S
T T
A A
T T

Cytoplasm

Nucleus P Smad2

Smad4

S S
T T +
A A ++
T T P Smad2 Smad4

Cytoplasm
Fig. 13.1.7 Hormone signalling via the JAK-​STAT pathway. See text for
explanation. Nucleus

for TR, is generated from circulating thyroxine by the action of type

1 or type 2 deiodinase enzymes expressed in the liver and central
nervous system respectively; the enzyme 5α reductase converts tes- +
++
tosterone to dihydrotestosterone in tissues of the male external geni- P Smad2 Smad4
talia. In contrast, the enzyme 11β-​hydroxysteroid dehydrogenase
type 2 catabolizes cortisol in the renal cells, thereby enabling the
mineralocorticoid receptor to respond selectively to aldosterone ra- Fig. 13.1.8 Hormone signalling by the transforming growth factor
ther than to glucocorticoid, which it is also capable of binding with peptide family. See text for explanation.
high affinity.
Hormone
Finally, in contrast to classical effects of steroid hormones to
modulate gene expression, recent evidence indicates that they can
also modulate cellular functions such as hormone secretion or neur-
onal excitability within seconds or minutes. These rapid effects of
steroid hormones occur independent of the genome and can occur Extracellular
either by hormone interaction with a cell surface receptor or by Plasma
direct interaction of the nuclear receptor with cytoplasmic signalling Membrane
Kinase homology
molecules. Intracellular
domain
Ion channel

Guanylyl
cyclase
Genetic defects and endocrine disease domain

Most endocrine diseases can be divided into conditions of hor-

mone excess, hormone deficiency, and hormone resistance. Defects
in genes involved in hormone synthesis and action give rise to a
spectrum of disorders (Tables 13.1.6 and 13.1.7). Both germline GTP cGMP PKG

gene defects causing inherited syndromes and somatic mutations

leading to acquired endocrine cellular dysfunction have been
described.
PDE
Defects in developmental transcription factors are usually associ-
ated with endocrine gland hypoplasia: mutations in HESX-​1 cause Fig. 13.1.9 Hormone signalling via membrane guanylyl cyclases,
optic and pituitary hypoplasia with agenesis of the corpus callosum; which act as receptors for peptides. See text for explanation.
2256 SECTION 13 Endocrine disorders

Table 13.1.5 Hormone signalling via nuclear receptors Table 13.1.6 Genetic defects in transcription factors or nuclear
receptors and endocrine disorders
Nuclear receptor Hormone
Homodimeric Gene Disorder or phenotype

GR Cortisol Transcription factors

MR Aldosterone HESX-​1 Septo-​optic dysplasia

Oestradiol POU1F1/​PROP-​1 GH, PRL, TSH deficiencies

ERα/​β
TBX19 ACTH deficiency
PR Progesterone
TTF-​1/​TTF-​2/​PAX-​8 Thyroid dysgenesis
AR Testosterone, dihydrotestosterone
SRY XY female
Heterodimeric
Nuclear receptors
TRα/​β Triiodothyronine
DAX-​1/​SF-​1 Adrenal insufficiency, hypogonadism, and
RARα/​β/​γ all-​trans-​Retinoic acid
disorders of sex development (DSD)
RXRα/​β/​γ 9-​cis-​Retinoic acid
VDR Hereditary vitamin D-​resistant rickets
VDR 1,25-​Dihydroxyvitamin D3
AR Androgen insensitivity syndrome or spinal and
PPARα/​β/​γ Unsaturated fatty acids, eicosanoids bulbar muscular atrophy

AR, androgen receptor; ER, oestrogen receptor α or β subtypes; GR, glucocorticoid

ERα Tall stature and osteoporosis
receptor; MR, mineralocorticoid receptor; PPAR, peroxisome proliferator-​activated GR Glucocorticoid resistance
receptor α, β, or γ subtypes; PR, progesterone receptor; RAR, retinoic acid receptor α, β
or γ subtypes; RXR, retinoid X receptor α, β, or γ subtypes; TR, thyroid hormone receptor TRβ Resistance to thyroid hormone
α or β subtypes; VDR, vitamin D receptor.
PPARγ Lipodystrophic insulin resistance

both Pit-​1 (POU1F1) and PROP-​1 mutations disrupt development

of multiple pituitary cell types resulting in a combination of hor-
mone deficiencies; defects in TTF-​1, TTF-​2, and PAX-​8 result in Mutations in DAX-​1 or SF-​1, orphan members of the nuclear
thyroid dysgenesis manifesting as neonatal hypothyroidism; muta- receptor family, disrupt both adrenal and gonadal development.
tions in the SRY gene lead to failure of testis development and sex Defects in other nuclear receptors (e.g. VDR, TR, GR) are char-
reversal in XY males. acterized by tissue resistance to their respective hormone ligands.
Vitamin D resistance leads to rickets together with abnormalities
(a) Cytoplasm of skin differentiation, hair growth, and lymphocyte function, em-
Nucleus phasizing its important extraskeletal actions. Point mutations in
the androgen receptor are associated with a spectrum of pheno-
Corepressor
‘complex’ BTFs types ranging from complete feminization of XY individuals to
Histone mildly impaired virilization in men. In addition, expansion of a
deacetylation
RXR NR Repression polyglutamine repeat sequence in the N-​terminal domain of AR
is associated with adult-​onset neuronal degeneration leading to
spinal and bulbar muscular atrophy. A homozygous defect in the
oestrogen receptor in a male led to failure of epiphyseal closure re-
HRE sulting in tall stature together with severe osteoporosis. These mani-
festations suggest that testosterone effects on the male skeleton are,
in part, mediated by its enzymatic conversion to oestrogens.
(b) Cytoplasm A growing number of disorders associated with defects in trans-
Nucleus membrane receptors or their signalling intermediates have been
L described (Table 13.1.7). However, in addition to mutations which
NR NR
Coactivator
disrupt protein function, gain-​of-​function mutations causing con-
‘complex’ stitutive activation of the receptor or signalling protein also occur.
Histone
L
Acetylation
With GPCRs, diverse loss-​of-​function mutations, occurring most
RXR NR Activation
or
frequently in the extracellular domain, block hormone binding or
signalling, leading to insensitivity to hormone action. Such hor-
BTFs mone resistance can lead to both hypofunction (e.g. ACTH, TSH
receptors) or hypoplasia (e.g. LH, FSH receptors) of target glands
HRE expressing the receptor. Conversely, gain-​of-​function mutations
in GPCRs typically occur in the third intracellular loop, causing
constitutive activation of the receptor in the absence of hormonal
Fig. 13.1.10 Transcriptional regulation by nuclear receptors. (a) In the ligand. Again, the functional consequence is either autonomous
absence of hormone, a subset of heterodimeric nuclear receptors (thyroid,
retinoic acid) recruit corepressors to inhibit gene transcription. (b) Hormone hyperfunction (e.g. calcium, LH, FSH receptors) or excessive
occupancy of homodimeric or heterodimeric receptors promotes their neoplastic proliferation (e.g. TSH receptor, RET tyrosine kinase
association with coactivators, leading to transcriptional activation. receptor) of the target tissues in which the receptor is expressed
 13.1 Principles of hormone action 2257

Table 13.1.7 Genetic defects in membrane receptors or signalling and endocrine disorders

Gene Loss-​of-​function mutation Gain-​of-​function mutation

G protein-​coupled receptor
TRH Central hypothyroidism
GHRH GH deficiency with short stature
GnRH Central hypogonadotropic hypogonadism
KiSS 1 Central hypogonadotropic hypogonadism Precocious puberty
NK3R (TACR3) Central hypogonadotropic hypogonadism
Arginine vasopressin 2 (V2) Nephrogenic diabetes insipidus Nephrogenic syndrome of inappropriate antidiuresis
Melanocortin 2 (ACTH) Family (isolated) glucocortisol deficiency
Ca Familial hypocalciuric hypercalcaemia (FHH) Familial hypercalciuric hypocalcaemia
TSH TSH resistance Familial non​autoimmune hyperthyroidism, familial pregnancy-​limited
hyperthyroidism, autonomous thyroid adenomas
LH Leydig cell hypoplasia (males); primary Male-​limited precocious puberty
amenorrhoea (females)
FSH Hypofertility (males); ovarian dysgenesis (females) FSH-​independent spermatogenesis (males); spontaneous ovarian
hyperstimulation syndrome (females)
PTH/​PTHrP Blomstrand chondrodysplasia Jansen’s metaphyseal chondrodysplasia
Melanocortin 4 Extreme obesity
Tyrosine kinase receptor
RET Hirschprung’s disease MEN2: medullary thyroid carcinoma, phaeochromocytoma
parathyroid neoplasia
Insulin Insulin resistance
Cytokine receptors
GH Laron dwarfism
Leptin Obesity
Guanyly cyclase receptors
CNP Acromesomelic dysplasia, type Maroteaux Skeletal overgrowth and macrodactyly
Signalling pathway
Gsα PTH, TSH, LH resistance Albright’s hereditary Somatotroph adenomas, thyroid adenomas, McCune–​Albright
osteodystrophy syndrome
Giα Ovary, adrenal, thyroid tumours
AKT2 Insulin resistance

(Table 13.1.7). Constitutive activation of signal transduction may

also result from G protein mutations. Here, specific amino acid sub- FURTHER READING
stitutions in Gsα inhibit its intrinsic GTPase activity, and the GTP-​ Braverman LE, Cooper D (eds) (2012). Werner & Ingbar’s the thyroid;
bound protein constitutively activates adenylate cyclase leading to a fundamental and clinical text, 10th edition. Lippincott Williams &
cAMP accumulation. Somatic Gsα mutations occur in a proportion Wilkins, Philadelphia.
of pituitary GH secreting and thyroid adenomas; more widespread Jameson JL, DeGroot LJ (eds) (2015). Endocrinology, 7th edition.
expression of a somatic Gsα mutation occurring early in develop- Elsevier, Philadelphia.
Lodish H, et al. (2016). Molecular cell biology, 8th edition. W.H.
ment, leads to polyostotic fibrous dysplasia, café au lait skin pig-
Freeman, San Francisco, CA.
mentation, and hyperfunction of multiple endocrine glands,
Melmed S, et al. (eds) (2016). Williams’ textbook of endocrinology, 13th
constituting the McCune–​Albright syndrome. Similarly, germline
edition. Elsevier, Philadelphia.
loss-​of-​function mutations which reduce cellular Gsα activity, are Strauss JF, Barbieri RL (eds) (2019). Yen & Jaffe’s reproductive endocri-
associated with resistance to multiple hormones together with char- nology, 8th edition. Elsevier Saunders, Philadelphia.
acteristic bone anomalies (Albright’s hereditary osteodystrophy).
13.2
Pituitary disorders

CONTENTS with target gland hormone secretion are usually sufficient for as-
sessment of TSH (thyroxine), FSH/​ LH (testosterone or oestra-
13.2.1 Disorders of the anterior pituitary gland 2258
Niki Karavitaki and John A.H. Wass diol) and prolactin; dynamic testing is required for the ACTH/​
cortisol axis and determination of GH deficiency or excess; (2) radio-
13.2.2 Disorders of the posterior pituitary gland 2277 logical assessment—​MRI is the modality of choice; and (3) neuro-​
Niki Karavitaki, Shahzada K. Ahmed, and John A.H. Wass
ophthalmological evaluation, including assessment of visual acuity,
visual fields, and fundoscopy.
Management—​the availability of sensitive hormonal assays, re-
placement hormones, and hypothalamic peptides, together with
refined neuroimaging methods and neurosurgical techniques, has
increased our ability to identify precisely and successfully treat most
patients with diseases of the anterior pituitary gland.
13.2.1 Disorders of the anterior
Growth hormone
pituitary gland GH deficiency—​in children this causes growth failure, and in adults
Niki Karavitaki and John A.H. Wass features including decreased energy and quality of life, and increase
in fat mass/​decrease in muscle mass. The insulin tolerance test is con-
sidered the ‘gold standard’ for diagnosis. Goals of GH treatment in
ESSENTIALS adults are to achieve an appropriate clinical response while avoiding
side effects, and an IGF-​1 level in the middle of the reference range.
The anterior pituitary gland produces growth hormone (GH), lutein- GH excess—​this causes acromegaly, which develops insidiously
izing hormone (LH), follicle-​stimulating hormone (FSH), adrenocor- with multiple clinical features, most notably including local tumour
ticotropic hormone (ACTH), thyroid-​stimulating hormone (TSH), effects, and increase in size of hands, feet, jaw, and skull. Biochemical
and prolactin. Their secretion is regulated by hypothalamic-​releasing diagnosis is made by confirming absence of suppression of GH in
and inhibitory factors delivered via portal capillaries, and by negative the oral glucose tolerance test, and by increased serum IGF-​1 levels.
feedback inhibition of the cognate hormones produced by target Management options include: (1) surgery—​with trans-​sphenoidal
endocrine glands such as the thyroid and adrenal cortex. surgery the treatment of choice for most patients; (2) drugs—​
Clinical features—​presentation of pituitary disease, mostly associ- including dopamine receptor agonists, somatostatin receptor lig-
ated with a space-​occupying lesion, may result from (1) local mass ands (e.g. octreotide, lanreotide) and GH receptor antagonists (e.g.
effects—​often causing headache, visual field defects (most typic- pegvisomant); and (3) radiotherapy—​generally offered for tumours
ally bitemporal hemianopia or upper temporal quadrantanopia) that have recurred or persisted after surgery in patients with resist-
and ocular nerve palsies; (2) pituitary hormone deficits—​producing ance to or intolerance of medical treatment.
wide-​ranging effects as a result of single or multiple deficiencies,
with GH and gonadotropins (LH and FSH) usually affected first, fol- FSH and LH
lowed much later by ACTH and TSH; and/​or (3) pituitary hormone Gonadotropin deficiency—​this presents in women with oligo/​amenor-
hypersecretion, usually arising as a consequence of neoplastic prolif- rhoea, loss of libido, dyspareunia, hot flushes, and infertility; and in
eration of particular cell types within the gland, producing complex men with loss of libido; impaired sexual function; mood impairment;
and disabling syndromes such as Cushing’s disease or acromegaly. loss of facial, scrotal, and trunk hair; decreased muscle bulk and en-
Investigation—​this includes testing for (1) hormonal hyper-​or ergy. Diagnosis in women is based on clinical features in association
hyposecretion—​measurements of basal levels of pituitary hormones with FSH and LH levels that are ‘inappropriately normal’ or low in
 13.2.1 Disorders of the anterior pituitary gland 2259

premenopausal women and low in postmenopausal women; in men function. First-​

line treatment usually comprises surgery with or
there is low morning serum testosterone with low or ‘inappropriately without adjuvant external beam irradiation.
normal’ gonadotropins. Treatment comprises appropriate replace- Hypophysitis—​ may be primary (granulomatous, xanthomatous
ment therapy. or lymphocytic) or caused by a known agent or systemic disease.
Differential diagnosis is from pituitary adenoma. Optimal treatment
Prolactin
for the inflammatory process has not been established and replace-
Prolactinomas are the most common pituitary adenomas and typ- ment of defective endocrine function is required.
ically present with galactorrhoea and hypogonadism, manifesting
in men as impotence, infertility, and decreased libido, and in
women as oligo/​amenorrhoea and infertility. Secondary causes of
hyperprolactinaemia must be excluded in any patient with an ele- Introduction
vated serum prolactin and serum prolactin levels usually parallel tu-
mour size in those with prolactinomas. Dopaminergic agonists (e.g. The pituitary gland or hypophysis cerebri was first described by
cabergoline, bromocriptine, pergolide, quinagolide) are the primary Galen of Pergamon in the 2nd century ad, and is considered to be
therapy. the ‘master gland’ integrating hormonal signals that control nu-
merous endocrine and metabolic functions. Since the demonstra-
ACTH tion of the hypothalamic control of pituitary function by Harris
Chronic ACTH deficiency is associated with fatigue, pallor, anorexia, in Oxford in the 1950s, our understanding of the physiology and
weight loss, hypotension, hyponatraemia, hypoglycaemia, and eo- pathophysiology of the pituitary gland has broadened. The devel-
sinophilia. The insulin tolerance test is considered the ‘gold standard’ opment of radioimmunoassays in the 1960s, the extraction of hypo-
for diagnosis. Glucocorticoid deficiency can be life-​threatening and thalamic factors principally by Schally and Guillemin in the 1970s,
hence replacement with hydrocortisone (or other steroid) in a dose the advances in immunocytochemistry, electron microscopy, and in
and timing to mimic the normal pattern of cortisol secretion should situ hybridization methods, as well as the expansion of molecular
begin as soon as the diagnosis is confirmed. biology have increased this understanding. Finally, the advances in
Cushing’s disease is caused by chronic exposure to endogenous modern imaging techniques and in pituitary surgery combined with
glucocorticoids (Cushing’s syndrome) produced by the adrenal cortex the development of medical treatments for pituitary tumours have
in response to excess ACTH production by a pituitary corticotroph greatly expanded the therapeutic possibilities, providing successful
adenoma. and safe outcomes in most patients.
TSH
Central hypothyroidism is diagnosed when the concentration of thy-
Anatomy and embryology
roxine is decreased and the level of TSH levels is usually normal or
low. Clinical presentation is as for primary hypothyroidism. Treatment
The pituitary gland consists of the anterior lobe (adenohypophysis),
is with thyroxine.
the posterior lobe (neurohypophysis), and an intermediate zone. The
Other conditions adenohypophysis derives from the stomodeal ectoderm which in-
Hypopituitarism—​can be caused by a range of conditions including vaginates by the third week of gestation forming Rathke’s pouch.
pituitary and non​pituitary tumours, hypophysitis, pituitary apoplexy, In the sixth week of gestation it comes in contact with the infun-
Sheehan’s syndrome (postpartum), brain injury (traumatic, surgical, dibulum. A remnant of the pharyngeal hypophysis may be found
irradiation, postinfective), and granulomatous diseases. Clinical in adults, forming the pharyngeal pituitary located in the midline
manifestations depend mainly on the underlying disease, as well of the nasopharynx. The posterior lobe originates from the neural
as the type and the degree of the hormonal deficits. Diagnosis and primordium as an outpouching from the floor of the third ventricle
treatment of each pituitary hormone deficit is as just described. at the fourth week of gestation. The intermediate lobe arises from
Pituitary adenomas—​the most common cause of pituitary disease; the posterior portion of Rathke’s pouch. This area normally contains
may be functioning (resulting in syndromes of hormonal excess) microcytic remnants of Rathke’s pouch, which rarely become clin-
or non​ functioning (presenting with mass effects). Treatment in- ically significant. The portal system starts developing at the seventh
volves surgery, radiotherapy, or medical therapy as described earlier. week and is completed at around the 20th week of gestation. The
Pituitary carcinomas are very rare. body of the sphenoid bone and the sella turcica arise from the fusion
Pituitary apoplexy—​occurs primarily in patients with pre-​existing of hypophyseal cartilage plates on either side of the developing pi-
pituitary adenomas; results from acute haemorrhage or infarction of tuitary. The sella is well formed by the seventh week and matures by
the pituitary gland and is characterized by sudden onset of head- endochondral ossification.
ache, vomiting, visual disturbance, ophthalmoplegia, and altered The pituitary measures around 13 mm transversely, 9 mm
consciousness. Initial management requires close monitoring of fluid anteroposteriorly, and 6 mm vertically. It weighs approximately
and electrolyte balance and immediate replacement of deficient 100 mg. It increases during pregnancy to almost twice its normal
hormones, especially corticosteroids. Some authorities recommend size, and decreases in older people. The gland is centrally located
urgent surgical decompression in some cases. at the base of the brain in the sella turcica within the sphenoid
Craniopharyngiomas—​ these epithelial tumours can present bone. It is attached to the hypothalamus by the pituitary stalk and
with pressure effects and/​or compromised hypothalamo-​pituitary a fine vascular network. The gland lacks leptomeninges. The sella
turcica is lined by periosteal dura mater; the dura properly covers
2260 SECTION 13 Endocrine disorders

(a) −
Hypothalamus
TRH Somatostatin
+ −

T4 T3
−
Pituitary

(b) Lamina terminalis

T3T4 TSH
Third ventricle
+
Optic chiasm
Pituitary stalk with Pineal gland
upper capillary
Mamillary body
loop of portal Median eminence
vessels of hypothalamus Thyroid
Sphenoid sinus
Anterior pituitary
Posterior pituitary
Fourth ventricle Fig. 13.2.1.2 Diagram of the hypothalamo-​pituitary–​thyroid axis
showing negative feedback loops. TRH, thyrotropin-​releasing hormone;
Marrow in Pons TSH, thyroid-​stimulating hormone.
sphenoid
bone Medulla

follicles within the gland, and folliculostellate cells (less than 5% of

Fig. 13.2.1.1 Sagittal MRI scan of normal pituitary gland and an the adenohypophyseal cells), which have a physiological role that is
anatomical line drawing. not clear.
The anterior pituitary receives most of its blood supply from
the hypothalamo-​ hypophyseal portal system (primary plexus,
the lateral aspects of the cavernous sinuses and constitutes the sellar long portal venous system, and secondary plexus), which origin-
diaphragm. The cavernous sinuses are on either side of the sella, lat- ates from the capillary plexus of the median eminence and su-
eral and superior to the sphenoid sinuses, and contain important perior stalk derived from the terminal ramifications of the superior
neurovascular structures including the cavernous segments of the and inferior hypophyseal arteries. This system carries blood and
internal carotid arteries and the cranial nerves III, IV, V, and VI. The hypophysiotropic hormones down to the stalk. The remainder of
optic chiasm is located superiorly and is separated from the pituitary
by the suprasellar cistern and the sellar diaphragm (Figs. 13.2.1.1
and 13.2.1.2). Table 13.2.1.1 Hormone-​producing cells in anterior pituitary gland
The anterior lobe comprises nearly 80% of the gland and includes
Type of cell Approximate Distribution
the pars distalis, pars intermedia, and pars tuberalis. Staining char-
percentage of
acteristics divide the pars distalis into a central ‘mucoid wedge’ and adenohypophyseal
two ‘lateral wings’. On light microscopy the cells of the anterior lobe cells
show variation in size, shape, and histochemical staining features. Somatotrophs or 50% Greatest density in lateral
They are organized in nests and cords, and are separated by a com- GH cells wings
plex capillary network. The pars intermedia is poorly developed in Lactotrophs or PRL cells 20% Mainly in posterior
humans and lies between the pars distalis and the posterior pituitary. portions of lateral wings
Large numbers of cells in the central zone are basophilic and pro- Corticotrophs or 15–​20% Mainly middle and
duce adrenocorticotropic hormone (ACTH), luteinizing hormone ACTH cells posterior portions of
mucoid edge
(LH), follicle-​stimulating hormone (FSH), and thyrotropic hor-
mone (TSH). Most of the cells in the lateral wings are acidophilic Gonadotrophs or FSH 10% Evenly distributed
and LH cells (produce throughout anterior lobe
and produce growth hormone (GH) and, less frequently, prolactin FSH and LH in isolation
(PRL) (Table 13.2.1.1). or by the same cell)
The pars tuberalis is an extension of the anterior lobe along the Thyrotropes or TSH cells 5% Mainly in anterior part of
pituitary stalk. It is formed by normal acini of pituitary cells dis- mucoid edge
tributed around surface portal vessels. The anterior lobe also in- ACTH, adrenocorticotropic hormone; GH, growth hormone; FSH, follicle-​stimulating
cludes follicular cells, derived from secretory cells and constituting hormone; LH, luteinizing hormone; PRL, prolactin; TSH, thyrotropic hormone.
 13.2.1 Disorders of the anterior pituitary gland 2261

the blood supply is through the pituitary capsular vessels originating implicated in the network contributing to the meaningful function
from the superior hypophyseal arteries. The venous drainage from of the pituitary gland. Finally, the anterior pituitary synthesizes sev-
the anterior pituitary is through the cavernous sinuses into the pe- eral peptides, growth factors, and cytokines that play an important
trosal sinuses and the internal jugular veins. part in autocrine and/​or paracrine control of pituitary secretion
The anterior lobe has no direct innervation, apart from a few sym- and/​or cell proliferation.
pathetic nerve fibres spreading to the anterior lobe along blood ves-
sels. The hypothalamic regulation is exerted via the neurohormonal
link with the hypothalamic regulatory peptides reaching the pitu- Clinical features of pituitary disease
itary via the portal vessels.
The clinical features of pituitary disease, mostly associated with a
space-​occupying lesion, may result from local mass effects and/​or
General physiology pituitary hormone deficits or hypersecretion.
The local mass effects depend on the size of the tumour and its
The secretion of the anterior pituitary hormones is under elegant anatomical position. Headache is usually the consequence of dural
regulation exerted by hypothalamic peptides and, with the exception stretching. It can be variable (occipital, retro-​orbital, bitemporal)
of prolactin, by the negative feedback (at both the hypothalamic and and is often non​specific. The neuro-​ophthalmological effects in-
pituitary level) of hormones from the target glands (Fig. 13.2.1.3). clude visual field defects (usually bitemporal hemianopia or upper
The hypothalamic peptides are secreted in the median eminence and temporal quadrantanopia or any unilateral or bilateral visual field
are transferred to the anterior pituitary gland via the hypothalamic–​ defect) from compression of the optic chiasm (Fig. 13.2.1.4) and
pituitary portal system. They integrate environmental and neural in- squint, ptosis, or papillary dilatation from ocular nerve palsies
formation and bind to specific high affinity cell membrane receptors caused by lateral tumour extension. Compression of the first or
of the particular pituitary cell type. Failure of the target gland results second branch of the trigeminal nerve may rarely result in facial pain.
in decreased negative feedback and increased hypothalamic and pi- Very large pituitary tumours obstructing the fourth ventricle or the
tuitary secretion. Primary overactivity of the target gland results in foramen of Monro cause hydrocephalus and expansion of the lateral
increased negative feedback and decreased hypothalamic and pitu- ventricles. Inferior invasion and erosion of the sellar floor may result
itary secretion. Additional ‘short-​loop’ feedback, in which pituitary in recurrent sinusitis, cerebrovascular fluid rhinorrhoea, and recur-
hormones affect the secretory activity of the hypothalamus, is also rent meningitis. Extension into the temporal lobe may rarely be as-
sociated with temporal lobe epilepsy and to the cerebral peduncles
with motor and/​or sensory disturbances. Superior expansion to the
Central input hypothalamus may be associated with hypothalamic dysfunction

Hypothalamus
Releasing hormones Temporal visual field Nasal visual field
and inhibiting
factors

Anterior
pituitary
Negative feedback

Posterior
pituitary
X X

Nasal retinal
fibres
ADH compressed by
Oxytocin tumour Optic
Temporal
GH ACTH PRL nerve
retinal fibres
LH/FSH TSH
Target glands Optic
Peripheral hormones chiasm

Fig. 13.2.1.3 Regulation of the hypothalamic–​pituitary–​peripheral

function. The anterior pituitary produces GH, LH/​FSH, ACTH, TSH, and
PRL. The secretion of these hormones is regulated by hypothalamic-​ Fig. 13.2.1.4 Neuro-​ophthalmological pathways and the classical
releasing and hypothalamic-​inhibiting factors and by negative feedback bitemporal hemianopia that results from compression of the central
inhibition of their peripheral hormones. optic chiasm by a pituitary tumour. However, any degree of unilateral or
Reprinted from Schneider HJ, et al. (2007). Hypopituitarism. Lancet, 369, 1461–​70, © bilateral visual deficit can occur depending on the anatomical site of the
(2007), with permission from Elsevier. lesion.
2262 SECTION 13 Endocrine disorders

including disorders of appetite, thirst, temperature regulation, and Furthermore, the GH secretion is influenced by several factors
consciousness. including nutritional status and stress. As a result of these variables,
The pituitary hormone deficits attributed to a pituitary tumour random levels are of limited value in clinical practice and dynamic
tend to occur in a specific order, with GH and gonadotropins af- endocrine tests are usually needed.
fected first, followed later by ACTH and TSH. Diabetes insipidus is
almost never a presenting feature of pituitary adenomas. The clinical FSH/​LH
manifestations of hypopituitarism are presented separately for each Serum FSH and LH are secreted in a pulsatile manner. However,
anterior pituitary hormone. it is rare for tests other than basal measurements of gonadotropin
In case of a functioning pituitary adenoma, the clinical manifest- hormones and sex-​steroid levels to be required for the evaluation
ations depend on the type or types of anterior pituitary hormone(s) of the pituitary–​gonadal axis. The gonadotropins need to be in-
hypersecreted and are also presented separately for each anterior pi- terpreted taking into account the simultaneous levels of the target
tuitary hormone. gland hormone, as well as the clinical picture of the patient. Thus, in
men, a low serum testosterone in conjunction with low or ‘inappro-
priately normal’ gonadotropins suggests hypogonadotropic hypo-
Pituitary assessment strategy gonadism. In women, the interpretation is more complex because
of the significant changes in the levels of the gonadotropins during
The investigation of suspected anterior pituitary disease includes the various phases of the menstrual cycle. A normal menstrual
testing for hormonal hyperfunction or hypofunction, radiological cycle with normal luteal phase serum progesterone (days 18–​25 of
assessment, and neuro-​ophthalmological evaluation. the cycle) makes gonadotropin deficiency very unlikely. In cases of
amenorrhoea, the measurements of gonadotropins, PRL, oestra-
Testing of pituitary function
diol, and human chorionic gonadotropin (possible pregnancy) are
The optimum methods for testing anterior pituitary function and needed.
the interpretation of the results are the subject of continuing de-
bate. The diagnostic evaluation of pituitary hypofunction has many ACTH
complementary limbs. First, it is necessary to demonstrate target The ACTH molecule undergoes rapid proteolytic degradation
organ hormonal insufficiency. Paired testing of both hormones in and, therefore, blood samples must be collected in a cold syringe,
the pituitary–​target organ feedback loop (e.g. serum testosterone placed in an ethylenediaminetetraacetic acid (EDTA) tube at 4°C,
and gonadotropins), sometimes in combination with provocative and immediately frozen. ACTH secretion is pulsatile with a circa-
testing, will prove that target organ failure is consequent upon lack dian rhythm and it increases during stress. As a result, the inter-
of stimulation by the relevant pituitary tropic hormone. Additional pretation of the measurements should take into account the time of
tests may be necessary to clarify whether the pituitary itself is at fault sample collection, whether the sample was taken from an indwelling
or whether the pituitary failure is secondary to understimulation by cannula in place for at least 30 min, and whether the patient was
the hypothalamus. stressed. Simultaneous measurement of plasma cortisol is important
to check the appropriateness of the ACTH levels.
Basal pituitary function tests
Measurements of basal levels of pituitary hormones with target PRL
gland hormone secretion are usually sufficient for cases of pituitary PRL is secreted in a pulsatile fashion and also shows an increase in
dysfunction involving TSH (thyroxine), FSH/​LH (testosterone or the early morning hours. Stress may cause mild elevations of the
oestradiol), and PRL. When interpreting basal measurements of hormone and, therefore, the stress of venepuncture should be taken
pituitary hormones, several factors need to be taken into account: into account when assessing the results.
• With the exception of PRL, the interpretation of the anterior pitu- TSH
itary hormonal levels should be done in relation to the level of the
target hormone. The new ultrasensitive assays for TSH have made dynamic testing
unnecessary and random sampling therefore provides meaningful
• The pulsatile secretion of the anterior pituitary hormones may
information.
make a single, random blood sample not representative of the total
secretion (e.g. GH). Dynamic endocrine tests
• Specific factors including time of day, stress, fed, or fasting, asleep
In general, the more dynamic the physiological system in health,
or awake, and stage of pubertal development may influence the
the more likely will be the need for a dynamic test to investigate its
results.
possible malfunction in disease. The provocative tests include those
Currently, the modern chemiluminescent assays and mass spec- that stimulate hormone release indirectly (e.g. insulin tolerance
trometry methods are used for measurement of hormone concentra- test) and those that stimulate hormone release directly by injecting
tions; these methods have the advantages of increased automation pharmacological doses of synthetically manufactured peptides (e.g.
and improved sensitivity and specificity. short Synacthen test). Currently, the combined anterior pituitary
function test with the administration of LH-​releasing hormone
GH (LHRH) and thyrotropin-​releasing hormone (TRH) is not used in
The marked pulsatile secretion of GH results in values in a normal clinical practice, as basal hormone measurements provide the ne-
subject ranging from undetectable to more than 80 mU/​ litre. cessary diagnostic information. Thus, only disorders of ACTH and
 13.2.1 Disorders of the anterior pituitary gland 2263

GH secretion need dynamic endocrine testing with stimulation or (or 1.5 mg if body weight >90 kg) glucagon subcutaneously with
suppression tests, according the presenting picture. blood sampling for cortisol, GH, and glucose at times 0, 90, 120, 150,
The most commonly used tests in clinical practice are described 180, and 210 min. The contraindications for this test include phaeo-
next. chromocytoma or insulinoma, glycogen storage disease, and severe
hypocortisolaemia. The interpretation of results relies on criteria
Insulin tolerance test established for the insulin tolerance test. The injection may cause
This test is considered the gold standard for assessing the integrity nausea, abdominal pain, and vomiting. Glucagon is a less powerful
of the ACTH–​cortisol axis, as well as the GH reserve. The hypogly- stimulus to ACTH release and false-​negative results may be seen in
caemia induced by the intravenous injection of insulin is a powerful up to 20% of patients. In some false-​negative results, no rise in the
stimulus, which in the intact pituitary and hypothalamus induces blood glucose is achieved after the glucagon injection.
ACTH and GH release, as well as a rise, therefore, in the serum cor-
tisol levels. It has been proposed that the peak cortisol levels of pa- Growth hormone-​releasing hormone (GHRH) plus arginine test
tients undergoing major surgery are comparable to those achieved The GHRH plus arginine test is used as an alternative to the insulin
during the insulin-​ induced hypoglycaemia. The test should be tolerance or glucagon test for assessment of the GH reserve. The
undertaken only under close supervision at skilled centres. The pa- protocol involves intravenous infusion of GHRH 1 µg/​kg (maximum
tient should be fasted from midnight and the test started at 9.00 a.m. dose 100 µg) followed by arginine infusion 0.5 g/​kg (maximum 35
At 0 min, 0.1 to 0.15 IU/​kg (or 0.3 IU/​kg for those with acromegaly, g) over 30 minutes. With blood sampling for GH at times 0, 30, 45,
Cushing’s syndrome, or other conditions with insulin resistance) of 60, 75, 90, 105, and 120 min. The cut-​offs for GH response are BMI-​
soluble human insulin is injected intravenously and blood is drawn related and false normal GH response may be seen if GH deficiency
at times 0, 30, 45, 60, 90, and 120 min. During the procedure, pulse is attributed to hypothalamic damage (e.g. following irradiation).
rate, blood pressure, and manifestations of hypoglycaemia should
be recorded. Blood glucose must fall to less than 2.2 mmol/​litre (to Oral glucose tolerance test
provide an adequate stimulus) in order to interpret the cortisol and The evaluation of GH hypersecretion requires a suppression test.
GH levels. A normal cortisol response is a rise to 500–​550 nmol/​ Increased blood glucose levels inhibit GH secretion and the admin-
litre or above (depending on the hormone assay). Severe GH defi- istration of oral glucose is used in suspected acromegaly. The test is
ciency in adults is diagnosed if the peak GH is less than 3 μg/​litre. performed at 9.00 a.m. with the patient fasted from midnight. Blood
Contraindications include ischaemic heart disease, epilepsy, or samples are drawn for measurement of glucose and GH at times 0,
unexplained blackouts, severe long-​standing hypoadrenalism, un- 30, 60, 90, and 120 min. Immediately after the first blood sample,
treated hypothyroidism, and glycogen storage disease. Many phys- 75 g of glucose are dissolved in water and given to the patient. In
icians are uncomfortable with the use of this test in older people. normal individuals serum GH should reach undetectable levels.
Failure of suppression or a paradoxical rise in GH suggest acro-
Short Synacthen test megaly. False-​positive results may be seen in uncontrolled diabetes
This test has been advocated as an alternative to the insulin tolerance mellitus, obesity, liver disease, renal insufficiency, malnutrition, or
test for assessing the ACTH reserve. The rationale for its use is that anorexia. During late adolescence, when GH secretion is maximal,
chronic underexposure of the adrenal glands to ACTH (following GH may also fail to be suppressed.
prolonged corticosteroid therapy or due to hypothalamic–​pituitary
disease) will result in a blunted cortisol response to exogenously Radiological assessment
administered ACTH. It involves the injection of a pharmacological Currently, the imaging modality of choice for patients with suspected
dose (250 µg) of ACTH with measurement of the cortisol response pituitary pathology is MRI. CT is an acceptable alternative if MRI
30 min later. The correlation between cortisol levels 30 min after the is contraindicated. The advantages of MRI are direct multiplanar
injection of Synacthen and the peak cortisol achieved during the in- scanning, lack of ionizing radiation, and good anatomical tissue dis-
sulin tolerance test is excellent; stimulated cortisol concentrations of crimination without the need for pharmaceutical contrast agents.
500–​550 nmol/​litre or less (depending on assay) suggest ACTH de- The evaluation of the pituitary and the hypothalamus is optimal in
ficiency. This test does not differentiate primary from secondary ad- sagittal and coronal planes. The only disadvantage of MRI (apart
renal insufficiency. It requires no specialist staff and the only reported from the cost) is its relative insensitivity to pathological calcifica-
side effect is allergy in patients with atopy. It cannot be used in cases tion and lack of signal from corticated bone. CT or even plain film
of acute hypopituitarism as it takes at least 2 weeks for the adrenal radiography may be required to demonstrate pathological calcifi-
zona fasciculata to involute following withdrawal of ACTH stimu- cation. The structures of the sellar region are best visualized using
lation. In recent years, much interest has arisen in the use of a lower T1-​weighted sequences, which produce images with dark cerebro-
dose of ACTH (1 µg), as the injected bolus of 250 µg is considered spinal fluid, grey brain and pituitary, and white fat. Corticated bone
supraphysiological; this has not gained widespread acceptance. returns low signal and appears dark, but bone marrow fat returns high
signal and appears white. The nuclei of the hypothalamus cannot be
Glucagon stimulation test distinguished, but if phospholipid vesicles are present in the neuro-
The glucagon stimulation test is used as an alternative to the insulin hypophysis they are apparent as high signal areas. The need for routine
tolerance test for assessment of the ACTH/​cortisol and GH reserve. intravenous administration of paramagnetic agents is controversial
The subcutaneous injection of glucagon causes a transient rise in (however, it increases the pick-​up rate of pituitary microadenomas).
plasma glucose and, during the subsequent fall in glucose, ACTH These agents do not cross the blood–​brain barrier and, therefore, the
and GH are released. The test involves the administration of 1 mg pituitary gland and stalk enhance and appear whiter on T1-​weighted
2264 SECTION 13 Endocrine disorders

images. The hypothalamus and the optic chiasm do not enhance if the success and complication rates are mainly associated with the size
blood–​brain barrier is intact. Blood vessels, meninges, and mucosa of and extensions of the tumour and any previous therapy, as well as the
the paranasal sinuses will enhance. Dynamic MRI has been used to experience and expertise of the neurosurgeon.
study the timing of intravenously administered gadolinium uptake
by the hypophysis (see Figs. 13.2.1.1, 13.2.1.2).
Apart from its complementary role to MRI in detecting patho- Pituitary radiotherapy
logical calcification, CT scanning is the imaging modality of choice
for patients who are unable to undergo MRI (extreme claustrophobia, After the improvement of surgical techniques and the availability of
presence of cardiac pacemakers, or other implants such as intracra- medical therapy for prolactinomas, pituitary irradiation is no longer
nial aneurysm clips or traumatic metallic fragments). Multislice prescribed routinely for the management of pituitary tumours. It is
spiral CT scanners produce images of sufficient quality to demon- mainly reserved for patients who are not fit to undergo surgery, for
strate sellar anatomy on unenhanced images. Intravenous injection those who have had an unsuccessful operation, or for those showing
of iodinated contrast media is used to improve tissue contrast and it tumour recurrence.
is taken up by the hypophysis in the same way as gadolinium. Thus, Conventional irradiation uses a linear accelerator and is admin-
macroadenomas or craniopharyngiomas enhance and are better de- istered in a fractionated manner to a total dose of 4500 cGy in daily
lineated, but demonstration of microadenomas within a morpho- doses not exceeding 180 cGy over a 5-​to 6-​week period. Hormonal
logically normal pituitary depends on differential uptake rates. hypersecretion shows a rapid fall within the first 2 years with the de-
cline continuing for up to 20 years. Radiotherapy is also considered
Neuro-​ophthalmological evaluation an effective modality for decreasing the recurrence rates of pituitary
The neuro-​ ophthalmological evaluation in suspected pituitary tumours.
pathology includes assessment of the visual acuity (with the use of With modern technology and careful planning, the use of multiple
Snellen charts), assessment of the visual fields (by confrontation fixed fields from linear accelerators, and careful fractionation, the
using a red pin and formally by the Goldmann perimetry test or by risk of radiation-​induced late complications is small. These include
visual evoked responses), and fundoscopy (to check for optic at- hypopituitarism and visual impairment; oncogenesis and cognitive
rophy, retinal vein engorgement, or papilloedema). Vision is usually impairment occur infrequently. With increasing time after irradi-
lost gradually, except in cases of pituitary apoplexy when it may be ation, anterior pituitary function assessment will show compromised
sudden. Successful decompression of the optic nerves and chiasm reserve in gonadotropins and GH, followed later by ACTH and TSH.
achieved surgically or by medical therapy results in marked im- It has been reported that by 10 years after radiotherapy, 47% of pa-
provement of visual function; this becomes apparent within hours tients were hypogonadal, 30% were hypoadrenal, and 16% were hypo-
or days of surgery continuing thereafter for 6 months or more. The thyroid. Therefore, any patient who has received pituitary irradiation
chance of complete reversal of any visual field defects is higher if the needs lifelong follow-​up aiming for the early diagnosis of hormonal
duration of compression of the optic chiasm is short (<1 year). deficits. Notably, the total dose and the dose per daily fraction influ-
ence the risk of hypopituitarism. Optic nerve/​chiasmal damage can be
avoided by keeping the daily fractionated dose to less than 200 cGy.
Pituitary surgery From the available data, the incidence of late carcinogenesis cannot
be estimated with certainty, but it is unlikely to be more than 1 to 2%.
Currently, the main aims of pituitary surgery are to cure any endo- Recently introduced techniques include intensity modulated ra-
crine excess and to reverse the pressure effects (particularly the visual diation therapy, proton beam radiation therapy, stereotactic radio-
compromise and the pituitary dysfunction) without causing mor- therapy, and stereotactic radiosurgery (producing a highly localized
bidity or mortality. For all pituitary tumours, except prolactinomas, deposition of radiation on the target, at the perimeter of which there
surgery is the treatment of choice. It is also indicated when other is a fast ‘fall off ’ of the isodoses, thereby sparing the surrounding
therapies have not been successful or in case of tumour recurrence. normal tissue from high doses of irradiation). Following stereo-
The trans-​sphenoidal approach (via the translabial or transethmoidal tactic radiosurgery, there is a faster early reduction of the excessive
route) with the microscopic or endoscopic technique) is most com- secretory hormone product; hypopituitarism can also occur.
monly used and, compared with the transfrontal route, it is less time The selection of the optimal radiation treatment modality should
consuming, less traumatic, and associated with less morbidity. The be based on the size and extent of the adenoma, the postoperative
trans-​sphenoidal approach is less successful for large tumours with endocrine situation for secretory tumours, and the pituitary hor-
significant invasion to neighbouring structures. In pituitary aden- mone reserve. For small, discrete tumours located in the fossa,
omas the tumour is usually soft and white and can be easily removed radiosurgery seems to be a good option. This technique is also useful
by curettes and suction. Other tumours may also be recognized for patients with recurrence who have already received conventional
during surgery, including meningiomas or craniopharyngiomas. radiotherapy.
Complications include cerebrospinal fluid leakage, impaired anterior
pituitary function, diabetes insipidus (most commonly temporary),
the syndrome of inappropriate secretion of antidiuretic hormone Anterior pituitary hormones
(usually transient), visual deterioration, meningitis, headache (at-
tributed to haematoma in the air sinuses, meningitis, hyponatraemia, GH
or abscess), vascular damage, epilepsy, frontal lobe damage, hypo- Human GH is a single chain protein of 191 amino acids containing
thalamic damage, and intracranial oedema/​ haemorrhage. The two disulphide bonds. It is produced by the somatotroph cells and it
 13.2.1 Disorders of the anterior pituitary gland 2265

has several similarities to prolactin and the placental lactogen mol- those with liver disease, hypothyroidism, or poorly controlled dia-
ecule. Nearly 75% of the hormone circulates as a 22-​kDa protein, 5 betes. Although IGF-​1 levels usually reflect the integrated secretory
to 10% as a smaller 20-​kDa isoform, and the remainder consists of activity of GH, subtly elevated GH levels may not uniformly induce
glycosylated and sulphated isoforms. GH is secreted in an episodic high IGF-​1.
manner (pulses occurring every 3–​4 h) that is modified by age and The main actions of GH are the promotion of skeletal growth,
sex. The most profound discharge occurs during deep sleep (phases mainly of long bones, and the regulation of several metabolic ac-
III and IV). Its secretion is under complex neuroregulatory control. tions. In the muscles GH promotes the incorporation of amino acids
The hypothalamic participation is exerted through GH-​releasing and protein synthesis, and in the adipose tissue it promotes free fatty
hormone (GHRH) and somatostatin, which reach the pituitary gland acid release.
via the hypothalamo-​pituitary portal vessels. GHRH stimulates both
synthesis and secretion of GH, whereas somatostatin inhibits the re- Disorders of GH secretion
lease but not the synthesis of the hormone. Ghrelin, the endogenous GH deficiency
ligand of the GH secretagogue receptor localized mainly in the The manifestations of GH deficiency are shown in Table 13.2.1.2.
stomach, may also be implicated in the control of GH secretion. The Given its pulsatile secretion, the measurements of random GH
somatotroph cell is also regulated by negative feedback at the pitu- levels do not distinguish between normal and compromised GH
itary level by the circulating insulin-​like growth factor 1 (IGF-​1) and secretion; multiple sampling for GH would be ideal but in clinical
by ‘short-​loop’ feedback on the hypothalamus by GH. The secretion practice this is not a practical procedure. Therefore, the diagnosis of
of GH is greater in women and it shows a decrease with age in both GH deficiency requires stimulation testing, unless all other pituitary
sexes. Amino acids (e.g. arginine, leucine), sleep, exercise, stress, a hormones are deficient and the IGF-​1 is low (in these patients the
fall in blood glucose, poorly controlled diabetes mellitus type 1, hep- likelihood of GH deficiency is 99%). The biochemical criteria for
atic cirrhosis, anorexia nervosa, central α-​adrenergic agonists, and the diagnosis of adult GH deficiency are complicated by the lack of
acetylcholine agonists enhance GH secretion. Oestrogens increase normative data that are age-​adjusted and sex-​adjusted, by the assay
the pulse amplitude of GH. β-​Antagonists augment the stimulatory variability, and by the stimulus used. Among the available tests the
effect of other stimuli. Agents lowering acetylcholine tone suppress insulin tolerance test is considered the gold standard. Severe GH de-
GH release. Hyperglycaemia in normal subjects acutely suppresses ficiency in adults is diagnosed if the peak GH is less than 3 μg/​litre.
GH secretion. Obesity is associated with decreased GH release and In children the secretory capacity of GH is higher and a cut-​off of 10
emotional deprivation may inhibit GH secretion in children. GH μg/​litre is used. The GHRH plus arginine test has been shown to re-
levels are decreased in pregnancy due to the negative feedback by liably detect severe GH deficiency in a lean adult population when a
the GH variant secreted by the placenta. cut-​off of 9 μg/​litre is used. The response to this test declines greatly
GH exerts its actions through a specific 638-​amino acid receptor with increasing body mass index and the above cut-​off in obese pa-
belonging to the class I haematopoietin or cytokine/​GH/​PRL re- tients is associated with a high proportion of false-​positive results.
ceptor superfamily. It shows a wide distribution including muscle, Furthermore, as GHRH directly stimulates the pituitary, it can give a
adipose and immune tissues, liver, mammary gland, bones, kidneys, falsely normal GH response in patients with GH deficiency of hypo-
brain, and embryonic stem cells. It is a single membrane-​spanning thalamic origin. Other alternative tests, but less commonly used in
type I glycoprotein with an extracellular ligand-​binding domain, a clinical practice, include the GHRH plus GH-​releasing peptide-​
single 24-​amino acid hydrophobic transmembrane region, and an 6 test, the glucagon test, the arginine test, the l-​dopa test, and the
intracellular domain. The signal transduction requires dimerization clonidine test. Normal serum levels of IGF-​1 do not exclude a diag-
of the receptor, which is facilitated by the GH binding. The down- nosis of GH deficiency.
stream signalling pathways resulting in GH actions include, but are The main targets of GH therapy in children with GH deficiency
probably not limited to, the signal transducer and activator of tran- are to normalize height during childhood and to reach normal adult
scription, mitogen-​activated-​kinase (MAP), and phosphoinositide height. The benefits of treatment with GH among adult patients have
3-​kinase (PI3) pathways. Abnormalities in the GH receptor occur in been reported in several domains: body composition (decrease in
Laron’s dwarfism, which is characterized by failure of growth, high total body fat content, increase in muscle mass), exercise capacity,
levels of GH, and low IGF-​1. bone health (increase in bone mineral density with greater effects
Up to 60% of the circulating serum GH is bound to the GH-​
binding protein, which corresponds to part of the extracellular do-
main of the GH receptor. The binding reduces the clearance rate of
the hormone and thus prolongs its half-​life. Table 13.2.1.2 Manifestations of GH deficiency
The effects of GH are mediated either directly or mainly indir-
Children Adults
ectly via the production of IGF-​1 by the liver, bones, and other
Growth failure Relative increase in fat mass
types of tissues. IGF-​1 is a polypeptide of 70 amino acids and acts
in an endocrine, paracrine, or autocrine fashion. It circulates bound Relative decrease in muscle mass
to a group of binding proteins; IGF binding protein-​3 is the main Increased serum low-​density lipoprotein cholesterol
carrier of IGF-​1 and plays an important role in regulating its bio- Decreased bone mineral density
activity. IGF-​1 induces cell proliferation and inhibits apoptosis. Its Increased risk of cardiovascular disease
levels are determined by sex and genetic factors, are highest during
Increased inflammatory cardiovascular risk markers
late adolescence, and decline throughout adulthood. The produc-
Decreased energy and quality of life
tion of IGF-​1 is suppressed in malnourished patients, as well as in
2266 SECTION 13 Endocrine disorders

at vertebral sites), cardiovascular risk factors (decrease in blood Box 13.2.1.1 Clinical features of acromegaly
pressure, reduction of C-​reactive protein, increase in high-​density
lipoprotein, and decrease in low-​density lipoprotein and total chol- Local tumour effects
esterol), and quality of life. In adults, the dosing plans have evolved • Pituitary enlargement
from weight-​based dosing to individualized dose-​titration strategies • Visual field defects
• Cranial nerve palsy
with the goals being an appropriate clinical response, an avoidance
• Headache
of side effects, and an IGF-​1 level in the middle of the age-​adjusted
reference range. In general, women require higher doses of GH Somatic systems
to achieve the same IGF-​1 response (much higher GH doses were • Acral enlargement including thickness of soft tissue of hands and feet
also needed to achieve the same IGF-​1 levels in women receiving Musculoskeletal system
oral oestrogen replacement, but this does not apply when oestro- • Gigantism
gens are offered as patches). Furthermore, as GH secretion normally • Prognathism
decreases with age, older patients require lower doses of GH. The • Jaw malocclusion
duration of GH replacement therapy in adults is unclear; if bene- • Arthralgias and arthritis
fits are apparent, there is no particular reason to stop treatment. • Carpal tunnel syndrome
• Acroparesthaesia
On the other hand, if there are no benefits following around 1 year
• Proximal myopathy
of treatment, discontinuing GH therapy may be appropriate. Most
• Hypertrophy of frontal bones
adverse effects are dose related and are attributed to fluid reten-
tion (paraesthesias, joint stiffness, peripheral oedema, arthralgia, Skin and gastrointestinal system
and myalgia). In children, there is a risk of slipped capital femoral • Hyperhidrosis
epiphysis. With the current dosing regimens, there may be a slight • Oily texture
• Skin tags
excess risk of diabetes mellitus. Other complications of GH therapy
• Colon polyps
include retinopathy, benign intracranial hypertension, and gynae-
comastia. GH replacement may cause a decrease of serum free thy- Cardiovascular system
roxine levels (perhaps due to increased deiodination of thyroxine) • Left ventricular hypertrophy
and of serum cortisol levels (revealing central hypoadrenalism that • Asymmetric septal hypertrophy
had been masked, probably due to enhanced conversion of cortisone • Cardiomyopathy
• Hypertension
to cortisol during the GH-​deficient state). GH treatment is contra-
• Congestive heart failure
indicated in the presence of an active malignancy.
Pulmonary system
Acromegaly • Sleep disturbances
Acromegaly is the syndrome resulting from GH hypersecretion. • Sleep apnoea (central and obstructive)
Its incidence is estimated to be approximately three cases per • Narcolepsy
1 million persons per year, and its prevalence is about 60 per Visceromegaly
million. More than 90% of patients with acromegaly have a be- • Tongue
nign monoclonal GH-​secreting pituitary adenoma surrounded • Thyroid gland
by non​hyperplastic pituitary tissue. Cosecretion of PRL has been • Salivary glands
described in about 25% of GH-​secreting adenomas. More than • Liver
70% of somatotroph tumours are macroadenomas at diagnosis. • Spleen
Younger patients usually present with more rapidly growing tu- • Kidney
• Prostate
mours. Rarely, acromegaly is associated with familial occurrence
[including multiple endocrine neoplasia type 1 or 4, familial Endocrine and metabolic systems
isolated pituitary adenoma (related in several cases with muta- Reproduction
tions in the aryl hydrocarbon receptor-​interacting protein (AIP) • Menstrual abnormalities
gene), and Carney’s syndrome]. X-​linked acrogigantism (X-​LAG