Oxford textbook of medicine [6 ed.] 9780198746690, 0198746695, 9780198815334, 0198815336, 9780198815358, 0198815352, 9780198815372, 0198815379, 9780198847410, 0198847416

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Oxford Textbook of

Medicine

More comprehensive, more authoritative, and more international than any other textbook, the Oxford Textbook of Medicine focuses on offering perspective and practical guidance on the clinical management and prevention of disease. Introductory sections focus on the patient experience, medical ethics, and clinical decision-making, outlining a philosophy which has always characterized the Oxford Textbook of Medicine. It is humane, thought-provoking, and aims to instil in readers an understanding of the role of medicine in society and the contribution it can make to the health of populations. In addition, it does not shy away from discussion of controversial aspects of modern medicine. As always, there is detailed coverage of all areas of internal medicine by the world’s very best authors. The Oxford Textbook of Medicine seeks to embody advances in understanding and practice that have arisen through scientific research. The integration of basic science and clinical practice is unparalleled, and throughout the book the implications of research for medical practice are explained. The core clinical medicine sections offer in-depth coverage of the traditional specialty areas. The Oxford Textbook of Medicine has unsurpassed detail on infectious diseases: the most comprehensive coverage to be found in any textbook of medicine. Other sections of note include stem cells and regenerative medicine; inequalities in health; medical aspects of pollution and climate change; travel and expedition medicine; bioterrorism and forensic medicine; pain; medical disorders in pregnancy; nutrition; psychiatry; and drug-related problems in general medical practice. The section on acute medicine is designed to give immediate access to information when it is needed quickly. In response to ongoing user feedback, there have been substantial changes to ensure that the Oxford Textbook of Medicine continues to meet the needs of its readers. Chapter essentials give accessible overviews of the content and a new design ensures that the textbook is easy to read and navigate. The evidence base and references continue to be at the forefront of research.

Medicine

The Oxford Textbook of Medicine is the foremost international textbook of medicine. Unrivalled in its coverage of the scientific aspects and clinical practice of internal medicine and its subspecialties, it is a fixture in the offices and wards of physicians around the world, as well as being a key resource for medico-legal practitioners.

Oxford Textbook of

VOLUME

2

SECTIONS 10-15

Firth Conlon Cox ISBN 978-0-19-885345-9

9 780198 853459

INTERNATIONAL EDITION

Oxford Textbook of

SIXTH EDITION

1

2

2

Medicine SIXTH EDITION VOLUME 2

edited by

John D. Firth Christopher P. Conlon Timothy M. Cox

ONLY FOR SA LE I N I N D I A , B A N GLA D ESH , SR I LA N K A , N EPA L, B H UTA N , A N D M YA N M A R AND NOT FOR EXP O RT T H ER EF RO M . N OT F O R SA LE I N A N Y OT H ER CO UN T RY I N T H E WO R LD

Oxford Textbook of

Medicine

Oxford Textbook of

Medicine SIXTH EDITION Volume 2: Sections 10–15

EDITED BY

John D. Firth Christopher P. Conlon Timothy M. Cox

1

3 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Oxford University Press 2020 The moral rights of the authors have been asserted First Edition published in 1983 Second Edition published in 1987 Third Edition published in 1996 Fourth Edition published in 2003 Fifth Edition published in 2010 Sixth Edition published in 2020 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2018933144 Set ISBN: 978–0–19–874669–0 Volume 1: 978–0–19–881533–4 Volume 2: 978–0–19–881535–8 Volume 3: 978–0–19–881537–2 Volume 4: 978–0–19–884741–0 Only available as part of a set Printed in Malaysia by Vivar Printing Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-​to-​date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-​pregnant adult who is not breast-​feeding Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.

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

In 1983, David Weatherall, John Ledingham, and David Warrell launched the first edition of the Oxford Textbook of Medicine. That era of medicine looked entirely different from today but the need for a scholarly repository of medical knowledge remains as important as ever. Medicine is now firmly in a digital age; sources of information abound and are readily available and the field is moving so quickly that it is harder than ever to provide up to date relevant information for the profession. Despite this, the sixth edition of the Oxford Textbook of Medicine still provides the foundation of knowledge upon which good clinical practice is based. Never before has there been such a rapid advance of medical knowledge and practice. Since the first edition of the Oxford Textbook of Medicine, medical practice has reduced cardiovascular mortality by up to 70% in Western countries, there are now multiple new therapies for diseases such as rheumatoid arthritis and multiple sclerosis, disorders where the descriptions of therapeutic options in the first edition were necessarily brief. Cancer is now increasingly managed with immune and targeted therapies. Whole new diseases have appeared (Hepatitis C and HIV) and have been either controlled or conquered with drug therapy. The sequencing of the human genome seemed an impossible dream in 1983 while today we have sequenced more than a million genomes and have had insights into rare disease and cancer that were unimaginable then. Life expectancy has risen by nine years for men and ten for women in the United Kingdom, creating a demographic shift that will fundamentally change society and medicine forever. The pace of change has been dramatic. The Oxford Textbook of Medicine gained a reputation by moving medical practice forward from the Oslerian view of medicine originally expounded in his text book the Principles and Practice of Medicine into an era of more molecular and scientifically based understanding of disease. Constrained by the lack of tools for exploring the molecular basis of pathogenesis, Osler was limited in how he could describe the world of disease, largely based on bedside observations or those from the post-​mortem room. The Oxford Textbook of Medicine shifted this focus and aligned it with the emerging field of molecular medicine which has begun to create a new taxonomy of disease but also an approach to therapy which is based on pathogenesis. There has been a wave of new information, with new insights appearing weekly into the underlying molecular events associated with disease. Diseases characterized by phenotype are now broken down into multiple subtypes and disease is being individualized. This is rapidly leading to a very significant change in our perception of pathogenesis as well as the classification and

nomenclature of disease, all crucial roles for a textbook of medicine. We now are aware that many of the classic definitions of diseases such as diabetes or cancer were descriptions of phenotypic characteristics. Interrogation of these disorders at a molecular level has demonstrated that these terms mask disease subtypes defined by molecular pathology where natural history and response to therapy may differ. Combine this with the explosion of new diseases coming from studies of rare disease and there is a challenge to conventional disease nomenclature. This molecular precision creates real opportunities for targeted highly effective therapies, but it also creates challenges for the model of drug discovery when novel treatments can only be used in increasingly small patient populations. These are major issues for medicine, health systems, but also textbooks such as this one where, historically, the stewardship of disease nomenclature has been maintained. The therapeutic options available to practising clinicians have also advanced beyond all recognition since the first edition of the Oxford Textbook of Medicine. We have seen an era of biologic therapy which has provided important new therapeutic alternatives for many hard-​ to-​treat diseases including cancer. We are now entering a new era where modalities such as gene therapy and interfering RNA therapeutics have demonstrated their utility in the clinic. Similarly, an era of cell therapy has also begun which will provide important new alternatives to some diseases. These new therapeutic alternatives and other opportunities for improving healthcare using medical technology or novel diagnostics such as sequencing also bring with them the challenge of how healthcare systems can continue to be affordable, either for individuals in private healthcare settings, or in state-​funded, single-​payer systems. In this context, it is remarkable that the authors and editors of the Oxford Textbook of Medicine have managed to sustain both its relevance and the accuracy of its content. The pace at which our understanding of disease, our therapeutic options, and our healthcare systems are likely to change makes it nearly impossible for a textbook of medicine to be truly comprehensive given the speed of change, the impact of new innovations and the multiple additional sources of information available to practitioners. The Oxford Textbook of Medicine has provided remarkable levels of detail in this rapidly changing world but, more importantly, the textbook continues to provide a source for readers to access information on the fundamental features of disease. This foundational knowledge remains crucial to our ability to understand, diagnose, and treat patients whether they are in the developing world or

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Foreword

Western healthcare systems. Having a source of such information across all major diseases accessible in a single source remains the bedrock of both teaching and practising medicine. The foundations provided by the Oxford Textbook of Medicine form a core of knowledge which practising clinicians will continue to need. The editors of this edition have been faithful to the vision of the original three editors. Science, in all its forms, is at the heart of our

understanding of disease and has enabled progress in clinical medicine to occur at a remarkable pace. By providing a textbook that describes the foundations of our understanding of disease and its management, the editors have successfully given us an authoritative text which practising clinicians will find invaluable to support their day-​to-​day decisions. David Weatherall, one of the three original editors and who died in 2018, would be gratified by this new edition.

Preface Changes in medicine The Oxford Textbook of Medicine is published online and has been regularly updated for many years, but the production of a new and very substantially updated edition provides a moment when it is natural and proper to reflect on what has changed in medicine—​and what has not—​in recent years. In the context of burgeoning social changes and inequality across the world, we have cause to weigh and consider exactly what modern medicine has to offer patients and their doctors. Here we reflect on aspects of Medicine that are changing rapidly and set out a vision for this in the sixth edition of the Oxford Textbook of Medicine.

Demand, capacity, magic solutions, and the need for perspective Within all healthcare systems, in rich and poor nations alike, most physicians feel the inexorable rise in demand and are struggling to provide adequate ‘capacity’—​the term commonly applied by healthcare managers charged with the impossible task of constraining expenditure while serving political masters who, almost without exception, promise more and more and blame inefficiency and ‘unwarranted variation’ for the failure to deliver. In response to the difficulties, claims are made that some new technological advance, be it sequencing of patients’ genomes, healthcare apps, the application of artificial intelligence or ‘Quality Improvement’ methodology, will provide the solutions. In the Oxford Textbook of Medicine, we do not shy away from these aspects and have several new chapters that consider how rich and ‘resource-​poor’ countries might best invest their revenues on health. It is often very hard for practising physicians, who care for patients as individuals, to maintain their bearings within the unfamiliar and depersonalized world of modern healthcare management. Many are left wondering whether those who organize health services ‘live on this planet’, or ‘did any working doctor check out that latest directive from above?’. When clinical outcomes that really matter are difficult to quantify, doctors find themselves and their services judged by spurious measures of ‘productivity’ in the process of healthcare ‘delivery’. Unrealistic and often clinically irrelevant targets might drive the thinking of the insurers, managers, and politicians, but who can determine the human and clinical value of the care provided? Timeliness of care is important and sometimes crucial for salutary outcomes, but disaster strikes when clock-​driven targets are blindly pursued for all patients irrespective of clinical urgency and to the exclusion of all else, including patients with greater clinical need. In the morass created by financial constraints and zealous political control of health services exercised by those without clinical

responsibility, it is rare for doctors be able to stand back and perceive genuine improvements. However, it is certainly true that today we have greater potential to prevent and treat disease and to maintain health than ever before. It is our hope that the Oxford Textbook of Medicine will inform doctors about these changes and provide good guidance as to how they can be translated into clinical practice.

Advances in biomedical sciences We seek to embody advances in understanding and practice that have arisen through scientific research. In the ten years since publication of the last edition of this book there has been spectacular progress in the application of science in medicine, especially the understanding of genomics and molecular cell biology. These include: in diagnostics, non-​invasive prenatal diagnosis of chromosome abnormalities and monogenic disease by sampling maternal plasma for cell-​free fetal DNA, a technique which also holds promise for screening and monitoring of cancers; in metabolic disease, the introduction of molecular therapies that address the defective chloride transport in cystic fibrosis; in oncology, increased understanding of cancer immunity leading to the development of immunotherapies for cancers. Our authors include the very best in their fields. The founding editor and author in this edition, the late David Weatherall, was a recipient of the Lasker-​Koshland Special Achievement Award in Medical Science. Two new authors have received the Nobel Prize recently—​Professor Tu Youyou the 2015 prize for Medicine or Physiology, and Sir Greg Winter the 2018 prize for Chemistry. Another new author, Professor Y.M. Dennis Lo, was one of two winners of China’s inaugural Future Science Prize in 2016. Beyond scientific development, the introduction of new technologies into practice typically leads to a sequence of events including initial ‘hype’ from many in the field, with extravagant claims of potential benefit. After an interval, these claims are followed by a more realistic assessment of what the technology can—​and cannot—​ provide. Frequently, this familiar pattern is driven by powerful commercial influences which can corrupt thinking in a manner that generates a climate in which those with views contrary to the big battalions are inevitably marginalized. In this edition of the Oxford Textbook of Medicine we have strived to bring an authentic perspective and realism to recommendations for treatment. We sense, for instance, that the excitement generated by the sequencing of patients’ genomes continues to increase, but that this trajectory is flattening and expectations becoming more realistic. For patients very likely to have genetic disorders, diagnoses can be made for a proportion that was unimaginable until recently, but for most patients with the degenerative and/​or polygenic diseases that are the greatest burden

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to health, evidence of clinical benefit from genome sequencing remains elusive. Beyond the progress in genomics and cell biology there has been immense interest in bioinformatics and, especially with the enthusiasm of major biomedical charities such as The Wellcome Trust, for ‘big data’, and the opportunities that these bring to the practice of medicine. However, while there are plentiful examples of genomics and cell biology having been translated productively from the bench to the bedside, with enormous benefit to patients, examples of transforming clinical impact from big data and bioinformatics are sparse. But examples there are, such as in the analysis of outbreaks of the scourges Clostridium difficile and methicillin-​resistant Staphylococcus aureus (MRSA). These discoveries give hope for the future as we learn which problems are tractable with this type of approach and which are not.

One hundred and fifty years ago, Darwin’s 1859 masterpiece on evolution was entitled ‘On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life’. The ‘less favoured’ undoubtedly have poorer health outcomes, due largely to the persistent social ill of inequality, in poor as well as ostensibly rich countries. Continuing the tradition of previous editions, we have contributions that discuss the impact of social determinants of health, also thoughtful chapters on human disasters (by another Nobel laureate, Prof Amartya Sen), and the practical and critically important aspects of humanitarian medicine. In addition, the modern problems of pollution and climate change are examined. We contend that all doctors would benefit from reading these chapters.

Clinical skill

There are continuing changes in patients’ expectations, particularly those of articulate patients suffering from long-​term conditions and residing in countries with a rich provision of healthcare. A paternalistic medical approach is no longer acceptable, and several patients have contributed greatly to the book by taking the opportunity to tell us how they think doctors should behave towards them and care for them. However, we are very aware that one size does not fit all, and that many patients want a doctor who will give them clear recommendations and not keep repeating a bewildering (to the patient) variety of options and ask them to choose. The mature and able physician will be alert and sensitive to those patients who want this and will provide them with clear advice, and we have endeavoured to ensure that the Oxford Textbook of Medicine will assist.

Until recently, it would have been, to paraphrase Thomas Jefferson, regarded as self-​evident that the key requirements of a good physician are the ability and will to obtain an informative history, carry out a thorough physical examination, formulate a relevant differential diagnosis, instigate appropriate investigations, advise and administer correct treatment, including best efforts to relieve symptoms in all cases. These skills, and the commitment to use them, are often forgotten when healthcare is described in the commercial terms of demand and capacity. While advances in biomedical sciences have dramatically improved the outcome for some diseases, and Paul Erhlich’s century-​ old magische Kugel (magic bullet) has whetted our appetite for wonder, it is prudent to recall Thomas Szasz: ‘Formerly, when religion was strong and science weak, men mistook magic for medicine; now, when science is strong and religion weak, men mistake medicine for magic’. The term ‘personalized’ medicine imputes remarkable and as yet unproven powers, excepting in a very few cases, to gene sequencing and molecular therapies, while the patient wants to be treated as a person. It is also alarming to us that some medical curricula increasingly focus on process, ‘behaviours’, and ‘communication skills’, to the detriment of medical content or mature guidance and attitudes to lifelong learning. There is a tendency to forget the very essence of being, and how to become, a physician in the time-​ honoured understanding of the role. In the Oxford Textbook of Medicine we unashamedly emphasize the primacy of history, examination, differential diagnosis, investigation, and treatment. Without a firm grasp of these essentials the doctor cannot provide good care for patients, and nor can anyone else. Furthermore, having a firm understanding of clinical context and a well-​informed clinical perspective is an essential prerequisite for driving biomedical research into avenues that really matter.

The broader context of health and disease The world has become a smaller place. We are now in an era when many regard not having a smartphone as an index of deprivation. An event that has happened on a different continent can, as a result of social media, become known to millions of people within hours—​the term ‘viral’ has been rightfully translated from communicable illness to global phenomenon. Narratives transmitted in this way often concern disasters, wars, and disease, and they are typically handled by the media in a sensationalized and superficial manner.

Patients and their expectations

Access to medical knowledge The ever-​expanding world of the smartphone and tablet device gives patients, families, doctors, and other healthcare professionals ready access to more information about medicine than all but a very few would have thought possible a decade ago. This has many benefits but often leaves users of the internet thoroughly perplexed, and some desperate people vulnerable to online quackery. Those wanting details of particular studies will naturally refer to the original literature. Those wanting in-​depth reviews of particular subjects can refer to diverse resources: these are typically good at apprising the reader of plentiful options for investigation, diagnosis, or management, but often leave them uncertain of what a clinically experienced expert in the field would actually recommend. In the sections that form the bulk of the Oxford Textbook of Medicine, we have selected experts with specific clinical experience and given them this task, and we contend that they have met the challenge.

Acknowledgements The Oxford Textbook of Medicine is a large undertaking: this edition, the most substantial so far, comprises 647 chapters and covers 6654 printed pages, and its production has required an extraordinary coordination of effort from many quarters. In darker moments the editors feared that the process would never end, but as we have read and edited the chapters along the way, we have experienced the joy of learning a huge amount of medicine, often in fields far removed from our own. For this we are very grateful to our contributors, including those whose submissions were delayed!

Preface

We wish to make particular acknowledgement of our friend and senior colleague, David Warrell, an editor from the first edition of this textbook, senior editor of the fourth and fifth editions, and author in this edition. We and our readers, notably those seeking information on tropical diseases and especially any who have been bitten by snakes, about which his knowledge is truly prodigious, owe him a great debt. We thank Helen Liepman, with whom we remain good friends: she has overseen and directed matters at Oxford University Press and coped in a steadfastly pleasant and professional way with expressions of editorial frustration caused by our failure to understand a

publishing process that at times seemed to be Byzantine in its complexity, as might perhaps be expected in an ancient university. We also thank Anna Kirton, Jamie Oates, and Jess White at Oxford University Press for their considerable efforts on behalf of the book. Finally, we record that the editors’ personal lives have remained calm, and we are very grateful to Helen, Jenny, and Sue for their indulgence of our bizarre editorial pursuit. John D. Firth Christopher P. Conlon Timothy M. Cox

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Section editors Jon G. Ayres  Emeritus Professor of Environmental and Respiratory Medicine, University of Birmingham, Birmingham, UK Section 10: Environmental medicine, occupational medicine, and poisoning Christopher P. Conlon  Professor of Infectious Diseases, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 8: Infectious diseases; Section 25: Disorders of the eye; Section 29: Biochemistry in medicine Cyrus Cooper  MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK Section 20: Disorders of the skeleton Timothy M. Cox  Professor of Medicine Emeritus, Director of Research, University of Cambridge; Honorary Consultant Physician, Addenbrooke’s Hospital, Cambridge, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 12: Metabolic disorders Jeremy Dwight  Previously John Radcliffe Hospital, Oxford, UK Section 16: Cardiovascular disorders Simon Finfer  Malcolm Fisher Department of Intensive Care Medicine, Royal North Shore Hospital, and The George Institute for Global Health, University of New South Wales, Sydney, Australia Section 17: Critical care medicine John D. Firth  Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 21: Disorders of the kidney and urinary tract; Section 27: Forensic medicine; Section 28: Sport and exercise medicine; Section 30: Acute medicine Mark Gurnell  University of Cambridge Medical School, Cambridge, UK Section 13: Endocrine disorders

Chris Hatton  Cancer and Haematology Centre, Churchill Hospital, Oxford, UK Section 22: Haematological disorders Deborah Hay  Honorary Consultant Haematologist, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 22: Haematological disorders Roderick J. Hay  King’s College London, London, UK Section 23: Disorders of the skin Christopher Kennard  Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK Section 24: Neurological disorders Finbarr C. Martin  Population Health Sciences, King’s College London, London, UK Section 6: Old age medicine Catherine Nelson-Piercy  Obstetric Medicine, Women’s Health Academic Centre, King’s Health Partners, King’s College London, London, UK Section 14: Medical disorders in pregnancy Jack Satsangi  Oxford Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 15: Gastroenterological disorders Pallav L. Shah  Imperial College London, London, UK Section 18: Respiratory disorders Michael Sharpe  Psychological Medicine Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK Section 26: Psychiatric and drug-related disorders Jackie Sherrard  Wycombe General Hospital, High Wycombe, Bucks, UK Section 9: Sexually transmitted diseases Richard A. Watts  Department of Rheumatology, Ipswich Hospital, Ipswich, UK; Norwich Medical School, University of East Anglia, Norwich, UK Section 19: Rheumatological disorders Bee Wee  Associate Professor of Palliative Care, University of Oxford, Oxford, UK Section 7: Pain and palliative care Katherine Younger  School of Biological and Health Sciences, Technological University Dublin, Ireland Section 11: Nutrition

Contents Volume 1 List of abbreviations xxxv List of contributors xlv

2.2 Evolution: Medicine’s most basic science  39 Randolph M. Nesse and Richard Dawkins

2.3 The Global Burden of Disease: Measuring the health of populations  43

SECTION 1 Patients and their treatment Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 1.1 On being a patient  3 Christopher Booth†

1.2 A young person’s experience of chronic disease  6 1.3 What patients wish you understood  8 Rosamund Snow†

1.4 Why do patients attend and what do they want from the consultation?  14 Des Spence

1.5 Medical ethics  20 Mike Parker, Mehrunisha Suleman, and Tony Hope

1.6 Clinical decision-​making  26 Timothy E.A. Peto and Philippa Peto

Theo Vos, Alan Lopez, and Christopher Murray

2.4 Large-​scale randomized evidence: Trials and meta-​analyses of trials  51 Colin Baigent, Richard Peto, Richard Gray, Natalie Staplin, Sarah Parish, and Rory Collins

2.5 Bioinformatics  67 Afzal Chaudhry

2.6 Principles of clinical pharmacology and drug therapy  71 Kevin O’Shaughnessy

2.7 Biological therapies for immune, inflammatory, and allergic diseases  100 John D. Isaacs and Nishanthi Thalayasingam

2.8 Traditional medicine exemplified by traditional Chinese medicine  108 Fulong Liao, Tingliang Jiang, and Youyou Tu

2.9 Engaging patients in therapeutic development  118 Emil Kakkis and Max Bronstein

SECTION 2 Background to medicine Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 2.1 Science in medicine: When, how, and what  33 William F. Bynum

2.10 Medicine quality, physicians, and patients  124 Paul N. Newton

2.11 Preventive medicine  127 David Mant

2.12 Medical screening  137 Nicholas Wald and Malcolm Law

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.

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Contents

2.14 Deprivation and health  157

3.9 Circulating DNA for molecular diagnostics  299

Harry Burns

2.15 How much should rich countries’ governments spend on healthcare?  161 Allyson M. Pollock and David Price

2.16 Financing healthcare in low-​income developing countries: A challenge for equity in health  168 Luis G. Sambo, Jorge Simões, and Maria do Rosario O. Martins

2.17 Research in the developed world  177

Y.M. Dennis Lo and Rossa W.K. Chiu

SECTION 4 Immunological mechanisms Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 4.1 The innate immune system  307 Paul Bowness

Jeremy Farrar

2.18 Fostering medical and health research in resource-​constrained countries  181 Malegapuru W. Makgoba and Stephen M. Tollman

4.2 The complement system  315 Marina Botto and Matthew C. Pickering

4.3 Adaptive immunity  325 Paul Klenerman and Constantino López-​Macias

2.19 Regulation versus innovation in medicine  185 Michael Rawlins

4.4 Immunodeficiency  337 Sophie Hambleton, Sara Marshall, and Dinakantha S. Kumararatne

2.20 Human disasters  188 Amartya Sen

2.21 Humanitarian medicine  193

4.5 Allergy  368 Pamela Ewan

Amy S. Kravitz

2.22 Complementary and alternative medicine  201

4.6 Autoimmunity  379 Antony Rosen

Edzard Ernst

4.7 Principles of transplantation immunology  392 Elizabeth Wallin and Kathryn J. Wood

SECTION 3 Cell biology Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 3.1 The cell  209 George Banting and Jean Paul Luzio

3.2 The genomic basis of medicine  218

SECTION 5 Principles of clinical oncology Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 5.1 Epidemiology of cancer  411 Anthony Swerdlow and Richard Peto

Paweł Stankiewicz and James R. Lupski

3.3 Cytokines  236 Iain B. McInnes

3.4 Ion channels and disease  246 Frances Ashcroft and Paolo Tammaro

3.5 Intracellular signalling  256 R. Andres Floto

3.6 Apoptosis in health and disease  266 Mark J. Arends and Christopher D. Gregory

3.7 Stem cells and regenerative medicine  281 Alexis J. Joannides, Bhuvaneish T. Selvaraj, and Siddharthan Chandran

5.2 The nature and development of cancer: Cancer mutations and their implications  445 James D. Brenton and Tim Eisen

5.3 The genetics of inherited cancers  456 Rosalind A. Eeles

5.4 Cancer immunity and immunotherapy  471 Charles G. Drake

5.5 Clinical features and management  487 Tim Eisen and Martin Gore†

5.6 Systemic treatment and radiotherapy  497 Rajesh Jena and Peter Harper

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

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 Old age medicine

SECTION 8 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

Duncan J. Maskell and James L.N. Wood

6.2 Frailty and sarcopenia  521 Andrew Clegg and Harnish Patel

6.3 Optimizing well-​being into old age  532

8.1.2 Clinical features and general management of patients with severe infections  656

Peter Watkinson and Duncan Young

Steve Iliffe

6.4 Older people and urgent care  539 Simon Conroy and Jay Banerjee

6.5 Older people in hospital  548 Graham Ellis, Alasdair MacLullich, and Rowan Harwood

6.6 Supporting older peoples’ care in surgical and oncological services  563 Jugdeep Dhesi and Judith Partridge

8.2 The patient with suspected infection  662 8.2.1 Clinical approach  662

Christopher J. Ellis 8.2.2 Fever of unknown origin  664

Steven Vanderschueren 8.2.3 Nosocomial infections  669

Ian C.J.W. Bowler and Matthew Scarborough 8.2.4 Infection in the immunocompromised host  673

Jon Cohen and Elham Khatamzas

6.7 Drugs and prescribing in the older patient  571 Miles Witham, Jacob George, and Denis O’Mahony

6.8 Falls, faints, and fragility fractures  579 Fiona Kearney and Tahir Masud

6.9 Bladder and bowels  589 Susie Orme and Danielle Harari

6.10 Neurodegenerative disorders in older people  601 John Hindle

6.11 Promotion of dignity in the life and death of older patients  612

8.2.5 Antimicrobial chemotherapy  684

Maha Albur, Alasdair MacGowan, and Roger G. Finch

8.3 Immunization  706 David Goldblatt and Mary Ramsay

8.4 Travel and expedition medicine  713 Susanna Dunachie and Christopher P. Conlon

8.5 Viruses  723 8.5.1 Respiratory tract viruses  723

Malik Peiris 8.5.2 Herpesviruses (excluding Epstein–​Barr virus)  734

J.G.P. Sissons†

Eileen Burns and Claire Scampion

8.5.3 Epstein–​Barr virus  754

Alan B. Rickinson and M.A. Epstein

SECTION 7 Pain and palliative care Section editor: Bee Wee 7.1 Introduction to palliative care  623

8.5.4 Poxviruses  764

Geoffrey L. Smith 8.5.5 Mumps: Epidemic parotitis  769

B.K. Rima 8.5.6 Measles  772

Hilton C. Whittle and Peter Aaby

Susan Salt

7.2 Pain management  629

8.5.7 Nipah and Hendra virus encephalitides  784

C.T. Tan

Marie Fallon

7.3 Symptoms other than pain  634 Regina McQuillan

†

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

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8.5.8 Enterovirus infections  787

Philip Minor and Ulrich Desselberger 8.5.9 Virus infections causing diarrhoea and vomiting  797

Philip R. Dormitzer and Ulrich Desselberger 8.5.10 Rhabdoviruses: Rabies and rabies-​related lyssaviruses  805

Mary J. Warrell and David A. Warrell 8.5.11 Colorado tick fever and other arthropod-​borne reoviruses  819

Mary J. Warrell and David A. Warrell 8.5.12 Alphaviruses  821

Ann M. Powers, E.E. Ooi, L.R. Petersen, and D.J. Gubler 8.5.13 Rubella  827

Pat Tookey and J.M. Best 8.5.14 Flaviviruses excluding dengue  830

Shannan Lee Rossi and Nikos Vasilakis 8.5.15 Dengue  845

Bridget Wills and Yee-​Sin Leo 8.5.16 Bunyaviridae  852

James W. Le Duc and D.A. Bente 8.5.17 Arenaviruses  862

Jan H. ter Meulen 8.5.18 Filoviruses  870

Jan H. ter Meulen 8.5.19 Papillomaviruses and polyomaviruses  877

Raphael P. Viscidi, Chen Sabrina Tan, and Carole Fakhry 8.5.20 Parvovirus B19  886

Kevin E. Brown 8.5.21 Hepatitis viruses (excluding hepatitis C virus)  889

Matthew Cramp, Ashwin Dhanda, and Nikolai V. Naoumov 8.5.22 Hepatitis C virus  896

Paul Klenerman, Katie J.M. Jeffery, Ellie J. Barnes, and Jane Collier 8.5.23 HIV/​AIDS  901

Sarah Fidler, Timothy E.A. Peto, Philip Goulder, and Christopher P. Conlon 8.5.24 HIV in low-​and middle-​income countries  933

Alison D. Grant and Kevin M. De Cock 8.5.25 HTLV-​1, HTLV-​2, and associated diseases  941

Kristien Verdonck and Eduardo Gotuzzo 8.5.26 Viruses and cancer  945

Robin A. Weiss 8.5.27 Orf and Milker’s nodule  947

Emma Aarons and David A. Warrell

8.5.28 Molluscum contagiosum  949

David A. Warrell and Christopher P. Conlon 8.5.29 Newly discovered viruses  951

Susannah J.A. Froude and Harriet C. Hughes

8.6 Bacteria  958 8.6.1 Diphtheria  959

Delia B. Bethell and Tran Tinh Hien 8.6.2 Streptococci and enterococci  965

Dennis L. Stevens and Sarah Hobdey 8.6.3 Pneumococcal infections  975

Anthony Scott 8.6.4 Staphylococci  991

Kyle J. Popovich, Robert A. Weinstein, and Bala Hota 8.6.5 Meningococcal infections  1010

Petter Brandtzaeg 8.6.6 Neisseria gonorrhoeae  1025

Jackie Sherrard and Magnus Unemo 8.6.7 Enterobacteria and bacterial food poisoning  1032

Hugh Pennington 8.6.8 Pseudomonas aeruginosa  1041

G.C.K.W. Koh and Sharon J. Peacock 8.6.9 Typhoid and paratyphoid fevers  1044

Christopher M. Parry and Buddha Basnyat 8.6.10 Intracellular klebsiella infections (donovanosis and rhinoscleroma)  1051

John Richens and Nicole Stoesser 8.6.11 Anaerobic bacteria  1055

Anilrudh A. Venugopal and David W. Hecht 8.6.12 Cholera  1060

Aldo A.M. Lima and Richard L. Guerrant 8.6.13 Haemophilus influenzae  1066

Esther Robinson 8.6.14 Haemophilus ducreyi and chancroid  1071

Nigel O’Farrell 8.6.15 Bordetella infection  1073

Cameron C. Grant 8.6.16 Melioidosis and glanders  1076

Sharon J. Peacock 8.6.17 Plague: Yersinia pestis  1081

Michael Prentice 8.6.18 Other Yersinia infections: Yersiniosis  1086

Michael Prentice 8.6.19 Pasteurella  1088

Marina S. Morgan 8.6.20 Francisella tularensis infection  1091

Petra C.F. Oyston

Contents

8.6.21 Anthrax  1094

8.6.42 Coxiella burnetii infections (Q fever)  1257

Arthur E. Brown 8.6.22 Brucellosis  1102

Thomas J. Marrie 8.6.43 Bartonellas excluding B. bacilliformis  1262

Juan D. Colmenero and Pilar Morata

Bruno B. Chomel, Henri-​Jean Boulouis, Matthew J. Stuckey, and Jean-​Marc Rolain

8.6.23 Tetanus  1109

C. Louise Thwaites and Lam Minh Yen

8.6.44 Bartonella bacilliformis infection  1272

A. Llanos-​Cuentas and C. Maguiña-​Vargas

8.6.24 Clostridium difficile  1115

David W. Eyre and Mark H. Wilcox

8.6.45 Chlamydial infections  1278

Patrick Horner, David Mabey, David Taylor-​Robinson, and Magnus Unemo

8.6.25 Botulism, gas gangrene, and clostridial gastrointestinal infections  1120

Dennis L. Stevens, Michael J. Aldape, and Amy E. Bryant

8.6.46 Mycoplasmas  1295

Jørgen Skov Jensen and David Taylor-​Robinson

8.6.26 Tuberculosis  1126

Richard E. Chaisson and Jean B. Nachega 8.6.27 Disease caused by environmental mycobacteria  1150

Jakko van Ingen 8.6.28 Leprosy (Hansen’s disease)  1154

Diana N.J. Lockwood 8.6.29 Buruli ulcer: Mycobacterium ulcerans infection  1167

Bouke de Jong, Françoise Portaels, and Wayne M. Meyers

8.6.47 A checklist of bacteria associated with infection in humans  1307

John Paul

8.7 Fungi (mycoses)  1338 8.7.1 Fungal infections  1338

Roderick J. Hay 8.7.2 Cryptococcosis  1359

William G. Powderly, J. William Campbell, and Larry J. Shapiro

8.6.30 Actinomycoses  1170

Klaus P. Schaal

8.7.3 Coccidioidomycosis  1361

Gregory M. Anstead

8.6.31 Nocardiosis  1176

Roderick J. Hay 8.6.32 Rat bite fevers (Streptobacillus moniliformis and Spirillum minus infection)  1179

Andrew F. Woodhouse 8.6.33 Lyme borreliosis  1181

Gary P. Wormser, John Nowakowski, and Robert B. Nadelman 8.6.34 Relapsing fevers  1188

David A. Warrell 8.6.35 Leptospirosis  1198

Nicholas P.J. Day 8.6.36 Nonvenereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta  1204

Michael Marks, Oriol Mitjà, and David Mabey

8.7.4 Paracoccidioidomycosis  1364

M.A. Shikanai-​Yasuda 8.7.5 Pneumocystis jirovecii  1371

Robert F. Miller and Christopher P. Eades 8.7.6 Talaromyces (Penicillium) marneffei infection  1375

Romanee Chaiwarith, Khuanchai Supparatpinyo, and Thira Sirisanthana 8.7.7 Microsporidiosis  1378

Louis M. Weiss

8.8 Protozoa  1384 8.8.1 Amoebic infections  1384

Richard Knight 8.8.2 Malaria  1395

Nicholas J. White and Arjen M. Dondorp

8.6.37 Syphilis  1210

Phillip Read and Basil Donovan

8.8.3 Babesiosis  1414

Philippe Brasseur

8.6.38 Listeriosis  1223

Herbert Hof

8.8.4 Toxoplasmosis  1416

Oliver Liesenfeld and Eskild Petersen

8.6.39 Legionellosis and Legionnaires’ disease  1226

Diego Viasus and Jordi Carratalà

8.8.5 Cryptosporidium and cryptosporidiosis  1424

Simone M. Cacciò

8.6.40 Rickettsioses  1230

Karolina Griffiths, Carole Eldin, Didier Raoult, and Philippe Parola

8.8.6 Cyclospora and cyclosporiasis  1432

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.

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8.8.7 Cystoisosporiasis  1436

8.11.2 Liver fluke infections  1551

Louis M. Weiss

Ross H. Andrews, Narong Khuntikeo, Paiboon Sithithaworn, and Trevor N. Petney

8.8.8 Sarcocystosis (sarcosporidiosis)  1438

John E. Cooper

8.11.3 Lung flukes (paragonimiasis)  1558

Udomsak Silachamroon and Sirivan Vanijanonta

8.8.9 Giardiasis and balantidiasis  1440

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

Reto Brun and Johannes Blum 8.8.12 Chagas disease  1459

Michael A. Miles 8.8.13 Leishmaniasis  1467

Antony D.M. Bryceson and Diana N.J. Lockwood

John Paul

8.13 Pentastomiasis (porocephalosis, linguatulosis/​linguatuliasis, or tongue worm infection)  1582 David A. Warrell

8.8.14 Trichomoniasis  1475

Jane Schwebke

8.9 Nematodes (roundworms)  1478 8.9.1 Cutaneous filariasis  1478

Gilbert Burnham 8.9.2 Lymphatic filariasis  1487

Richard Knight 8.9.3 Guinea worm disease (dracunculiasis)  1495

Richard Knight 8.9.4 Strongyloidiasis, hookworm, and other gut strongyloid nematodes  1500

Michael Brown 8.9.5 Gut and tissue nematode infections acquired by ingestion  1506

Peter L. Chiodini 8.9.6 Angiostrongyliasis  1516

Richard Knight

8.10 Cestodes (tapeworms)  1520 8.10.1 Cestodes (tapeworms)  1520

Richard Knight 8.10.2 Cystic hydatid disease (Echinococcus granulosus)  1529

Pedro L. Moro, Hector H. Garcia, and Armando E. Gonzalez 8.10.3 Cysticercosis  1533

Hector H. Garcia and Robert H. Gilman

8.11 Trematodes (flukes)  1540 8.11.1 Schistosomiasis  1540

David Dunne and Birgitte Vennervald

SECTION 9 Sexually transmitted diseases Section editor: Jackie Sherrard 9.1 Epidemiology of sexually transmitted infections  1589 David Mabey and Anita Vas-​Falcao

9.2 Sexual behaviour  1597 Catherine H. Mercer and Anne M. Johnson

9.3 Sexual history and examination  1600 Gary Brook, Jackie Sherrard, and Graz A. Luzzi

9.4 Vaginal discharge  1603 Paul Nyirjesy

9.5 Urethritis  1606 Patrick Horner

9.6 Genital ulceration  1610 Patrick French and Raj Patel

9.7 Anogenital lumps and bumps  1613 Henry J.C. de Vries and Charles J.N. Lacey

9.8 Pelvic inflammatory disease  1622 Jonathan D.C. Ross

9.9 Principles of contraception  1626 Zara Haider

Index

Contents

Volume 2 List of abbreviations  xxxv List of contributors  xlv

10.3.8 Disasters: Earthquakes, hurricanes, floods, and volcanic eruptions  1713

Peter J. Baxter 10.3.9 Bioterrorism  1718

SECTION 10 Environmental medicine, occupational medicine, and poisoning Section editor: Jon G. Ayres 10.1 Environmental medicine, occupational medicine, and poisoning—​Introduction  1637 Jon G. Ayres

10.2 Occupational health  1638 10.2.1 Occupational and environmental health  1638

Raymond Agius and Debasish Sen 10.2.2 Occupational safety  1652

Lawrence Waterman 10.2.3 Aviation medicine  1656

Manfred S. Green

10.4 Poisoning  1725 10.4.1 Poisoning by drugs and chemicals  1725

John A. Vale, Sally M. Bradberry, and D. Nicholas Bateman 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals  1778

David A. Warrell 10.4.3 Poisonous fungi  1817

Hans Persson and David A. Warrell 10.4.4 Poisonous plants  1828

Michael Eddleston and Hans Persson

10.5 Podoconiosis (nonfilarial elephantiasis)  1833 Gail Davey

Michael Bagshaw 10.2.4 Diving medicine  1664

David M. Denison and Mark A. Glover 10.2.5 Noise  1671

David Koh and Tar-​Ching Aw† 10.2.6 Vibration  1673

Tar-​Ching  Aw†

10.3 Environment and health  1677 10.3.1 Air pollution and health  1677

Om P. Kurmi, Kin Bong Hubert Lam, and Jon G. Ayres 10.3.2 Heat  1687

Michael A. Stroud 10.3.3 Cold  1689

Michael A. Stroud 10.3.4 Drowning  1691

Peter J. Fenner 10.3.5 Lightning and electrical injuries  1696

Chris Andrews 10.3.6 Diseases of high terrestrial altitudes  1701

Tyler Albert, Erik R. Swenson, Andrew J. Pollard, Buddha Basnyat, and David R. Murdoch 10.3.7 Radiation  1709

Jill Meara †

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

SECTION 11 Nutrition Section editor: Katherine Younger 11.1 Nutrition: Macronutrient metabolism  1839 Keith N. Frayn and Rhys D. Evans

11.2 Vitamins  1855 Tom R. Hill and David A. Bender

11.3 Minerals and trace elements  1871 Katherine Younger

11.4 Severe malnutrition  1880 Alan A. Jackson

11.5 Diseases of affluent societies and the need for dietary change  1891 J.I. Mann and A.S. Truswell

11.6 Obesity  1903 I. Sadaf Farooqi

11.7 Artificial nutrition support  1914 Jeremy Woodward

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SECTION 12 Metabolic disorders Section editor: Timothy M. Cox 12.1 The inborn errors of metabolism: General aspects  1929 Timothy M. Cox and Richard W.E. Watts†

12.2 Protein-​dependent inborn errors of metabolism  1942 Georg F. Hoffmann and Stefan Kölker

12.3 Disorders of carbohydrate metabolism  1985

12.12 The acute phase response, hereditary periodic fever syndromes, and amyloidosis  2199 12.12.1 The acute phase response and C-​reactive protein  2199

Mark B. Pepys 12.12.2 Hereditary periodic fever syndromes  2207

Helen J. Lachmann, Stefan Berg, and Philip N. Hawkins 12.12.3 Amyloidosis  2218

Mark B. Pepys and Philip N. Hawkins

12.13 α1-​Antitrypsin deficiency and the serpinopathies  2235 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

Timothy M. Cox 12.3.3 Disorders of galactose, pentose, and pyruvate metabolism  2003

Timothy M. Cox

12.4 Disorders of purine and pyrimidine metabolism  2015 Anthony M. Marinaki, Lynette D. Fairbanks, and Richard W.E. Watts†

12.5 The porphyrias  2032 Timothy M. Cox

12.6 Lipid disorders  2055 Jaimini Cegla and James Scott

12.7 Trace metal disorders  2098 12.7.1 Hereditary haemochromatosis  2098

William J.H. Griffiths and Timothy M. Cox 12.7.2 Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease  2115

Michael L. Schilsky and Pramod K. Mistry

12.8 Lysosomal disease  2121 Patrick B. Deegan and Timothy M. Cox

12.9 Disorders of peroxisomal metabolism in adults  2157 Anthony S. Wierzbicki

12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias  2174 Sonia Fargue, Dawn S. Milliner, and Christopher J. Danpure

12.11 A physiological approach to acid–​base disorders: The roles of ion transport and body fluid compartments  2182 Julian Seifter †

It is with great regret that we report that Richard W.E. Watts died on 11 February, 2018.

SECTION 13 Endocrine disorders Section editor: Mark Gurnell 13.1 Principles of hormone action  2245 Rob Fowkes, V. Krishna Chatterjee, and Mark Gurnell

13.2 Pituitary disorders  2258 13.2.1 Disorders of the anterior pituitary gland  2258

Niki Karavitaki and John A.H. Wass 13.2.2 Disorders of the posterior pituitary gland  2277

Niki Karavitaki, Shahzada K. Ahmed, and John A.H. Wass

13.3 Thyroid disorders  2284 13.3.1 The thyroid gland and disorders of thyroid function  2284

Anthony P. Weetman and Kristien Boelaert 13.3.2 Thyroid cancer  2302

Kristien Boelaert and Anthony P. Weetman

13.4 Parathyroid disorders and diseases altering calcium metabolism  2313 R.V. Thakker

13.5 Adrenal disorders  2331 13.5.1 Disorders of the adrenal cortex  2331

Mark Sherlock and Mark Gurnell 13.5.2 Congenital adrenal hyperplasia  2360

Nils P. Krone and Ieuan A. Hughes

13.6 Reproductive disorders  2374 13.6.1 Ovarian disorders  2374

Stephen Franks, Kate Hardy, and Lisa J. Webber 13.6.2 Disorders of male reproduction and male hypogonadism  2386

P.-​M.G. Bouloux 13.6.3 Benign breast disease  2406

Gael M. MacLean

Contents

13.6.4 Sexual dysfunction  2408

Ian Eardley

14.9 Liver and gastrointestinal diseases of 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 Bryony Jones and Anne Dornhorst

Gary Butler 13.7.2 Normal puberty and its disorders  2428

Fiona Ryan and Sejal Patel 13.7.3 Normal and abnormal sexual differentiation  2435

S. Faisal Ahmed and Angela K. Lucas-​Herald

13.8 Pancreatic endocrine disorders and multiple endocrine neoplasia  2449

14.11 Endocrine disease in pregnancy  2638 David Carty

14.12 Neurological conditions in pregnancy  2642 Pooja Dassan

14.13 The skin in pregnancy  2648 Gudula Kirtschig and Fenella Wojnarowska

B. Khoo, T.M. Tan, and S.R. Bloom

13.9 Diabetes and hypoglycaemia  2464 13.9.1 Diabetes  2464

Colin Dayan and Julia Platts 13.9.2 Hypoglycaemia  2531

14.14 Autoimmune rheumatic disorders and vasculitis in pregnancy  2655 May Ching Soh and Catherine Nelson-​Piercy

14.15 Maternal infection in pregnancy  2671 Rosie Burton

Mark Evans and Ben Challis

13.10 Hormonal manifestations of nonendocrine disease  2541 Thomas M. Barber and John A.H. Wass

14.16 Fetal effects of maternal infection  2678 Lawrence Impey

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

SECTION 14 Medical disorders in pregnancy

14.19 Maternal critical care  2701 Rupert Gauntlett

14.20 Prescribing in pregnancy  2706 Lucy MacKillop and Charlotte Frise

Section editor: Catherine Nelson-​Piercy 14.1 Physiological changes of normal pregnancy  2563 David J. Williams

14.21 Contraception for women with medical diseases  2711 Aarthi R. Mohan

14.2 Nutrition in pregnancy  2568 David J. Williams

14.3 Medical management of normal pregnancy  2575 David J. Williams

14.4 Hypertension in pregnancy  2583 Fergus McCarthy

14.5 Renal disease in pregnancy  2589 Kate Wiles

14.6 Heart disease in pregnancy  2597 Catherine E.G. Head

14.7 Thrombosis in pregnancy  2606 Peter K. MacCallum and Louise Bowles

14.8 Chest diseases in pregnancy  2613 Meredith Pugh and Tina Hartert

SECTION 15 Gastroenterological disorders Section editor: Jack Satsangi 15.1 Structure and function of the gastrointestinal tract  2721 Michael E.B. FitzPatrick and Satish Keshav†

15.2 Symptoms of gastrointestinal disease  2727 Jeremy Woodward

15.3 Methods for investigation of gastroenterological disease  2734 15.3.1 Colonoscopy and flexible sigmoidoscopy  2734

James E. East and Brian P. Saunders †

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

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Contents

15.3.2 Upper gastrointestinal endoscopy  2740

James E. East and George J. Webster 15.3.3 Radiology of the gastrointestinal tract  2748

Fiachra Moloney and Michael Maher 15.3.4 Investigation of gastrointestinal function  2757

Jervoise Andreyev

15.4 Common acute abdominal presentations  2765 15.4.1 The acute abdomen  2765

Simon J.A. Buczacki and R. Justin Davies 15.4.2 Gastrointestinal bleeding  2771

Vanessa Brown and T.A. Rockall

15.5 Immune disorders of the gastrointestinal tract  2783 Joya Bhattacharyya and Arthur Kaser

15.6 The mouth and salivary glands  2797 John Gibson and Douglas Robertson

15.7 Diseases of the oesophagus  2828 Rebecca C. Fitzgerald and Massimiliano di Pietro

15.8 Peptic ulcer disease  2849 Joseph Sung

15.9 Hormones and the gastrointestinal tract  2862 15.9.1 Hormones and the gastrointestinal tract  2862

Rebecca Scott, T.M. Tan, and S.R. Bloom 15.9.2 Carcinoid syndrome  2870

B. Khoo, T.M. Tan, and S.R. Bloom

15.10 Malabsorption  2875 15.10.1 Differential diagnosis and investigation of malabsorption  2875

Alastair Forbes and Victoria Mulcahy 15.10.2 Bacterial overgrowth of the small intestine  2879

Stephen J. Middleton and Raymond J. Playford 15.10.3 Coeliac disease  2884

Peter D. Mooney and David S. Sanders 15.10.4 Gastrointestinal lymphomas  2892

Kikkeri N. Naresh 15.10.5 Disaccharidase deficiency  2902

Timothy M. Cox 15.10.6 Whipple’s disease  2909

Florence Fenollar and Didier Raoult 15.10.7 Effects of massive bowel resection  2911

Stephen J. Middleton, Simon M. Gabe, and Raymond J. Playford 15.10.8 Malabsorption syndromes in the tropics  2916

Vineet Ahuja and Govind K. Makharia

15.11 Crohn’s disease  2925 Miles Parkes and Tim Raine

15.12 Ulcerative colitis  2937 Jeremy Sanderson and Peter Irving

15.13 Irritable bowel syndrome  2951 Adam D. Farmer and Qasim Aziz

15.14 Colonic diverticular disease  2960 Nicolas C. Buchs, Roel Hompes, Shazad Q. Ashraf, and Neil J.McC. Mortensen

15.15 Congenital abnormalities of the gastrointestinal tract  2967 Holm H. Uhlig

15.16 Cancers of the gastrointestinal tract  2977 Peter L. Labib, J.A. Bridgewater, and Stephen P. Pereira

15.17 Vascular disorders of the gastrointestinal tract  2997 Ray Boyapati

15.18 Gastrointestinal infections  3008 Sarah O’Brien

15.19 Miscellaneous disorders of the bowel  3025 Alexander Gimson

15.20 Structure and function of the liver, biliary tract, and pancreas  3032 William Gelson and Alexander Gimson

15.21 Pathobiology of chronic liver disease  3043 Wajahat Z. Mehal

15.22 Presentations and management of liver disease  3049 15.22.1 Investigation and management of jaundice  3049

Jane Collier 15.22.2 Cirrhosis and ascites  3058

Javier Fernández and Vicente Arroyo 15.22.3 Portal hypertension and variceal bleeding  3068

Marcus Robertson and Peter Hayes 15.22.4 Hepatic encephalopathy  3080

Paul K. Middleton and Debbie L. Shawcross 15.22.5 Liver failure  3089

Jane Macnaughtan and Rajiv Jalan 15.22.6 Liver transplantation  3100

John G. O’Grady

15.23 Hepatitis and autoimmune liver disease  3108 15.23.1 Hepatitis A to E  3108

Graeme J.M. Alexander and Kate Nash

Contents

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, William J.H. Griffiths, Simon M. Rushbrook, and Michael E.D. Allison

15.23.3 Primary biliary cholangitis  3127

Jessica K. Dyson and David E.J. Jones 15.23.4 Primary sclerosing cholangitis  3135

Kate D. Lynch and Roger W. Chapman

15.24 Other liver diseases  3142 15.24.1 Alcoholic liver disease  3142

15.24.7 Liver and biliary diseases in infancy and childhood  3191

Richard J. Thompson

15.25 Diseases of the gallbladder and biliary tree  3196 Colin Johnson and Mark Wright

Ewan Forrest 15.24.2 Nonalcoholic fatty liver disease  3147

Quentin M. Anstee and Christopher P. Day

15.26 Diseases of the pancreas  3209 15.26.1 Acute pancreatitis  3209

R. Carter, Euan J. Dickson, and C.J. McKay

15.24.3 Drug-​induced liver disease  3155

Guruprasad P. Aithal

15.26.2 Chronic pancreatitis  3218

Marco J. Bruno and Djuna L. Cahen

15.24.4 Vascular disorders of the liver  3166

Alexander Gimson

15.26.3 Tumours of the pancreas  3227

James R.A. Skipworth and Stephen P. Pereira

15.24.5 The liver in systemic disease  3169

James Neuberger

Index

Volume 3 List of abbreviations  xxxv List of contributors  xlv

16.3 Clinical investigation of cardiac disorders  3294 16.3.1 Electrocardiography  3294

Andrew R. Houghton and David Gray 16.3.2 Echocardiography  3314

SECTION 16 Cardiovascular disorders Section editor: Jeremy Dwight 16.1 Structure and function  3241 16.1.1 Blood vessels and the endothelium  3241

Keith Channon and Patrick Vallance 16.1.2 Cardiac physiology  3253

Rhys D. Evans, Kenneth T. MacLeod, Steven B. Marston, Nicholas J. Severs, and Peter H. Sugden

16.2 Clinical presentation of heart disease  3276 16.2.1 Chest pain, breathlessness, and fatigue  3276

Jeremy Dwight 16.2.2 Syncope and palpitation  3284

K. Rajappan, A.C. Rankin, A.D. McGavigan, and S.M. Cobbe

James D. Newton, Adrian P. Banning, and Andrew R.J. Mitchell 16.3.3 Cardiac investigations: Nuclear, MRI, and CT  3326

Nikant Sabharwal, Andrew Kelion, Theodoros Karamitos, and Stefan Neubauer 16.3.4 Cardiac catheterization and angiography  3339

Edward D. Folland

16.4 Cardiac arrhythmias  3350 Matthew R. Ginks, D.A. Lane, A.D. McGavigan, and Gregory Y.H. Lip

16.5 Cardiac failure  3390 16.5.1 Epidemiology and general pathophysiological classification of heart failure  3390

Theresa A. McDonagh and Kaushik Guha 16.5.2 Acute cardiac failure: Definitions, investigation, and management  3397

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

xxiii

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Contents

16.5.4 Cardiorenal syndrome  3421

Darren Green and Philip A. Kalra 16.5.5 Cardiac transplantation and mechanical circulatory support  3428

Jayan Parameshwar and Steven Tsui

16.6 Valvular heart disease  3436 Michael Henein

16.7 Diseases of heart muscle  3459 16.7.1 Myocarditis  3459

Jay W. Mason and Heinz-​Peter Schultheiss 16.7.2 The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular  3468

Oliver P. Guttmann and Perry Elliott 16.7.3 Specific heart muscle disorders  3489

Oliver P. Guttmann and Perry Elliott

16.8 Pericardial disease  3501 Michael Henein

16.9 Cardiac involvement in infectious disease  3509 16.9.1 Acute rheumatic fever  3509

Jonathan R. Carapetis 16.9.2 Endocarditis  3519

James L. Harrison, John L. Klein, William A. Littler, and Bernard D. Prendergast 16.9.3 Cardiac disease in HIV infection  3534

Peter F. Currie 16.9.4 Cardiovascular syphilis  3539

Krishna Somers

16.10 Tumours of the heart  3544 Thomas A. Traill

16.11 Cardiac involvement in genetic disease  3551 Thomas A. Traill

16.12 Congenital heart disease in the adult  3559 S.A. Thorne

16.13 Coronary heart disease  3596 16.13.1 Biology and pathology of atherosclerosis  3596

Robin P. Choudhury, Joshua T. Chai, and Edward A. Fisher 16.13.2 Coronary heart disease: Epidemiology and prevention  3603

Goodarz Danaei and Kazem Rahimi 16.13.3 Management of stable angina  3616

Adam D. Timmis 16.13.4 Management of acute coronary syndrome  3626

Rajesh K. Kharbanda and Keith A.A. Fox

16.13.5 Percutaneous interventional cardiac procedures  3655

Edward D. Folland 16.13.6 Coronary artery bypass and valve surgery  3666

Rana Sayeed and David Taggart

16.14 Diseases of the arteries  3674 16.14.1 Acute aortic syndromes  3674

James D. Newton, Andrew R.J. Mitchell, and Adrian P. Banning 16.14.2 Peripheral arterial disease  3680

Janet Powell and Alun Davies 16.14.3 Cholesterol embolism  3688

Christopher Dudley

16.15 The pulmonary circulation  3691 16.15.1 Structure and function of the pulmonary circulation  3691

Nicholas W. Morrell 16.15.2 Pulmonary hypertension  3695

Nicholas W. Morrell

16.16 Venous thromboembolism  3711 16.16.1 Deep venous thrombosis and pulmonary embolism  3711

Paul D. Stein, Fadi Matta, and John D. Firth 16.16.2 Therapeutic anticoagulation  3729

David Keeling

16.17 Hypertension  3735 16.17.1 Essential hypertension: Definition, epidemiology, and pathophysiology  3735

Bryan Williams and John D. Firth 16.17.2 Essential hypertension: Diagnosis, assessment, and treatment  3753

Bryan Williams and John D. Firth 16.17.3 Secondary hypertension  3778

Morris J. Brown and Fraz A. Mir 16.17.4 Mendelian disorders causing hypertension  3796

Nilesh J. Samani and Maciej Tomaszewski 16.17.5 Hypertensive urgencies and emergencies  3800

Gregory Y.H. Lip and Alena Shantsila

16.18 Chronic peripheral oedema and lymphoedema  3811 Peter S. Mortimer

16.19 Idiopathic oedema of women  3823 John D. Firth

Contents

18.1.2 Airways and alveoli  3937

SECTION 17 Critical care medicine Section editor: Simon Finfer 17.1 The seriously ill or deteriorating patient  3829 Carole Foot and Liz Hickson

17.2 Cardiac arrest  3839 Gavin D. Perkins, Jasmeet Soar, Jerry P. Nolan, and David A. Gabbott

17.3 Anaphylaxis  3849 Anthony F.T. Brown

17.4 Assessing and preparing patients with medical conditions for major surgery  3860 Tom Abbott and Rupert Pearse

17.5 Acute respiratory failure  3867 Susannah Leaver, Jeremy Cordingley, Simon Finney, and Mark Griffiths

17.6 Circulation and circulatory support in the critically ill  3881 Michael R. Pinsky

17.7 Management of raised intracranial pressure  3892 David K. Menon

17.8 Sedation and analgesia in the ICU  3898 Michael C. Reade

17.9 Metabolic and endocrine changes in acute and chronic critical illness  3906 Eva Boonen and Greet Van den Berghe

17.10 Palliative and end-​of-​life care in the ICU  3914 Phillip D. Levin and Charles L. Sprung

17.11 Diagnosis of death and organ donation  3918 Paul Murphy

17.12 Persistent problems and recovery after critical illness  3925 Mark E. Mikkelsen and Theodore J. Iwashyna

SECTION 18 Respiratory disorders Section editor: Pallav L. Shah 18.1 Structure and function  3933 18.1.1 The upper respiratory tract  3933

Pallav L. Shah, J.R. Stradling, and S.E. Craig

Peter D. Wagner and Pallav L. Shah

18.2 The clinical presentation of respiratory disease  3947 Samuel Kemp and Julian Hopkin

18.3 Clinical investigation of respiratory disorders  3956 18.3.1 Respiratory function tests  3956

G.J. Gibson 18.3.2 Thoracic imaging  3970

Susan J. Copley and David M. Hansell 18.3.3 Bronchoscopy, thoracoscopy, and tissue biopsy  3992

Pallav L. Shah

18.4 Respiratory infection  4004 18.4.1 Upper respiratory tract infections  4004

P. Little 18.4.2 Pneumonia in the normal host  4008

Wei Shen Lim 18.4.3 Nosocomial pneumonia  4022

Wei Shen Lim 18.4.4 Mycobacteria  4026

Hannah Jarvis and Onn Min Kon 18.4.5 Pulmonary complications of HIV infection  4031

Julia Choy and Anton Pozniak

18.5 The upper respiratory tract  4040 18.5.1 Upper airway obstruction  4040

James H. Hull and Matthew Hind 18.5.2 Sleep-​related breathing disorders  4048

Mary J. Morrell, Julia Kelly, Alison McMillan, and Matthew Hind

18.6 Allergic rhinitis  4059 Stephen R. Durham and Hesham A. Saleh

18.7 Asthma  4067 Alexandra Nanzer-​Kelly, Paul Cullinan, and Andrew Menzies-​Gow

18.8 Chronic obstructive pulmonary disease  4098 Nicholas S. Hopkinson

18.9 Bronchiectasis  4142 R. Wilson and D. Bilton

18.10 Cystic fibrosis  4151 Andrew Bush and Caroline Elston

xxv

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Contents

18.11 Diffuse parenchymal lung diseases  4166 18.11.1 Diffuse parenchymal lung disease: An introduction  4166

F. Teo and A.U. Wells 18.11.2 Idiopathic pulmonary fibrosis  4177

P.L. Molyneaux, A.G. Nicholson, N. Hirani, and A.U. Wells 18.11.3 Bronchiolitis obliterans and cryptogenic organizing pneumonia  4185

Vasilis Kouranos and A.U. Wells 18.11.4 The lung in autoimmune rheumatic disorders  4191

M.A. Kokosi and A.U. Wells 18.11.5 The lung in vasculitis  4200

G.A. Margaritopoulos and A.U. Wells

18.12 Sarcoidosis  4208 Robert P. Baughman and Elyse E. Lower

18.13 Pneumoconioses  4219 P.T. Reid

18.15 Chronic respiratory failure  4282 Michael I. Polkey and P.M.A. Calverley

18.16 Lung transplantation  4292 P. Hopkins and A.J. Fisher

18.17 Pleural diseases  4305 D. de Fonseka, Y.C. Gary Lee, and N.A. Maskell

18.18 Disorders of the thoracic cage and diaphragm  4328 John M. Shneerson and Michael I. Polkey

18.19 Malignant diseases  4338 18.19.1 Lung cancer  4338

S.G. Spiro and N. Navani 18.19.2 Pulmonary metastases  4360

S.G. Spiro 18.19.3 Pleural tumours  4361

Y.C. Gary Lee 18.19.4 Mediastinal tumours and cysts  4368

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 18.14.2 Eosinophilic pneumonia  4238

S.J. Bourke and G.P. Spickett 18.14.3 Lymphocytic infiltrations of the lung  4241

S.J. Bourke 18.14.4 Hypersensitivity pneumonitis  4244

S.J. Bourke and G.P. Spickett 18.14.5 Pulmonary Langerhans’ cell histiocytosis  4256

S.J. Bourke 18.14.6 Lymphangioleiomyomatosis  4257

S.J. Bourke 18.14.7 Pulmonary alveolar proteinosis  4259

S.J. Bourke 18.14.8 Pulmonary amyloidosis  4261

S.J. Bourke 18.14.9 Lipoid (lipid) pneumonia  4263

S.J. Bourke 18.14.10 Pulmonary alveolar microlithiasis  4265

S.J. Bourke 18.14.11 Toxic gases and aerosols  4267

Chris Stenton 18.14.12 Radiation pneumonitis  4271

S.J. Bourke 18.14.13 Drug-​induced lung disease  4272

S.J. Bourke

SECTION 19 Rheumatological disorders Section editor: Richard A. Watts 19.1 Joints and connective tissue—​structure and function  4379 Thomas Pap, Adelheid Korb-​Pap, Christine Hartmann, and Jessica Bertrand

19.2 Clinical presentation and diagnosis of rheumatological disorders  4386 Christopher Deighton and Fiona Pearce

19.3 Clinical investigation  4395 Michael Doherty and Peter C. Lanyon

19.4 Back pain and regional disorders  4406 Carlo Ammendolia and Danielle Southerst

19.5 Rheumatoid arthritis  4415 Kenneth F. Baker and John D. Isaacs

19.6 Spondyloarthritis and related conditions  4441 Jürgen Braun and Joachim Sieper

19.7 Infection and arthritis  4457 Graham Raftery and Muddassir Shaikh

19.8 Reactive arthritis  4464 Carmel B. Stober and Hill Gaston

19.9 Osteoarthritis  4470 Andrew J. Barr and Philip G. Conaghan

Contents

19.10 Crystal-​related arthropathies  4482 Edward Roddy and Michael Doherty

20.3 Osteomyelitis  4688 Martin A. McNally and Anthony R. Berendt

19.11 Autoimmune rheumatic disorders and vasculitides  4495

20.4 Osteoporosis  4696

19.11.1 Introduction  4495

20.5 Osteonecrosis, osteochondrosis, and osteochondritis dissecans  4703

David A. Isenberg and Ian Giles 19.11.2 Systemic lupus erythematosus and related disorders  4499

Anisur Rahman and David A. Isenberg 19.11.3 Systemic sclerosis (scleroderma)  4513

Nicholas C. Harvey, Juliet Compston, and Cyrus Cooper

Gavin Clunie

20.6 Bone cancer  4709 Helen Hatcher

Christopher P. Denton and Carol M. Black 19.11.4 Sjögren’s syndrome  4532

Wan-​Fai  Ng 19.11.5 Inflammatory myopathies  4537

Ingrid E. Lundberg, Hector Chinoy, and Robert Cooper 19.11.6 Large vessel vasculitis  4546

Raashid Luqmani and Cristina Ponte 19.11.7 ANCA-​associated vasculitis  4556

David Jayne 19.11.8 Polyarteritis nodosa  4569

Loïc Guillevin 19.11.9 Small vessel vasculitis  4573

Richard A. Watts 19.11.10 Behçet’s syndrome  4579

Sebahattin Yurdakul, Izzet Fresko, and Hasan Yazici 19.11.11 Polymyalgia rheumatica  4584

Bhaskar Dasgupta and Eric L. Matteson 19.11.12 Kawasaki disease  4590

Brian W. McCrindle

19.12 Miscellaneous conditions presenting to the rheumatologist  4598 Stuart Carter, Lisa Dunkley, and Ade Adebajo

SECTION 21 Disorders of the kidney and urinary tract Section editor: John D. Firth 21.1 Structure and function of the kidney  4717 Steve Harper and Robert Unwin

21.2 Electrolyte disorders  4729 21.2.1 Disorders of water and sodium homeostasis  4729

Michael L. Moritz and Juan Carlos Ayus 21.2.2 Disorders of potassium homeostasis  4748

John D. Firth

21.3 Clinical presentation of renal disease  4764 Richard E. Fielding and Ken Farrington

21.4 Clinical investigation of renal disease  4781 Andrew Davenport

21.5 Acute kidney injury  4807 John D. Firth

21.6 Chronic kidney disease  4830 Alastair Hutchison

21.7 Renal replacement therapy  4861 21.7.1 Haemodialysis  4861

Robert Mactier

SECTION 20 Disorders of the skeleton

21.7.2 Peritoneal dialysis  4874

Section editor: Cyrus Cooper

21.7.3 Renal transplantation  4879

20.1 Skeletal disorders—​general approach and clinical conditions  4615 B. Paul Wordsworth and M.K. Javaid

20.2 Inherited defects of connective tissue: Ehlers–​Danlos syndrome, Marfan’s syndrome, and pseudoxanthoma elasticum  4670 N.P. Burrows

Simon Davies Nicholas Torpey and John D. Firth

21.8 Glomerular diseases  4909 21.8.1 Immunoglobulin A nephropathy and IgA vasculitis (HSP)  4909

Jonathan Barratt and John Feehally 21.8.2 Thin membrane nephropathy  4918

Peter Topham and John Feehally

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Contents

21.8.3 Minimal-​change nephropathy and focal segmental glomerulosclerosis  4919

Moin Saleem and Lisa Willcocks

21.10.6 Haemolytic uraemic syndrome  5027

Edwin K.S. Wong and David Kavanagh 21.10.7 Sickle cell disease and the kidney  5032

Claire C. Sharpe

21.8.4 Membranous nephropathy  4928

An S. De Vriese and Fernando C. Fervenza

21.10.8 Infection-​associated nephropathies  5034

A. Neil Turner

21.8.5 Proliferative glomerulonephritis  4933

Alan D. Salama and Mark A. Little

21.10.9 Malignancy-​associated renal disease  5041

A. Neil Turner

21.8.6 Membranoproliferative glomerulonephritis  4937

Tabitha Turner-​Stokes and Mark A. Little 21.8.7 Antiglomerular basement membrane disease  4943

Mårten Segelmark and Thomas Hellmark

21.9 Tubulointerstitial diseases  4951 21.9.1 Acute interstitial nephritis  4951

Simon D. Roger 21.9.2 Chronic tubulointerstitial nephritis  4956

Marc E. De Broe, Channa Yamasumana, Patrick C. D’Haese, Monique M. Elseviers, and Benjamin Vervaet

21.10.10 Atherosclerotic renovascular disease  5044

Philip A. Kalra and Diana Vassallo

21.11 Renal diseases in the tropics  5049 Vivekanand Jha

21.12 Renal involvement in genetic disease  5065 D. Joly and J.P. Grünfeld

21.13 Urinary tract infection  5074 Charles Tomson and Neil Sheerin

21.14 Disorders of renal calcium handling, urinary stones, and nephrocalcinosis  5093 Christopher Pugh, Elaine M. Worcester, Andrew P. Evan, and Fredric L. Coe

21.10 The kidney in systemic disease  4975 21.10.1 Diabetes mellitus and the kidney  4975

Rudolf Bilous

21.15 The renal tubular acidoses  5104 John A. Sayer and Fiona E. Karet

21.10.2 The kidney in systemic vasculitis  4988

David Jayne 21.10.3 The kidney in rheumatological disorders  5001

Liz Lightstone and Hannah Beckwith 21.10.4 The kidney in sarcoidosis  5012

Ingeborg Hilderson and Jan Donck

21.16 Disorders of tubular electrolyte handling  5112 Nine V.A.M. Knoers and Elena N. Levtchenko

21.17 Urinary tract obstruction  5124 Muhammad M. Yaqoob and Kieran McCafferty

21.18 Malignant diseases of the urinary tract  5136 Tim Eisen, Freddie C. Hamdy, and Robert A. Huddart

21.10.5 Renal involvement in plasma cell dyscrasias,

immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias  5016 Pierre Ronco, Frank Bridoux, and Arnaud Jaccard

21.19 Drugs and the kidney  5150 Aine Burns and Caroline Ashley

Index

Volume 4 List of abbreviations  xxxv List of contributors  xlv

22.1 Introduction to haematology  5169 Chris Hatton

22.2 Haematopoiesis  5172

SECTION 22 Haematological disorders Section editors: Chris Hatton and Deborah Hay

22.2.1 Cellular and molecular basis of haematopoiesis  5172

Paresh Vyas and N. Asger Jakobsen 22.2.2 Diagnostic techniques in the assessment of haematological malignancies  5181

Wendy N. Erber

Contents

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 22.3.2 Myelodysplastic syndromes  5197

Charlotte K. Brierley and David P. Steensma

Vijay G. Sankaran 22.6.2 Anaemia: pathophysiology, classification, and clinical features  5359

David J. Weatherall† and Chris Hatton

22.3.3 Acute myeloid leukaemia  5205

Nigel Russell and Alan Burnett

22.6.3 Anaemia as a challenge to world health  5366

David J. Roberts and David J. Weatherall†

22.3.4 Chronic myeloid leukaemia  5213

Mhairi Copland and Tessa L. Holyoake†

22.6.4 Iron metabolism and its disorders  5371

Timothy M. Cox and John B. Porter

22.3.5 The polycythaemias  5227

Daniel Aruch and Ronald Hoffman 22.3.6 Thrombocytosis and essential thrombocythaemia  5239

Daniel Aruch and Ronald Hoffman

22.6.5 Anaemia of inflammation  5402

Sant-​Rayn Pasricha and Hal Drakesmith 22.6.6 Megaloblastic anaemia and miscellaneous deficiency anaemias  5407

A.V. Hoffbrand

22.3.7 Primary myelofibrosis  5247

Evan M. Braunstein and Jerry L. Spivak 22.3.8 Eosinophilia  5254

22.6.7 Disorders of the synthesis or function of haemoglobin  5426

Deborah Hay and David J. Weatherall†

Peter F. Weller 22.3.9 Histiocytosis  5259

Chris Hatton

22.4 Lymphoid disease  5263

22.6.8 Anaemias resulting from defective maturation of red cells  5450

Stephen J. Fuller and James S. Wiley 22.6.9 Disorders of the red cell membrane  5456

22.4.1 Introduction to lymphopoiesis  5263

Caron A. Jacobson and Nancy Berliner

Patrick G. Gallagher 22.6.10 Erythrocyte enzymopathies  5463

22.4.2 Acute lymphoblastic leukaemia  5269

H. Josef Vormoor, Tobias F. Menne, and Anthony V. Moorman

Alberto Zanella and Paola Bianchi

22.4.3 Hodgkin lymphoma  5280

Vijaya Raj Bhatt and James O. Armitage

Lucio Luzzatto 22.6.12 Acquired haemolytic anaemia  5479

22.4.4 Non-​Hodgkin lymphoma  5288

Vijaya Raj Bhatt and James O. Armitage 22.4.5 Chronic lymphocytic leukaemia  5302

Clive S. Zent and Aaron Polliack 22.4.6 Plasma cell myeloma and related monoclonal gammopathies  5310

S. Vincent Rajkumar and Robert A. Kyle

22.5 Bone marrow failure  5325

Amy Powers and Leslie Silberstein

22.7 Haemostasis  5490 22.7.1 The biology of haemostasis and thrombosis  5490

Gilbert C. White, II, Harold R. Roberts, and Nigel S. Key 22.7.2 Evaluation of the patient with a bleeding tendency  5509

Trevor Baglin

22.5.1 Inherited bone marrow failure syndromes  5325

Irene Roberts and Inderjeet S. Dokal 22.5.2 Acquired aplastic anaemia and pure red cell aplasia  5336

Judith C.W. Marsh, Shreyans Gandhi, and Ghulam J. Mufti 22.5.3 Paroxysmal nocturnal haemoglobinuria  5348

22.7.3 Thrombocytopenia and disorders of platelet function  5520

Nicola Curry and Susie Shapiro 22.7.4 Genetic disorders of coagulation  5532

Eleanor S. Pollak and Katherine A. High 22.7.5 Acquired coagulation disorders  5546

Lucio Luzzatto

†

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

22.6.11 Glucose-​6-​phosphate dehydrogenase deficiency  5472

T.E. Warkentin

†

It is with great regret that we report that David J. Weatherall died on 8 December, 2018.

xxix

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Contents

22.8 Transfusion and transplantation  5563 22.8.1 Blood transfusion  5563

D.S. Giovanniello and E.L. Snyder 22.8.2 Haemopoietic stem cell transplantation  5579

23.16 Cutaneous reactions to drugs  5752 Sarah Walsh, Daniel Creamer, and Haur Yueh Lee

23.17 Management of skin disease  5761 Rod Sinclair

E.C. Gordon-​Smith and Emma C. Morris

SECTION 23 Disorders of the skin Section editor: Roderick J. Hay 23.1 Structure and function of skin  5591 John A. McGrath

23.2 Clinical approach to the diagnosis of skin disease  5596 Vanessa Venning

23.3 Inherited skin disease  5602 Thiviyani Maruthappu and David P. Kelsell

23.4 Autoimmune bullous diseases  5612 Kathy Taghipour and Fenella Wojnarowska

23.5 Papulosquamous disease  5621 Christopher E.M. Griffiths

23.6 Dermatitis/​eczema  5630 Peter S. Friedmann, Michael J. Arden-​Jones, and Roderick J. Hay

23.7 Cutaneous vasculitis, connective tissue diseases, and urticaria  5639 Volha Shpadaruk and Karen E. Harman

23.8 Disorders of pigmentation  5677 Eugene Healy

23.9 Photosensitivity  5688 Hiva Fassihi and Jane McGregor

23.10 Infections of the skin  5695 Roderick J. Hay

23.11 Sebaceous and sweat gland disorders  5699 Alison M. Layton

23.12 Blood and lymphatic vessel disorders  5709 Peter S. Mortimer and Roderick J. Hay

23.13 Hair and nail disorders  5724 David de Berker

23.14 Tumours of the skin  5732 Edel O’Toole

23.15 Skin and systemic diseases  5743 Clive B. Archer and Charles M.G. Archer

SECTION 24 Neurological disorders Section editor: Christopher Kennard 24.1 Introduction and approach to the patient with neurological disease  5775 Alastair Compston and Christopher Kennard

24.2 Mind and brain: Building bridges between neurology, psychiatry, and psychology  5778 Adam Zeman

24.3 Clinical investigation of neurological disease  5781 24.3.1 Lumbar puncture  5781

R. Rhys Davies and Andrew J. Larner 24.3.2 Electrophysiology of the central and peripheral nervous systems  5785

Christian Krarup 24.3.3 Imaging in neurological diseases  5802

Andrew J. Molyneux, Shelley Renowden, and Marcus Bradley 24.3.4 Investigation of central motor pathways: Magnetic brain stimulation  5817

K.R. Mills

24.4 Higher cerebral function  5821 24.4.1 Disturbances of higher cerebral function  5821

Peter J. Nestor 24.4.2 Alzheimer’s disease and other dementias  5830

Jonathan M. Schott

24.5 Epilepsy and disorders of consciousness  5860 24.5.1 Epilepsy in later childhood and adulthood  5860

Arjune Sen and M.R. Johnson 24.5.2 Narcolepsy  5882

Matthew C. Walker 24.5.3 Sleep disorders  5886

Paul J. Reading 24.5.4 Syncope  5896

Andrew J. Larner 24.5.5 The unconscious patient  5901

David Bates

Contents

24.5.6 Brainstem death and prolonged disorders of consciousness  5908

Ari Ercole, Peter J. Hutchinson, and John D. Pickard

24.6 Disorders of the special senses  5913 24.6.1 Visual pathways  5913

Sara Ajina and Christopher Kennard 24.6.2 Eye movements and balance  5922

Michael Strupp and Thomas Brandt 24.6.3 Hearing loss  5931

Linda Luxon

24.7 Disorders of movement  5937 24.7.1 Subcortical structures: The cerebellum, basal ganglia, and thalamus  5937

Mark J. Edwards and Penelope Talelli 24.7.2 Parkinsonism and other extrapyramidal diseases  5946

Elisaveta Sokolov, Vinod K. Metta, and K. Ray Chaudhuri 24.7.3 Movement disorders other than Parkinson’s disease  5956

Bettina Balint and Kailash Bhatia 24.7.4 Ataxic disorders  5976

Nicholas Wood

24.8 Headache  5987 Peter J. Goadsby

24.9 Brainstem syndromes  6006 David Bates

24.10 Specific conditions affecting the central nervous system  6010 24.10.1 Stroke: Cerebrovascular disease  6010

J. van Gijn (revised by Peter M. Rothwell) 24.10.2 Demyelinating disorders of the central nervous system  6026

Alasdair Coles and Siddharthan Chandran 24.10.3 Traumatic brain injury  6042

Tim Lawrence and Laurence Watkins 24.10.4 Intracranial tumours  6048

Jeremy Rees 24.10.5 Idiopathic intracranial hypertension  6054

Alexandra Sinclair

24.11 Infections of the central nervous system  6060 24.11.1 Bacterial infections  6060

Diederik van de Beek and Guy E. Thwaites 24.11.2 Viral infections  6082

Fiona McGill, Jeremy Farrar, Bridget Wills, Menno De Jong, David A. Warrell, and Tom Solomon

24.11.3 Intracranial abscesses  6097

Tim Lawrence and Richard S.C. Kerr 24.11.4 Neurosyphilis and neuro-​AIDS  6100

Hadi Manji 24.11.5 Human prion diseases  6109

Simon Mead and R.G. Will

24.12 Disorders of cranial nerves  6120 Robert D.M. Hadden

24.13 Disorders of the spinal cord  6127 24.13.1 Diseases of the spinal cord  6127

Anu Jacob and Andrew J. Larner 24.13.2 Spinal cord injury and its management  6135

Wagih El Masri(y) and Michael Barnes

24.14 Diseases of the autonomic nervous system  6150 Christopher J. Mathias and David A. Low

24.15 The motor neuron diseases  6166 Tom Jenkins, Alice Brockington, and Pamela J. Shaw

24.16 Diseases of the peripheral nerves  6176 Robert D.M. Hadden

24.17 Inherited neurodegenerative diseases  6197 Swati Sathe

24.18 Disorders of the neuromuscular junction  6295 David Hilton-​Jones and Jacqueline Palace

24.19 Disorders of muscle  6304 24.19.1 Structure and function of muscle  6304

Michael G. Hanna and Enrico Bugiardini 24.19.2 Muscular dystrophy  6310

Kate Bushby and Chiara Marini-​Bettolo 24.19.3 Myotonia  6328

David Hilton-​Jones 24.19.4 Metabolic and endocrine disorders  6334

David Hilton-​Jones and Richard Edwards 24.19.5 Mitochondrial disease  6343

Patrick F. Chinnery and D.M. Turnbull

24.20 Developmental abnormalities of the central nervous system  6350 Chris M. Verity, Jane A. Hurst, and Helen V. Firth

24.21 Acquired metabolic disorders and the nervous system  6368 Neil Scolding

24.22 Neurological complications of systemic disease  6376 Neil Scolding

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24.23 Paraneoplastic neurological syndromes  6384 Jeremy Rees

24.24 Autoimmune encephalitis and Morvan’s syndrome  6393 Camilla Buckley and Angela Vincent

26.5.3 Organic psychoses  6482

Curtis McKnight and Jason Caplan 26.5.4 Alcohol misuse  6486

Jonathan Wood 26.5.5 Substance misuse  6490

Stephen Potts 26.5.6 Depressive disorder  6493

Joseph Cerimele and Lydia Chwastiak

SECTION 25 Disorders of the eye

26.5.7 Bipolar disorder  6498

Section editor: Christopher P. Conlon

26.5.8 Anxiety disorders  6501

25.1 The eye in general medicine  6399 Tasanee Braithwaite, Richard W.J. Lee, and Peng T. Khaw

Kate E.A. Saunders and John Geddes Ted Liao and Steve Epstein 26.5.9 Acute stress disorder, adjustment disorders, and post-​traumatic stress disorder  6506

Jonathan I. Bisson

SECTION 26 Psychiatric and drug-​related disorders Section editor: Michael Sharpe 26.1 General introduction  6445 Michael Sharpe

26.2 The psychiatric assessment of the medical patient  6447 Jane Walker, Roger Smyth, and Michael Sharpe

26.3 Common psychiatric presentations in medical patients  6454 26.3.1 Confusion  6454

Bart Sheehan and Thomas Jackson 26.3.2 Self-​harm  6457

Kate E.A. Saunders and Keith Hawton 26.3.3 Medically unexplained symptoms  6460

Michael Sharpe 26.3.4 Low mood  6462

Jane Walker

26.5.10 Eating disorders  6509

Christopher G. Fairburn 26.5.11 Schizophrenia  6513

Stephen M. Lawrie 26.5.12 Somatic symptom and related disorders  6517

Michael Sharpe 26.5.13 Personality disorders  6520

Iain Jordan

26.6 Changing unhealthy behaviours  6524 26.6.1 Brief interventions for excessive alcohol consumption  6524

Amy O’Donnell, Eileen Kaner, and Nick Heather 26.6.2 Obesity and weight management  6529

Susan Jebb and Paul Aveyard 26.6.3 Smoking cessation  6533

Paul Aveyard

26.7 Psychiatry, liaison psychiatry, and psychological medicine  6536 Michael Sharpe

26.4 Psychiatric treatments in the medically ill  6465 26.4.1 Psychopharmacology in medical practice  6465

Philip J. Cowen 26.4.2 Psychological treatments  6470

Michael Sharpe and Simon Wessely

26.5 Specific psychiatric disorders  6475 26.5.1 Delirium  6475

Bart Sheehan 26.5.2 Dementia  6478

Bart Sheehan

SECTION 27 Forensic medicine Section editor: John D. Firth 27.1 Forensic and legal medicine  6541 Jason Payne-​James, Paul Marks, Ralph Bouhaidar, and Steven B. Karch

Contents

SECTION 28 Sport and exercise medicine

SECTION 30 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 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

Index

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Abbreviations 5-​FU 5-​HIAA 5-​HT 5-​HT AAA AAFB AASLD AAV ABC ABCDE ABG ABMR ABPA ABPM ACE AChE ACPA ACR ACS ACTH AD ADEM ADH ADL ADME ADPKD ADR ADRT AECA AF AFP AGT aGVHD AHA aHUS AIF AIHA AIN AIP AIS AKI ALD

5-​fluorouracil 5-​hydroxyindoleacetic  acid 5-​hydroxytryptamine 5-​hydroxytryptamine acquired aplastic anaemia acid-​and alcohol-​fast bacilli American Association for the Study of Liver Diseases antineutrophil cytoplasm autoantibody-associated vasculitis (also aplastic anaemia ATP-​binding cassette airway, breathing, circulation, disability, and exposure arterial blood gas antibody-​mediated rejection allergic bronchopulmonary aspergillosis ambulatory blood pressure measurement angiotensin-​converting  enzyme acetylcholinesterase, define at first mention anticitrullinated peptide/​protein antibodies American College of Rheumatology (also albumin:creatinine ratio) acute coronary syndromes adrenocorticotropic hormone Alzheimer’s disease acute disseminated encephalomyelitis antidiuretic hormone activities of daily living absorption, distribution, metabolism, and excretion autosomal dominant polycystic kidney disease adverse drug reaction advanced decision to refuse treatment antiendothelial cell antibodies atrial fibrillation α-​fetoprotein alanine–​glyoxylate aminotransferase acute graft-​versus-​host disease American Heart Association atypical haemolytic uraemic syndrome apoptosis-​inducing  factor autoimmune haemolytic anaemia acute interstitial nephritis autoimmune pancreatitis (also acute interstitial pneumonia) androgen insensitivity syndromes acute kidney injury alcoholic liver disease

ALF ALL alloSCT ALP ALS ALT AMA AML AMLR AMT ANA ANC ANCA ANP AOSD AP APA APC APCM APL APS APTT AR ara-​C ARB ARDS ARF ARH ARPKD ART ARVC ARVD AS ASAS ASCT ASD ASH ASOT AST ATG ATP ATRA AV AVN

acute liver failure acute lymphoblastic leukaemia allogeneic stem cell transplantation alkaline phosphatase amyotrophic lateral sclerosis alanine aminotransferase antimitochondrial antibody acute myeloid leukaemia autologous mixed lymphocyte reactions Abbreviated Mental Test antinuclear autoantibodies absolute neutrophil count antineutrophil cytoplasmic antibodies atrial natriuretic peptide adult-​onset Still’s disease alternative pathway aldosterone-​producing adenoma antigen presenting cell active physiological conservative management acute promyelocytic leukaemia antiphospholipid syndrome activated partial thromboplastin time androgen receptor cytosine arabinoside angiotensin receptor blocker adult respiratory distress syndrome acute renal failure autosomal recessive hypercholesterolaemia autosomal recessive polycystic kidney disease antiretroviral therapy arrhythmogenic right ventricular cardiomyopathy atherosclerotic renovascular disease ankylosing spondylitis Assessment of SpondyloArthritis International Society autologous stem cell transplantation atrial septal defect Action on Smoking and Health antistreptolysin O titre aspartate aminotransferase antithymocyte globulin adenosine triphosphate all-​trans-​retinoic  acid aortic valve arteriovenous nipping

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Abbreviations AVSD AZA BCAA BCC BCG BEN BH4 BHS BICC BKV BM BMD BMF BMI BMP BNF BNP BOS BP BPG BRAO BRVO BSEP BSP BTS BUN CA CABG CAF CAH CAM CAMT CAP CAPS CaR CAT CBT CCB CCK CCP CCQ CCV CCyR CD CDA CDC CEA CETP CF CFA cfDNA CFS CFTR CFU CGA CGRP cGVHD

atrioventricular septal defect azacitidine branched-​chain amino acid basal cell carcinoma bacillus Calmette–​Guérin Balkan endemic nephropathy tetrahydrobiopterin British Hypertension Society betaferon in chronic viral cardiomyopathy BK polyomavirus bone marrow bone mineral density bone marrow failure body mass index bone morphogenic protein British National Formulary B-​type natriuretic peptide bronchiolitis obliterans syndrome blood pressure biphosphoglycerate branch artery occlusion branch retinal vein occlusion haemolysis, elevated liver enzymes, and low platelet count bromosulphthalein British Thoracic Society blood urea nitrogen carbohydrate antigen coronary artery bypass grafting Comprehensive Assessment for Frailty congenital adrenal hyperplasia Confusion Assessment Method congenital amegakaryocytic thrombocytopenia community-​acquired pneumonia cryopyrin-​associated periodic syndromes calcium-​sensing receptor COPD assessment test cognitive behaviour therapy calcium channel blocker cholecystokinin anticyclic citrullinated peptide Clinical COPD questionnaire clathrin-​coated vesicles complete cytogenetic response cluster of differentiation congenital dyserythropoietic anaemia donation after circulatory death carcinoembryonic antigen cholesteryl ester transfer protein cystic fibrosis cryptogenic fibrosing alveolitis cell-​free  DNA Clinical Frailty Scale cystic fibrosis transmembrane regulator colony forming unit comprehensive geriatric assessment calcitonin gene-​related peptide chronic graft-​versus-​host disease

CHAD CHD CHF CHM CINAC CINCA CISN CK CKD CKD-​EPI CLL CML CMR CMS CMT CMV CNI CNS CNSHA CO CoA COPD COX CPAP CPM CPP CPPS CPR CR CRDQ CREST CRF CRH CRIM CRP CRT CS CSF CT CTA CTCA CTD CTEPH CTL CVD CVID CVS CXR CYP CZT DAEC DALY DAMP DASH DAT

cold haemagglutinin disease coronary heart disease congestive heart failure Commission on Human Medicines chronic interstitial nephritis in agricultural communities chronic infantile neurological, cutaneous, and articular syndrome coumarin-​induced skin necrosis creatine kinase chronic kidney disease Chronic Kidney Disease Epidemiology Collaboration chronic lymphocytic leukaemia chronic myeloid leukaemia cardiac magnetic resonance congenital myasthenic syndrome Charcot–​Marie–​Tooth disease cytomegalovirus calcineurin inhibitor central nervous system congenital non-​spherocytic haemolytic anaemia cardiac output coenzyme A chronic obstructive pulmonary disease cyclooxygenase continuous positive airway pressure central pontine myelosis central precocious puberty chronic pelvic pain syndrome cardiopulmonary resuscitation complete remission Chronic Respiratory Disease Questionnaire calcinosis, Raynaud’s, oesophageal dysmotility, sclerodactyly, telangiectasia chronic renal failure corticotropin-​releasing hormone cross-​immunoreactive material C-​reactive protein cardiac resynchronization therapy continuous smokers cerebrospinal fluid/​colony-​stimulating  factor computed tomography computed tomography angiography computed tomography coronary angiography connective tissue disease chronic thromboembolic pulmonary hypertension cytotoxic T-​lymphocyte cardiovascular disease common variable immunodeficiency chorionic villus sampling chest radiograph cytochrome P450 cadmium zinc telluride diffusely adherent Escherichia coli disability-​adjusted life year damage-​associated molecular pattern Dietary Approaches to Stop Hypertension direct antiglobulin test

 Abbreviations DBA DBD DBP DC DCA DCCT DCD DCI dcSSc DCT DDAVP DDD DECAF DGP DHG DIC DIC DILI DILV DIP DISC DISH DLB DLBCL DMARD DMD DMSA DNACPR DNR DOAC DOCA DOPPS DORV DPI DRE DRESS dRTA DSA DTC DTPA DVT DXA EACTS EAggEC EANM EAPCI EASL EATL EBV ECD ECF ECG ECLAM ECM

Diamond–​Blackfan anaemia donation after brain death diastolic blood pressure dyskeratosis congenita (also dendritic cell) directional coronary atherectomy Diabetes Control and Complications Trial donation after circulatory death decompression illness diffuse cutaneous systemic sclerosis distal convoluted tubule 1-​deamino-​8-​d-​arginine vasopressin dense deposit disease dyspnoea, eosinopenia, consolidation, acidosis, and atrial fibrillation deamidated gliadin peptide dihydroxyglutarate disseminated intravascular coagulation disseminated intravascular coagulation drug-​induced liver injury double-​inlet left ventricle desquamative interstitial pneumonia death-​initiating signalling complex diffuse idiopathic skeletal hyperostosis dementia with Lewy bodies diffuse large B-​cell lymphoma disease-​modifying antirheumatic drug disease-​modifying drugs (can also mean Duchenne muscular dystrophy) dimercaptosuccinic acid do-​not-​attempt-​cardiopulmonary resuscitation do not resuscitate direct oral anticoagulant desoxycorticosterone Dialysis Outcomes and Practice Patterns Study double-​outlet right ventricle dry powder inhalers digital rectal examination drug reaction with eosinophilia and systemic symptoms distal renal tubular acidosis donor-​specific antibodies direct to consumer diethylenetriaminepentaacetic acid deep vein thrombosis dual energy X-​ray absorptiometry European Association for Cardio-​Thoracic Surgery enteroaggregative Escherichia coli European Association of Nuclear Medicine European Association of Percutaneous Cardiovascular Interventions European Association for the Study of the Liver enteropathy-​associated T-​cell lymphoma Epstein–​Barr  virus extended criteria donor extracellular fluid electrocardiogram European community lupus activity measure extracellular matrix

ECV EDMD EDRF EDTA EDV EEG EELV EGF eGFR EGPA EIEC EIS ELCA ELISA EM EMA EMG EMS ENA ENaC ENT EOL EoO EPCR EPEC EPO ER ERA ERC ERCP ERNV ERS ESA ESC ESGE ESH ESKD ESR ESRD ESS ESWL ETEC EUS EVLP EVO FA FACIT FAK FAP FBC FCAS FCHL FDA FDG FDG-​PET FDP FEV FEV1

extracellular volume Emery–​Dreifuss muscular dystrophy endothelial-​derived relaxing factor European Dialysis and Transplant Association end-​diastolic  volume electroencephalography end expiratory lung volume epidermal growth factor estimated glomerular filtration rate eosinophilic granulomatosis with polyangiitis enteroinvasive Escherichia coli endoscopic injection sclerotherapy excimer laser coronary atherectomy enzyme-​linked immunosorbent assay erythema multiforme (also electron microscopy) endomysial antibody electromyography early morning urethral smear extractable nuclear antigens epithelial sodium channel ear, nose, or throat end of life eosinophilic oesophagitis endothelial cell protein C receptor enteropathogenic Escherichia coli erythropoietin endoplasmic reticulum European Renal Association endoscopic retrograde cholangiography endoscopic retrograde cholangiopancreatography equilibrium radionuclide ventriculography European Respiratory Society erythropoiesis-​stimulating  agent European Society of Cardiology European Society of Gastrointestinal Endoscopy European Society of Hypertension end-​stage kidney disease erythrocyte sedimentation rate end-​stage renal disease EULAR sicca score extracorporeal shock-​wave lithotripsy enterotoxigenic Escherichia coli endoscopic ultrasonography ex-​vivo lung perfusion endoscopic variceal obturation Fanconi’s anaemia fibril-​associated collagen with interrupted triple focal adhesion kinase familial adenomatous polyposis full blood count familial cold autoinflammatory syndrome familial combined hyperlipidaemia Food and Drug Administration fluorodeoxyglucose fluorodeoxyglucose-​positron emission tomography fibrinogen-​degradation product forced expiratory volume forced expiratory volume in 1 s

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xxxviii

Abbreviations FFR FGF FH FISH FL FLC FMF FMTC FNAB FNH FOB FODMAPs

fractional flow reserve fibroblast growth factor familial hypercholesterolaemia fluorescent in situ hybridization follicular lymphoma free light chain familial Mediterranean fever familial medullary thyroid carcinoma fine needle aspiration biopsy focal nodular hyperplasia faecal occult blood fermentable oligosaccharides, disaccharides, monosaccharides, and polyols FRC functional residual capacity FSGS focal segmental glomerulosclerosis FSH follicular stimulating hormone FTD frontotemporal dementia FVC forced vital capacity FVU first voided urine G6PD glucose-​6-​phosphate dehydrogenase GABA γ-​aminobutyric  acid GAD generalized anxiety disorder GALT gut-​associated lymphoid tissue GAVE gastric antral vascular ectasia GBD Global Burden of Disease GBM glomerular basement membrane G-​CSF granulocyte colony-​stimulating factor GCA giant cell arteritis GCS Glasgow Coma Score GDF growth differentiation factors GEP gastroenteropancreatic GFB glomerular filtration barrier GFR glomerular filtration rate GH growth hormone GI gastrointestinal GIB gastrointestinal bleeding GIE glucocorticoid inhibitory element GIP gastric inhibitor peptide GIST gastrointestinal stromal tumour GLP glucagon-​like peptide GM-​CSF granulocyte–​macrophage colony-​stimulating  factor GM/​MS gas chromatography–​mass spectrometry GN glomerulonephritis GnRH gonadotropin-​releasing hormone GOLD Global Initiative for Obstructive Lung Disease GOMMID glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits GORD gastro-​oesophageal reflux disease GOV gastro-​oesophageal varices GP glycoprotein (also general practitioner) GPA granulomatosis with polyangiitis GPCR G-​protein-​coupled-​receptors GPI glycosylphosphatidylinositol GRACE Global Registry of Acute Coronary Events GRADE Grading of Recommendations, Assessment, Development and Evaluations GRHPR glyoxylate/​hydroxypyruvate reductase

GSD GSGS GSH GU GUM GVHD GVL GWAS H&E HAART HAND HAV HBc HBeAG HBIg HBPM HBsAG HBV HCC HCG HCV HD HDF HDL HDL-​C HDU HDV HE HELLP HES hESC HETE HEV HF HFA HFnEF HFOV HFV HHT HHV HIF HIV HIV-​OL HK HL HLA HLH HLHS HMA HOGA HPA HPG HPLC HPP HPRT HPV

glycogen storage disease focal segmental glomerulosclerosis glutathione gonococcal urethritis genitourinary medicine graft-​versus-​host disease graft-​versus-​leukaemia genome-​wide association study haematoxylin and eosin stain highly active antiretroviral therapy HIV-​associated neurocognitive disorder hepatitis A virus hepatitis B core hepatitis B e antigen hepatitis B immunoglobulin home blood pressure measurement hepatitis B surface antigen hepatitis B virus hepatocellular carcinoma human chorionic gonadotropin hepatitis C virus haemodialysis haemodiafiltration high-​density lipoprotein high-​density lipoprotein cholesterol high-​dependency  unit hepatitis D virus hepatic encephalopathy or hereditary elliptocytosis haemolysis, elevated liver enzymes and low platelets hypereosinophilic syndrome human embryonic stem cell hydroxyeicosatetraenoic acid hepatitis E virus haemofiltration Heart Failure Association heart failure with a normal ejection fraction high-​frequency oscillatory ventilation high-​frequency ventilation hereditary haemorrhagic telangiectasis/​ 15-​hydroxy-​5,8,10-​hepatrotrienoic  acid human herpesvirus hypoxia-​inducible factors human immunodeficiency virus human immunodeficiency virus oral lesion high molecular weight kininogen hepatic lipase human leucocyte antigen haemophagocytic lymphohistiocytosis hypoplastic left heart syndrome hypomethylating agent 4-​hydroxy-​2-​oxoglutarate aldolase hypothalamic-​pituitary-​adrenal hypothalamic-​pituitary-​gonadal high-​performance liquid chromatography hereditary pyropoikilocytosis hypoxanthine-​guanine phosphoribosyltransferase human papillomavirus

 Abbreviations HRA HRCT HRT HS HSC HSCT HSP HSPC HSV HUS HUV IADL IAS IBD IBS IBS-​C IBS-​D IBS-​M IC ICAM ICD ICP ICS ICU IDA IDL IEC IF IFG IFN Ig IgAN IgE IGF IgG4-​RD IgG4-​SC IGV IHD IHME IIH IIP IL ILC ILD IMA INR IPAF IPEX IPF IPI iPSC IPSID IRIDA IRIS IRM IRV

high-​resolution anoscopy high-​resolution computed tomography hormone replacement therapy hereditary spherocytosis haematopoietic stem cell or hepatic stellate cell haemopoietic stem cell transplantation Henoch–​Schönlein purpura haematopoietic stem and progenitor cell herpes simplex virus haemolytic uraemic syndrome hypocomplementaemic urticarial vasculitis instrumental activities of daily living insulin autoimmune syndrome irritable bowel disease irritable bowel syndrome irritable bowel syndrome with constipation irritable bowel syndrome with diarrhoea irritable bowel syndrome with alternating constipation and diarrhoea intercalated cell intercell adhesion molecules implantable cardioverter-​defibrillator intracranial pressure inhaled oral corticosteroids intensive care unit iminodiacetic acid intermediate-​density lipoprotein intestinal epithelial cell intrinsic factor impaired fasting glucose interferon immunoglobulin immunoglobulin A nephropathy immunoglobulin E insulin-​like growth factors immunoglobulin G4-​related disease immunoglobulin G4-​related sclerosing cholangitis isolated gastric varices ischaemic heart disease Institute for Health Metrics and Evaluation idiopathic intracranial hypertension idiopathic interstitial pneumonias interleukin innate lymphoid cell interstitial lung disease inferior mesenteric artery international normalized ratio interstitial pneumonitis with autoimmune features immunodysregulation polyendocrinopathy enteropathy X-​linked idiopathic pulmonary fibrosis International Prognostic Index induced pluripotent stem cell immunoproliferative small intestinal disease iron-​refractory iron deficiency anaemia immune reconstitution inflammatory syndrome immunoradiographic assay Inspiratory and expiratory reserve volume

ISH ISHLT ISIS ISWT ITP ITU IV IVC IVF IVIG IVU JE JIA JNC KDIGO LA LAMA LBBB LCAT LCH lcSSc LDH LDL LDL-​C LFT LGE LGMD LGV LH LIC LINQ LIP LKM LMICs LMN LMWH LMWP LOLA LP LPL LPLR LTOT LV LVDD LVEF LVOT LVRS LVSD MAG3 MAGIC MAHA MALT MAO MAP MAPK MBD M-​CSF

International Society of Hypertension International Society for Heart and Lung Transplantation International Study of Infarct Survival incremental shuttle walking test immune thrombocytopenia intensive care unit intravenous inferior vena cava in vitro fertilization intravenous immunoglobulin intravenous urography Japanese encephalitis juvenile idiopathic arthritis Joint National Committee Kidney Disease: Improving Global Outcomes left atrium long-​acting antimuscarinic agents left bundle branch block lecithin–​cholesterol acyltransferase Langerhans’ cell histiocytosis limited cutaneous systemic sclerosis lactate dehydrogenase low-​density lipoprotein low-​density lipoprotein cholesterol liver function test late gadolinium enhancement limb-​girdle muscular dystrophy lymphogranuloma venereum luteinizing hormone liver iron content Lung Information Needs Questionnaire lymphocytic interstitial pneumonia liver–​kidney microsomal low-​and middle-​income countries lower motor neuron low molecular weight heparin low molecular weight protein l-​ornithine l-​arginine lumbar puncture lipoprotein lipase lipoprotein lipase receptor long-​term oxygen therapy left ventricle left ventricular diastolic dysfunction left ventricular ejection fraction left ventricular outflow tract lung volume reduction surgery left ventricular systolic dysfunction mercaptoacetyltriglycine MAGnesium in Coronaries microangiopathic haemolytic anaemia mucosa-​associated lymphoid tissue monoamine oxidase inhibitor mean arterial pressure mitogen-​activated protein kinase mineral and bone disorder macrophage colony-​stimulating factor

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Abbreviations MCHC MCL MCNS MCpEF MCV MDE MDI MDRD MDS MED MELD MEN MERFF mESC MGRS MGUS MHC MHRA MIC MIDD MKD MM MMA MMF MMP MMR MN MND MoCA MPA MPO MPS MR MRA MRC MRCP MRI MRSA MS MS/​MS MSA MSC MSH MSU MTC mTOR MUS MWS NAAT NABQI NADH NADPH

mean cell haemoglobin concentration mantle cell lymphoma minimal change nephrotic syndrome myocarditis with preserved left ventricular ejection fraction mean corpuscular volume myeloma-​defining  event metered dose inhalers Modification of Diet in Renal Disease myelodysplastic syndrome minimal erythema dose Model for End-​Stage Liver Disease multiple endocrine neoplasia myoclonic epilepsy and ragged red fibres mouse embryonic stem cell monoclonal gammopathy of renal significance monoclonal gammopathy of undetermined significance major histocompatibility complex Medicines and Healthcare Products Regulatory Agency minimum inhibitory concentration monoclonal immunoglobulin deposition diseases mevalonate kinase deficiency malignant melanoma methylmalonic acid mycophenolate mofetil matrix metalloproteinase mismatch repair membranous nephropathy motor neuron disease Montreal Cognitive Assessment microscopic polyangiitis myeloperoxidase mucopolysaccharidosis (also myocardial perfusion scintigraphy) magnetic resonance magnetic resonance angiography (can also be medicine regulatory authority) Medical Research Council magnetic resonance cholangiopancreatography magnetic resonance imaging methicillin-​resistant Staphylococcus aureus multiple sclerosis tandem mass spectroscopy multiple-​system atrophy mesenchymal stromal cell melanocyte-​stimulating hormone midstream urine medullary thyroid carcinoma mammalian target of rapamycin medically unexplained symptoms Muckle–​Wells syndrome nucleic acid amplification testing N-​acetyl-​p-​benzoquinone  imine reduced nicotinamide-​adenine dinucleotide reduced nicotinamide-​adenine dinucleotide phosphate

NAFLD NAIT NASH NCAM NEP NET

nonalcoholic fatty liver disease neonatal alloimmune thrombocytopenia nonalcoholic steatohepatitis neural-​cell adhesion molecule neutral endopeptidase neuroendocrine tumour or neutrophil extracellular trap NETT National Emphysema Therapy Trial NEWS National Early Warning Score NGF nerve growth factor NGS next-​generation sequencing NHDL-​C non-​high-​density lipoprotein cholesterol NHL non-​Hodgkin’s lymphoma NHS National Health Service (UK) NICE National Institute for Health and Care Excellence NIPPV non-​invasive nasal positive-​pressure ventilation NIPT non-​invasive prenatal testing NIV non-​invasive ventilation NK natural killer NKT natural killer T NLST National Lung Screening Trial NMS neuroleptic malignant syndrome NMSC non-​melanoma skin cancer NNH number needed to harm NNT number needed to treat NOTT Nocturnal Oxygen Treatment Trial NREM non-​rapid eye movement NRT nicotine replacement therapy NSAID non-​steroidal anti-​inflammatory  drug NSCLC non-​small cell lung cancer NSIP non-​specific interstitial pneumonia NSTEMI non-​ST-​elevation myocardial infarction NTD neural tube defect NTM non-​tuberculous mycobacterial NT-​proBNP N-​terminal B-​type natriuretic peptide NYHA New York Heart Association OAF osteoclast-​activating  factor OAPR odds of being affected given a positive result OB obliterative bronchiolitis OCD obsessive–​compulsive disorder OCT optical coherence tomography OD once daily OECD Organisation for Economic Cooperation and Development OED other eating disorders OLP oral lichen planus OMIM Online Mendelian Inheritance in Man OMT optimal medical therapy OPAT outpatient parenteral antibiotic therapy OR odds ratio OS overall survival OSA obstructive sleep apnoea OTB oral tuberculosis PA pernicious anaemia (also pulmonary artery) PACAP pituitary adenylate cyclase activating polypeptide PAF platelet activating factor PAH polycyclic aromatic hydrocarbons (can also mean pulmonary hypertension)

 Abbreviations PAOP PAS PASI PASP PBD PBM PCC PCH PCI PCNSL Pco

PCP PCR PCT PCV PCWP PD PDA PDC PDD PDGF PE PEACH PEEP PEF PEG PET PFO PFS PGK PHARC PICS PID PIGN PK PKD PKU PLA2R PMN PMR PNH Po2

POC POMC PP PPI ppm PPS PPV PR3 PRCA PRI PRPP

pulmonary artery occlusion pressure periodic acid–​Schiff Psoriasis Area and Severity Index pulmonary artery systolic pressure polyglucosan body disease peripheral blood mononuclear cell prothrombin complex concentrate paroxysmal cold haemoglobinuria (also pulmonary capillary haemangiomatosis) percutaneous coronary intervention primary central nervous system lymphoma partial pressure of carbon dioxide Pneumocystis jirovecii pneumonia polymerase chain reaction (also protein:creatinine ratio) proximal convoluted tubule pneumococcal conjugate vaccine pulmonary capillary wedge pressure peritoneal dialysis (also Parkinson’s disease) patent ductus arteriosus pyruvate dehydrogenase complex Parkinson’s disease dementia platelet-​derived growth factor pleural effusion (can also mean pulmonary embolism) Pelvic Inflammatory Disease Evaluation and Clinical Health positive end expiratory pressure peak expiratory flow percutaneous endoscopic gastrostomy position emission tomography patent foramen ovale progression-​free survival phosphoglycerate kinase polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract post-​intensive care syndrome pelvic inflammatory disease postinfectious glomerulonephritis pyruvate kinase pyruvate kinase deficiency (also polycystic kidney disease) phenylketonuria phospholipase A2 receptor polymorphonuclear neutrophil polymyalgia rheumatica paroxysmal nocturnal haemoglobinuria partial pressure of oxygen point of care pro-​opiomelanocortin polypeptide proton pump inhibitor parts per million Palliative Performance Scale porcine parvovirus proteinase 3 pure red cell aplasia population reference intake phosphoribosyl pyrophosphate

PRR PRrP PSA PSC PSP PT PTC PTCA PTH PTHrP PTLD PTP PTSD PUVA PV PVE PVOD PVR PYY QALY RA RAAS RAS RAVV RBBB RBF RCA RCC RCDP RCT RDA REM RF RI RNA RNI RNP ROC RP RRT RTA RV RVOTO SA SABR SBP SCC SCD SCI SCID SCLC SCMR SCN sdLDL SDS

pattern-​recognition receptor parathyroid-​hormone-​related protein prostate-​specific antigen primary sclerosing cholangitis primary spontaneous pneumothorax prothrombin time percutaneous transhepatic cholangiography percutaneous transluminal coronary angioplasty parathyroid hormone PTH/​PTH-​related peptide post-​transplant lymphoproliferative disorder post-​transfusion purpura post-​traumatic stress disorder psoralen ultraviolet A pemphigus vulgaris (also plasmas viscosity test) prosthetic valve endocarditis pulmonary veno-​occlusive disease pulmonary vascular resistance peptide tyrosine-​tyrosine quality-​adjusted life year rheumatoid arthritis (can also mean right atrium) renin–​angiotensin–​aldosterone  system renin–​angiotensin system (also renal artery stenosis or restrictive allograft syndrome right atrioventricular valve right bundle branch block rat bite fevers right coronary artery renal cell carcinoma rhizomelic chondrodysplasia punctata randomized controlled trial recommended dietary allowance rapid eye movement rheumatoid factor resistivity index ribonucleic acid reference nutrient intake ribonucleoprotein receiver–​operator characteristic ribosomal protein renal replacement therapy renal tubular acidosis residual volume (also right ventricle) right ventricular outflow tract obstruction short-​axis stereotactic ablative body radiotherapy spontaneous bacterial peritonitis (also systolic blood pressure) squamous cell carcinoma sickle cell disease (also sudden cardiac death) spinal cord injuries severe combined immunodeficiency small cell lung cancer Society for Cardiovascular Magnetic Resonance sickle cell nephropathy or severe congenital neutropenia small dense low-​density lipoprotein Shwachman–​Diamond syndrome

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Abbreviations SEER SGRQ SHBG SHEC SIADH

Surveillance, Epidemiology, and End Results St George’s Respiratory Questionnaire sex hormone binding globulin Shiga toxin-​producing Escherichia coli syndrome of inappropriate antidiuretic hormone secretion SIRS systemic inflammatory response syndrome SLB surgical lung biopsy SLE systemic lupus erythematosus SM smouldering myeloma SMA superior mesenteric artery (also smooth muscle antibody) SMC smooth muscle cell sMDRD simplified Modification of Diet in Renal Disease SMR standardized mortality ratio SNGFR single-​nephron glomerular filtration rate SNP single nucleotide polymorphism SNS sympathetic nervous system SOD sphincter of Oddi disorder SPC Summary of Product Characteristics SPD storage pool deficiency SPECT single-​positron emission computed tomography SPF sun protection factor SSc systemic sclerosis SSD somatic symptom disorder SSFP steady-​state free precession SSRI selective serotonin reuptake inhibitor STEMI ST elevation myocardial infarction STI sexually transmitted infection STOPP/​START set of inappropriate combinations of medicines and disease (STOPP) and a set of recommended treatments for given conditions (START) suPAR soluble urokinase plasminogen activating receptor SVC superior vena cava SVR systemic vascular resistance TACE transarterial chemoembolization TAE transarterial embolization TALH thick ascending limb of Henle TAR thrombocytopenia with absent radii TAVI transcatheter aortic valve implantation TB tuberculosis TBLC transbronchial lung cryobiopsy TBM tuberculous meningitis TC total cholesterol TCA tricyclic antidepressant TCPC total cavopulmonary connection TCR T-​cell receptor TCT thrombin clotting time TdT terminal deoxyribonucleotidyl transferase TEC transient erythroblastopenia of childhood TEN toxic epidermal necrolysis TF transcription factor (also tissue factor) TFPI tissue factor pathway inhibitor TG triglyceride TGF transforming growth factor TGFα, TGFβ transforming growth factor-​α, -​β TGN trans Golgi network

THR THRIVE TIA TIBC TIMI TINU TIPS TK TKI TKR TLC TLR TMA t-​MDS TNF TNFα tPA TPN TPN TRAIL TRAPS Treg TROPHY TSH TTD tTG TTIP TTKG TTP TURBT TV UAER UCB UDCA UDP UI UIP UKELD UKM UKMEC UKPDS ULN UMN UPR URR URTI UTI UV UVL UVR V/​Q VARD VATS VC vCJD

total hip replacement Treatment of HDL to Reduce the Incidence of Vascular Events transient ischaemic attack total iron-​binding capacity thrombolysis in myocardial infarction tubulointerstitial nephritis uveitis transjugular intrahepatic portosystemic shunt tyrosine kinase tyrosine kinase inhibitor total knee replacement total lung capacity Toll-​like receptor thrombotic microangiopathy therapy-​related myelodysplastic syndrome(s) tumour necrosis factor tumour necrosis factor-​α tissue plasminogen activator total parenteral nutrition total parenteral nutrition TNF-​related apoptosis-​inducing  ligand tumour necrosis factor receptor-​associated periodic syndrome regulatory T (cell) Trial of Preventing Hypertension thyroid-​stimulating hormone thiazide-​type diuretic tissue transglutaminase Transatlantic Trade and Investment Partnership transtubular potassium concentration gradient thrombotic thrombocytopenic purpura transurethral resection of bladder tumour tricuspid valve urinary albumin excretion rate umbilical cord blood ursodeoxycholic acid uridine diphosphate urinary incontinence usual interstitial pneumonia United Kingdom Model for End-​Stage Liver Disease urea kinetic modelling UK Medical Eligibility Criteria United Kingdom Prospective Diabetes Study upper limit of normal upper motor neuron unfolded protein response urea reduction ratio upper respiratory tract infection urinary tract infection ultraviolet ultraviolet light ultraviolet radiation ventilation/​perfusion video-​assisted retroperitoneal debridement video-​assisted thoracoscopic surgery vital capacity variant Creutzfeldt–​Jakob disease

 Abbreviations VDRL VEGF VEOIBD VIP VKA VLA VLCFA VLDL VSD VTE VWD VWF

Venereal Diseases Research Laboratory vascular endothelial growth factor very early-​onset inflammatory bowel disease vasoactive intestinal peptide vitamin K antagonist vertical long axis very long-​chain fatty acid very low-​density lipoprotein ventricular septal defect venous thromboembolism von Willebrand’s disease von Willebrand factor

VZV WBC WCC WGS WHO WM X-​ALD XLH YLDs YLL ZASP

varicella zoster virus white blood cell white cell count whole genome sequencing World Health Organization Waldenström’s macroglobulinaemia X-​linked adrenoleukodystrophy X-​linked hypophosphataemia years lived with disability years of life lost Z-​line associated protein

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Contributors Peter Aaby Bandim Health Project, INDEPTH

Network, Bissau, Guinea-​Bissau, West Africa 8.5.6: Measles Emma Aarons Consultant Virologist and Infectious Disease Physician, Rare and Imported Pathogens Laboratory, Public Health England, Salisbury, Wiltshire, UK 8.5.27: Orf and Milker’s nodule Tom Abbott William Harvey Research Institute, Queen Mary University of London, UK 17.4: Assessing and preparing patients with medical conditions for major surgery Ade Adebajo Faculty of Medicine, Dentistry and Health, University of Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist Raymond Agius Occupational Medicine, University of Manchester, UK 10.2.1: Occupational and environmental health S. Faisal Ahmed School of Medicine, University of Glasgow, Royal Hospital for Children, Glasgow, UK 13.7.3: Normal and abnormal sexual differentiation Shahzada K. Ahmed Department of Otorhinolaryngology, Queen Elizabeth Hospital, Birmingham, UK 13.2.2: Disorders of the posterior pituitary gland Vineet Ahuja Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India 15.10.8: Malabsorption syndromes in the tropics Guruprasad P. Aithal NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham; Nottingham Digestive Diseases Centre, The University of Nottingham, Nottingham, UK 15.24.3: Drug-​induced liver disease Sara Ajina Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.6.1: Visual pathways Tyler Albert VA Puget Sound Health Care System, Division of General Internal Medicine, University of Washington, Seattle, WA, USA 10.3.6: Diseases of high terrestrial altitudes Maha Albur University of Bristol, Bristol, UK 8.2.5: Antimicrobial chemotherapy Michael J. Aldape Veterans Affairs Medical Center, Infectious Diseases Section, Boise, ID, USA 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections

Graeme J.M. Alexander UCL Professor, UCL

Institute for Liver and Digestive Health, Royal Free Hospital, London, UK 15.23.1: Hepatitis A to E; 15.24.6: Primary and secondary liver tumours Michael E.D. Allison Liver Unit, Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, UK 15.24.6: Primary and secondary liver tumours Carlo Ammendolia Faculty of Medicine, University of Toronto, Toronto, Canada; Rebecca MacDonald Centre for Arthritis and Autoimmune Diseases, Division of Rheumatology, Mount Sinai Hospital, Toronto, Canada 19.4: Back pain and regional disorders Chris Andrews Faculty of Medicine, University of Queensland, Herston, Qld 4029, Australia 10.3.5: Lightning and electrical injuries Ross H. Andrews Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Professor of Parasitology, Imperial College London, Faculty of Medicine, St Mary’s Campus, London, UK 8.11.2: Liver fluke infections Jervoise Andreyev Consultant Gastroenterologist, United Lincolnshire Hospitals Trust; Honorary Professor, The School of Medicine, University of Nottingham, UK 15.3.4: Investigation of gastrointestinal function Gregory M. Anstead Division of Infectious Diseases, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Immunosuppression and Infectious Diseases Clinics, Department of Medicine, South Texas Veterans Health Care System, San Antonio, TX, USA 8.7.3: Coccidioidomycosis Quentin M. Anstee Professor of Experimental Hepatology and Honorary Consultant Hepatologist, Faculty of Medical Sciences, Newcastle University and Freeman Hospital Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 15.24.2: Non​alcoholic fatty liver disease Charles M.G. Archer Department of Dermatology, Oxford University Hospitals NHS Trust, Oxford, UK 23.15: Skin and systemic diseases

Clive B. Archer Consultant Dermatologist and

Honorary Senior Clinical Lecturer, St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust & King’s College London, Guy’s Hospital, London, UK 23.15: Skin and systemic diseases Michael J. Arden-​Jones Consultant Dermatologist, University of Southampton, Southampton, UK 23.6: Dermatitis/​eczema Mark J. Arends University of Edinburgh Division of Pathology, Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK 3.6: Apoptosis in health and disease J. Arendt Emeritus Professor of Endocrinology, University of Surrey, Guildford, UK 13.11: The pineal gland and melatonin James O. Armitage The Joe Shapiro Professor of Medicine, Division of Oncology/​Hematology, University of Nebraska Medical Center, Omaha, NE, USA 22.4.3: Hodgkin lymphoma; 22.4.4: Non-​Hodgkin lymphoma Vicente Arroyo Professor of Medicine at the University of Barcelona Medical School; Chairman of the European Association for the Study of the Liver Chronic Liver Failure Consortium (EASL-​CLIF Consortium) and President of the European Foundation for the Study of Chronic Liver Failure (EF-​C LIF), Barcelona, Spain 15.22.2: Cirrhosis and ascites Daniel Aruch Icahn School of Medicine at Mount Sinai, New York, NY, USA 22.3.5: The polycythaemias; 22.3.6: Thrombocytosis and essential thrombocythaemia Frances Ashcroft Professor of Physiology, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK 3.4: Ion channels and disease Caroline Ashley Lead Specialist Pharmacist, Centre for Nephrology, Royal Free Hospital, London, UK 21.19: Drugs and the kidney Shazad Q. Ashraf Consultant Colorectal Surgeon, Department of Colorectal Surgery, Queen Elizabeth Hospital, Birmingham University Hospitals, Birmingham, UK 15.14: Colonic diverticular disease

xlvi

Contributors

Paul Aveyard Nuffield Department of Primary Care

Health Sciences, University of Oxford, Oxford, UK 26.6.2: Obesity and weight management; 26.6.3: Smoking cessation Tar-​Ching Aw† Abu Dhabi National Oil Company, United Arab Emirates 10.2.5: Noise; 10.2.6 Vibration Jon G. Ayres Emeritus Professor of Environmental and Respiratory Medicine, Universty of Birmingham, Birmingham, UK 10.1: Environmental medicine, occupational medicine, and poisoning; 10.3.1: Air pollution and health Juan Carlos Ayus Renal Consultants of Houston, Houston, TX, USA; University of California Irvine, Orange, CA, USA 21.2.1: Disorders of water and sodium homeostasis Qasim Aziz Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK 15.13: Irritable bowel syndrome Trevor Baglin Previously Cambridge Haemophilia and Thrombophilia Centre, Department of Haematology, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK 22.7.2: Evaluation of the patient with a bleeding tendency Michael Bagshaw Aviation Medicine, King’s College, London, UK 10.2.3: Aviation medicine Colin Baigent Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Kenneth F. Baker Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 19.5: Rheumatoid arthritis Bettina Balint Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, Queen Square, London, UK; Department of Neurology, University Hospital Heidelberg, University of Heidelberg, Germany 24.7.3: Movement disorders other than Parkinson’s disease Jay Banerjee College of Life Sciences, University of Leicester, Leicester, UK 6.4: Older people and urgent care Adrian P. Banning Oxford University Hospitals NHS Trust, Oxford, UK 16.3.2: Echocardiography; 16.14.1 Acute aortic syndromes George Banting Medical Sciences Building, University of Bristol, Bristol, UK 3.1: The cell Thomas M. Barber University of Warwick, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK 13.10: Hormonal manifestations of non-​endocrine disease †

E.J. Barnes Nuffield Department of Medicine,

University of Oxford, Oxford, UK 8.5.22: Hepatitis C virus Michael Barnes University of Newcastle, Newcastle upon Tyne, UK; Christchurch Group, Janet Barnes Unit, Birmingham, UK 24.13.2: Spinal cord injury and its management Andrew J. Barr Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK 19.9: Osteoarthritis Jonathan Barratt Professor of Renal Medicine, University of Leicester; Honorary Consultant Nephrologist, University Hospitals of Leicester, Leicester, UK 21.8.1: Immunoglobulin A nephropathy and IgA vasculitis (HSP) Buddha Basnyat Oxford University Clinical Research Unit -​Nepal; Patan Academy of Health Sciences, Nepal 8.6.9 Typhoid and paratyphoid fevers; 10.3.6: Diseases of high terrestrial altitudes D. Nicholas Bateman, Pharmacology, Toxicology and Therapeutics, University of Edinburgh, Edinburgh, UK 10.4.1: Poisoning by drugs and chemicals David Bates Clinical Neurology, Newcastle University, Newcastle on Tyne, UK 24.5.5: The unconscious patient; 24.9: Brainstem syndromes Robert P. Baughman University of Cincinnati Medical Center, Cincinnati, OH, USA 18.12: Sarcoidosis Peter J. Baxter School of Clinical Medicine, Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK 10.3.8: Disasters: Earthquakes, hurricanes, floods, and volcanic eruptions Hannah Beckwith Specialist Registrar, Imperial College Healthcare NHS Trust Renal and Transplant Centre, Hammersmith Hospital, London, UK 21.10.3: The kidney in rheumatological disorders Diederik van de Beek Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 24.11.1: Bacterial infections David A. Bender University College London, London, UK 11.2: Vitamins D.A. Bente University of Texas Medical Branch, Galveston, TX, USA 8.5.16: Bunyaviridae Anthony R. Berendt Oxford University Hospitals NHS Foundation Trust, Oxford, UK 20.3: Osteomyelitis Stefan Berg Consultant in Pediatric Rheumatology and Immunology, Queen Silvia Children’s Hospital, Goteborg, Sweden 12.12.2 Hereditary periodic fever syndromes David de Berker Bristol Dermatology Centre, University Hospitals Bristol, Bristol, UK 23.13: Hair and nail disorders

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

Nancy Berliner H. Franklin Bunn Professor of

Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 22.3.1: Granulocytes in health and disease; 22.4.1: Introduction to lymphopoiesis Jessica Bertrand Experimental Orthopedics, University Hospital Magdeburg, Magdeburg, Germany 19.1: Joints and connective tissue—​structure and function J.M. Best King’s College London, London, UK 8.5.13: Rubella Delia B. Bethell Oxford University Hospitals NHS Foundation Trust, Oxford, UK 8.6.1: Diphtheria Kailash Bhatia Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, UK 24.7.3: Movement disorders other than Parkinson’s disease Vijaya Raj Bhatt Assistant Professor, Division of Hematology-​Oncology, University of Nebraska Medical Center, Omaha, NE, USA 22.4.3: Hodgkin lymphoma; 22.4.4: Non-​Hodgkin lymphoma Joya Bhattacharyya Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK 15.5: Immune disorders of the gastrointestinal tract Paola Bianchi Oncohematology Unit—​ Pathophysiology of Anemias Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore, Milan, Italy 22.6.10: Erythrocyte enzymopathies Rudolf Bilous Professor of Clinical Medicine, Newcastle University, Newcastle upon Tyne; Academic Centre, James Cook University Hospital, Middlesbrough, UK 21.10.1: Diabetes mellitus and the kidney D. Bilton Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.9: Bronchiectasis Jonathan I. Bisson Division of Psychological Medicine and Clinical Neurosciences, University of Cardiff, Cardiff, UK 26.5.9: Acute stress disorder, adjustment disorders, and post-​traumatic stress disorder Carol M. Black Newnham College, Cambridge, UK 19.11.3: Systemic sclerosis (scleroderma) S.R. Bloom Head of Division of Diabetes, Endocrinology and Metabolism, Hammersmith Hospital, Imperial College London, London, UK 13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.1: Hormones and the gastrointestinal tract; 15.9.2: Carcinoid syndrome Johannes Blum Medical Services, Swiss Tropical and Public Health Institute, Basel, Switzerland 8.8.11: Human African trypanosomiasis

Contributors

Kristien Boelaert University of Birmingham,

Birmingham, UK 13.3.1: The thyroid gland and disorders of thyroid function; 13.3.2: Thyroid cancer Eva Boonen Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University, B-​3000 Leuven, Belgium 17.9: Metabolic and endocrine changes in acute and chronic critical illness Christopher Booth† Wellcome Institute for the History of Medicine, Wellcome Building, London, UK 1.1: On being a patient Marina Botto Professor, Imperial College London, London, UK 4.2: The complement system Ralph Bouhaidar Consultant Forensic Pathologist, NHS Lothian; Honorary Senior Lecturer, Edinburgh University, Edinburgh; Training Programme Director for Forensic Histopathology (Scotland), UK 27.1: Forensic and legal medicine Henri-​Jean Boulouis Ecole Nationale Vétérinaire d’Alfort, Maisons-​Alfort, France 8.6.43: Bartonellas excluding B. bacilliformis P.-​M.G. Bouloux Centre for Neuroendocrinology, University College London Medical School, London, UK 13.6.2: Disorders of male reproduction and male hypogonadism S.J. Bourke Royal Victoria Infirmary, Newcastle upon Tyne, UK 18.14.1: Diffuse alveolar haemorrhage; 18.14.2: Eosinophilic pneumonia; 18.14.3: Lymphocytic infiltrations of the lung; 18.14.4: Hypersensitivity pneumonitis; 18.14.5: Pulmonary Langerhans’ cell histiocytosis; 18.14.6: Lymphangioleiomyomatosis; 18.14.7: Pulmonary alveolar proteinosis; 18.14.8: Pulmonary amyloidosis; 18.14.9: Lipoid (lipid) pneumonia; 18.14.10: Pulmonary alveolar microlithiasis; 18.14.12: Radiation pneumonitis; 18.14.13: Drug-​induced lung disease Ian C.J.W. Bowler Oxford University Hospitals NHS Foundation Trust, Oxford, UK; University of Oxford, Oxford, UK 8.2.3: Nosocomial infections Louise Bowles Consultant Haematologist, Barts Health NHS Trust, London, UK 14.7: Thrombosis in pregnancy Paul Bowness Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK 4.1: The innate immune system Ray Boyapati Department of Gastroenterology, Monash Health, Victoria, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Vic, Australia 15.17: Vascular disorders of the gastrointestinal tract Sally M. Bradberry NPIS (Birmingham Unit) and West Midlands Poisons Unit, City Hospital, †

Birmingham; School of Biosciences, University of Birmingham, Birmingham, UK 10.4.1: Poisoning by drugs and chemicals Marcus Bradley North Bristol NHS Trust, Bristol, UK 24.3.3: Imaging in neurological diseases Tasanee Braithwaite Locum Consultant, Moorfields Eye Hospital NHS Foundation Trust, London, UK 25.1: The eye in general medicine Thomas Brandt Ludwig Maximilians University, Munich, Germany 24.6.2: Eye movements and balance Petter Brandtzaeg Emeritus Professor, Department of Paediatrics, Oslo University Hospital, Oslo, Norway 8.6.5: Meningococcal infections Philippe Brasseur Institut de Recherche pour le Développement, Dakar, Sénégal, West Africa 8.8.3: Babesiosis Jürgen Braun Medical Director, Rheumazentrum Ruhrgebiet, Herne, Germany; Chair of Rheumatology, Ruhr University, Bochum, Germany 19.6: Spondyloarthritis and related conditions Evan M. Braunstein Hematology Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA 22.3.7: Primary myelofibrosis James D. Brenton Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK 5.2: The nature and development of cancer: Cancer mutations and their implications J.A. Bridgewater Professor and Consultant in Medical Oncology, UCL Cancer Institute, London, UK 15.16: Cancers of the gastrointestinal tract Frank Bridoux Professor of Nephrology, Department of Nephrology, Hôpital Jean Bernard, Poitiers, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Charlotte K. Brierley Department of Haematology, Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 22.3.2: Myelodysplastic syndromes Alice Brockington University of Sheffield, Sheffield, UK 24.15: The motor neuron diseases Max Bronstein Advocacy and Science Policy, Every Life Foundation, Washington, DC, USA 2.9: Engaging patients in therapeutic development Gary Brook London North West University Healthcare NHS Trust, London, UK 9.3: Sexual history and examination Arthur E. Brown Research Consultant, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand 8.6.21: Anthrax

It is with great regret that we report that Christopher Booth died on 13 July, 2012.

Anthony F.T. Brown Department of Emergency

Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Qld, Australia 17.3: Anaphylaxis Kevin E. Brown Virus Reference Department, Public Health England, London, UK 8.5.20: Parvovirus B19 Michael Brown Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.9.4: Strongyloidiasis, hookworm, and other gut strongyloid nematodes Morris J. Brown Professor of Endocrine Hypertension, Queen Mary University of London, William Harvey Heart Centre, London, UK 16.17.3: Secondary hypertension Vanessa Brown Specialist Registrar, Royal Surrey County Hospital, Guildford, UK 15.4.2: Gastrointestinal bleeding Reto Brun Parasite Chemotherapy Unit, Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland 8.8.11: Human African trypanosomiasis Marco J. Bruno Erasmus Medical Center, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands 15.26.2: Chronic pancreatitis Amy E. Bryant Research Professor, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, ID, USA 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections Antony D.M. Bryceson London School of Hygiene and Tropical Medicine, London, UK 8.8.13: Leishmaniasis Nicolas C. Buchs Consultant Colorectal Surgeon, Clinic for Visceral and Transplantation Surgery, Department of Surgery, University Hospitals of Geneva, Geneva, Switzerland 15.14: Colonic diverticular disease Camilla Buckley MRC Clinician Scientist and Honorary Consultant, Department of Clinical Neurology, University of Oxford, Oxford, UK 24.24: Autoimmune encephalitis and Morvan’s syndrome Simon J.A. Buczacki Honorary Consultant Colorectal Surgeon, Cambridge Colorectal Unit, Addenbrooke’s Hospital, Cambridge, UK 15.4.1: The acute abdomen Enrico Bugiardini MRC Centre for Neuromuscular Disease, University College London, London, UK 24.19.1: Structure and function of muscle Alan Burnett Former Professor of Haematology, Cardiff University, Cardiff, UK 22.3.3: Acute myeloid leukaemia Gilbert Burnham John Hopkins Bloomberg School of Public Health, Baltimore, MD, USA 8.9.1: Cutaneous filariasis Aine Burns Consultant Nephrologist and Director of Postgraduate Medical Education, Centre for Nephrology, Royal Free NHS Trust and University College Medical School, London, UK 21.19: Drugs and the kidney

xlvii

xlviii

Contributors

Eileen Burns Leeds Centre for Older People’s

Medicine, Leeds Teaching Hospitals NHS Trust, Leeds, UK 6.11: Promotion of dignity in the life and death of older patients Harry Burns University of Strathclyde, UK 2.14: Deprivation and health N.P. Burrows Consultant Dermatologist, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 20.2: Inherited defects of connective tissue: Ehlers–​Danlos syndrome, Marfan syndrome, and pseudoxanthoma elasticum Rosie Burton Khayelitsha District Hospital, Corner of Walter Sisulu and Streve Biko Roads, Khayelitsha, Cape Town, Africa; Department of Medicine, University of Cape Town, Cape Town, Africa 14.15: Maternal infection in pregnancy Andrew Bush Imperial College London, London, UK; National Heart and Lung Institute, London, UK; Royal Brompton and Harefield NHS Foundation Trust, London, UK 18.10: Cystic fibrosis Kate Bushby Newcastle University John Walton Centre for Muscular Dystrophy Research, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, International Centre for Life, Newcastle upon Tyne, UK 24.19.2: Muscular dystrophy Gary Butler University College London Hospital and UCL Great Ormond Street Institute of Child Health, London, UK 13.7.1: Normal growth and its disorders William F. Bynum Professor Emeritus, University College London, London, UK 2.1: Science in medicine: When, how, and what Simone M. Cacciò European Union Reference Laboratory for Parasites, Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Rome, Italy 8.8.5: Cryptosporidium and cryptosporidiosis Djuna L. Cahen Erasmus Medical Center, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands 15.26.2: Chronic pancreatitis P.M.A. Calverley School of Clinical Sciences, University of Liverpool, Liverpool, UK 18.15: Chronic respiratory failure Jason Caplan Dignity Health Medical Group; St. Joseph’s Hospital and Medical Center; Creighton University School of Medicine; Phoenix, AZ, USA 26.5.3: Organic psychoses Jonathan R. Carapetis Telethon Kids Institute, University of Western Australia and Perth Children’s Hospital, Perth, Australia 16.9.1: Acute rheumatic fever Jordi Carratalà Department of Infectious Diseases, Hospital Universitari de Bellvitge -​IDIBELL, Division of Health Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain 8.6.39: Legionellosis and Legionnaires’ disease

R. Carter Consultant Pancreaticobiliary Surgeon,

West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis Stuart Carter Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist David Carty Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, Glasgow, UK 14.11: Endocrine disease in pregnancy Jaimini Cegla Imperial College London, London, UK 12.6: Lipid disorders Joseph Cerimele University of Washington, Washington, DC, USA 26.5.6: Depressive disorder Joshua T. Chai Department of Cardiovascular Medicine, University of Oxford, Oxford, UK 16.13.1: Biology and pathology of atherosclerosis Richard E. Chaisson Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA 8.6.26: Tuberculosis Romanee Chaiwarith Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection Ben Challis University of Cambridge Medical School, Cambridge, UK 13.9.2: Hypoglycaemia Siddharthan Chandran Euan MacDonald Centre for Clinical Brain Sciences (CCBS), University of Edinburgh, Edinburgh, UK 3.7: Stem cells and regenerative medicine; 24.10.2: Demyelinating disorders of the central nervous system Keith Channon John Radcliffe Hospital, Oxford, UK 16.1.1: Blood vessels and the endothelium Roger W. Chapman Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford; Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.23.4: Primary sclerosing cholangitis V. Krishna Chatterjee University of Cambridge Medical School, Cambridge, UK 13.1: Principles of hormone action Afzal Chaudhry Chief Clinical Information Officer, Cambridge University Hospitals, Cambridge, UK 2.5: Bioinformatics K. Ray Chaudhuri National Parkinson Foundation Centre of Excellence, King’s College, Denmark Hill Campus, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Patrick F. Chinnery University of Newcastle, Newcastle upon Tyne, UK 24.19.5: Mitochondrial disease

Hector Chinoy University of Manchester,

Manchester, UK 19.11.5: Inflammatory myopathies Peter L. Chiodini Hospital for Tropical Diseases, University College London Hospitals, London, UK 8.9.5: Gut and tissue nematode infections acquired by ingestion Rossa W.K. Chiu Choh-​Ming Li Professor of Chemical Pathology, Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, China 3.9: Circulating DNA for molecular diagnostics Bruno B. Chomel School of Veterinary Medicine, University of California, CA, USA 8.6.43: Bartonellas excluding B. bacilliformis Robin P. Choudhury University of Oxford, Oxford, UK 16.13.1: Biology and pathology of atherosclerosis Julia Choy National Health Service, London, UK 18.4.5: Pulmonary complications of HIV infection Lydia Chwastiak Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA 26.5.6: Depressive disorder Andrew L. Clark Chair of Clinical Cardiology and Honorary Consultant Cardiologist, Hull York Medical School, Castle Hill Hospital, Hull, UK 16.5.2: Acute cardiac failure: Definitions, investigation, and management; 16.5.3: Chronic heart failure: Definitions, investigation, and management Andrew Clegg Academic Unit of Elderly Care and Rehabilitation, University of Leeds, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK 6.2: Frailty and sarcopenia John G.F. Cleland National Heart and Lung Institute, Royal Brompton and Harefield Hospitals Trust London, UK; Hull York Medical School, University of Hull, Hull, UK 16.5.2: Acute cardiac failure: Definitions, investigation, and management; 16.5.3 Chronic heart failure: Definitions, investigation, and management Gavin Clunie Cambridge University Hospitals NHS

Foundation Trust, Cambridge, UK 20.5: Osteonecrosis, osteochondrosis, and osteochondritis dissecans

S.M. Cobbe Previously Consultant Cardiologist,

Glasgow Royal Infirmary; former BHF Walton Professor of Medical Cardiology, University of Glasgow, Glasgow, UK 16.2.2: Syncope and palpitation

Fredric L. Coe The University of Chicago Medicine,

Chicago, IL, US 21.1: Structure and function of the kidney

Sian Coggle Consultant Physician, Cambridge

University Hospitals, Cambridge, UK 30.1: Acute medical presentations; 30.2: Practical procedures

Jon Cohen Brighton and Sussex Medical School,

Brighton, UK 8.2.4: Infection in the immunocompromised host

Contributors

Alasdair Coles Cambridge School of Clinical

Medicine, Cambridge, UK 24.10.2: Demyelinating disorders of the central nervous system Jane Collier Consultant Hepatologist, John Radcliffe Hospital, Oxford, UK 8.5.22: Hepatitis C virus; 15.22.1: Investigation and management of jaundice Rory Collins Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Juan D. Colmenero Infectious Diseases Service, Regional University Hospital, Málaga, Spain 8.6.22: Brucellosis Alastair Compston Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK 24.1: Introduction and approach to the patient with neurological disease Juliet Compston University of Cambridge School of Clinical Medicine and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 20.4: Osteoporosis Philip G. Conaghan Leeds University, Leeds, UK 19.9: Osteoarthritis Christopher P. Conlon Professor of Infectious Diseases, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.4: Travel and expedition medicine; 8.5.23: HIV/​ AIDS; 8.5.28: Molluscum contagiosum Simon Conroy Department of Health Sciences, University of Leicester, Leicester, UK 6.4: Older people and urgent care Cyrus Cooper MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK 20.4: Osteoporosis John E. Cooper University of Cambridge, Cambridge, UK 8.8.8: Sarcocystosis (sarcosporidiosis) Robert Cooper University of Liverpool, Liverpool, UK 19.11.5: Inflammatory myopathies Mhairi Copland Professor of Translational Haematology, Section of Experimental Haematology, Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK 22.3.4: Chronic myeloid leukaemia Susan J. Copley Imperial College Healthcare NHS Trust, London, UK 18.3.2: Thoracic imaging Jeremy Cordingley Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK 17.5: Acute respiratory failure Philip J. Cowen University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.4.1: Psychopharmacology in medical practice

Timothy M. Cox Professor of Medicine Emeritus,

Director of Research, University of Cambridge; Honorary Consultant Physician, Addenbrooke’s Hospital, Cambridge, UK 1.1: An older patient’s story; 12.1: The inborn errors of metabolism: General aspects; 12.3.1: Glycogen storage diseases; 12.3.2: Inborn errors of fructose metabolism; 12.3.3: Disorders of galactose, pentose, and pyruvate metabolism; 12.5: The porphyrias; 12.7.1: Hereditary haemochromatosis; 12.8: Lysosomal disease; 13.11: The pineal gland and melatonin; 15.10.5: Disaccharidase deficiency; 22.6.4: Iron metabolism and its disorders S.E. Craig Oxford Sleep Unit, Churchill Hospital, Oxford, UK 18.1.1: The upper respiratory tract Matthew Cramp South West Liver Unit and Peninsula Schools of Medicine and Dentistry, Derriford Hospital, Plymouth, UK 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Robin A.F. Crawford Addenbrooke’s Hospital, Cambridge, UK 14.18: Malignant disease in pregnancy Daniel Creamer King’s College Hospital, London, UK 23.16: Cutaneous reactions to drugs Tim Crook North Middlesex Hospital, London, UK 5.7: Medical management of breast cancer Paul Cullinan Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.7: Asthma Peter F. Currie Perth Royal Infirmary, Perth and Ninewells Hospital and Medical School, Dundee, UK 16.9.3: Cardiac disease in HIV infection Nicola Curry Consultant Haematologist, Oxford University Hospitals NHS Foundation Trust, Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK 22.7.3: Thrombocytopenia and disorders of platelet function Goodarz Danaei Department of Global Health and Population, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA 16.13.2: Coronary heart disease: Epidemiology and prevention Christopher J. Danpure Emeritus Professor of Molecular Cell Biology, University College London, London, UK 12.10: Hereditary disorders of oxalate metabolism: The primary hyperoxalurias Bhaskar Dasgupta University of Essex, Essex, UK; Anglia Ruskin University, East Anglia, UK; Southend University Hospital NHS Foundation Trust, Essex, UK 19.11.11: Polymyalgia rheumatica Pooja Dassan Consultant Neurologist, Imperial College Healthcare NHS Trust and London North West University Healthcare NHS Trust, London, UK 14.12: Neurological conditions in pregnancy

Andrew Davenport Professor of Dialysis and ICU

Nephrology, UCL Department of Nephrology, Royal Free Hospital, University College London, London, UK 21.4: Clinical investigation of renal disease Gail Davey Centre for Global Health Research, Brighton and Sussex Medical School, Brighton, UK 10.5: Podoconiosis Alun Davies Imperial College School of Medicine, London, UK 16.14.2: Peripheral arterial disease Helen E. Davies University Hospital of Wales, Cardiff, UK 18.19.4: Mediastinal tumours and cysts R Justin Davies Consultant Colorectal Surgeon, Cambridge Colorectal Unit, Addenbrooke’s Hospital, Cambridge, UK 15.4.1: The acute abdomen P.D.O. Davies Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, UK 8.6.27: Disease caused by environmental mycobacteria R. Rhys Davies Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.3.1: Lumbar puncture Simon Davies Professor of Nephrology and Dialysis Medicine, Institute for Science and Technology in Medicine, Keele University, Keele; Consultant Nephrologist, University Hospital of North Midlands, Stoke-​on-​Trent,  UK 21.7.2: Peritoneal dialysis Richard Dawkins New College, University of Oxford, Oxford, UK 2.2: Evolution: Medicine’s most basic science Christopher P. Day Vice-​Chancellor and President, Newcastle University and Freeman Hospital Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 15.24.2: Non​alcoholic fatty liver disease Nicholas P.J. Day Mahidol-​Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 8.6.35: Leptospirosis; 8.6.41: Scrub typhus Colin Dayan University of Cardiff, Wales, UK 13.9.1: Diabetes Marc E. De Broe Professor of Medicine, Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium 21.9.2: Chronic tubulointerstitial nephritis Kevin M. De Cock Center for Global Health, Atlanta, GA, USA 8.5.24: HIV in low-​and middle-​income countries An S. De Vriese Division of Nephrology, AZ Sint-​Jan Brugge-​Oostende AV, Brugge, Belgium 21.8.4: Membranous nephropathy Patrick B. Deegan Consultant Metabolic Physician, Lysosomal Disorders Unit, Cambridge University Hospitals, Cambridge, UK 12.8 Lysosomal disease

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Contributors

Christopher Deighton Royal Derby Hospital,

Derby, UK 19.2 Clinical presentation and diagnosis of rheumatological disorders David M. Denison Emeritus Professor of Clinical Physiology, Royal Brompton Hospital and Imperial College London, London, UK 10.2.4: Diving medicine Christopher P. Denton Centre for Rheumatology, Division of Medicine, University College London (UCL) Medical School, Royal Free Hospital, London, UK 19.11.3: Systemic sclerosis (scleroderma) Ulrich Desselberger University of Cambridge, Cambridge, UK 8.5.8: Enterovirus infections; 8.5.9: Virus infections causing diarrhoea and vomiting Patrick C. D’Haese Head of Laboratory of Pathophysiology, University of Antwerp, Campus Drie Eiken, Wilrijk, Belgium 21.9.2: Chronic tubulointerstitial nephritis Ashwin Dhanda Plymouth Hospitals NHS Trust, Plymouth, UK 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Jugdeep Dhesi Guys and St Thomas’ Hospitals, London, UK 6.6: Supporting older peoples’ care in surgical and oncological services Euan J. Dickson Consultant Pancreaticobiliary Surgeon, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis Michael Doherty University of Nottingham, Nottingham, UK 19.3: Clinical investigation; 19.10: Crystal-​related arthropathies Inderjeet S. Dokal Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts Health NHS Trust, London, UK 22.5.1: Inherited bone marrow failure syndromes Jan Donck Department of Nephrology, AZ Sint-​ Lucas, Ghent, Belgium 21.10.4: The kidney in sarcoidosis Arjen M. Dondorp Mahidol-​Oxford Tropical Medicine Research Unit, Bangkok, Thailand 8.8.2: Malaria Basil Donovan University of New South Wales, NSW, Australia 8.6.37: Syphilis Philip R. Dormitzer Pfizer Vaccine Research and Development, Pearl River, NY, USA 8.5.9: Virus infections causing diarrhoea and vomiting Anne Dornhorst Imperial College Hospital, London, UK 14.10: Diabetes in pregnancy Charles G. Drake New York Presbyterian and Columbia University Medical Center, New York, USA 5.4: Cancer immunity and immunotherapy

Hal Drakesmith MRC Human Immunology Unit,

Weatherall Institute of Molecular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, UK 22.6.5: Anaemia of inflammation Christopher Dudley Consultant Nephrologist, The Richard Bright Renal Unit, Southmead Hospital, North Bristol NHS Trust, Bristol, UK 16.14.3: Cholesterol embolism Susanna Dunachie Oxford University Hospitals NHS Trust, Oxford, UK 8.4: Travel and expedition medicine Lisa Dunkley Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist David Dunne University of Cambridge, Cambridge, UK; Wellcome Trust-​Cambridge, Centre for Global Health Research, UK; CAPREx, THRiVE-​Cambridge, and Cambridge-​Africa 8.11.1: Schistosomiasis Stephen R. Durham National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London, UK 18.6: Allergic rhinitis Jeremy Dwight John Radcliffe Hospital, Oxford, UK 16.2.1: Chest pain, breathlessness, and fatigue Jessica K. Dyson Newcastle University and Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK 15.23.3: Primary biliary cholangitis Christopher P. Eades University College London, London, UK 8.7.5: Pneumocystis jirovecii Ian Eardley St James’s Hospital, Leeds, UK 13.6.4: Sexual dysfunction James E. East Consultant Gastroenterologist, Translational Gastroenterology Unit, John Radcliffe Hospital; Associate Professor of Gastroenterology and Endoscopy, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 15.3.1: Colonoscopy and flexible sigmoidoscopy; 15.3.2: Upper gastrointestinal endoscopy Lars Eckmann Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA 8.8.9: Giardiasis and balantidiasis Michael Eddleston Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK 10.4.4: Poisonous plants Mark J. Edwards St George’s University of London, London, UK 24.7.1: Subcortical structures: The cerebellum, basal ganglia, and thalamus Richard Edwards School of Clinical Sciences, University of Bristol, Bristol, UK 24.19.4: Metabolic and endocrine disorders Rosalind A. Eeles The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK 5.3: The genetics of inherited cancers

Tim Eisen Department of Oncology, University

of Cambridge, Cambridge, UK; Oncology Early Clinical Development, AstraZeneca, Cambridge, UK 5.2: The nature and development of cancer: Cancer mutations and their implications; 5.5: Clinical features and management; 21.18: Malignant diseases of the urinary tract Wagih El Masri(y) Keele University, Newcastle-​ under-​Lyme, UK; The Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK 24.13.2: Spinal cord injury and its management Carole Eldin University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Perry Elliott St Bartholomew’s Hospital, London, UK; Institute of Cardiovascular Science, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular; 16.7.3: Specific heart muscle disorders Christopher J. Ellis Heart of England Foundation Trust, Birmingham, UK; University of Birmingham, Birmingham, UK 8.2.1: Clinical approach Graham Ellis Monklands Hospital, Airdrie, Lanarkshire, UK 6.5: Older people in hospital Monique M. Elseviers Centre for Research and Innovation in Care (CRIC), University of Antwerp, Antwerp; Heymans Institute of Clinical Pharmacology, Ghent University, Ghent, Belgium 21.9.2: Chronic tubulointerstitial nephritis Caroline Elston Respiratory Medicine and Adult Cystic Fibrosis, King’s College Hospital, London, UK 18.10: Cystic fibrosis M.A. Epstein Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK 8.5.3: Epstein–​Barr  virus Steve Epstein MedStar Georgetown University Hospital and Georgetown University School of Medicine, Washington, DC, USA 26.5.8: Anxiety disorders Wendy N. Erber Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, WA, Australia 22.2.2: Diagnostic techniques in the assessment of haematological malignancies Ari Ercole Neurosciences Critical Care Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Edzard Ernst Emeritus Professor, University of Exeter, Exeter, UK 2.22: Complementary and alternative medicine Andrew P. Evan Indiana University School of Medicine, Indianapolis, IN, USA 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis Mark Evans University of Cambridge Medical School, Cambridge, UK 13.9.2: Hypoglycaemia

Contributors

Rhys D. Evans Department of Physiology, Anatomy

and Genetics, University of Oxford, Oxford, UK 11.1 Nutrition: Macronutrient metabolism; 16.1.2: Cardiac physiology Pamela Ewan Allergy Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 4.5: Allergy David W. Eyre Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 8.6.24 Clostridium difficile Lynette D. Fairbanks Purine Research Laboratory, Viapath, St Thomas’ Hospital, London, UK 12.4 Disorders of purine and pyrimidine metabolism Christopher G. Fairburn Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.5.10: Eating disorders Carole Fakhry Johns Hopkins Medical Institution, Baltimore, MD, USA 8.5.19: Papillomaviruses and polyomaviruses Marie Fallon St Columba’s Hospice Chair of Palliative Medicine, University of Edinburgh, Edinburgh, UK 7.2: Pain management Sonia Fargue University of Alabama at Birmingham, Birmingham, AL, USA 12.10: Hereditary disorders of oxalate metabolism: The primary hyperoxalurias Adam D. Farmer Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London; Department of Gastroenterology, University Hospitals of North Midlands, Stoke-​on-​Trent, UK 15.13: Irritable bowel syndrome I. Sadaf Farooqi Wellcome-​MRC Institute of Metabolic Science, University of Cambridge, UK 11.6: Obesity Jeremy Farrar Wellcome Trust, London, UK 2.17: Research in the developed world; 24.11.2: Viral infections Ken Farrington Lister Hospital, East and North Hertfordshire NHS Trust, Stevenage, UK 21.3: Clinical presentation of renal disease Hiva Fassihi King’s College London, London, UK 23.9: Photosensitivity John Feehally Emeritus Consultant Nephrologist, University Hospitals of Leicester; Honorary Professor of Renal Medicine, University of Leicester, Leicester, UK 21.8.1: Immunoglobulin A nephropathy and IgA vasculitis (HSP); 21.8.2: Thin membrane nephropathy Peter J. Fenner School of Public Health, Tropical Medicine and Rehabilitation Sciences, James Cook University, Townsville, Qld, Australia 10.3.4: Drowning Florence Fenollar Aix-​Marseille Université, URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, IHU Méditerranée Infection, Marseille, France 15.10.6: Whipple’s disease

Javier Fernández Consultant Hepatologist, Head of

Liver ICU, Liver Unit, Hospital Clinic Barcelona; Associate Professor, University of Barcelona Medical School, Barcelona, Spain; Member of the European Foundation for the Study of Chronic Liver Failure (EF-​CLIF) 15.22.2: Cirrhosis and ascites Fernando C. Fervenza Professor of Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, USA 21.8.4: Membranous nephropathy Sarah Fidler Professor of HIV Medicine, Imperial College London, London, UK 8.5.23: HIV/​AIDS Richard E. Fielding Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 21.3: Clinical presentation of renal disease Roger G. Finch Nottingham University Hospitals, NHS Trust, Nottingham, UK 8.2.5: Antimicrobial chemotherapy Simon Finney Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK 17.5: Acute respiratory failure Helen V. Firth Addenbrookes Hospital Cambridge, Cambridge, UK 24.20: Developmental abnormalities of the central nervous system John D. Firth Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK 16.16.1: Deep venous thrombosis and pulmonary embolism; 16.17.1: Essential hypertension: Definition, epidemiology, and pathophysiology; 16.17.2: Essential hypertension: Diagnosis, assessment, and treatment; 16.19: Idiopathic oedema of women; 21.2.2: Disorders of potassium homeostasis; 21.5: Acute kidney injury; 21.7.3: Renal transplantation; 30.1: Acute medical presentations; 30.2: Practical procedures A.J. Fisher Professor of Respiratory Transplant Medicine, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK 18.16: Lung transplantation Edward A. Fisher Departments of Medicine, Pediatrics, and Cell Biology, Smilow Research Centre, New York, NY, USA 16.13.1: Biology and pathology of atherosclerosis Rebecca C. Fitzgerald Professor of Cancer Prevention and MRC Programme Leader, MRC Cancer Unit, University of Cambridge, Hutchison/​MRC Research Centre, Cambridge, UK 15.7: Diseases of the oesophagus Michael E.B. FitzPatrick Department of Gastroenterology, Oxford University Hospitals, Oxford; Senior Research Fellow, Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.1: Structure and function of the gastrointestinal tract R. Andres Floto Molecular Immunity Unit, Department of Medicine, University of Cambridge,

UK; Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, UK 3.5: Intracellular signalling Edward D. Folland University of Massachusetts Medical School, MA, USA 16.3.4: Cardiac catheterization and angiography; 16.13.5: Percutaneous interventional cardiac procedures D. de Fonseka Academic Respiratory Unit, University of Bristol, Bristol, UK 18.17: Pleural diseases Carole Foot Royal North Shore Hospital, NSW, Australia 17.1: The seriously ill or deteriorating patient Alastair Forbes Norwich Medical School,  University of East Anglia, Norwich, UK 15.10.1: Differential diagnosis and investigation of malabsorption Ewan Forrest Consultant Hepatologist and Honorary Clinical Associate Professor, Department of Gastroenterology, Glasgow Royal Infirmary and the University of Glasgow, Glasgow UK 15.24.1: Alcoholic liver disease Rob Fowkes Royal Veterinary College, London, UK 13.1: Principles of hormone action Keith A.A. Fox Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK 16.13.4: Management of acute coronary syndrome Stephen Franks Imperial College London, London, UK 13.6.1: Ovarian disorders Keith N. Frayn Radcliffe Department of Medicine, University of Oxford, Oxford, UK 11.1: Nutrition: Macronutrient metabolism Patrick French Mortimer Market Centre, Central and North West London NHS Trust, London, UK; University College London, London, UK 9.6: Genital ulceration Izzet Fresko Division of Rheumatology, Department of Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey 19.11.10: Behçet’s syndrome Peter S. Friedmann Emeritus Professor of Dermatology, University of Southampton, Southampton, UK 23.6: Dermatitis/​eczema Charlotte Frise Obstetric Medicine and Acute General Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 14.20: Prescribing in pregnancy Susannah J.A. Froude Consultant Microbiology and Infectious Diseases, Public Health Wales, Cardiff, UK 8.5.29: Newly discovered viruses Stephen J. Fuller Associate Professor, Medicine Sydney Medical School Nepean, The University of Sydney, Sydney, Australia 22.6.8: Anaemias resulting from defective maturation of red cells David A. Gabbott Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK 17.2: Cardiac arrest

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Contributors

Simon M. Gabe Consultant Gastroenterologist,

Intestinal Failure and Academic Unit, St Mark’s Hospital, London, UK 15.10.7: Effects of massive bowel resection Patrick G. Gallagher Professor of Pediatrics, Genetics and Pathology, Yale University, New Haven, CT, USA 22.6.9: Disorders of the red cell membrane Shreyans Gandhi King’s College Hospital/​King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Hector H. Garcia Center for Global Health, Tumbes and Department of Microbiology, Universidad Peruana Cayetano Heredia, and Cysticercosis Unit, Instituto Nacional de Ciencias Neurologicas, Lima, Peru 8.10.2: Cystic hydatid disease (Echinococcus granulosus); 8.10.3: Cysticercosis Hill Gaston University of Cambridge, Cambridge, UK 19.8: Reactive arthritis Rupert Gauntlett Critical Care Medicine and Obstetric Anaesthesia, Royal Victoria Infirmary, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK 14.19: Maternal critical care John Geddes University of Oxford, Oxford, UK 26.5.7: Bipolar disorder William Gelson Consultant Hepatologist, Hepatobiliary and Liver Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 15.20: Structure and function of the liver, biliary tract, and pancreas Jacob George Department of Clinical Pharmacology and Therapeutics, University of Dundee, Dundee, UK 6.7: Drugs and prescribing in the older patient G.J. Gibson Newcastle University, Newcastle upon Tyne, UK 18.3.1: Respiratory function tests John Gibson Professor of Oral Medicine and Honorary Consultant in Oral Medicine, Institute of Dentistry, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK 15.6: The mouth and salivary glands J. van Gijn University Medical Center Utrecht, Utrecht, the Netherlands 24.10.1 Stroke: Cerebrovascular disease Ian Giles Centre for Rheumatology, Department of Medicine, University College London, London, UK 19.11.1: Introduction Robert H. Gilman Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA 8.10.3: Cysticercosis Alexander Gimson Consultant Hepatologist, Hepatobiliary and Liver Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 15.19: Miscellaneous disorders of the bowel; 15.20: Structure and function of the liver, biliary tract, and pancreas; 15.24.4: Vascular disorders of the liver Matthew R. Ginks Oxford University Hospitals NHS Trust, Oxford, UK 16.4: Cardiac arrhythmias †

D.S. Giovanniello Medical Director, American Red

Cross, Biomedical Services, Connecticut Blood Services Region, Farmington, CT, USA 22.8.1: Blood transfusion Mark A. Glover Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.2.4: Diving medicine Peter J. Goadsby NIHR-​Wellcome Trust King’s Clinical Research Facility, King’s College London, London, UK 24.8: Headache David Goldblatt University College London, London, UK 8.3: Immunization Armando E. Gonzalez Center for Global Health, Tumbes, Universidad Peruana Cayetano Heredia, and Department of Veterinary Epidemiology and Economics, School of Veterinary Medicine, Universidad Nacional Mayor de San Marcos, Lima, Peru 8.10.2: Cystic hydatid disease (Echinococcus granulosus) E.C. Gordon-​Smith Professor of Haematology, St George’s Hospital, University of London, London, UK 22.8.2: Haemopoietic stem cell transplantation Martin Gore† The Royal Marsden, London, UK; The Institute of Cancer Research, University of London, London, UK 5.5: Clinical features and management Eduardo Gotuzzo Universidad Peruana Cayetano Heredia, Lima, Peru 8.5.25: HTLV-​1, HTLV-​2, and associated diseases Philip Goulder University of Oxford, Oxford, UK 8.5.23: HIV/​AIDS Alison D. Grant Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.5.24: HIV in low-​and middle-​income countries Cameron C. Grant The University of Auckland, New Zealand; Starship Children’s Health, Auckland, New Zealand 8.6.15: Bordetella infection David Gray Department of Cardiovascular Medicine, Nottingham University Hospitals NHS Trust, Nottingham, UK 16.3.1: Electrocardiography Richard Gray Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials John R. Graybill Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA 8.7.3: Coccidioidomycosis Darren Green Division of Cardiovascular Sciences, University of Manchester, Manchester, UK 16.5.4: Cardiorenal syndrome Manfred S. Green Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.3.9: Bioterrorism

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

Christopher D. Gregory University of Edinburgh

Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, UK 3.6: Apoptosis in health and disease Christopher E.M. Griffiths Salford Royal NHS Foundation Trust, University of Manchester, Manchester, UK 23.5: Papulosquamous disease Karolina Griffiths University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Mark Griffiths Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK; Imperial College London, London, UK 17.5: Acute respiratory failure William J.H. Griffiths Consultant Hepatologist, Department of Hepatology, Addenbrooke’s Hospital, Cambridge, UK 12.7.1: Hereditary haemochromatosis; 15.24.6: Primary and secondary liver tumours J.P. Grünfeld Hôpital Universitaire Necker, Paris, France 21.12: Renal involvement in genetic disease D.J. Gubler Director, Program on Emerging Infectious Disease, Duke-NUS Graduate Medical School, Singapore; Asian Pacific Institute of Tropical Medicine and Infectious Diseases, University of Hawaii, Honolulu 8.5.12: Alphaviruses Richard L. Guerrant Center for Global Health, School of Medicine, University of Virginia, VA, USA 8.6.12: Cholera Kaushik Guha Portsmouth Hospitals NHS Trust, Portsmouth, UK 16.5.1: Epidemiology and general pathophysiological classification of heart failure Nishan Guha Oxford University Hospitals NHS Foundation Trust, Oxford, UK 29.1: The use of biochemical analysis for diagnosis and management Loïc Guillevin Department of Internal Medicine, National Referral Center for Rare Autoimmune and Systemic Diseases, INSERM U1060, Hôpital Cochin, Assistance Publique–​ Hôpitaux de Paris, University Paris Descartes, Paris, France 19.11.8: Polyarteritis nodosa Mark Gurnell University of Cambridge Medical School, Cambridge, UK 13.1: Principles of hormone action; 13.5.1 Disorders of the adrenal cortex Oliver P. Guttmann St Bartholomew’s Hospital, London, UK; Institute of Cardiovascular Science, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular; 16.7.3: Specific heart muscle disorders Robert D.M. Hadden Consultant Neurologist, King’s College Hospital, London, UK 24.12: Disorders of cranial nerves; 24.16: Diseases of the peripheral nerves

Contributors

Zara Haider Kingston Hospital NHS Trust,

Surrey, UK 9.9: Principles of contraception Sophie Hambleton Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK; Paediatric Immunology and Infectious Diseases, Great North Children’s Hospital, Newcastle upon Tyne, UK 4.4: Immunodeficiency Freddie C. Hamdy Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 21.18: Malignant diseases of the urinary tract Michael G. Hanna National Hospital for Neurology and Neurosurgery, Queen Square, London, UK 24.19.1: Structure and function of muscle David M. Hansell Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.3.2: Thoracic imaging Danielle Harari Guy’s and St Thomas’ Hospitals and King’s College London, London, UK 6.9: Bladder and bowels Kate Hardy Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, London, UK 13.6.1: Ovarian disorders Karen E. Harman Department of Dermatology, University Hospitals of Leicester NHS Trust, Leicester, UK 23.7: Cutaneous vasculitis, connective tissue diseases, and urticaria Peter Harper London Oncology Centre, London, UK 5.6: Systemic treatment and radiotherapy; 5.7: Medical management of breast cancer Steve Harper Consultant Renal and Transplant Medicine, Southmead Hospital, Bristol; Honorary Professor, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK; Honorary Professor, School of Medicine, University of Exeter, Exeter, UK 21.1: Structure and function of the kidney James L. Harrison London Deanery, London, UK 16.9.2: Endocarditis Tina Hartert Division of Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA 14.8: Chest diseases in pregnancy Christine Hartmann Institute of Musculoskeletal Medicine, University of Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Nicholas C. Harvey MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK 20.4: Osteoporosis Rowan Harwood Nottingham University Hospitals NHS Trust and University of Nottingham, Queens Medical Centre, Nottingham, UK 6.5: Older people in hospital

Helen Hatcher Consultant Medical Oncologist,

Cambridge University Hospitals, Cambridge, UK 20.6: Bone cancer Chris Hatton Cancer and Haematology Centre, Churchill Hospital, Oxford, UK 22.1: Introduction to haematology; 22.3.9: Histiocytosis; 22.6.2: Anaemia: Pathophysiology, classification, and clinical features Philip N. Hawkins Professor of Medicine, National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, University College London, London, UK 12.12.2 Hereditary periodic fever syndromes; 12.12.3 Amyloidosis Keith Hawton Centre for Suicide Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.3.2: Self-​harm Deborah Hay Honorary Consultant Haematologist, Nuffield Department of Medicine, University of Oxford, Oxford, UK 22.6.7: Disorders of the synthesis or function of haemoglobin; 22.6.9: Disorders of the red cell membrane Roderick J. Hay King’s College London, London, UK 8.6.31: Nocardiosis; 8.7.1: Fungal infections; 23.6: Dermatitis/​eczema; 23.10: Infections of the skin; 23.12: Blood and lymphatic vessel disorders Peter Hayes Professor of Hepatology, Liver Unit, University of Edinburgh; and Royal Infirmary of Edinburgh, Edinburgh, UK 15.22.3: Portal hypertension and variceal bleeding Catherine E.G. Head Consultant Cardiologist, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 14.6: Heart disease in pregnancy Eugene Healy Dermatopharmacology, Southampton General Hospital, University of Southampton, UK 23.8: Disorders of pigmentation Nick Heather Department of Psychology, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption David W. Hecht Loyola University Health System, IL, USA 8.6.11: Anaerobic bacteria Thomas Hellmark Department of Clinical Sciences, Lund University, Lund, Sweden 21.8.7: Antiglomerular basement membrane disease Michael Heneghan Professor of Hepatology and Consultant Hepatologist, Institute of Liver Studies, King’s College Hospital, London, UK 14.9: Liver and gastrointestinal diseases of pregnancy Michael Henein Umeå University, Sweden; Canterbury Christ Church University, Canterbury, UK 16.6: Valvular heart disease; 16.8: Pericardial disease

Martin F. Heyworth Department of Medicine,

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 8.8.9: Giardiasis and balantidiasis

Liz Hickson Royal North Shore Hospital, NSW,

Australia 17.1: The seriously ill or deteriorating patient

Tran Tinh Hien Oxford University Clinical Research

Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.6.1: Diphtheria

Katherine A. High Professor of Pediatrics Emerita,

Perelman School of Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; President and Head of R&D, Spark Therapeutics, Philadelphia, PA, USA 22.7.4: Genetic disorders of coagulation

Ingeborg Hilderson Department of Medical

Oncology, University Hospital Ghent, Ghent, Belgium 21.10.4: The kidney in sarcoidosis

Tom R. Hill Population Health Sciences

Institute, Newcastle University, Newcastle upon Tyne, UK 11.2: Vitamins

David Hilton-​Jones Muscular Dystrophy

Campaign, Muscle and Nerve Centre, Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK 24.18: Disorders of the neuromuscular junction; 24.19.3: Myotonia; 24.19.4 Metabolic and endocrine disorders

Matthew Hind Royal Brompton Hospital

and National Heart and Lung Institute, Imperial College School of Medicine, London, UK 18.5.1: Upper airway obstruction; 18.5.2: Sleep-​ related breathing disorders

John Hindle Betsi Cadwaladr University Health

Board, Llandudno Hospital; School of Psychology, Bangor University, Bangor, UK 6.10: Neurodegenerative disorders in older people

N. Hirani Royal Infirmary, Edinburgh, UK

18.11.2: Idiopathic pulmonary fibrosis

Gideon M. Hirschfield Lily and Terry Horner

Chair in Autoimmune Liver Disease Research, Toronto Centre for Liver Disease, Department of Medicine, University of Toronto, Toronto General Hospital, Toronto, Canada 15.23.2: Autoimmune hepatitis

Sarah Hobdey Veterans Medical Hospital, Boise,

ID, USA 8.6.2: Streptococci and enterococci

Herbert Hof MVZ Labor Limbach, Heidelberg,

Germany 8.6.38: Listeriosis

A.V. Hoffbrand Emeritus Professor of Haematology,

University College, London, UK 22.6.6: Megaloblastic anaemia and miscellaneous deficiency anaemias

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Contributors

Ronald Hoffman Albert A. and Vera G. List,

Professor of Medicine, Division of Hematology/​ Oncology; Director, Myeloproliferative Disorders Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA 22.3.5: The polycythaemias; 22.3.6: Thrombocytosis and essential thrombocythaemia Georg F. Hoffmann Department of General Pediatrics, University of Heidelberg, Heidelberg, Germany 12.2 Protein-​dependent inborn errors of metabolism Tessa L. Holyoake† Professor of Experimental Haematology, Section of Experimental Haematology, Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK 22.3.4: Chronic myeloid leukaemia Roel Hompes Consultant Colorectal Surgeon, Academic Medical Centre Amsterdam, University of Amsterdam, the Netherlands 15.14: Colonic diverticular disease Tony Hope St Cross College, University of Oxford, Oxford, UK 1.5: Medical ethics Julian Hopkin Medicine and Health, School of Medicine, Swansea University, Swansea, UK 18.2: The clinical presentation of respiratory disease P. Hopkins Medical Director, Queensland Lung Transplant Service, Chermside, Qld, Australia 18.16: Lung transplantation Nicholas S. Hopkinson National Heart and Lung Institute, Imperial College, London, UK 18.8: Chronic obstructive pulmonary disease Patrick Horner Population Health Sciences, University of Bristol, Bristol, UK 8.6.45: Chlamydial infections; 9.5: Urethritis Bala Hota Rush University, Chicago, IL USA 8.6.4: Staphylococci Andrew R. Houghton Grantham and District Hospital, Grantham, UK; University of Lincoln, Lincoln, UK 16.3.1: Electrocardiography Robert A. Huddart The Institute of Cancer Research, London, UK 21.18: Malignant diseases of the urinary tract Harriet C. Hughes Consultant Microbiology and Infectious Diseases, Public Health Wales, Cardiff, UK 8.5.29: Newly discovered viruses Ieuan A. Hughes University of Cambridge, Cambridge, UK 13.5.2: Congenital adrenal hyperplasia James H. Hull The Royal Brompton Hospital, London, UK 18.5.1: Upper airway obstruction Adam Hurlow Leeds Teaching Hospitals NHS Trust, Leeds, UK 7.4: Care of the dying person Jane A. Hurst Great Ormond Street Hospital, London, UK 24.20: Developmental abnormalities of the central nervous system

†

Alastair Hutchison Medical Director and Professor

of Renal Medicine, Dorset County Hospital, Dorchester, UK 21.6: Chronic kidney disease Peter J. Hutchinson University of Cambridge, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Steve Iliffe Research Department of Primary Care and Population Health, University College London, London, UK 6.3: Optimizing well-​being into old age Lawrence Impey Obstetrics and Fetal Medicine, The Women’s Centre, John Radcliffe Hospital, Oxford, UK 14.16: Fetal effects of maternal infection Jakko van Ingen Radboud University Medical Centre, Nijmegen, the Netherlands 8.6.27: Disease caused by environmental mycobacteria Peter Irving Department of Gastroenterology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 15.12: Ulcerative colitis John D. Isaacs Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 2.7 Biological therapies for immune, inflammatory, and allergic diseases; 19.5: Rheumatoid arthritis David A. Isenberg Centre for Rheumatology, Department of Medicine, University College London, London, UK 19.11.1: Introduction; 19.11.2: Systemic lupus erythematosus and related disorders Theodore J. Iwashyna Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Center for Clinical Management Research, Department of Veterans Affairs, Ann Arbor, MI, USA; Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic, Australia 17.12: Persistent problems and recovery after critical illness Arnaud Jaccard Service d’hématologie clinique et de thérapie cellulaire, CHU de Limoges—​Hôpital Dupuytren, Limoges, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Alan A. Jackson Southampton General Hospital, Southampton, UK 11.4: Severe malnutrition Thomas Jackson Queen Elizabeth Hospital, Birmingham, UK 26.3.1: Confusion Anu Jacob National Neuromyelitis Optica Service, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.13.1: Diseases of the spinal cord

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

Caron A. Jacobson Division of Hematologic

Malignancies, Dana-​Farber Cancer Institute, Boston, MA, USA 22.4.1: Introduction to lymphopoiesis N. Asger Jakobsen Clinical Research Fellow, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK 22.2.1: Cellular and molecular basis of haematopoiesis Rajiv Jalan Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK 15.22.5: Liver failure Hannah Jarvis Respiratory Medicine, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK 18.4.4: Mycobacteria M.K. Javaid Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, UK 20.1: Skeletal disorders—​general approach and clinical conditions David Jayne Professor of Clinical Autoimmunity, Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK 19.11.7: ANCA-​associated vasculitis; 21.10.2: The kidney in systemic vasculitis Susan Jebb Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK 26.6.2: Obesity and weight management Katie J.M. Jeffery Oxford University Hospitals NHS Foundation Trust, Department of Microbiology, John Radcliffe Hospital, Oxford, UK 8.5.22: Hepatitis C virus Rajesh Jena Cambridge University Hospitals, Cambridge, UK 5.6: Systemic treatment and radiotherapy Tom Jenkins University of Sheffield, Sheffield, UK 24.15: The motor neuron diseases Jørgen Skov Jensen Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark 8.6.46: Mycoplasmas Vivekanand Jha Executive Director, The George Institute for Global Health, New Delhi, India; Professor of Nephrology, University of Oxford, Oxford, UK 21.11: Renal diseases in the tropics Tingliang Jiang Professor, Department of Pharmacology, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine Alexis J. Joannides University of Cambridge, Cambridge, UK 3.7: Stem cells and regenerative medicine Anne M. Johnson Centre for Molecular Epidemiology and Translational Research, Institute for Global Health, University College London, London, UK 9.2: Sexual behaviour

Contributors

Colin Johnson Emeritus Professor of Surgical Sciences,

University of Southampton, Southampton, UK 15.15: Diseases of the gallbladder and biliary tree M.R. Johnson Professor of Neurology and Genomic Medicine, Faculty of Medicine, Department of Brain Sciences, Imperial College, London, UK 24.5.1: Epilepsy in later childhood and adulthood Elaine Jolly University of Cambridge, Cambridge, UK 30.1: Acute medical presentations; 30.2: Practical procedures D. Joly Necker-​Enfants Malades Hospital, Paris, France 21.12: Renal involvement in genetic disease Bryony Jones Imperial College Hospital, London, UK 14.10: Diabetes in pregnancy David E.J. Jones Institute of Cellular Medicine, Newcastle University and Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK 15.23.3: Primary biliary cholangitis Bouke de Jong Institute of Tropical Medicine, Antwerp, Belgium 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection Menno De Jong Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 24.11.2: Viral infections Iain Jordan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.5.13: Personality disorders Emil Kakkis Ultragenyx Pharmaceutical Inc., Novato, CA, USA 2.9: Engaging patients in therapeutic development Philip A. Kalra Consultant and Honorary Professor of Nephrology, Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, UK 16.5.4 Cardiorenal syndrome; 21.10.10: Atherosclerotic renovascular disease Eileen Kaner Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption Theodoros Karamitos Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Niki Karavitaki Queen Elizabeth Hospital, Birmingham, UK 13.2.1: Disorders of the anterior pituitary gland; 13.2.2: Disorders of the posterior pituitary gland Steven B. Karch Consultant in Cardiac Pathology and Toxicology, Berkeley, CA, USA 27.1: Forensic and legal medicine Fiona E. Karet Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 21.15: The renal tubular acidoses Arthur Kaser Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK 15.5: Immune disorders of the gastrointestinal tract

†

David Kavanagh Institute of Genetic Medicine,

Newcastle University, Newcastle upon Tyne, UK 21.10.6: Haemolytic uraemic syndrome Fiona Kearney Nottingham University Hospitals Trust, Nottingham, UK 6.8: Falls, faints, and fragility fractures David Keeling Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK 16.16.2: Therapeutic anticoagulation Andrew Kelion Oxford University Hospitals NHS Foundation Trust, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Julia Kelly Royal Brompton and Harefield NHS Trust, London, UK 18.5.2: Sleep-​related breathing disorders Paul Kelly Professor of Tropical Gastroenterology, Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK; TROPGAN Group, Department of Internal Medicine, University of Zambia School of Medicine, Lusaka, Zambia 8.8.6: Cyclospora and cyclosporiasis David P. Kelsell London Medical School, London, UK 23.3: Inherited skin disease Samuel Kemp Royal Brompton Hospital, London, UK 18.2: The clinical presentation of respiratory disease Christopher Kennard Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.1: Introduction and approach to the patient with neurological disease; 24.6.1: Visual pathways Richard S.C. Kerr Oxford University Hospitals NHS Foundation Trust, Oxford, UK 24.11.3: Intracranial abscesses Satish Keshav† Department of Gastroenterology, Oxford University Hospitals NHS Foundation Trust, Oxford; Professor of Gastroenterology, Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.1: Structure and function of the gastrointestinal tract Nigel S. Key Harold R. Roberts Professor of Medicine, Division of Hematology-​Oncology, University of North Carolina, Chapel Hill, NC, USA 22.7.1: The biology of haemostasis and thrombosis Rajesh K. Kharbanda John Radcliffe Hospital, Oxford, UK 16.13.4: Management of acute coronary syndrome Elham Khatamzas Regional Infectious Diseases Unit, NHS Lothian, Edinburgh, UK 8.2.4: Infection in the immunocompromised host Peng T. Khaw Professor and Consultant Ophthalmic Surgeon; Director of Research, Development and Innovation; Director, NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK 25.1: The eye in general medicine

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

B. Khoo University College London, London, UK

13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.2: Carcinoid syndrome Nine V.A.M. Knoers Professor in Clinical Genetics, Department of Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands 21.16: Disorders of tubular electrolyte handling Stefan Kölker Consultant, Pediatric Metabolic Medicine, University Children’s Hospital, Heidelberg; Department of General Pediatrics, Division of Inborn Metabolic Diseases, Heidelberg, Germany 12.2 Protein-​dependent inborn errors of metabolism Nils P. Krone University of Sheffield, Sheffield, UK 13.5.2: Congenital adrenal hyperplasia Narong Khuntikeo Director, Cholangiocarcinoma Research Institute (CARI), Director, Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Thailand; Faculty of Medicine, Khon Kaen University, Thailand; Associate Professor, Department of Surgery, Faculty of Medicine, Khon Kaen University, Thailand 8.11.2: Liver fluke infections Gudula Kirtschig Tübingen, Germany 14.13: The skin in pregnancy Suzanne Kite Leeds Teaching Hospitals NHS Trust, Leeds, UK 7.4: Care of the dying person John L. Klein Guy’s and St Thomas’ NHS Foundation Trust, London, UK 16.9.2: Endocarditis Paul Klenerman Nuffield Department of Medicine, University of Oxford, Oxford, UK 4.3: Adaptive immunity; 8.5.22: Hepatitis C virus Richard Knight Department of Microbiology, University of Nairobi, Nairobi, Kenya 8.8.1: Amoebic infections; 8.8.10: Blastocystis infection; 8.9.2: Lymphatic filariasis; 8.9.3: Guinea worm disease (dracunculiasis); 8.9.6: Angiostrongyliasis; 8.10.1: Cestodes (tapeworms) David Koh PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, SSH School of Public Health, National University of Singapore, Singapore 10.2.5: Noise G.C.K.W. Koh Diseases of the Developing World, Alternative Drug Development, GlaxoSmithKline, UK 8.6.8: Pseudomonas aeruginosa M.A. Kokosi Royal Brompton and Harefield NHS Trust, London, UK 18.11.4: The lung in autoimmune rheumatic disorders Onn Min Kon Respiratory Medicine, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK; National Heart and Lung Institute, Imperial College London, London, UK 18.4.4: Mycobacteria

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Contributors

Adelheid Korb-​Pap Institute of Experimental

Musculoskeletal Medicine, University Hospital Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Vasilis Kouranos Royal Brompton and Harefield NHS Trust, London, UK 18.11.3: Bronchiolitis obliterans and cryptogenic organizing pneumonia Christian Krarup Region Hovedstaden, Denmark 24.3.2: Electrophysiology of the central and peripheral nervous systems Amy S. Kravitz United States Agency for International Development (USAID), Washington DC, USA 2.21: Humanitarian medicine Dinakantha S. Kumararatne Depatment of Clinical Immunology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 4.4: Immunodeficiency Om P. Kurmi Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.3.1: Air pollution and health Robert A. Kyle Professor of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA 22.4.6: Plasma cell myeloma and related monoclonal gammopathies Peter L. Labib Clinical Research Fellow, Institute for Liver and Digestive Health, Royal Free Campus, University College London, London, UK 15.16: Cancers of the gastrointestinal tract Charles J.N. Lacey Hull York Medical School, University of York, York, UK 9.7: Anogenital lumps and bumps Helen J. Lachmann Senior Lecturer, National Amyloidosis Centre and Centre for Acute Phase Proteins, University College London Medical School, London, UK 12.12.2: Hereditary periodic fever syndromes Robin H. Lachmann Consultant in Inherited Metabolic Disease, Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK 12.3.1: Glycogen storage diseases Ralph Lainson† Ex Director, the Wellcome Parisitology Unit, and research-worker, Department of Parasitology, Instiuto Evandro Chagas, Rodovia, Barro Levilầndia, Ananindeua, Pará, Brazil 8.8.6: Cyclospora and cyclosporiasis Kin Bong Hubert Lam University of Oxford, Oxford, UK 10.3.1: Air pollution and health D.A. Lane Faculty of Medicine, Department of Medicine, Imperial College London, London, UK 16.4: Cardiac arrhythmias Peter C. Lanyon Nottingham University Hospitals Trust, Nottingham, UK 19.3: Clinical investigation Andrew J. Larner Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.3.1: Lumbar puncture; 24.5.4: Syncope; 24.13.1: Diseases of the spinal cord †

Malcolm Law Wolfson Institute of Preventive

Medicine, St Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary University of London, London, UK 2.12 Medical screening Tim Lawrence Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.10.3: Traumatic brain injury; 24.11.3: Intracranial abscesses Stephen M. Lawrie Division of Psychiatry, University of Edinburgh, Edinburgh, UK 26.5.11: Schizophrenia Alison M. Layton Harrogate and District NHS Foundation Trust, Harrogate, UK 23.11: Sebaceous and sweat gland disorders James W. Le Duc Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX, USA 8.5.16: Bunyaviridae Susannah Leaver St George’s NHS Foundation Trust, London, UK 17.5: Acute respiratory failure Y.C. Gary Lee Faculty of Health and Medical Sciences, UWA Medical School, University of Western Australia, Perth, WA, Australia 18.17: Pleural diseases; 18.19.3 Pleural tumours; 18.19.4 Mediastinal tumours and cysts Haur Yueh Lee National Heart Centre Singapore, Singapore, China; Kings Drugs Reaction Group, King’s College London, London, UK 23.16: Cutaneous reactions to drugs Richard W.J. Lee Director, Uveitis and Scleritis Service, National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, London, UK 25.1: The eye in general medicine Evelyne de Leeuw Centre for Health Equity Training, Research and Evaluation, UNSW Sydney, South Western Sydney Local Health District, Ingham Institute, Australia 2.13: Health promotion Yee-​Sin Leo National Centre for Infectious Disease, Tan Tock Seng Hospital, Singapore; Yong Loo Lin School of Medicine and Saw Swee Hock School of Public Health, National University of Singapore, Singapore; Lee Kong Chian School of Medicine, Singapore 8.5.15: Dengue Phillip D. Levin Intensive Care Unit, Shaare Zedek Medical Center, Jerusalem, Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem, Israel 17.10: Palliative and end-​of-​life care in the ICU Elena N. Levtchenko Professor in Pediatric Nephrology, Catholic University Leuven, Leuven, the Netherlands 21.16: Disorders of tubular electrolyte handling Su Li Department of Epidemiology, Guangxi Medical University, Nanning, Guangxi, China 5.7: Medical management of breast cancer Fulong Liao Professor, Biomechanopharmacology, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine

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

Ted Liao MedStar Georgetown University Hospital

and Georgetown University School of Medicine, Washington DC, USA 26.5.8: Anxiety disorders Oliver Liesenfeld Roche Molecular Systems, Pleasanton, CA, USA 8.8.4: Toxoplasmosis Liz Lightstone, Professor of Renal Medicine, Centre for Inflammatory Disease, Faculty of Medicine, Imperial College London, London, UK 21.10.3: The kidney in rheumatological disorders Wei Shen Lim Consultant Respiratory Physician and Honorary Professor of Medicine, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK 18.4.2: Pneumonia in the normal host; 18.4.3: Nosocomial pneumonia Aldo A.M. Lima Biomedicine Center and Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil 8.6.12: Cholera Gregory Y.H. Lip Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, UK; Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark 16.4: Cardiac arrhythmias; 16.17.5: Hypertensive urgencies and emergencies Mark A. Little Professor of Nephrology and Consultant Nephrologist, Trinity Health Kidney Centre, Trinity College Dublin; Tallaght and Beaumont Hospitals, Dublin, Ireland 21.8.5: Proliferative glomerulonephritis; 21.8.6: Membranoproliferative glomerulonephritis P. Little University of Southampton, Southampton, UK 18.4.1: Upper respiratory tract infections William A. Littler The Priory Hospital, Birmingham, UK 16.9.2: Endocarditis A. Llanos-​Cuentas School of Public Health and Administration, Universidad Peruana Cayetano Heredia, Lima, Peru 8.6.44: Bartonella bacilliformis infection Y.M. Dennis Lo Li Ka Shing Professor of Medicine, Department of Chemical Pathology, The Chinese University of Hong Kong, China 3.9: Circulating DNA for molecular diagnostics Diana N.J. Lockwood London School of Hygiene and Tropical Medicine, London, UK 8.6.28: Leprosy (Hansen’s disease); 8.8.13: Leishmaniasis David A. Lomas Vice Provost (Health) and Head of UCL Medical School, University College London, London, UK 12.13: α1-​Antitrypsin deficiency and the serpinopathies; 15.24.6 Primary and secondary liver tumours Alan Lopez University of Melbourne, Melbourne, Vic, Australia 2.3: The Global Burden of Disease: Measuring the health of populations

Contributors

Constantino López-Macias Mexican Society of

Immunology, Mexico; University of Oxford, Oxford, UK 4.3: Adaptive immunity David A. Low Liverpool John Moores University, Liverpool, UK 24.14: Diseases of the autonomic nervous system Elyse E. Lower University of Cincinnati Medical Center, Cincinnati, OH, USA 18.12: Sarcoidosis Katharine Lowndes Department of Haematology, Royal Hampshire County Hospital, Winchester UK 14.17: Blood disorders in pregnancy Angela K. Lucas-​Herald School of Medicine, University of Glasgow, Royal Hospital for Children, Glasgow, UK 13.7.3: Normal and abnormal sexual differentiation Ingrid E. Lundberg Rheumatology Unit, Department of Medicine, Sloan, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden 19.11.5: Inflammatory myopathies James R. Lupski Department of Molecular and Human Genetics, Department of Pediatrics, Human Genome Sequencing Center, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA 3.2: The genomic basis of medicine Raashid Luqmani Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford Rheumatology Department, Nuffield Orthopaedic Centre, Oxford, UK 19.11.6: Large vessel vasculitis Linda Luxon National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London, UK 24.6.3: Hearing loss Jean Paul Luzio Cambridge Institute for Medical Research, Cambridge, UK 3.1: The cell Lucio Luzzatto Department of Haematology, Muhimbili University of Health and Allied Sciences Dar es Salaam, Tanzania 22.5.3: Paroxysmal nocturnal haemoglobinuria; 22.6.11: Glucose-​6-​phosphate dehydrogenase deficiency Graz A. Luzzi Wycombe General Hospital, High Wycombe, UK 9.3: Sexual history and examination Kate D. Lynch Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford; Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.23.4: Primary sclerosing cholangitis David Mabey Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta; 8.6.45: Chlamydial infections; 9.1: Epidemiology of sexually transmitted infections Peter K. MacCallum Senior Lecturer in Haematology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK 14.7: Thrombosis in pregnancy

Alasdair MacGowan Department of Medical

Microbiology, North Bristol NHS Trust, Bristol, UK 8.2.5: Antimicrobial chemotherapy Lucy Mackillop Obstetric Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 14.20 Prescribing in pregnancy Gael M. MacLean Oxford University Hospitals NHS Foundation Trust, Oxford, UK 13.6.3: Benign breast disease Kenneth T. MacLeod National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, London, UK 16.1.2: Cardiac physiology Alasdair MacLullich Edinburgh University, Edinburgh, UK 6.5: Older people in hospital Jane Macnaughtan Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK 15.22.5: Liver failure Robert Mactier Consultant Nephrologist, Glasgow Renal and Transplant Unit, South Glasgow University Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK 21.7.1: Haemodialysis C. Maguiña-​Vargas School of Medicine, Universidad Peruana Cayetano Heredia, Lima, Peru 8.6.44: Bartonella bacilliformis infection Michael Maher Professor of Radiology, University College Cork and Consultant Radiologist, Cork University Hospital and Mercy University Hospital, Cork, Ireland 15.3.3: Radiology of the gastrointestinal tract Malegapuru W. Makgoba National Health Ombud, Pretoria, South Africa; College of Health Science, University of KwaZulu-​Natal, Durban, South Africa; National Planning Commission of South Africa; Universities of Natal and KwaZulu-​Natal, Durban, South Africa; MRC (SA), Cape Town, South Africa 2.18: Fostering medical and health research in resource-​constrained countries Govind K. Makharia Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India 15.10.8: Malabsorption syndromes in the tropics Hadi Manji The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK 24.11.4: Neurosyphilis and neuro-​AIDS J.I. Mann Edgar Diabetes and Obesity Research Centre (EDOR), Department of Human Nutrition, University of Otago, Dunedin, New Zealand 11.5: Diseases of affluent societies and the need for dietary change David Mant University of Oxford, Oxford, UK 2.11: Preventive medicine G.A. Margaritopoulos Royal Brompton and Harefield NHS Trust, London, UK 18.11.5: The lung in vasculitis

Anthony M. Marinaki Purine Research Laboratory,

Viapath, St Thomas’ Hospital, London, UK 12.4: Disorders of purine and pyrimidine metabolism Chiara Marini-​Bettolo Newcastle University John Walton Centre for Muscular Dystrophy Research, Newcastle upon Tyne Hospital NHS Foundation Trust, Institute of Genetic Medicine, International Centre for Life, Newcastle upon Tyne, UK 24.19.2: Muscular dystrophy Michael Marks Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta Paul Marks Honorary Consultant Neurosurgeon, Harrogate District Hospital, Harrogate; Her Majesty’s Senior Coroner for the City of Kingston upon Hull and the County of the East Riding of Yorkshire; Vice President, Faculty of Forensic and Legal Medicine, London, UK; Honorary Professor of Neurosurgery, College of Medicine, University of Malawi, Malawi 27.1: Forensic and legal medicine Thomas J. Marrie Department of Medicine, Dalhousie University, Nova Scotia, Canada 8.6.42: Coxiella burnetii infections (Q fever) Judith C.W. Marsh King’s College Hospital, King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Sara Marshall Wellcome Trust, London, UK 4.4: Immunodeficiency Steven B. Marston National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, UK 16.1.2: Cardiac physiology Maria do Rosario O. Martins University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health Thiviyani Maruthappu Kelsell Group, Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London, Queen Mary University of London, London, UK 23.3: Inherited skin disease Duncan J. Maskell University of Cambridge, Cambridge, UK 8.1.1: Biology of pathogenic microorganisms N.A. Maskell Academic Respiratory Unit, University of Bristol, UK 18.17: Pleural diseases Jay W. Mason Cardiology Division, University of Utah College of Medicine, Salt Lake City, UT, USA 16.7.1: Myocarditis Tahir Masud Nottingham University Hospitals Trust, Nottingham, UK 6.8: Falls, faints, and fragility fractures Christopher J. Mathias Stoke Poges, UK 24.14: Diseases of the autonomic nervous system

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Contributors

Fadi Matta Associate Professor, Department of

Osteopathic Medical Specialties, Collage of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA 16.16.1: Deep venous thrombosis and pulmonary embolism Eric L. Matteson Division of Rheumatology, Divisions of Rheumatology and Epidemiology, Mayo Clinic College of Medicine, Rochester, MN, USA 19.11.11: Polymyalgia rheumatica Kieran McCafferty Consultant Nephrologist, Barts Health NHS Trust, London, UK 21.17: Urinary tract obstruction Fergus McCarthy Division of Women’s Health, Women’s Health Academic Centre KHP, St. Thomas’ Hospital, London, UK 14.4: Hypertension in pregnancy Brian W. McCrindle University of Toronto, Toronto, Canada; The Hospital for Sick Children, Toronto, ON, Canada 19.11.12: Kawasaki disease Theresa A. McDonagh King’s College Hospital, Denmark Hill, London, UK 16.5.1: Epidemiology and general pathophysiological classification of heart failure A.D. McGavigan Flinders University, SA, Australia 16.2.2: Syncope and palpitation; 16.4: Cardiac arrhythmias Fiona McGill Institute of Infection and Global Health, University of Liverpool, Liverpool, UK 24.11.2: Viral infections John A. McGrath Genetic Skin Disease Group, St John’s Institute of Dermatology, King’s College London (Guy’s Campus), London, UK 23.1: Structure and function of skin Alastair McGregor Department of Tropical Medicine and Infectious Diseases, London Northwest Hospitals NHS Trust, London, UK; Department of Medicine, Imperial College London, London, UK 8.11.4: Intestinal trematode infections Jane McGregor Clinical Senior Lecturer and Honorary Consultant Dermatologist, Blizard Institute, Barts and the London School Medicine and Dentistry, London, UK 23.9: Photosensitivity Iain B. McInnes University of Glasgow, Glasgow, UK 3.3: Cytokines C.J. McKay Consultant Pancreaticobiliary Surgeon, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis William J. McKenna The Heart Hospital, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular Curtis McKnight Dignity Health Medical Group; St. Joseph’s Hospital and Medical Center; Creighton University School of Medicine, Phoenix, AZ, USA 26.5.3: Organic psychoses

Alison McMillan East and North Hertfordshire NHS

Trust, Stevenage, UK 18.5.2: Sleep-​related breathing disorders Martin A. McNally The Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford University Hospitals, Oxford, UK 20.3: Osteomyelitis Regina McQuillan St Francis Hospice and Beaumont Hospital, Dublin, Ireland 7.3: Symptoms other than pain Simon Mead MRC Prion Unit, University College London, Institute of Prion Diseases; NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, Queen Square, London, UK 24.11.5: Human prion diseases Jill Meara Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.3.7: Radiation Wajahat Z. Mehal Section of Digestive Diseases Yale University, New Haven, CT, USA 15.21: Pathobiology of chronic liver disease Tobias F. Menne Consultant Haematologist, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK 22.4.2: Acute lymphoblastic leukaemia David K. Menon Division of Anaesthesia, University of Cambridge, UK; Neurosciences Critical Care Unit, Royal College of Anaesthetists, London, UK; Queens’ College, Cambridge, UK; National Institute for Health Research, UK 17.7: Management of raised intracranial pressure Andrew Menzies-​Gow Royal Brompton Hospital, London, UK 18.7: Asthma Catherine H. Mercer Professor of Sexual Health Science, Centre for Population Research in Sexual Health and HIV, Institute for Global Health, University College London, London, UK 9.2: Sexual behaviour Vinod K. Metta Neurology, National Hospital for Neurology and Neurosurgery, University College London, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Jan H. ter Meulen Philipps University Marburg, 35043 Marburg, Germany 8.5.17: Arenaviruses; 8.5.18: Filoviruses Wayne M. Meyers Department of Environmental and Infectious Disease Sciences, Armed Forces Institute of Pathology, Washington DC, USA 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection Paul K. Middleton Clinical Research Fellow, Institute of Liver Studies, Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, UK 15.22.4: Hepatic encephalopathy

Stephen J. Middleton Consultant

Gastroenterologist, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge; Consultant Gastroenterologist (Hon.) St Mark’s Hospital, Harrow, London; Associate Professor (Hon.) Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK 15.10.2: Bacterial overgrowth of the small intestine; 15.10.7: Effects of massive bowel resection Mark E. Mikkelsen Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 17.12: Persistent problems and recovery after critical illness Michael A. Miles Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.8.12: Chagas disease Robert F. Miller University College London, London, UK 8.7.5: Pneumocystis jirovecii Dawn S. Milliner Emeritus Professor of Medicine and Pediatrics at the Mayo Clinic Alix School of Medicine, Rochester, MN, USA 12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias K.R. Mills King’s College London, London, UK 24.3.4: Investigation of central motor pathways: Magnetic brain stimulation Philip Minor National Institute for Biological Standards and Control (NIBSC), Ridge, UK 8.5.8: Enterovirus infections Fraz A. Mir Department of Medicine, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK 16.17.3: Secondary hypertension Pramod K. Mistry Professor of Pediatrics and Medicine, Chief, Pediatric Gastroenterology and Hepatology, Yale School of Medicine, New Haven, CT, USA 12.7.2 Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease Andrew R.J. Mitchell Jersey General Hospital, Jersey, UK 16.3.2: Echocardiography; 16.14.1: Acute aortic syndromes Oriol Mitjà Barcelona Institute for Global Health, University of Barcelona, Spain; Lihir Medical Centre, InternationalSOS, Lihir Island, Papua New Guinea 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta Aarthi R. Mohan Obstetrics and Maternal Medicine, University Hospitals Bristol NHS Foundation Trust, Bristol, UK 14.21: Contraception for women with medical diseases Fiachra Moloney Consultant Radiologist, Department of Radiology, Cork University Hospital, Cork, Ireland 15.3.3: Radiology of the gastrointestinal tract P.L. Molyneaux Royal Brompton and Harefield NHS Trust, London, UK 18.11.2: Idiopathic pulmonary fibrosis

Contributors

Andrew J. Molyneux The Manor Hospital, Oxford, UK

24.3.3: Imaging in neurological diseases Peter D. Mooney Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK 15.10.3: Coeliac disease Anthony V. Moorman Professor of Genetic Epidemiology, Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK 22.4.2: Acute lymphoblastic leukaemia Pilar Morata Department of Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain 8.6.22: Brucellosis Marina S. Morgan Royal Devon and Exeter NHS Foundation Trust, Exeter, UK 8.6.19: Pasteurella Michael L. Moritz Professor of Pediatrics, University of Pittsburgh School of Medicine, Clinical Director, Division of Nephrology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA 21.2.1: Disorders of water and sodium homeostasis Pedro L. Moro Immunization Safety Office, Division of Healthcare Quality Promotion, NCEZID, Centers for Disease Control and Prevention, Atlanta, GA, USA 8.10.2: Cystic hydatid disease (Echinococcus granulosus) Mary J. Morrell Imperial College London, London, UK 18.5.2: Sleep-​related breathing disorders Nicholas W. Morrell British Heart Foundation Professor of Cardiopulmonary Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, UK 16.15.1: Structure and function of the pulmonary circulation; 16.15.2: Pulmonary hypertension Emma C. Morris Professor, Division of Infection and Immunity, UCL Institute of Immunity and Transplantation, Royal Free Campus, Royal Free Hospital, London, UK and Honorary Consultant, University College London Medical School, London, UK 22.8.2: Haemopoietic stem cell transplantation Neil J.McC. Mortensen Professor of Colorectal Surgery, Nuffield Department of Surgery, University of Oxford; Honorary Consultant Colorectal Surgeon, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 15.14: Colonic diverticular disease Peter S. Mortimer St George’s University of London; St George’s Hospital, London; Royal Marsden Hospital, London, UK 16.18: Chronic peripheral oedema and lymphoedema; 23.12: Blood and lymphatic vessel disorders Ghulam J. Mufti King’s College Hospital/​King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Victoria Mulcahy Norwich Medical School, University of East Anglia, Norwich, UK 15.10.1: Differential diagnosis and investigation of malabsorption

David R. Murdoch Professor and Head of

Pathology, University of Otago, Christchurch, New Zealand 10.3.6: Diseases of high terrestrial altitudes Paul Murphy NHS Blood and Transplant, Bristol, UK 17.11: Diagnosis of death and organ donation Christopher Murray University of Washington, WA, USA 2.3: The Global Burden of Disease: Measuring the health of populations Jean B. Nachega Departments of Epidemiology, Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA USA; Department of Medicine, Centre for Infectious Diseases, Stellenbosch University, Tygerberg, Cape Town, South Africa 8.6.26: Tuberculosis Robert B. Nadelman Division of Infectious Diseases, Department of Medicine, New York Medical College, Valhalla, NY, USA 8.6.33: Lyme borreliosis Alexandra Nanzer-​Kelly Guys and St Thomas’ Hospital, London, UK 18.7: Asthma Nikolai V. Naoumov Novartis Pharma, Basel, Switzerland 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Kikkeri N. Naresh Department of Histopathology, Imperial College Healthcare NHS Trust and Imperial College, London, UK 15.10.4: Gastrointestinal lymphomas Kate Nash University Hospital Southampton NHS Foundation Trust, Southampton, UK 15.23.1: Hepatitis A to E N. Navani University College Hospital, London, UK 18.19.1: Lung cancer Catherine Nelson-​Piercy Obstetric Medicine, Women’s Health Academic Centre, King’s Health Partners, King’s College London, London, UK 14.14: Autoimmune rheumatic disorders and vasculitis in pregnancy Randolph M. Nesse Center for Evolution and Medicine, Arizona State University, AZ, USA 2.2: Evolution: Medicine’s most basic science Peter J. Nestor German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany 24.4.1: Disturbances of higher cerebral function Stefan Neubauer Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT James Neuberger Hon Consultant Physician, Liver Unit, Queen Elizabeth Hospital, Birmingham, UK 15.24.5: The liver in systemic disease

James D. Newton Oxford University Hospitals NHS

Trust, Oxford, UK 16.3.2: Echocardiography; 16.14.1: Acute aortic syndromes Paul N. Newton Lao-​Oxford-​Mahosot Hospital-​ Wellcome Trust Research Unit (LOMWRU), Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR; Nuffield Department of Medicine, University of Oxford, Oxford; Infectious Diseases Data Observatory (IDDO), University of Oxford, Oxford, UK 2.10: Medicine quality, physicians, and patients Wan-​Fai Ng Newcastle University and NIHR Newcastle Biomedical, Research Centre for Ageing and Chronic Diseases, Newcastle upon Tyne, UK 19.11.4: Sjögren’s syndrome A.G. Nicholson Royal Brompton and Harefield NHS Trust; Professor of Respiratory Pathology, National Heart and Lung Institute, Imperial College School of Medicine, London, UK 18.11.2: Idiopathic pulmonary fibrosis Jerry P. Nolan Warwick Medical School, Coventry; Royal United Hospital, Bath, UK 17.2: Cardiac arrest John Nowakowski New York Medical College, NY, USA 8.6.33: Lyme borreliosis Paul Nyirjesy Drexel University College of Medicine, Philadelphia, PA, USA 9.4: Vaginal discharge Sarah O’Brien Modelling, Evidence and Policy Group, School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, UK 15.18: Gastrointestinal infections Amy O’Donnell Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption Nigel O’Farrell Ealing Hospital, London North West University Healthcare NHS Trust, London, UK 8.6.14: Haemophilus ducreyi and chancroid John G. O’Grady Institute of Liver Studies, King’s College Hospital, London, UK 15.22.6: Liver transplantation Denis O’Mahony Department of Medicine, University College Cork and Department of Geriatric Medicine, Cork University Hospital, Cork, Ireland 6.7: Drugs and prescribing in the older patient E.E. Ooi Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 8.5.12: Alphaviruses Susie Orme Barnsley Hospital NHS Foundation Trust, Barnsley, UK 6.9: Bladder and bowels Kevin O’Shaughnessy Division of Experimental Medicine and Immunotherapeutics, Department of Medicine, University of Cambridge, Cambridge, UK 2.6: Principles of clinical pharmacology and drug therapy

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Contributors

Edel O’Toole Centre for Cutaneous Research,

Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry; and Department of Dermatology, Barts and the London NHS Trust, London, UK 23.14: Tumours of the skin Petra C.F. Oyston Biomedical Sciences, DSTL Porton Down, Salisbury, UK 8.6.20: Francisella tularensis infection Jacqueline Palace Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.18: Disorders of the neuromuscular junction Thomas Pap Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Jayan Parameshwar Consultant Cardiologist, Royal Papworth Hospital, Cambridge, UK 16.5.5: Cardiac transplantation and mechanical circulatory support Daniel H. Paris University of Oxford, Oxford, UK; Rickettsial Research (Oxford Tropical Network); Mahidol-​Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand 8.6.41: Scrub typhus Sarah Parish Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Mike Parker Ethox Centre, Oxford, UK 1.5: Medical ethics Miles Parkes Consultant Gastroenterologist, Cambridge University Hospitals, Cambridge, UK 15.11: Crohn’s disease Philippe Parola University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Christopher M. Parry Clinical Sciences, Liverpool School of Tropical Medicine, and Institute of Infection and Global Health, University of Liverpool, UK; School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan 8.6.9: Typhoid and paratyphoid fevers Judith Partridge Guys and St Thomas’ Hospitals London, UK 6.6: Supporting older peoples’ care in surgical and oncological services Sant-​Rayn Pasricha MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, UK 22.6.5: Anaemia of inflammation Harnish Patel Academic Geriatric Medicine, University of Southampton, Southampton, UK 6.2: Frailty and sarcopenia Raj Patel Solent NHS Trust, Southampton, UK 9.6: Genital ulceration Sejal Patel Oxford Childrens Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 13.7.2: Normal puberty and its disorders

John Paul SE region, National Infection Service,

Public Health England, UK 8.6.47: A checklist of bacteria associated with infection in humans; 8.12: Non​venomous arthropods Jason Payne-​James Specialist in Forensic and Legal Medicine and Consultant Forensic Physician; Lead Medical Examiner, Norfolk and Norwich University Hospital, Norfolk, UK; Honorary Clinical Professor, William Harvey Research Institute, Queen Mary University of London, UK; Consultant Editor-​in-​Chief, Journal of Forensic and Legal Medicine; Director, Forensic Healthcare Services Ltd, Southminster, UK 27.1: Forensic and legal medicine Sharon J. Peacock University of Cambridge, Cambridge, UK 8.6.8: Pseudomonas aeruginosa; 8.6.16: Melioidosis and glanders Fiona Pearce Clinical Lecturer, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham City Hospital, Nottingham, UK 19.2: Clinical presentation and diagnosis of rheumatological disorders Rupert Pearse Queen Mary University of London, London, UK 17.4: Assessing and preparing patients with medical conditions for major surgery Malik Peiris School of Public Health, The University of Hong Kong, Hong Kong, Special Administrative Region of China 8.5.1: Respiratory tract viruses Neil Pendleton School of Biological Sciences, Faculty Biology Medicine and Health and Manchester Institute for Collaborative Research in Ageing, University of Manchester, Manchester, UK 6.1: Ageing and clinical medicine Hugh Pennington University of Aberdeen, Aberdeen, UK 8.6.7: Enterobacteria and bacterial food poisoning Mark B. Pepys Director, Wolfson Drug Discovery Unit, and Honorary Consultant Physician, National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, University College London, London, UK 12.12.1 The acute phase response and C-​reactive protein; 12.12.3 Amyloidosis Stephen P. Pereira Professor of Hepatology and Gastroenterology, Institute for Liver and Digestive Health, University College London; Consultant Hepatologist and Gastroenterologist, University College Hospital and Royal Free Hospital, London, UK 15.16: Cancers of the gastrointestinal tract; 15.26.3: Tumours of the pancreas Gavin D. Perkins Warwick Medical School, Coventry; Intensive Care Unit, Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK 17.2: Cardiac arrest David J. Perry Previously Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK 14.17: Blood disorders in pregnancy

Hans Persson Swedish Poisons Centre,

Stockholm, Sweden 10.4.3: Poisonous fungi; 10.4.4: Poisonous plants Eskild Petersen Department of Infectious Diseases and Clinical Microbiology, Aarhus University Hospital Skejby, Aarhus, Denmark 8.8.4: Toxoplasmosis L.R. Petersen Director, Division of Vector-borne Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA 8.5.12: Alphaviruses Trevor N. Petney Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Department of Paleontology and Evolution, Organization/​ University State Museum of Natural History, Karlsruhe, Germany 8.11.2: Liver fluke infections Philippa Peto Consultant in Renal and Acute Medicine, Queen Elizabeth Hospital, Lewisham and Greenwich NHS Trust, London, UK 1.6: Clinical decision-​making Richard Peto Nuffield Department of Population Health, University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials; 5.1: Epidemiology of cancer Timothy E.A. Peto Nuffield Department of Clinical Medicine, University of Oxford; John Radcliffe Hospital, Oxford, UK 1.6: Clinical decision-​making; 8.5.23: HIV/​AIDS John D. Pickard University of Cambridge, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Matthew C. Pickering Imperial College London, London, UK 4.2: The complement system Massimiliano di Pietro Senior Clinical Investigator Scientist and Consultant Gastroenterologist, MRC Cancer Unit, University of Cambridge, Hutchison/​MRC Research Centre, Cambridge, UK 15.7: Diseases of the oesophagus Michael R. Pinsky Professor Critical Care Medicine, Bio­engineering, Cardiovascular Disease and Anesthesiology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA 17.6: Circulation and circulatory support in the critically ill Julia Platts University of Cardiff, Cardiff, UK 13.9.1: Diabetes Raymond J. Playford, Professor of Medicine, University of Plymouth, Plymouth, UK; Vice President Research Strategy, Pantheryx Inc., Boulder, CO, USA 15.10.2: Bacterial overgrowth of the small intestine; 15.10.7: Effects of massive bowel resection Michael I. Polkey Royal Brompton and Harefield NHS Trust, London, UK 18.15: Chronic respiratory failure; 18.18 Disorders of the thoracic cage and diaphragm

Contributors

Eleanor S. Pollak Associate Professor of Pathology

and Laboratory Medicine (retired), Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA 22.7.4: Genetic disorders of coagulation Andrew J. Pollard Professor of Paediatric Infection and Immunity at the University of Oxford, Director of the Oxford Vaccine Group, Fellow of St Cross College and Honorary Consultant Paediatrician at the Children’s Hospital, Oxford, UK 10.3.6: Diseases of high terrestrial altitudes Aaron Polliack Emeritus Professor, Hadassah University Hospital and Hebrew University Medical School, Jerusalem, Israel 22.4.5: Chronic lymphocytic leukaemia Allyson M. Pollock Queen Mary University of London, London, UK 2.15: How much should rich countries’ governments spend on healthcare? Cristina Ponte Department of Rheumatology, Hospital de Santa Maria -​CHLN, Lisbon Academic Medical Centre, Lisbon, Portugal; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK 19.11.6: Large vessel vasculitis Kyle J. Popovich Rush University, Chicago, IL, USA 8.6.4: Staphylococci Françoise Portaels Institute of Tropical Medicine, Antwerp, Belgium 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection John B. Porter Professor of Haematology and Consultant Haematologist, University College London Hospitals, London, UK 22.6.4: Iron metabolism and its disorders Stephen Potts Department of Psychological Medicine, Edinburgh Royal Infirmary, Edinburgh, UK 26.5.5: Substance misuse William G. Powderly Division of Infectious Diseases and Institute for Public Health, Washington University in St. Louis, MO, USA 8.7.2: Cryptococcosis Janet Powell Department of Surgery and Cancer, Imperial College, London, UK 16.14.2: Peripheral arterial disease Amy Powers Associate Professor of Pathology, John A Burns School of Medicine, University of Hawaii, Department of Pathology, Honolulu, HI, USA 22.6.12: Acquired haemolytic anaemia Ann M. Powers Centers for Disease Control and Prevention, Atlanta, GA, USA 8.5.12: Alphaviruses Anton Pozniak Department of HIV and GUM, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK 18.4.5: Pulmonary complications of HIV infection Bernard D. Prendergast John Radcliffe Hospital, Oxford, UK 16.9.2: Endocarditis

Michael Prentice School of Microbiology,

University College Cork, Cork, Ireland 8.6.17: Plague: Yersinia pestis; 8.6.18: Other Yersinia infections: Yersiniosis David Price Queen Mary University of London, London, UK 2.15: How much should rich countries’ governments spend on healthcare? Christopher Pugh Nuffield Department of Medicine, University of Oxford, Oxford, UK 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis Meredith Pugh Division of Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA 14.8: Chest diseases in pregnancy Graham Raftery South Tyneside and Sunderland NHS Foundation Trust, Sunderland, UK 19.7: Infection and arthritis Kazem Rahimi The George Institute for Global Health, University of Oxford, Oxford, UK 16.13.2: Coronary heart disease: Epidemiology and prevention Anisur Rahman Centre for Rheumatology, University College London, London, UK 19.11.2: Systemic lupus erythematosus and related disorders Tim Raine IBD Lead and Consultant Gastroenterologist, Cambridge University Hospital, Cambridge, UK 15.11: Crohn’s disease K. Rajappan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 16.2.2: Syncope and palpitation S. Vincent Rajkumar Edward W. and Betty Knight Scripps Professor of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA 22.4.6: Plasma cell myeloma and related monoclonal gammopathies Mary Ramsay Health Protection Agency, London, UK 8.3: Immunization A.C. Rankin Glasgow Royal Infirmary, Glasgow, UK 16.2.2: Syncope and palpitation Didier Raoult University Hospital Institute  Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses; 15.10.6: Whipple’s disease Michael Rawlins Medicines and Healthcare Products Regulatory Agency, London, UK 2.19: Regulation versus innovation in medicine Phillip Read University of New South Wales, Kensington, NSW, Australia 8.6.37: Syphilis Michael C. Reade Burns, Trauma and Critical Care Research Centre, Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, Qld, Australia; Joint Health Command, Australian Defence Force, Canberra, ACT, Australia 17.8: Sedation and analgesia in the ICU Paul J. Reading Department of Sleep Medicine, The James Cook University Hospital, Middlesbrough, UK 24.5.3: Sleep disorders

Jeremy Rees National Hospital for Neurology and

Neurosurgery, London, UK; UCL Institute of Neurology, London, UK 24.23: Paraneoplastic neurological syndromes; 24.10.4: Intracranial tumours P.T. Reid Respiratory Unit, Western General Hospital, Edinburgh, UK 18.13: Pneumoconioses Shelley Renowden North Bristol NHS Trust, Bristol, UK 24.3.3: Imaging in neurological diseases John Richens Research Department of Infection and Population Health, University College London, London, UK 8.6.10: Intracellular klebsiella infections (donovanosis and rhinoscleroma) Alan B. Rickinson Institute for Cancer Studies, University of Birmingham, Birmingham, UK 8.5.3: Epstein–​Barr  virus B.K. Rima Wellcome-​Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK 8.5.5: Mumps: Epidemic parotitis David J. Roberts Radcliffe Department of Medicine, University of Oxford; Department of Haematology, Oxford University Hospitals NHS Trust and NHS Blood and Transplant, Oxford, UK 22.6.3: Anaemia as a challenge to world health Harold R. Roberts Sarah Graham Kenan Professor of Medicine, Division of Hematology-​Oncology, University of North Carolina, Chapel Hill, NC, USA 22.7.1: The biology of haemostasis and thrombosis Irene Roberts Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK 22.5.1: Inherited bone marrow failure syndromes Douglas Robertson Senior Lecturer and Honorary Consultant in Restorative Dentistry, University of Glasgow, Glasgow, UK 15.6: The mouth and salivary glands Marcus Robertson Gastroenterologist and Hepatologist, Monash Health, Vic, Australia; Monash University Department of Medicine, Vic, Australia 15.22.3: Portal hypertension and variceal bleeding Esther Robinson Public Health England, Birmingham, UK 8.6.13: Haemophilus influenzae T.A. Rockall Professor of Colorectal Surgery, University of Surrey; Consultant Colorectal Surgeon, Royal Surrey County Hospital Guildford, UK 15.4.2: Gastrointestinal bleeding Edward Roddy Keele University, Keele, UK 19.10: Crystal-​related arthropathies Simon D. Roger Renal Physician, Conjoint Professor, School of Medicine and Public Health, University of Newcastle, Newcastle; Director, Department of Renal Medicine, Central Coast Local Health District, Gosford, NSW, Australia 21.9.1: Acute interstitial nephritis

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Contributors

Jean-​Marc Rolain IHU Méditerranée Infection,

Marseille, France 8.6.43: Bartonellas excluding B. bacilliformis Pierre Ronco Professor of Renal Medicine, University Pierre et Marie Curie, and Inserm Unit UMR_​S1155, Tenon Hospital, Paris, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Antony Rosen Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 4.6: Autoimmunity Jonathan D.C. Ross University Hospitals Birmingham NHS Trust, Birmingham, UK 9.8: Pelvic inflammatory disease Shannan Lee Rossi Department of Pathology, Center for Biodefense and Emerging Infectious Diseases; Member, Center for Tropical Diseases, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 8.5.14: Flaviviruses excluding dengue Peter M. Rothwell Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.10.1 Stroke: Cerebrovascular disease Simon M. Rushbrook Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK 15.24.6: Primary and secondary liver tumours Nigel Russell Professor of Haematology, Nottingham University, Nottingham, UK 22.3.3: Acute myeloid leukaemia Fiona Ryan Oxford Childrens Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 13.7.2: Normal puberty and its disorders Nikant Sabharwal Department of Cardiology, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Alan D. Salama University College London, London, UK 21.8.5: Proliferative glomerulonephritis Moin Saleem Professor of Paediatric Renal Medicine, University of Bristol Children’s Renal Unit, Bristol Royal Hospital for Children, Bristol, UK 21.8.3: Minimal change nephropathy and focal segmental glomerulosclerosis Hesham A. Saleh Charing Cross Hospital and Royal Brompton Hospital, London; Imperial College London, London, UK 18.6: Allergic rhinitis Susan Salt Trinity Hospice, Blackpool, UK 7.1: Introduction to palliative care Nilesh J. Samani Department of Cardiovascular Sciences, University of Leicester, Leicester, UK 16.17.4: Mendelian disorders causing hypertension Luis G. Sambo University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health David S. Sanders Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK 15.10.3: Coeliac disease

Jeremy Sanderson Department of Gastroenterology,

Guy’s and St Thomas’ NHS Foundation Trust, London, UK 15.12: Ulcerative colitis Vijay G. Sankaran Associate Professor of Pediatrics, Harvard Medical School, Division of Hematology/​Oncology, Boston Children’s Hospital, Dana-​Farber/​Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA 22.6.1: Erythropoiesis Swati Sathe Rutgers New Jersey Medical School, Newark, NJ, USA 24.17: Inherited neurodegenerative diseases Brian P. Saunders Consultant Gastroenterologist, St Mark’s Hospital, North West London Hospitals Trust; Adjunct Professor of Endoscopy, Imperial College London, London, UK 15.3.1: Colonoscopy and flexible sigmoidoscopy Kate E.A. Saunders University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.3.2: Self-​harm; 26.5.7: Bipolar disorder Rana Sayeed Oxford Heart Centre, Oxford University Hospitals NHS Trust, Oxford, UK 16.13.6: Coronary artery bypass and valve surgery John A. Sayer Institute Of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, UK 21.15: The renal tubular acidoses Claire Scampion Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK 6.11: Promotion of dignity in the life and death of older patients Matthew Scarborough Oxford University Hospitals NHS Foundation Trust, Oxford, UK; University of Oxford, Oxford, UK 8.2.3: Nosocomial infections Klaus P. Schaal Institute for Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany 8.6.30: Actinomycoses Michael L. Schilsky Associate Professor of Medicine, Medical Director, Adult Liver Transplant, Yale-​New Haven Transplantation Center, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA 12.7.2: Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease Jonathan M. Schott Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK 24.4.2: Alzheimer’s disease and other dementias Heinz-​Peter Schultheiss Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany 16.7.1: Myocarditis Jane Schwebke University of Alabama at Birmingham, AL, USA 8.8.14: Trichomoniasis Neil Scolding University of Bristol Institute of Clinical Neurosciences, Southmead Hospital, Bristol, UK 24.21: Acquired metabolic disorders and the nervous system; 24.22: Neurological complications of systemic disease

Anthony Scott KEMRI-​Wellcome Trust Research

Programme, Kilifi, Kenya; London School of Hygiene and Tropical Medicine, London, UK 8.6.3: Pneumococcal infections James Scott Imperial College London, London, UK 12.6: Lipid disorders Rebecca Scott Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK 15.9.1: Hormones and the gastrointestinal tract Mårten Segelmark Professor of Nephrology, Department of Clinical Sciences, Lund University and Department of Nephrology Skane University Hospital, Lund, Sweden 21.8.7: Antiglomerular basement membrane disease Julian Seifter Associate Professor of Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, USA 12.11: A physiological approach to acid–base disorders: The roles of ion transport and body fluid compartments Bhuvaneish T. Selvaraj University of Edinburgh, Edinburgh, UK 3.7: Stem cells and regenerative medicine Amartya Sen Harvard University, Cambridge, MA, USA 2.20: Human disasters Arjune Sen Oxford Epilepsy Research Group, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK 24.5.1: Epilepsy in later childhood and adulthood Debasish Sen Occupational Medicine, University of Manchester, UK 10.2.1: Occupational and environmental health Nicholas J. Severs National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, London, UK 16.1.2: Cardiac physiology Pallav L. Shah Imperial College London, London, UK 18.1.1: The upper respiratory tract; 18.1.2: Airways and alveoli; 18.3.3: Bronchoscopy, thoracoscopy, and tissue biopsy Muddassir Shaikh James Cook University Hospital, Middlesbrough, UK 19.7: Infection and arthritis Alena Shantsila University of Liverpool, Liverpool, UK 16.17.5: Hypertensive urgencies and emergencies Susie Shapiro Consultant Haematologist, Oxford University Hospitals NHS Foundation Trust, Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK 22.7.3: Thrombocytopenia and disorders of platelet function Claire C. Sharpe Professor of Renal Medicine, Faculty of Life Sciences and Medicine, King’s College London, London, UK 21.10.7: Sickle cell disease and the kidney

Contributors

Michael Sharpe Psychological Medicine Research,

University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.1: General introduction; 26.2: The psychiatric assessment of the medical patient; 26.3.3: Medically unexplained symptoms; 26.4.2: Psychological treatments; 26.5.12: Somatic symptom and related disorders; 26.7: Psychiatry, liaison psychiatry, and psychological medicine Pamela J. Shaw Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield; Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 24.15: The motor neuron diseases Debbie L. Shawcross Professor of Hepatology and Chronic Liver Failure, Institute of Liver Studies, Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, UK 15.22.4: Hepatic encephalopathy Bart Sheehan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.3.1: Confusion; 26.5.1: Delirium; 26.5.2: Dementia Neil Sheerin Professor of Nephrology, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK 21.13: Urinary tract infection Mark Sherlock General Medicine and Emergency Medicine, NHS, UK; Médecins Sans Frontières (MSF), Paris, France 13.5.1: Disorders of the adrenal cortex Jackie Sherrard Wycombe General Hospital, High Wycombe, UK 8.6.6: Neisseria gonorrhoeae; 9.3: Sexual history and examination M.A. Shikanai-​Yasuda Faculdade Medicina, University of São Paulo (FMUSP), Brazil 8.7.4: Paracoccidioidomycosis Brian Shine Oxford University Hospitals NHS Foundation Trust, Oxford, UK 29.1: The use of biochemical analysis for diagnosis and management John M. Shneerson Papworth Hospital, Papworth Everard, UK 18.18: Disorders of the thoracic cage and diaphragm Volha Shpadaruk Department of Dermatology, University Hospitals of Leicester NHS Trust, Leicester, UK 23.7: Cutaneous vasculitis, connective tissue diseases, and urticaria Joachim Sieper Free University, Berlin, Germany 19.6: Spondyloarthritis and related conditions Udomsak Silachamroon Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand 8.11.3: Lung flukes (paragonimiasis) Leslie Silberstein Director, Transfusion Medicine, Boston Children’s Hospital, Boston, MA, USA 22.6.12: Acquired haemolytic anaemia Jorge Simões University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health †

Alexandra Sinclair Institute of Metabolism and

Systems Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, The Medical School, University of Birmingham, Birmingham, UK 24.10.5: Idiopathic intracranial hypertension Rod Sinclair Department of Dermatology, University of Melbourne, Melbourne, Vic, Australia; Epworth Healthcare, Sinclair Dermatology Investigational Research, Education and Clinical Trials, East Melbourne, Vic, Australia 23.17: Management of skin disease Joseph Sinning Regional Cancer Care Associates, Hartford, CT, USA 22.3.1: Granulocytes in health and disease Thira Sirisanthana Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection J.G.P. Sissons† University of Cambridge School of Clinical Medicine, Cambridge, UK 8.5.2: Herpesviruses (excluding Epstein–​Barr  virus) Paiboon Sithithaworn Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Thailand; Professor Parasitology, Department of Parasitology, Faculty of Medicine, Khon Kaen University, Thailand 8.11.2: Liver fluke infections James R.A. Skipworth Consultant HPB and General Surgeon, Bristol Royal Infirmary, University Hospitals Bristol NHS Trust, Bristol, UK 15.26.3: Tumours of the pancreas Geoffrey L. Smith University of Cambridge, Cambridge, UK 8.5.4: Poxviruses Roger Smyth Department of Psychological Medicine, Edinburgh Royal Infirmary, Edinburgh, UK 26.2: The psychiatric assessment of the medical patient Rosamund Snow† BMJ, Tavistock Square, London, UK 1.3: What patients wish you understood E.L. Snyder Professor, Laboratory Medicine, Yale University Medical School; Director, Transfusion/​ Apheresis/​Tissue/​Cell Processing Services, Yale-​New Haven Hospital, New Haven, CT, USA 22.8.1: Blood transfusion Jasmeet Soar Intensive Care Unit, Southmead Hospital, North Bristol NHS Trust, Bristol, UK 17.2: Cardiac arrest May Ching Soh Silver Star Unit, Women’s Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 14.14: Autoimmune rheumatic disorders and vasculitis in pregnancy Elisaveta Sokolov Kings College Hospital, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Tom Solomon Institute of Infection and Global Health, University of Liverpool, Liverpool, UK 24.11.2: Viral infections

Krishna Somers Royal Perth Hospital, Perth, WA,

Australia 16.9.4: Cardiovascular syphilis Danielle Southerst NYU Langone Health, New York, NY, USA 19.4: Back pain and regional disorders Cathy Speed Consultant in Rheumatology, Sport and Exercise Medicine, Senior Physician, English Institute of Sport, Cambridge Centre for Health and Performance, Cambridge, UK 28.1: Sport and exercise medicine Des Spence Barclay Medical Centre, Maryhill Health Centre, Glasgow, UK 1.4: Why do patients attend and what do they want from the consultation? G.P. Spickett Regional Department of Immunology, Royal Victoria Infirmary, Newcastle upon Tyne, UK 18.14.1: Diffuse alveolar haemorrhage; 18.14.2: Eosinophilic pneumonia; 18.14.4: Hypersensitivity pneumonitis S.G. Spiro University College Hospital, London, UK 18.19.1: Lung cancer; 18.19.2: Pulmonary metastases David P. Steensma Institute Physician, Division of Hematologic Malignancies, Department of Medical Oncology, Dana-​Farber Cancer Institute; Associate Professor of Medicine, Harvard Medical School, Boston, MA, USA 22.3.2: Myelodysplastic syndromes Jerry L. Spivak Hematology Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA 22.3.7: Primary myelofibrosis Charles L. Sprung Department of Anesthesiology, Critical Care Medicine and Pain Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem, Israel 17.10: Palliative and end-​of-​life care in the ICU Paweł Stankiewicz Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 3.2: The genomic basis of medicine Natalie Staplin Clinical Trial Service Unit, University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Paul D. Stein Professor, Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA 16.16.1: Deep venous thrombosis and pulmonary embolism Chris Stenton Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK 18.14.11: Toxic gases and aerosols Dennis L. Stevens Infectious Diseases Section, VA Medical Center, Boise, ID, USA 8.6.2: Streptococci and enterococci; 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections Claire Steves King’s College London, London, UK 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.

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Contributors

Carmel B. Stober University of Cambridge,

Cambridge, UK 19.8: Reactive arthritis Nicole Stoesser Nuffield Department of Medicine Medical Sciences Division, University of Oxford, Oxford, UK 8.6.10: Intracellular klebsiella infections (donovanosis and rhinoscleroma) John R. Stradling Oxford Centre for Respiratory Medicine, John Radcliffe Hospital, Oxford, UK 18.1.1: The upper respiratory tract Michael A. Stroud Department of Medicine, University of Southampton, Southampton, UK 10.3.2: Heat; 10.3.3: Cold Michael Strupp Ludwig Maximilians University, Munich, Germany 24.6.2: Eye movements and balance Matthew J. Stuckey School of Veterinary Medicine, University of California, CA, USA 8.6.43: Bartonellas excluding B. bacilliformis Peter H. Sugden National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, UK 16.1.2: Cardiac physiology Mehrunisha Suleman Ethox Centre, Oxford, UK 1.5: Medical ethics Joseph Sung Professor of Medicine, lately President and Vice Chancellor, The Chinese University of Hong Kong, Shatin, Hong Kong, China 15.8: Peptic ulcer disease Khuanchai Supparatpinyo Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection Erik R. Swenson VA Puget Sound Health Care System, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA 10.3.6: Diseases of high terrestrial altitudes Anthony Swerdlow The Institute of Cancer Research, University of London, London, UK 5.1: Epidemiology of cancer David Taggart University of Oxford, Oxford, UK 16.13.6: Coronary artery bypass and valve surgery Kathy Taghipour The Whittington Health NHS Trust, London, UK 23.4: Autoimmune bullous diseases Penelope Talelli Homerton University Hospitals NHS Trust, UK 24.7.1: Subcortical structures: The cerebellum, basal ganglia, and thalamus Paolo Tammaro Associate Professor, Department of Pharmacology, University of Oxford, Oxford, UK 3.4: Ion channels and disease C.T. Tan University of Malaya, Kuala Lumpur, Malaysia 8.5.7: Nipah and Hendra virus encephalitides

Chen Sabrina Tan Harvard Medical School, Boston,

MA, USA 8.5.19: Papillomaviruses and polyomaviruses T.M. Tan Consultant in Diabetes, Endocrinology, and Metabolic Medicine, Imperial College London, London, UK 13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.1: Hormones and the gastrointestinal tract; 15.9.2: Carcinoid syndrome David Taylor-​Robinson Section of Retrovirology and GU Medicine, Department of Infectious Diseases, Wright-​Fleming Institute, Faculty of Medicine, Imperial College London, London, UK 8.6.45: Chlamydial infections; 8.6.46: Mycoplasmas F. Teo National University Hospital, National University Health System, Singapore, China 18.11.1: Diffuse parenchymal lung disease: An introduction R.V. Thakker Academic Endocrine Unit, University of Oxford, OCDEM, Churchill Hospital, Oxford, UK 13.4: Parathyroid disorders and diseases altering calcium metabolism Nishanthi Thalayasingam Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 2.7: Biological therapies for immune, inflammatory, and allergic diseases Richard J. Thompson Professor of Molecular Hepatology, Institute of Liver Studies, King’s College London, London, UK 15.24.7: Liver and biliary diseases in infancy and childhood S.A. Thorne University Hospital, Birmingham, UK 16.12: Congenital heart disease in the adult Guy E. Thwaites Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam 24.11.1: Bacterial infections C. Louise Thwaites Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.6.23: Tetanus Adam D. Timmis Barts Heart Centre, Queen Mary University London, London, UK 16.13.3: Management of stable angina Stephen M. Tollman University of the Witwatersrand, Johannesburg, South Africa; MRC/​Wits Rural Public Health and Health Transitions Research Unit, School of Public Health, Faculty of Health Sciences; INDEPTH Network (International Network for the Demographic Evaluation of Populations and Their Health), Accra, Ghana, South Africa; Centre for Global Health Research, Umeå University, Sweden 2.18: Fostering medical and health research in resource-​constrained countries Maciej Tomaszewski Division of Cardiovascular Sciences, University of Manchester, Manchester, UK 16.17.4: Mendelian disorders causing hypertension

Charles Tomson Consultant Nephrologist,

Freeman Hospital, Newcastle upon Tyne, UK 21.13: Urinary tract infection Pat Tookey Honorary Associate Professor, Population, Policy and Practice Research and Teaching Department, University College London Institute of Child Health, London, UK 8.5.13: Rubella Peter Topham Consultant Nephrologist, John Walls Renal Unit, University Hospitals of Leicester NHS Trust, Leicester, UK 21.8.2: Thin membrane nephropathy Nicholas Torpey Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK 21.7.3: Renal transplantation Thomas A. Traill Division of Cardiology, Johns Hopkins Hospital, Baltimore, MD, USA 16.10: Tumours of the heart; 16.11: Cardiac involvement in genetic disease A.S. Truswell University of Sydney, Sydney, NSW, Australia 11.5: Diseases of affluent societies and the need for dietary change Steven Tsui Consultant Cardiac Surgeon, Royal Papworth Hospital, Cambridge, UK 16.5.5: Cardiac transplantation and mechanical circulatory support Youyou Tu Professor, Department of Chemistry, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine D.M. Turnbull Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK 24.19.5: Mitochondrial disease A. Neil Turner Professor of Nephrology, University of Edinburgh, Queen’s Medical Research Institute (CIR), Edinburgh, UK 21.10.8: Infection-​associated nephropathies; 21.10.9: Malignancy-​associated renal disease Tabitha Turner-​Stokes MRC Clinical Research Fellow, Centre for Inflammatory Disease, Department of Medicine, Imperial College London, London, UK 21.8.6: Membranoproliferative glomerulonephritis Holm H. Uhlig Translational Gastroenterology Unit and Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Oxford, UK 15.15: Congenital abnormalities of the gastrointestinal tract Magnus Unemo WHO Collaborating Centre for Gonorrhoea and other STIs, Örebro University Hospital, Örebro, Sweden 8.6.6: Neisseria gonorrhoeae; 8.6.45 Chlamydial infections Robert Unwin Department of Renal Medicine, University College London, London, UK 21.1: Structure and function of the kidney

Contributors

John A. Vale National Poisons Information Service

(Birmingham Unit) and West Midlands Poisons Unit; City Hospital, Birmingham; School of Biosciences, University of Birmingham, Birmingham, UK 10.4.1: Poisoning by drugs and chemicals Patrick Vallance GlaxoSmithKline, London, UK 16.1.1: Blood vessels and the endothelium Greet Van den Berghe Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University, B-​3000 Leuven, Belgium 17.9: Metabolic and endocrine changes in acute and chronic critical illness Steven Vanderschueren Leuven Research Department of Microbiology, Immunology and Transplantation, Laboratory for Clinical Infectious and Inflammatory Disorders, Clinical Department of General Internal Medicine, University Hospital Leuven, B-​3000 Leuven, Belgium 8.2.2: Fever of unknown origin Sirivan Vanijanonta Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand 8.11.3: Lung flukes (paragonimiasis) Anita Vas-​Falcao London School of Hygiene and Tropical Medicine, London, UK 9.1: Epidemiology of sexually transmitted infections Nikos Vasilakis Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 8.5.14: Flaviviruses excluding dengue Diana Vassallo Specialist Registrar, Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, UK 21.10.10: Atherosclerotic renovascular disease Birgitte Vennervald Section for Parasitology and Aquatic Diseases, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 8.11.1: Schistosomiasis Vanessa Venning Department of Dermatology, Churchill Hospital, Oxford, UK 23.2: Clinical approach to the diagnosis of skin disease Anilrudh A. Venugopal Los Angeles, CA, USA 8.6.11: Anaerobic bacteria Kristien Verdonck Institute of Tropical Medicine, Antwerp, Belgium 8.5.25: HTLV-​1, HTLV-​2, and associated diseases Christopher M. Verity Addenbrookes Hospital, Cambridge, UK 24.20: Developmental abnormalities of the central nervous system Benjamin A. Vervaet Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium 21.9.2: Chronic tubulointerstitial nephritis †

Diego Viasus Division of Health Sciences, Faculty of

Medicine, Universidad del Norte, Barranquilla, Colombia 8.6.39: Legionellosis and Legionnaires’ disease Angela Vincent Hon Cons Immunology, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK 24.24: Autoimmune encephalitis and Morvan’s syndrome Raphael P. Viscidi Johns Hopkins Medical Institution, Baltimore, MD, USA 8.5.19: Papillomaviruses and polyomaviruses H. Josef Vormoor Clinical Director, Department of Hemato-​oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands 22.4.2: Acute lymphoblastic leukaemia Theo Vos University of Washington, WA, USA 2.3: The Global Burden of Disease: Measuring the health of populations Henry J.C. de Vries Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands 9.7: Anogenital lumps and bumps Paresh Vyas Professor of Haematology, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford; Consultant Haematologist, Department of Haematology, Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 22.2.1: Cellular and molecular basis of haematopoiesis Peter D. Wagner Division of Physiology at the Department of Medicine, University of California San Diego, CA, USA 18.1.2: Airways and alveoli Nicholas Wald Institute of Health Informatics, University College London, London; Population Health Research Institute, St George’s University of London, London; Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University, Rhode Island, USA 2.12: Medical screening Herman Waldmann Sir William Dunn School of Pathology, University of Oxford, Oxford, UK 3.8: The evolution of therapeutic antibodies Jane Walker Psychological Medicine Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.2: The psychiatric assessment of the medical patient; 26.3.4: Low mood Matthew C. Walker National Hospital of Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London, UK 24.5.2: Narcolepsy Elizabeth Wallin Transplant Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 4.7: Principles of transplantation immunology Sarah Walsh King’s College Hospital, London, UK 23.16: Cutaneous reactions to drugs

T.E. Warkentin Professor, Department of Pathology and

Molecular Medicine and Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada 22.7.5: Acquired coagulation disorders David A. Warrell Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 8.5.10: Rhabdoviruses: Rabies and rabies-​related lyssaviruses; 8.5.11: Colorado tick fever and other arthropod-​borne reoviruses; 8.5.27: Orf and Milker’s nodule; 8.5.28: Molluscum contagiosum; 8.6.34: Relapsing fevers; 8.13: Pentastomiasis (porocephalosis, linguatulosis/​linguatuliasis, or tongue worm infection); 10.4.2: Injuries, envenoming, poisoning, and allergic reactions caused by animals; 10.4.3: Poisonous fungi; 24.11.2: Viral infections Mary J. Warrell Oxford Vaccine Group, University of Oxford, Oxford, UK 8.5.10: Rhabdoviruses: Rabies and rabies-​related lyssaviruses; 8.5.11: Colorado tick fever and other arthropod-​borne reoviruses John A.H. Wass University of Oxford, Oxford, UK 13.2.1: Disorders of the anterior pituitary gland; 13.2.2: Disorders of the posterior pituitary gland; 13.10: Hormonal manifestations of non-​endocrine disease Lawrence Waterman Loughborough University, Loughborough, UK; Park Health and Safety Partnership, Aylesbury, UK 10.2.2: Occupational safety Laurence Watkins The National Hospital for Neurology and Neurosurgery, London, UK 24.10.3: Traumatic brain injury Peter Watkinson Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 8.1.2: Clinical features and general management of patients with severe infections Richard A. Watts Department of Rheumatology, Ipswich Hospital, Ipswich; Norwich Medical School, University of East Anglia, Norwich, UK 19.11.9: Small vessel vasculitis Richard W.E. Watts† Division of Inherited Metabolic Diseases, Northwick Park Hospital, London, UK 12.1: The inborn errors of metabolism: general aspects; 12.4: Disorders of purine and pyrimidine metabolism David J. Weatherall† Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK 22.6.2: Anaemia: Pathophysiology, classification, and clinical features; 22.6.3: Anaemia as a challenge to world health; 22.6.7: Disorders of the synthesis or function of haemoglobin G.J. Webb Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK 15.23.2: Autoimmune hepatitis Lisa J. Webber St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK 13.6.1: Ovarian disorders George J. Webster Consultant Hepatologist and Gastroenterologist, University College Hospital and Royal Free Hospital, London, UK 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.

lxv

lxvi

Contributors

Anthony P. Weetman University of Sheffield,

Sheffield, UK 13.3.1: The thyroid gland and disorders of thyroid function; 13.3.2: Thyroid cancer Robert A. Weinstein Rush University, Chicago, IL, USA 8.6.4: Staphylococci Louis M. Weiss Department of Pathology, Division of Parasitology and Tropical Medicine; Department of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, NY, USA 8.7.7: Microsporidiosis; 8.8.7: Cystoisosporiasis Robin A. Weiss University College London, London, UK 8.5.26: Viruses and cancer Peter F. Weller William Bosworth Castle Professor of Medicine, Harvard Medical School, Boston; Chief of the Infectious Diseases and the Allergy and Inflammation Divisions, Beth Israel Deaconess Medical Center, Boston, MD, USA 22.3.8: Eosinophilia A.U. Wells Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK 18.11.1: Diffuse parenchymal lung disease: An introduction; 18.11.2: Idiopathic pulmonary fibrosis; 18.11.3: Bronchiolitis obliterans and cryptogenic organizing pneumonia; 18.11.4: The lung in autoimmune rheumatic disorders; 18.11.5: The lung in vasculitis Simon Wessely Department of Psychological Medicine, King’s College London, London, UK 26.4.2: Psychological treatments Gilbert C. White, II Aster Chair for Medical Research, Executive Vice President for Research, Director, Blood Research Institute, Versiti; Professor of Medicine, Biochemistry, and Pharmacology, Associate Dean for Research, Medical College of Wisconsin, Milwaukee, WI, USA 22.7.1: The biology of haemostasis and thrombosis Nicholas J. White Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.8.2: Malaria Hilton C. Whittle Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.5.6: Measles Anthony S. Wierzbicki Department of Metabolic Medicine/​Chemical Pathology, Guy’s and St Thomas’ Hospitals, London, UK 12.9: Disorders of peroxisomal metabolism in adults Mark H. Wilcox Professor of Medical Microbiology, Microbiology, Old Medical School, Leeds General Infirmary, and University of Leeds, Leeds, UK 8.6.24: Clostridium difficile Kate Wiles Department of Women and Children’s Health, King’s College London, London, UK 14.5: Renal disease in pregnancy James S. Wiley Principal Research Fellow, Florey Institute of Neuroscience, and Mental Health Honorary Professor, University of Melbourne, Melbourne, Vic, Australia 22.6.8: Anaemias resulting from defective maturation of red cells

R.G. Will Professor of Clinical Neurology,

Department of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK 24.11.5: Human prion diseases Lisa Willcocks Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK 21.8.3: Minimal change nephropathy and focal segmental glomerulosclerosis Bryan Williams University College London, London, UK 16.17.1: Essential hypertension: Definition, epidemiology, and pathophysiology; 16.17.2: Essential hypertension: Diagnosis, assessment, and treatment David J. Williams Obstetric Physician, Institute for Women’s Health, University College London Hospital, London, UK 14.1: Physiological changes of normal pregnancy; 14.2: Nutrition in pregnancy; 14.3: Medical management of normal pregnancy Catherine Williamson Professor of Women’s Health, King’s College London and Honorary Consultant in Obstetric Medicine, St Thomas’ and King’s College Hospitals, London, UK 14.9: Liver and gastrointestinal diseases of pregnancy Bridget Wills Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.5.15: Dengue; 24.11.2: Viral infections R. Wilson Royal Brompton and Harefield NHS Trust, London, UK 18.9: Bronchiectasis Greg Winter MRC Laboratory of Molecular Biology, Cambridge, UK 3.8: The evolution of therapeutic antibodies Miles Witham AGE Research Group, NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle upon Tyne Hospitals Trust, Newcastle upon Tyne, UK 6.7: Drugs and prescribing in the older patient Fenella Wojnarowska Nuffield Department of Medicine, University of Oxford, Oxford, UK 14.13: The skin in pregnancy; 23.4: Autoimmune bullous diseases Edwin K.S. Wong Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK 21.10.6: Haemolytic uraemic syndrome James L.N. Wood University of Cambridge, Cambridge, UK 8.1.1: Biology of pathogenic microorganisms Jonathan Wood Substance Misuse Psychiatry, Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK 26.5.4: Alcohol misuse Kathryn J. Wood Transplant Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 4.7: Principles of transplantation immunology Nicholas Wood University College London, London, UK 24.7.4: Ataxic disorders

Andrew F. Woodhouse Department of Infection

and Tropical Medicine, Birmingham Heartlands Hospital, Birmingham, UK 8.6.32: Rat bite fevers (Streptobacillus moniliformis and Spirillum minus infection) Jeremy Woodward Cambridge Intestinal Failure and Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 11.7: Artificial nutrition support; 15.2: Symptoms of gastrointestinal disease Elaine M. Worcester Professor of Medicine, Nephrology Section, Department of Medicine, University of Chicago, Chicago, USA 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis B. Paul Wordsworth Emeritus Professor of Clinical Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Headington, Oxford, UK 20.1: Skeletal disorders—​general approach and clinical conditions Gary P. Wormser New York Medical College, NY, USA 8.6.33: Lyme borreliosis Mark Wright Consultant Gastroenterologist, University Hospital Southampton, Southampton, UK 15.25: Diseases of the gallbladder and biliary tree Channa Jayasumana Faculty of Medicine, Rajatrata University of Sri Lanka, Anuradhapura, Sri Lanka 21.9.2: Chronic tubulointerstitial nephritis Muhammad M. Yaqoob Barts Health NHS Trust, Renal Unit, Royal London Hospital, London, UK 21.17: Urinary tract obstruction Hasan Yazici Department of Medicine (Rheumatology), Academic Hospital, Istanbul, Turkey 19.11.10: Behçet’s syndrome Lam Minh Yen Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.6.23: Tetanus Duncan Young Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 8.1.2: Clinical features and general management of patients with severe infections Katherine Younger School of Biological and Health Sciences, Technological University Dublin, Dublin, Ireland 11.3: Minerals and trace elements Sebahattin Yurdakul Division of Rheumatology, Department of Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey 19.11.10: Behçet’s syndrome Alberto Zanella Oncohematology Unit—​ Pathophysiology of Anemias Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore, Milan, Italy 22.6.10: Erythrocyte enzymopathies Adam Zeman Professor of Cognitive and Behavioural Neurology, University of Exeter Medical School, Exeter, UK 24.2: Mind and brain: Building bridges between neurology, psychiatry, and psychology Clive S. Zent University of Rochester Medical Center, Rochester, NY, USA 22.4.5: Chronic lymphocytic leukaemia

SECTION 10

Environmental medicine, occupational medicine, and poisoning Section editor: Jon G. Ayres

10.1 Environmental medicine, occupational medicine, and poisoning—Introduction   1637 Jon G. Ayres

10.2 Occupational health   1638 10.2.1 Occupational and environmental health  1638

Raymond Agius and Debasish Sen 10.2.2 Occupational safety  1652

Lawrence Waterman and Michelle Twigg 10.2.3 Aviation medicine  1656

Michael Bagshaw 10.2.4 Diving medicine  1664

David M. Denison and Mark A. Glover 10.2.5 Noise  1671

David Koh and Tar-Ching Aw 10.2.6 Vibration  1673

Tar-Ching Aw

10.3 Environment and health   1677 10.3.1 Air pollution and health  1677

Om P. Kurmi, Kin Bong Hubert Lam, and Jon G. Ayres 10.3.2 Heat  1687

Michael A. Stroud 10.3.3 Cold  1689

Michael A. Stroud 10.3.4 Drowning  1691

Peter J. Fenner

10.3.5 Lightning and electrical injuries  1696

Chris Andrews 10.3.6 Diseases of high terrestrial altitudes  1701

Tyler Albert, Erik R. Swenson, Andrew J. Pollard, Buddha Basnyat, and David R. Murdoch 10.3.7 Radiation  1709

Jill Meara 10.3.8 Disasters: Earthquakes, hurricanes, floods, and

volcanic eruptions  1713 Peter J. Baxter 10.3.9 Bioterrorism  1718

Manfred S. Green

10.4 Poisoning   1725 10.4.1 Poisoning by drugs and chemicals  1725

John A. Vale, Sally M. Bradberry, and D. Nicholas Bateman 10.4.2 Injuries, envenoming, poisoning, and

allergic reactions caused by animals  1778 David A. Warrell 10.4.3 Poisonous fungi  1817

Hans Persson and David A. Warrell 10.4.4 Poisonous plants  1828

Michael Eddleston and Hans Persson

10.5 Podoconiosis (nonfilarial elephantiasis)   1833 Gail Davey

10.1

Environmental medicine, occupational medicine, and poisoning—Introduction Jon G. Ayres

The environment, both the occupational and the wider environment, can affect health in many ways, both adversely and beneficially. While to date many of these effects have been well understood, most specifically for the work environment, the importance of the wider environment as a cause of ill health has been less well studied on the basis that there is not much one can do about general exposures, such as the weather, or specific events, such as volcanic eruptions, apart from deal with the direct effects. However, increasing awareness of the importance of the environment on health, such as exposure to air pollution (both indoor and outdoor) and the short, medium, and long-​term effects of climate change, has resulted in better understanding of interventions that can improve health, or at least abrogate deleterious effects. Many environmental exposures are complex, often involving a range of potential agents. This has proved a real problem when trying to identify specific components that cause ill health, say in polluted air. Knowledge of these components would help in the design of interventions aimed at specific causal factors, rather than going for a blanket reduction in air pollution as a whole. This optimal approach has been helped by an improving ability to measure population exposure to particular environmental agents, leading to the establishment of much more refined population or individual dose response relationships that are crucial in understanding the efficacy of any interventions. In the future, improved technology will allow personal—​rather than population—​ exposure measurement of a wide range of exposures, allowing population-​based studies to determine exactly how important individual exposures are in conditions where multiple causal agents may be implicated. Climate change is another area where these sorts of problems occur, but is compounded by the fact that estimates of the effects

of climate change on health are based on forward projections from known existing causal links between environmental influences and health. These projections largely assume that these associations are linear, hence they are open to some uncertainty when considering quantification of the health burden, but the likely impacts are at least broadly agreed, even if the quantification is uncertain. These are summarized in Box 10.1.1 and cover a wide area, ranging from the impacts of temperature change itself through to changes in vector-​ based disease geography. Management of many of these situations are covered elsewhere in this textbook, if not in this section itself. However, it needs to be understood that the physician has an advisory and exemplary role with respect to climate change and health by personal actions (e.g. walking or using a bike rather than a car where possible), and by putting pressure on governments to sign up to and implement recommendations of International Climate Change agreements.

Box 10.1.1  How this section is divided This section is divided into three broad areas: 1 Environment and health—​incorporating such major issues as air pollution and climate change. 2 Work and health—​both the well-​recognized effects of work on health (e.g. back pain, stress, and so on) and the less well-​recognized, but equally important effects of health on work. 3 Poisoning—​there are many types of poison, natural and man-​made, to which we can become exposed, either intentionally or accidentally. Included are the adverse effects of medications and treatments. The subject matter discussed in this section of the textbook often overlaps with that in other sections, hence several key areas are flagged here but also covered elsewhere (e.g. occupational lung disease).

10.2

Occupational health

CONTENTS 10.2.1 Occupational and environmental health 1638 Raymond Agius and Debasish Sen

10.2.2 Occupational safety 1652 Lawrence Waterman

10.2.3 Aviation medicine 1656 Michael Bagshaw

10.2.4 Diving medicine 1664 David M. Denison and Mark A. Glover

10.2.5 Noise 1671 David Koh and Tar-​Ching Aw

10.2.6 Vibration 1673 Tar-​Ching Aw

10.2.1  Occupational and environmental health Raymond Agius and Debasish Sen ESSENTIALS Occupational diseases are those for which work or, specifically, exposures in the workplace are necessary causes. The most prevalent occupational diseases in developed countries today are musculoskeletal and psychological disorders (usually stress-​ related conditions), but generally occupationally related malignancies (e.g. mesothelioma related to asbestos exposure) have the most serious outcomes. The proportion of all cancers attributable to occupational exposures is about 4%, with occupationally related cancers almost exclusively concentrated in manual workers aged 20 or over in sectors such as mining, agriculture, and industry. When presented with a patient whose illness might possibly have been caused or aggravated by work or by other environmental factors, the physician can usefully adopt an approach similar to that used for determining causation in epidemiological studies, with

key issues being the temporality, reversibility, exposure-​response, strength of association, and specificity of the illness with exposure to the factor in question, also biological plausibility, consistency with other reports, and evidence of similar exposures producing similar illness. The prevention of occupational disease depends upon recognition of the condition as occupational, assessment of ‘exposure’ and hence determination of risk, education of stakeholders, control of the problem at source, audit of the risk management procedures, and perhaps health surveillance of those exposed using suitable techniques for the early detection of disease and a check on the effectiveness of the control measures. Extant health and safety legislation is driven mainly by risk assessment, and those who generate the risks are responsible for undertaking an assessment, the detail of 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 if their disease and work exposure seem related. If the disease and/​or work exposure are not scheduled, there may still be a case worthy of pursuit under common law. 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 recommendations in 1985 for its members ‘to develop progressively occupational health services for all workers’ and that ‘The provision made should be adequate and appropriate to the specific needs of the undertaking’.

Introduction ‘Disease’ results from a combination of genetic, behavioural, and ‘environmental’ factors, generally cumulating with the passage of time. However, proportionately, genetic factors explain very little of the burden of ill health. Therefore, it behoves us as physicians to consider, as a first alternative or as a ‘default’, environmental factors, ranging from the ambient air we breathe to our occupation, but including diet, micro-​organisms, and other exogenous factors as the prime determinants of disease.

10.2.1  Occupational and environmental health

As physicians we should, first and foremost, aim to protect individuals and society from such ill health through preventive measures. 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 happening, how they bring about adverse effects, and what structural, organizational, or behavioural interventions we should advocate to protect health and prevent ill health. When presented with a patient whose illness might possibly have been caused or aggravated by work or by other environmental factors, the physician might need to broaden their usual approach to history taking. Taking short cuts here can result in missing the diagnosis altogether and in losing a vital opportunity of making the patient better and of improving the fate of other coworkers. This additional information might be critical in attributing the illness to work. Bradford Hill postulated guidelines for determining causation in epidemiological studies, which lend themselves to be adapted for clinical purposes in an analogous manner (see Table 10.2.1.1). Moreover, when taking an occupational history, it is also important to determine exposure, and a job title. For example, ‘engineer’, is not enough; a description of what the job entails and what agents or energies are involved are a bare minimum. The full job description might need to go back several years—​pleural mesothelioma, for example, can occur half a century after the first exposure to asbestos. The workplace is where many people spend a significant proportion of their lives. Work is important for self-​esteem and well-​being (physical and psychological) as well as for the economic well-​being of the individual and society. Work is good for us as long as it is good work and, therefore, does not impose unacceptable risks to our health. Thus, in dealing with the individual, physicians, whatever their specialty or interest, need to explore occupational and other environmental causes of disease, to protect and better manage the patient concerned, and indirectly protect others from the same fate. Furthermore, the physician has a responsibility as part of managing the patient’s health to do their best to help the patient achieve and maintain gainful and fulfilling employment, whether this involves rehabilitation back to work, resolving presenteeism, or even

addressing health-​related issues standing in the way of achieving a job in the first place.

Definitions and scope: Occupational disease What then is an occupational disease? Put simply, it is a disease for which work or, specifically, exposures in the workplace are necessary causes. The answer often has far-​reaching consequences, both in terms of suitability of employment, compensation costs, the inclusion of controls against exposure, as well as legal or policy considerations. For silicosis (caused by airborne quartz), or mesothelioma (caused by asbestos), the disease is almost always caused by work and the key aetiological agent, silica, found in the workplace. But what about bronchial cancer in a joiner exposed to asbestos? Is it an occupational disease even though it is impossible to assess the precise contribution of occupational versus non​occupational factors (such as tobacco smoking) in any one individual? Epidemiologic research on the excess of illness that is attributable to work can be used to directly represent the impact of work on health at a population level, as well as occupational exacerbations of symptoms and disability in pre-​existing conditions, such as asthma brought on by irritants in the workplace. The most prevalent occupational diseases in developed countries today are musculoskeletal and psychological disorders (usually stress-​related conditions) but generally occupationally related malignancies have the most serious outcomes. However, when it comes to understanding the mechanism by which occupational diseases occur, two basic concepts immediately arise: the fact that in the case of two workers doing an identical job one will get the disease but the other may not; and the fact that with some workplace exposures, for example asbestos, the latency of the disease, in this case mesothelioma, may mean many years before the disease appears. These factors can make the diagnosis of occupational diseases difficult. On the other hand, failures of safety aspects of work are usually very obvious, especially if they lead to a workplace accident resulting in an injury or even death. Fig. 10.2.1.1 guides the clinician to an outline of the hazards to health arising from the workplace or other 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?

1639

1640

SECTION 10  Environmental medicine, occupational medicine, and poisoning

ERGONOMIC Heavy lifting, handling of loads Abnormal postures

PSYCHOLOGICAL Work overload or underload High demand—poor control Other stressors

PHYSICAL High noise exposure, or vibration Hot work Radiation (ionizing and nonionizing)

BIOLOGICAL

CHEMICAL Breathing in and/or handling chemicals or other hazardous substances; ingesting chemicals: mineral dusts, 'heavy metals', organic solvents, monomers, hardeners, etc.

Work with infected patients or laboratory work: blood–borne viruses, tuberculosis, leptospirosis

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 environment, which might include the patient’s workplace, in the differential diagnosis, it is important to determine, through the occupational history, the nature, duration, and intensity of any likely exposure, as illustrated in Fig. 10.2.1.1. The following are useful guides: 1. How was the task done? For example, was the adhesive applied

with a brush while the patient leant over it?

2. Was the airborne concentration of a dust or fume such that it

could be seen (although harmful particles are usually invisible to the naked eye), or the noise so loud that normal conversation was difficult? 3. Is local exhaust ventilation/​extraction provided for the machine or area where work is taking place? 4. Are the risks to health connected with work such that the employer has (or should have) supplied workers with certain items of personal protective equipment such as gloves or a mask? Different categories of harmful agents require different and specific forms of personal protection (e.g. rubber-​based gloves are not appropriate when handling solvents). The relationship between hazard, risk, and the eventual possible onset of disease is a very important one, since it goes beyond ‘clinching a diagnosis’ and extends to the crucial aspects of prevention of ill health, as illustrated in Fig. 10.2.1.2.

The size of the problem The International Labour Organization in 2013 estimated 2.34 million deaths each year from work-​related accidents and diseases, the vast

majority (2.02 million) dying from a range of work-​related diseases. This equates to 5500 deaths each and every day caused by various types of work-​related diseases. On top of this, the International Labour Organization (ILO) also estimates 160  million cases of non​ fatal work-​related diseases occurring annually worldwide. However, these figures might well be serious underestimates. In the United Kingdom, estimates for 2016/2017 indicate around 13 000 deaths each year are thought to be linked to past exposures at work; primarily to chemicals or dust. (Asbestos-related deaths, often with historic exposure, make up the greatest number dying from work-related cancers). The types and trends of reported, non​fatal diseases worldwide vary widely although some common features do exist: occupational lung diseases from exposure to workplace dusts, gases, vapours, and fumes; musculoskeletal disorders particularly low back pain; psychological disorders. In 2016/2017 an estimated 1.3 million people in the United Kingdom were suffering from an illness (longstanding as well as new) they believed was caused or made worse by their current work; 516 000 were new cases among those working in the previous 12 months, accounting for 25.7 million working days lost due to work-related ill health in 2016/2017. Around 79% of new work-​related conditions were either musculoskeletal disorders or stress, depression, or anxiety. Fig. 10.2.1.3 shows how the incident cases distribute by major category from a general practice perspective. 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 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-​ related diseases in the EU has been estimated to be at least €145 billion per year, excluding compensation costs (for asbestos-​related

10.2.1  Occupational and environmental health

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 Achieving improvement in capacity through occupational rehabilitation

USUAL MEDICAL INTERVENTION PLUS 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 personal litigation/​compensation costs. In Great Britain, costs of new cases of workplace illness are estimated at £8.6 billion (2012/​13 data), shared between cost to the individual worker (pain, grief, and suffering), the employer (lost productivity), and government (healthcare).

History of occupational disease Some industries, such as mining, have always been considered hazardous. The ancient Egyptians recognized this by restricting such work to slaves and criminals. Hippocrates emphasized the relationship between environment (air and water) and health, but the N = 6492 cases

1% 5% 2%

3% 2%

2% 47–​53

Enjoy your usual outdoor activities.

Adults and children with lung problems, and adults with heart problems, who experience symptoms, should consider reducing strenuous physical activity, particularly outdoors.

101–​120

201–​267

267–​354

>36–​41

67–​75

Moderate (6)

188–​213

468–​534

711–​887

59–​64

84–​91

High (8)

214–​240

535–​600

888–​1064

65–​70

92–​100

High (9)

Anyone experiencing discomfort such as sore eyes, cough, or sore throat should consider reducing activity, particularly outdoors.

Adults and children with lung problems, and adults with heart problems, should reduce strenuous physical exertion, particularly outdoors, and particularly if they experience symptoms. People with asthma may find they need to use their reliever inhaler more often. Older people should also reduce physical exertion.

161–​187

401–​467

533–​710

54–​58

76–​83

High (7)

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.

Enjoy your usual outdoor activities.

67–​100

135–​200

178–​266

24–​35

Accompanying health messages for individuals at risk

34–​66

68–​134

89–​177

12–​23

59–​66

24-​hr mean

51–​58

SO2

34–​50

PM2.5

17–​33

0–​16

24-​hr mean

PM10

Moderate (5)

Concentration of specific pollutants at different air pollution index bands

Moderate (4)

Sampling time

Low (3)

Pollutants (µg/​m3)

Low (2)

Low (1)

Air pollution index bands (value) →

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/​)

Anyone experiencing discomfort such as sore eyes, cough, or sore throat should consider reducing activity, particularly outdoors.

Adults and children with lung problems, adults with heart problems, and older people, should avoid strenuous physical activity. People with asthma may find they need to use their reliever inhaler more often.

≥241

≥601

≥1065

≥71

≥101

Very high (10)

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10.3.2  Heat

Air quality index Based on the air quality guidelines, government agencies around the world have drawn up variations of air quality index to communicate information about real-​time and short-​term forecast levels of air pollution and its possible associated health effects to the public. In the United Kingdom, on the advice of the Committee on Medical Effects of Air Pollutants (COMEAP), the Department for Environment Food and Rural Affairs (Defra) uses pollutant (PM10, PM2.5, SO2, NO2, and ozone) concentration data obtained from its national monitoring network and computer based models to derive a health-​based Daily Air Quality Index, which provides recommendations on the actions to be taken by the public based on the current and forecasted (next day) air pollution levels. The Daily Air Quality Index is a 10-​point scale divided into four colour-​coded bands: low (1–​3), moderate (4–​6), high (7–​9), and very high (10) (Table 10.3.1.4). Members of the public will first determine whether they are at risk from air pollution (from the additional information accompanying the Daily Air Quality Index), and read the health messages corresponding to the pollution band for recommended actions (e.g. reducing physical exertion). The main objective behind this is the prevention of adverse health effects from short-​term elevations in air pollution. It is anticipated that such a forewarning system could help sensitive individuals to modify their behaviour to reduce their individual exposure to the pollution, or reduce the severity of their symptoms.

10.3.2  Heat Michael A. Stroud ESSENTIALS Rising body temperature triggers behavioural and physiological responses including reduction in physical activity, alterations of clothing, skin vasodilatation, and sweating. Heat-​related illness is relatively common, especially with high humidity or prolonged physical activity. Risk can be reduced by acclimatization with repeated heat exposure, but some individuals seem to be particularly susceptible. Clinical presentations of heat-​related illness include (1) ‘heat exhaustion’—​the commonest manifestation, with symptoms including nausea, weakness, headache, and thirst. Patients appear dehydrated, complain of being hot, and are flushed and sweaty. Treatment requires rest and fluids, given orally or (in severe cases) intravenously. (2) ‘Heat stroke’ victims often complain of headache, may be drowsy or irritable, and may claim to feel cold. Core temperature is usually 38–​41°C, but the patient is shivering with dry, vasoconstricted skin. Treatment requires (a) aggressive rapid cooling—​tepid water and fan-​ assisted evaporation in the first instance, with more invasive measures (e.g. intraperitoneal fluids, if required); (b)  close biochemical monitoring; (c) supportive care for organ failure. There is significant mortality.

FURTHER READING Atkinson RW, et  al. (2015). Fine particle components and health—​ a systematic review and meta-​ analysis of epidemiological time series studies of daily mortality and hospital admissions. J Expo Sci Environ Epidemiol, 25, 208–​14. Brunekreef B, Holgate ST (2002). Air pollution and health. Lancet, 360, 1233–​41. Cohen AJ, et al. (2017). Estimates and 25-year trends of the global burden of disease attributable to ambient air pollution: an analysis of data from the Global Burden of Diseases study 2015. Lancet, 389, 1907–18. Gauderman WJ, et al. (2015). Association of improved air quality with lung development in children. N Engl J Med, 372, 905–​13. GBD Risk Factors Collaborators (2015). Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–​2013:  a systematic analysis for the Global Burden of Disease Study 2013. Lancet, 386, 2287–​323. Gordon SB, et al. (2014). Respiratory risks from household air pollution in low and middle income countries. Lancet Resp Med, 2, 823–​60. Kurmi OP, Lam KBH, Ayres JG (2012). Indoor air pollution and the lung in low-​and medium-​income countries. Eur Resp J, 40, 239–​54. Pope CAI, Ezzati M, Dockery DW (2009). Fine-​particulate air pollution and life expectancy in the United States. N Engl J Med, 360, 376–​86. Soule EK, et al. (2017). Electronic cigarette use and indoor air quality in a natural setting. Tob Control, 26, 109–​12. Thomas E, et  al. (2015). Improved stove interventions to reduce household air pollution in low and middle income countries: a descriptive systematic review. BMC Public Health, 15, 1–​15.

Thermoregulation in the heat Most of human evolution took place in Africa and hence all humans are heat tolerant. We try to maintain a near-​tropical microclimate against our skin, by using clothing to reduce heat loss to our surroundings. Thermal balance is regulated by the hypothalamus, which integrates information from skin temperature sensors with core temperature data from receptors within walls of large blood vessels and the brain. Rising temperatures trigger both behavioural and physiological responses. Behavioural changes include reducing physical activity, altering clothing, and seeking shade or cool shelter. Cold drinks are also helpful. Although these responses seem simplistic, decisions may not be straightforward. If physical activity is low and water is in short supply, it is better to increase clothing cover and protect yourself from high radiant heat inputs. If activity must be continued and water is freely available, minimal clothing to permit maximal sweat evaporation is preferable. Immediate physiological responses involve vasodilatation of skin and subcutaneous blood vessels to enhance surface heat loss from radiation, conduction, and convection. The vasodilatation is triggered by a sympathetic cholinergic reflex in response to skin warming, with additional direct effects of heat on arteriolar tone. In a resting person, skin vasodilatation can maintain thermal equilibrium in environmental temperatures up to 32°C, but with higher temperatures or heat production from activity, core temperatures will rise. This will trigger sweating to promote evaporative cooling.

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Heat acclimatization Repeated heat exposure can increase our capacity to lose heat by about 20-​fold. This is partly due to greater skin blood flow from increases in circulating volume and improved vasodilatory responses, but changes in sweating responses are more important. In the non​acclimatized, sweating is triggered by a rise in core temperature of about 1°C and maximum rates are limited to about 0.5 litre/​ h. Following acclimatization, a 0.5°C core rise will trigger the response and sweat rates may exceed 2.0 litre/​h. Acclimatization also leads to aldosterone-​mediated reductions in sodium loss in both sweat and urine. The acclimatized individual therefore requires no sodium supplementation and giving supplements can delay the acclimatization process. Avoiding them altogether, however, risks salt depletion in non​acclimatized persons during prolonged heat stress. Acclimatization develops swiftly and around 90% of maximum heat tolerance is present after 7–​10 days, on which core temperature has risen by more than 1°C for more than 1 h. Physical exertion combined with heat makes the changes even more rapid. After returning to cool environments, adaptation is lost in 20–​40 days.

Susceptibility to heat-​related illness Although we are generally heat tolerant, heat-​related illness is relatively common, and several factors increase vulnerability. Above an environmental temperature of about 35°C, we tend to gain heat from our surroundings, and this, along with metabolic heat production, can only be lost via evaporation of sweat. Hot environments with high humidity are therefore the greatest threat. Acclimatization status has a marked influence on heat-​related risks, the unacclimatized being prone to hyperthermia and salt depletion, while the fully acclimatized are vulnerable to dehydration from high sweat rates. Dehydration in itself limits sweating capacity and skin blood flow and hence increases risks. It can occur easily since thirst is a poor trigger for adequate drinking. Sweat rates in the acclimatized can also exceed gut capacity for water absorption. Prolonged physical activity can cause heat illness under quite modest environmental conditions. This is particularly common when individuals are obliged to wear clothing that is insulative or vapour-​impermeable. Military heat casualties are sometimes due to these factors, but there have also been fatalities in soldiers who have been susceptible to heat for no obvious cause. Such genetic or constitutional vulnerability should be suspected whenever a heat-​ related problem occurs following relatively modest heat stress. These people should be strongly advised to avoid similar circumstances in future. Obesity and poor physical fitness are further risk factors in the heat, as is diabetic autonomic dysfunction. Older people are generally heat sensitive and, in addition, are prone to problems from the increased circulatory demands of vasodilatation. Drugs can also induce heat illness (see following paragraphs).

Heat exhaustion Most casualties in hot environments suffer from heat exhaustion. There is usually a history of prolonged heat stress followed by nausea, weakness, headache, thirst, and sometimes collapse. Patients appear

dehydrated with a tachycardia and low blood pressure. If hyperthermic, the casualty should be complaining of feeling hot and will appear flushed and sweaty. The absence of these symptoms and signs, especially with a very high core temperature, suggests heat stroke. Heat exhaustion is ascribable to sodium and/​or water depletion, but discriminating between these can be difficult. Sodium depletion tends to be greater if the casualty was poorly acclimatized and hence sweated relatively more sodium than water. Conversely, water depletion is more common in acclimatized individuals. Muscle cramps or whole-​body dehydration without marked changes in haematocrit or serum proteins are suggestive of excessive sodium loss, but serum sodium tends to be normal in such cases unless enthusiastic fluid replacement without salt has led to hyponatraemia. This sometimes occurs in runners after completing marathons in hot environments. In predominantly water-​ depleted heat exhaustion, haematocrit, serum proteins, and serum sodium tend to be high. Renal impairment occurs in either form of heat exhaustion and the treatment of both types often requires 5–​10 litres of oral or intravenous fluids in the first 24 h. Sodium supplementation is given as appropriate, but if sodium status is uncertain, it is usually safer to provide some than to precipitate acute hyponatraemia.

Heat stroke Mild heat stroke has occurred when a hot environment or high activity levels have led to pyrexia with cerebral disturbance. Core temperature is usually 38–​41°C. The condition frequently follows heat exhaustion but temperature may have risen rapidly allowing no time for salt or water depletion. Sufferers have headaches and may be either drowsy or irritable. They often hyperventilate. The great danger is progression to more severe heat stroke, in which core temperature reaches levels that cause irreversible denaturing of proteins. This usually occurs at above 41.5°C. Damage is widespread and particularly affects brain, liver, kidney, and muscle. Furthermore, the hypothalamic thermoregulatory centre may fail, switching off vasodilatation and sweating, and switching on cold defences inappropriately. Patients may therefore claim to feel cold and on examination may be shivering with a dry, vasoconstricted skin. A disastrous vicious cycle of increasing temperatures can then ensue. Treatment for all heat stroke requires early recognition and rapid cooling. Tepid water and fan-​assisted evaporation may be more effective than immersion in cold water, which can limit heat loss by stimulating intense peripheral vasoconstriction. Intraperitoneal fluids, paralysis, and ventilation may be needed and, in extreme circiumstances, cooling by cardiac bypass should be considered. Hyperkalaemia, hypocalcaemia, acidosis, rhabdomyolysis, disseminated intravascular coagulation, and hepatic or renal failure are common complications. Ventricular fibrillation is a frequent terminal event. Even if apparently resuscitated and cooled successfully, a 12-​to 24-​h ‘lucid interval’ may precede major deterioration. Permanent neurological damage is common.

Drug-​induced heat illness Many drugs can cause mild degrees of pyrexia by inducing local or systemic inflammation or hypersensitivity. Some also increase susceptibility to environmental heat by inhibiting central thermoregulation (e.g. barbiturates and phenothiazines) or reducing sweating

10.3.3  Cold

capacity (e.g. anticholinergics). Salicylate overdose can generate heat stroke by increasing metabolic heat production while impairing hypothalamic regulation. There are two types of heat-​related drug reactions, however, which are particularly dangerous.

Malignant hyperpyrexia This is usually a dominantly inherited condition, although different gene defects may affect families. Administration of a variety of anaesthetic agents, including halothane and suxamethonium, leads to rapid, massive heat production from generalized increases in skeletal muscle tone. Contraction is triggered at the muscle cell membrane and hence neuromuscular blocking agents are ineffective. Intravenous dantrolene, an inhibitor of muscle calcium flux, is helpful and can be used along with ventilation and cooling/​supportive measures. Fatalities are common, and it is therefore important to avoid risks whenever possible. In patients with a relevant personal or family history, in whom an anaesthetic is unavoidable, oral dantrolene should be given prior to the use of low-​risk agents.

Neuroleptic malignant syndrome This condition has similarities to malignant hyperpyrexia but is induced by idiosyncratic reactions to normal doses of antidopaminergic drugs, including phenothiazines and butyrophenones. The onset is less rapid than malignant hyperpyrexia, occurring over a few days. The increased muscle tone is also induced presynaptically and hence neuromuscular blocking agents help. Some recreational drugs, such 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.

FURTHER READING Bouchama A, Knochel JP (2002). Heat stroke. N Engl J Med, 346, 1978–​88. Hodgson P (1991). Malignant hyperthermia and the neuroleptic malignant syndrome. In: Swash M, Oxbury J (eds) Clinical neurology, pp. 1344–​5. Churchill Livingstone, Edinburgh. Hubbard RW, Armstrong LE (1988). The heat illnesses: biochemical, ultrastructural, and fluid-​ electrolyte considerations. In:  Pandolf KB, Sawka MN, Gonzalez R (eds) Human performance physiology and environmental medicine at terrestrial extremes, pp. 305–​59. Benchmark, Indianapolis, IN.

10.3.3  Cold Michael A. Stroud ESSENTIALS Humans are poorly adapted to cold, which can cause hypothermia, non​freezing cold injury, and frostbite.

Hypothermia This occurs especially with wind and wetting, and is seen indoors in older people and those who are thin. At a core temperature of 35°C, victims complain of cold, act appropriately, shiver, and are peripherally vasoconstricted, but with further cooling they may become confused or drowsy and appropriate physiological responses disappear. Coma occurs at 26–​32°C, and death typically at 17–​26°C. General investigation and management is as for any comatose patient, but specific issues include (1) accurate measurement of core temperature requires a low-​reading rectal thermometer; (2) measurement of serum amylase (risk of pancreatitis) and creatine kinase (risk of rhabdomyolysis); (3) rewarming—​if onset of cooling was prolonged, rewarming should generally be slow; (4) diagnosis of death—​ apparently dead victims should be rewarmed whenever possible before resuscitation is abandoned.

Non​freezing cold injury This occurs when skin temperatures below 12°C are maintained for prolonged periods, particularly in water (e.g. trench foot). This causes local tissue damage, particularly to nerves, which can be permanent.

Frostbite Frozen tissues initially appear hard, white, and anaesthetic, but with rewarming become swollen, painful, and blistered. There may be irreversible necrosis, but initial appearances can be misleading and hence early amputation should be avoided. Once thawed, frostbite treatment is similar to that for burns.

Thermoregulation in the cold It has only been 10 000 to 15 000 years since ancestral humans dwelt exclusively in warm or hot climates. Humans are therefore poorly adapted to cold, and hypothermia occurs quite frequently even in temperate regions. With water immersion it may occur even in the tropics. In truly cold areas, there is also the risk of non​freezing cold injury and frostbite. Nevertheless, behavioural changes allow us to operate safely even in the coldest environments. Core temperatures in the cold are usually maintained by adjustments in clothing and physical activity. The latter can increase heat production from a resting 100 W to 1–​2 kW. This is very effective. Although it takes highly specialized, multilayered clothing 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 to decreased blood flow in the skin due to increased sympathetic adrenergic tone and direct cooling effects of cold on skin arterioles. 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 permanent peripheral cold injury. It is often this peripheral cooling that limits our capacity to work in the cold. Falling skin temperatures will also lead to higher resting muscle tone and shivering, especially when declining core temperature

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releases hypothalamic inhibition of shivering. These mechanisms can only increase resting heat production to around 500 W and, unlike newborn infants and some other mammals, adult humans cannot add significant non​shivering heat production to this figure.

Effects of falling core temperature Falling core temperature leads to progressive decline in function. At 34–​36°C, hypothermic individuals are conscious of feeling cold and try to move around, add clothing, or seek shelter. Simultaneously, physiological defences are activated. With further falls of temperature, mental and physical problems increase. Some people become withdrawn while others exhibit aggression or disinhibition. Once core temperatures reach 33–​34°C, victims often stagger and become confused or drowsy. It is also around this point that ‘paradoxical undressing’ may occur. This phenomenon is well described and appears to be due to hypothalamic dysfunction with alteration of set-​point temperature. Victims therefore feel warm or even hot and appropriate behavioural and physiological responses disappear. At core temperatures varying between 26 and 32°C coma will ensue, and between 17 and 26°C cardiac output becomes inadequate to sustain life for prolonged periods. The risk of ventricular fibrillation is also high. Nevertheless, successful resuscitations of victims with core temperatures below 15°C have been reported (see also Chapter 9.5.3).

Causes of hypothermia Several factors increase hypothermic risk. Wetting of skin or clothing extracts enormous amounts of heat and reduces insulation of garments. Complete immersion is particularly hazardous and worldwide more than 100 000 people per year die of cold shock or inexorable hypothermia in the water. This far exceeds deaths from drowning without cold. Winds also increase environmental cooling and a still air temperature of +5 °C equates to –​50 °C if wind speed is 40 km/​h. Coupled with rain, these effects often contribute to hypothermic accidents among hill walkers and mountaineers, although in these cases fatigue may contribute. Prolonged exertion depletes muscle glycogen which reduces heat production capacity from both exercise and shivering. Low blood glucose also impairs hypothalamic temperature control. Small, thin people cool easily because of their increased surface-​to-​volume ratios. They also have reduced subcutaneous insulation and low heat-​producing mass. A fat person can maintain core temperature at rest, even if mean skin temperature is 12°C, whereas a thin person struggles to maintain thermal equilibrium with a skin temperature of 25°C. However, rapid cooling can sometimes have benefits. A small child in cold water may cool so rapidly that vagally triggered bradycardia and lowered brain metabolic demands may permit successful resuscitation after very prolonged immersion. Older people may also be small and thin and are at risk of so-​ called ‘urban hypothermia’. Poverty, illness, immobility, malnutrition, and a less sensitive regulatory system may contribute, but in many cases hypothermia on admission to hospital is secondary to other pathology (e.g. a stroke may have led to prolonged immobility

in a cool environment). Drugs that impair consciousness or induce vasodilatation are risk factors, and alcohol is particularly hazardous. Alcoholics with no fixed abode and a tendency to hypoglycaemia are frequent urban cold casualties.

Hypothermic illness General management of the hypothermic casualty is similar to that for any comatose or semicomatose person. Abnormalities in blood gases, pH, electrolytes, and glucose are common, and pancreatitis or rhabdomyolysis are recognized complications. Accurate measurement of core temperature is surprisingly difficult. Axillary, tympanic, and oral temperatures can all be misleading. A low-​reading rectal thermometer is best. Hypothermia has one very specific risk. Pronouncement of death is fraught with difficulty since profound bradycardia, minimal stroke volume, and marked respiratory depression occur. The old adage that you are ‘never dead unless warm and dead’ must be taken seriously. A variety of rewarming methods are available. Warm blankets and hot drinks will suffice in many cases but, although they are widely used, metallized ‘space blankets’ are of no proven benefit. Warmed intravenous fluids are helpful and, in extreme cases, peritoneal warmed fluids or cardiac bypass can be used. Specialized equipment providing heated, humidified air also permits core rewarming. Hot 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, rewarming must be undertaken with extreme caution. In critical cases, where rapid rewarming is needed, full resuscitation facilities must be available, although safe defibrillation in the presence of water is impossible. Careful monitoring during rewarming is vital. Blood volumes are often low due to early cold-​induced diuresis, followed by the inability of hypothermic kidneys to retain salt and water. In immersion casualties, hydrostatic effects on the limbs may have promoted additional fluid loss and, if possible, these people must be kept recumbent throughout rescue and rewarming to minimize risks from extreme postural hypotension. Warming cell membranes are extremely unstable, and uncontrollable fluxes in potassium and other electrolytes may occur, although care must be taken in interpreting biochemical results from cold peripheral blood sampling.

Non​freezing cold injury Local temperatures of less than 12°C prevent normal membrane pumping and paralyse nerve and muscle conduction. If such cooling is prolonged, permanent damage may ensue. Immersion in cold water is particularly likely to cause this type of damage and soldiers in military campaigns are frequent victims of ‘trench foot’. Long-​term damage is likely whenever an anaesthetic, paralysed, cold region becomes hot, red, painful, and swollen after rewarming, although this change may take several days. Degeneration of nerve and muscle can then follow, leading to prolonged anaesthesia, muscle contractures, or inappropriate peripheral vascular control with intolerance to local heat or cold. There may be slow improvement over months or years.

10.3.4  Drowning

Frostbite Human tissues freeze at around –​2 °C. Ice forms outside cells but the remaining extracellular fluid becomes hyperosmolar and hence severe intracellular dehydration occurs. This denatures proteins. Vascular endothelial cells are particularly vulnerable, and following rewarming, small blood vessels may leak plasma and then become blocked by red cell sludge and clot. Additional ischaemic necrosis is then superimposed on the frost damage. Frozen tissues appear hard and white and are anaesthetic. Rewarming leads to pain and swelling, often accompanied by blistering. Deep-​freezing results in irreversible necrosis but appearances can be misleading, and early amputation of digits should be avoided. If still frozen, rewarming is best achieved rapidly by using immersion in water at 40–​42°C, although any thawing should be avoided if refreezing is likely. Once thawed, treatment is similar to that used for burns with prevention of infection paramount. Generous analgesia is required.

FURTHER READING Dexter WW (1990). Hypothermia. Safe and efficient methods of rewarming the patient. Postgrad Med, 88, 55–​8, 61–​4. Giesbrecht GG (2000). Cold stress, near drowning and accidental hypothermia: a review. Aviat Space Environ Med, 71, 733–​52. Granberg PO (1997). Cold injury. In: Chant ADB, Barros D’Sa AAB (eds) Emergency vascular practice, pp. 119–​34. Hodder Arnold, London. Hamlet MP (1988). Human cold injuries. In: Pandolf KB, Sawka MN, Gonzalez R (eds) Human performance physiology and environmental medicine at terrestrial extremes, pp. 435–​66. Benchmark, Indianapolis, IN. Stroud MA (1993). Environmental temperature and physiological function. In: Ulijaszek SJ, Strickland SS (eds) Seasonality and human ecology, pp. 38–​53. Cambridge University Press, Cambridge.

10.3.4  Drowning Peter J. Fenner ESSENTIALS Drowning is a major preventable cause of death, most frequently in children and in developing countries. Aspiration (whether of salt or fresh water) is usual in drowning and near-​drowning (known as non​fatal, or submersion injury) and leads to cardiac arrest within a few minutes. Death or severe neurological impairment occurs after submersion for more than 5–​10 min, but much longer durations may be tolerated in hypothermic conditions.

Prevention Precautions include proper supervision of children in recreation areas such as swimming pools, beaches, and river banks, and of

young children and epileptics in baths. Personal flotation devices (life jackets) are the best preventive strategy in boating activities. Prevention and rescue efforts of life-​savers are effective in swimming pools and on patrolled beaches.

Clinical features Prognosis cannot reliably be predicted, but cardiovascular status is a better prognostic indicator than neurological presentation. Patients who are neurologically responsive at the scene of immersion, in sinus rhythm and with reactive pupils, have good outcomes. Those who are asystolic on arrival at hospital and remain comatose for more than 3 h have a poor prognosis unless they are hypothermic. Patients with a normal chest radiograph on admission usually survive.

Management The factors that influence outcome are (1) immediate management—​ including rapid rescue; laying the victim on their side for assessment of the airway and breathing to assist drainage of any excess water from the 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 oropharyngeal airway, endotracheal tube, or laryngeal mask airway in comatose victims (if suitably skilled personnel are present). (2) Hospital management—​important elements are (a) ventilatory support to maintain adequate arterial oxygenation, which may involve the use of extracorporeal membrane oxygenation and/​or cardiopulmonary bypass in refractory cases; (b) colloid resuscitation, (c) recognition and treatment of complications (e.g. secondary pneumonia).

Definition Drowning has most recently been defined as ‘the process of experiencing respiratory impairment from submersion/​ immersion in liquid’. Outcomes of drowning should be classified as death, morbidity, 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 drowning remains difficult to diagnose at autopsy.

Mortality and morbidity Acute prolonged hypoxia causes haemodynamic effects, cerebral damage, and death. Neurological morbidity in survivors of near-​ drowning includes difficulties with learning, memory, attention and planning, and cerebral palsy. A large study of childhood immersions has shown that approximately 70% of survivors have no neurological deficit, 30% have some deficit; 3% will live in a permanent vegetative state.

Epidemiology The estimated incidence of drowning is 0.5  million per year, making it the fourth most common fatal injury worldwide in the

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global burden of disease. It is the seventh leading cause of death from unintentional injury in all ages and the second leading cause in children aged 1–​14 years. Incidences of drowning are highest in children up to 4 years old. In infants and toddlers under 12 months, bathtub and bucket immersions are the highest cause of drowning. Ten per cent (10%) of fatal bucket or tub immersions are attributable to child abuse. Smooth and slippery bathtubs are particularly 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 potentially effective preventive strategies such as fencing of swimming pools, providing education appropriate to the particular circumstances, or increased surveillance. Although there are few such preventive strategies for older children, drowning rates have declined dramatically in the last decade. Developing countries have the highest rates of drowning. Thirty-​ eight per cent (38%) of the world’s drownings occur in the Western Pacific region and Africa, where the drowning mortality rate is 13.1 per 100 000 population per year. Children aged 5–​14  years suffer the highest mortality rate. Children under the age of 5 years have the highest drowning mortality rate for both sexes. The mother’s age and literacy and family income are identified as risk factors. In Bangladesh, drowning has been shown to be a major cause of childhood mortality: among 1-​to 4-​year-​olds; there are 156 fatal drownings/​100 000 population per year. Younger males were at greatest risk of drowning in rural areas, mainly in ditches and ponds. In China, estimated drowning mortality rates for all age groups were 29.8/​100 000/​year for boys and 29.6 for girls. In the United States of America in 2000, more than 1400 children younger than 20 years drowned. It is the seventh leading cause of unintentional injury deaths for all ages, the second leading cause of all deaths from injury in children aged 1–​14 years and the third most common cause of fatality in people under 15 years (after car accidents and asphyxia). Many drownings occur during recreation in swimming pools, spas, hot tubs, lakes, rivers, or oceans. Approximately 53% of victims needed hospitalization or transfer for more specialized care. Drowning rates were highest among children up to 4 years old. Worldwide, ocean drownings are less common than freshwater drownings, probably because fewer children swim unsupervised in the ocean, and increasing numbers now swim on patrolled beaches in more-​developed countries, where prevention and the rescue efforts of life-​saving associations have proved effective. Rate of drowning varies with climate, availability of beaches, lakes, and other natural and artificial water sources, provision of life-​saving services, improvements in designs and rules for water craft, and the use of life jackets. Rock fishing carries a high risk of drowning and near-​drowning. A genetic basis has been suggested for unexplained drowning or near-​drowning.

Ethnicity White American children aged 1–​4 years drown twice as often as African-​American children of the same age. These accidents usually happen in residential swimming pools. Conversely, in the age group 5–​19 years, African-​Americans drown more often than white Americans. Australian aboriginal children drown more often than non​indigenous children. Worldwide, fatal drowning is generally more prevalent in indigenous races than in others.

Alcohol Alcohol affects vision, balance, movement, and reasoning and is a major risk factor for drowning in adolescent and adult swimmers, water craft operators, and passengers, who fall overboard while intoxicated. At the time of rescue, resuscitation, or death, 25–​50% of adult and adolescent victims of drowning had some exposure to alcohol.

Pathophysiology Aspiration is usual in drowning. Earlier figures had suggested that approximately 10–​15% of victims of drowning had not aspirated water but recent figures show an incidence of only 2%. In these cases, death may result from laryngeal spasm and asphyxia during submersion. Early animal studies in anaesthetized dogs showed that spontaneous respiratory efforts continued for around 60 s after immersion. Complete cardiac arrest supervenes after 4.5 min (mean 262 s). Recent Chinese bronchoscopic studies in anaesthetized dogs whose lungs were filled with seawater showed that the bronchi fill with bronchoalveolar fluid, causing increasing blood lactate dehydrogenase-​L and alkaline phosphatase levels. Electron microscopy shows injuries to type II alveolar epithelial cells, thickened respiratory mucosa, and platelet adherence. Haemodynamic effects following inspiration of liquid are similar. There is a rapid fall in cardiac output, while pulmonary capillary wedge pressure, central venous pressure, and pulmonary vascular resistance increase. Reduction in the dynamic compliance of the lungs is similar, following inspiration of all types of solutions. However, aspiration of large volumes of hypertonic seawater draws fluid into the lung from the circulation by osmosis, resulting in fluid-​ filled, non​ventilated, but perfused alveoli incapable of normal gas exchange while aspiration. Conversely, aspiration of large amounts of hypotonic freshwater may cause sufficient absorption of fluid into the circulation from the alveoli to cause both acute hypervolaemia and haemolysis. Within 1 h, pulmonary oedema develops, resulting in a decrease in circulating blood volume. Early studies suggested that 85% of human drowning victims aspirated 22 ml/​kg of water or less, but it has been estimated that about 10% of body weight of water may be absorbed from the lungs during freshwater drowning. Since the brain has a limited ability to maintain adenosine triphosphate levels anaerobically when cerebral blood flow is reduced, it suffers irreparable damage within 4–​6 min. Death or severe neurological impairment occurs after submersion of more than 5–​10 min. However, in hypothermic conditions, brain activity may be restored after up to 60 min of submersion apnoea. Bystanders’ estimates of submersion time are usually inaccurate.

Hypothermia (See Chapter 10.3.3.) A low body temperature generally indicates the severity of the drowning incident. Sudden immersion in ice water causes a reflex cardiorespiratory response, called ‘cold shock’, causing an initial gasp and hyperventilation despite hypocapnia and also hypertension. Continuous aspiration of cold water results in rapid core cooling, while the circulation is intact. Such victims may survive with little or no neurological deficit after long submersion with extreme hypoxia. After submersion for a maximum of 10 min in

10.3.4  Drowning

water at 16°C, a good outcome can be predicted in 96.6% of victims. New evidence supports the use of mild hypothermia for periods of 12–​24 h in comatose drowned victims. A  6-​year-​old boy, who presented with a rectal temperature of 16.4°C after a 65-​min submersion, survived, apparently neurologically intact when his blood was rewarmed in increments of 3°C over 96 min. However, later neuropsychological testing revealed cognitive difficulties, especially global memory impairment, despite the fact that MRI and magnetoencephalography were normal. In adults, success is less common. A notable exception was a 31-​year-​old man with a core temperature of 23°C who had been asystolic for 80 min, but was warmed by cardiopulmonary bypass and recovered. Despite discouraging data from animal studies, recent reports suggest that in hypothermic submersion-​ associated cardiac arrest, adrenaline and vasopressin may help to achieve the vasopressor response needed to restore spontaneous circulation prior to rewarming. This treatment could obviate prolonged mechanical cardiopulmonary resuscitation, or the use of extracorporeal circulation. It has proved effective in restoring spontaneous circulation, but one patient died of multiorgan failure 15 h later. In warm-​water drowning there appears to be no statistically significant correlation between duration of submersion and survival.

Causes of drowning Drowning occurs in many different situations: after accidental immersion in people with little or no swimming ability, with head and neck injury, following cardiac and neurological emergencies

(including epilepsy), as a result of alcohol and drugs, metabolic disease (including hypoglycaemia), and even child abuse and murder. In countries with long coastlines and many bathing beaches, drowning is common and is often caused by swimmers being caught in ‘rip currents’ (also known as ‘rips’) (large volumes of water returning back out to sea after onshore wave action) (Fig. 10.3.4.1); there is no such entity as the frequently suggested ‘undertow’. Swimmers in difficulty may be able to shout for help but, contrary to public opinion, those who are drowning do not. Most drowning victims adopt a characteristic vertical position in the water—​legs hanging vertically, head tilted back for quick exhalation and inhalation before bobbing underwater, with no time or sufficient breath to call for help. After only 20–​60 s, victims may submerge permanently.

Clinical features Prognostic indicators None of the recent developments in assessment, treatment, or equipment has improved survival rates among submersion victims. Prevention and rapid rescue remain the most effective means of reducing the toll. The key to a successful outcome and return to productive, full life is early bystander cardiopulmonary resuscitation, early and aggressive advanced life support methods (Fig. 10.3.4.2), induced hypothermia when appropriate, careful rewarming, including extracorporal membrane oxygenation, and extracorporal warming where needed. However, up to 25% of drowning victims presenting to the hospital emergency department will die and a 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.

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(a)

Rapid hypothermia from sudden submersion in cold water (see Chapter 10.3.3) carries a relatively good prognosis, compared to insidious hypothermia developed during prolonged submersion that results in cardiac arrest. Neurological status

(b)

Fig. 10.3.4.2  (a, b) Cardiopulmonary resuscitation including defibrillation being carried out on the beach by Australian surf life-​savers, in a man who suffered a cardiac arrest while swimming. Courtesy of P J Fenner.

be predicted from the initial clinical presentation, laboratory, or electrophysiological examinations, but those with a normal chest radiograph on admission usually survive; Pao2 may not relate to radiographic appearances. Although the cause and pathophysiological changes of pulmonary insufficiency vary depending on the type and volume of fluid aspirated, serum electrolyte and haemoglobin concentrations (or haematocrit) do not predict survival. Cardiovascular status This is a better guide to outcome than neurological status. Mortality is high in victims with circulatory arrest on admission, but those in sinus rhythm with reactive pupils, who are neurologically responsive at the scene of immersion, have good outcomes. Those who are asystolic on arrival at hospital and remain comatose for more than 3 h have a poor prognosis unless they are hypothermic.

Victims who are alert when medical help arrives have a survival rate approaching 100%, whereas the prognosis in those who are comatose 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 neurological 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 indicated 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, seizures, 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 βrhythms suggest a good outcome, whereas bad outcomes are suggested by high voltage, rhythmic δ-waves; biphasic sharp waves; monotonous EEG, ‘burst-​suppression’ pattern, and absence of βrhythms. Children who show no spontaneous movements and have abnormal brainstem function 24 h after submersion injury are likely to suffer severe neurological deficits or death.

Treatment Victims of submersion injury must be treated immediately for ventilatory insufficiency, hypoxia, and the resulting acidosis. A successful outcome depends on early effective resuscitation at the scene and on competent intensive life support. In-​water resuscitation is effective within 5 mins of the shore, or longer, if the victim shows signs of increased activity after the initial breaths of the shore.

Immediate Laying victims on their side for assessment of the airway and breathing will assist drainage of any excess water from the airways and lungs (Fig. 10.3.4.2). If necessary, on-​site cardiopulmonary resuscitation should be started as soon as possible using supplemental oxygen if available, preferably in the highest concentration (e.g.

10.3.4  Drowning

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 resuscitation. Respiratory and cardiopulmonary arrest may occur after an apparently successful rescue, mandating close, uninterrupted monitoring, and the early administration of oxygen to all immersion 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 maintain 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 reSwimming ability and safety skills of young children can be imfractory 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 sucgenation 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 sucAn 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 vessels have capsized and sunk have proved successful. In most age groups, more men drown than women. This probably Prevention of drowning 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 superdrownings in Brisbane, Australia, decreased after legislation made vised water parks, thanks to the large number of lifeguards on duty.

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FURTHER READING Bierens J, et  al. (eds) (2006). The handbook on drowning. Springer, Berlin. Hasibeder WR (2003). Drowning. Curr Opin Anaesthesiol, 16, 139–​45. Idris AH, et  al. (2003). Recommended guidelines for uniform reporting of data from drowning:  the ‘Utstein style’. Resuscitation, 59, 45–​57. Papa L, Hoelle R, Idris A (2005). Systematic review of definitions for drowning incidents. Resuscitation, 65, 255–​64. Piette MH, De Letter EA (2006). Drowning:  still a difficult autopsy diagnosis. Forensic Sci Int, 163, 1–​9. Salomez F, Vincent JL (2004). Drowning:  a review of epidemiology, pathophysiology, treatment and prevention. Resuscitation, 63, 261–​8. van Beeck EF, et  al. (2005). A new definition of drowning:  towards documentation and prevention of a global public health problem. Bull World Health Organ, 83, 853–​6.

10.3.5  Lightning and electrical injuries Chris Andrews ESSENTIALS Lightning Lightning strikes are rare accidents but carry a 10% case fatality, killing 0.1–​0.3 per million population each year. During thunderstorms, the risk is increased by sheltering under trees or by being on open water, on tractors, or in open fields or in outdoor activity. Lightning is considered to cause instant asystole. It is suspected clinically if someone is found collapsed in the open with linear or feathered burns (see next), exploded clothing, and ruptured eardrums. Victims are safe to handle, with most victims showing keraunoparalysis (cold, pulseless, mottled extremities, not unlike compartment syndromes). Immediate cardiopulmonary resuscitation is mandatory. Survivors might develop complications including pain syndromes and psychological sequelae. Burns are generally of minor consequence, unlike electrical injury. The most disabling consequences of the injury are generally the psychological sequelae.

Electric shock The term electrocution implies death from electric shock. Survivors are said to have been exposed to or received an electric shock. 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 overhead power lines, faulty power tools, and particularly using extension cords, are the most common causes, with metal ladders and antennae being particularly dangerous. Prevention is by implementing codes of safe practice.

Victims of electric shock might suffer prolonged attachment to the source of electric current and must be disconnected from the source before resuscitation. A victim still attached to a source of current is dangerous to touch. The most expedient method of disconnection is to turn the offending power off. Consequences of the shock include: (1) Immediate scale—​ventricular fibrillation, which is the mechanism of fatality, sometimes leading to persistent cardiac dysfunction in survivors; (2) Neurological and muscular manifestations, both early and late, including paraesthesiae, and pareses. In the early stages, generalized convulsions, respiratory embarrassment, due to tetanic spasm, and rhabdomyolysis may occur; (3) Burns, which might be severe and require expert surgical attention. Electroporation (a special form of cell membrane disruption 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 syndrome, which has its own unique character.

Introduction Lightning is a powerful force; it provides spectacular displays and has evoked an extensive mythology. It is poorly understood in medical terms and it is only recently that its characterization, physically and psychologically, has been made more plain. The comparatively recent discovery and distribution of electricity have had an equally profound effect, and provide truth to the adage that ‘electricity is a good servant and a bad master’. Generation of electricity occurs in several ways, but in the final analysis electrons are imbued with energy by a generator of electric current. From any given generator notionally one conductor emanates to be a source of current in the form of electrons, and this current is delivered by the conductor to a location where electrical work can be done. This conductor is generally termed the ‘active’ conductor. A second conductor is required to return the electrons in a less energetic state to the generator for re-​energization. This is the return path, or the neutral conductor. The electrical system is referenced to earth, and the second conductor might indeed be earth. Alternatively, a common method of injury occurs when an individual contacts the active conductor and earth simultaneously. While it could be argued that earth reference creates danger on the one hand, on the other technical considerations show that system stability and predictability is enhanced by earth reference.

Epidemiology Lightning injury 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

lightning shock is 10% and is around 0.3 per million population in the United States of America each year, but fewer than 0.1 per million in the United Kingdom. In the early part of the 20th century, most people struck by lightning were outdoor workers (67%) and outdoor recreationalists (28%). Nowadays, the breakdown is 45% and 50%, respectively, explained by changes in social and work habits. Indoor strikes (e.g. by current conducted through communication or power apparatus) continue to account for about 5% of these accidents, but few fatalities. Men are more often injured than women (1.67 males to 0.33 females); the age group most at risk is 20–​29  years. Risky situations include sheltering under trees (particularly), on open water, on tractors, in open fields, and playing outdoor sports, like golf. Regional differences correlate well with storm activity and population density in that area.

Electrical injury Electrocution ranks fifth in the causes of workplace death, accounting for the death of 10 000 workers each year in the United States, with a further 10 million being injured. Most of the victims work for utility companies, followed by mining and construction workers. Contact with power lines causes 53% of fatal shocks, and contact with power tools accounts for a further 22%. The most dangerous times of day seem to be between 10.00 a.m. and 3.00 p.m. on Mondays, Tuesdays, and Thursdays. Most of the victims are trade and labouring staff; sales, clerical, and professional categories are at least risk. Metal ladders and antennae are particularly dangerous and can easily be hoisted into overhead power lines. Codes of safe practice are written accordingly. In domestic situations, contact with overhead lines by ladders and poles is again important. Faulty, including amateur, repair of equipment, and faulty apparatus, wiring, and especially power and extension cords account for large numbers of deaths and injuries. Children are at particular risk. Death from domestic electric shock has shown a marked decrease with the introduction of residual current devices. These are items of good practice, and sense if current is diverted from the active supply to earth rather than neutral, and then interrupt the supply in a matter of milliseconds. These will not ameliorate every accident, but are considered to act in 80% of cases, notably active conductor to earth shocks. While they ameliorate the fatal effects in these cases, victims still can have several of the stated consequences.

Mechanisms of injury Lightning injury Lightning injury may be sustained in five separate ways: 1. A person might be struck directly. This might represent the most

common cause of fatality.

2. A nearby object, such as a tree or a building, might be struck,

and someone in direct contact with it might receive a shock.

3. Without direct contact an arc might ‘jump’ to a nearby person

from the struck object, thereby generating a ‘side flash’. This is particularly dangerous in the unwise event of sheltering under a tree.

4. As current disperses away from the base of a strike to ground, an

individual might divert current flowing in the ground through themselves. This is termed ‘shock due to increase in earth potential’, or simply ‘earth potential rise’. 5. A recently documented mechanism is the transient flow of current due to corona and streamer formation around the upper parts of an individual. The current to provide these streamers flows from ground through the individual to project upwards to reach a descending stroke from a cloud.

It has been found that both cardiac and respiratory function cease instantaneously under lightning strike, the cardiac arrest being asystolic. Cardiac function restarts under local pacemaker control, but respiratory function does not recommence, and secondary hypoxic cardiac arrest supervenes. The major cranial orifices are portals of entry for lightning current, and from there the pathways to the brainstem are short. Respiratory function is thought to be affected in the brainstem. Fluid channels (cerebrospinal fluid and blood) might be channels to the myocardium. The QT prolongation resulting from lightning injury can predispose to episodic arrhythmias. There is no evidence at all for one dictum, viz., that lightning inhibits body metabolism. Resuscitation is as urgent as with any other injury. There is no evidence for the notion sometimes quoted that resuscitation can be delayed in a lightning victim. There is similarly no evidence that metal on the head, or the presence of a mobile telephone (cellphone), predisposes to being struck.

Electrical injury With electric shock, it is important to assess the points of entry and exit and the pathway of current through the body. Once the pathway has been determined, a locus for expected injury can be established, and the flow of current can be estimated from the applied voltage divided by the impedance of the proposed pathway. Most impedance is in the skin barriers, and is non​linear. There is initial (contact) impedance, which decreases as current flow continues. Impedance also varies with time since application, contact surface area, and frequency. Contacts can be with the active and neutral (return) conductor, or with the active conductor and earth, with earth providing the return path to the generator. Indeed, these considerations become blurred 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 route back to the generator. Return paths are then shared between earth and neutral. For currents with a frequency of 15–​100 Hz, externally applied from hand to hand, or hand to foot, relevant variables characterizing the current are the threshold of perception (0.5 mA) and ‘let go’ current (10 mA). The threshold of fibrillation (where threat to life can occur) is a higher threshold again. For example, there is a 50% chance of fibrillation when 2000 mA is conducted for 10 ms, or at the other extreme 100 mA conducted for 10 s, in a hand to foot path. Direct internal application of less than 200 µA to the heart muscle can induce fibrillation. Dangerous current levels as well as impedance parameters are documented in standards.

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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 principles 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 rescuer. Immediate cardiopulmonary resuscitation is paramount. It has been stated that: Any person found with linear burns and clothing exploded off should be treated as the victim of a lightning strike. Feathering burns are pathognomic of lightning injury and occur in no other type of injury. . . . Another complex diagnostic of lightning injury includes linear or punctate burns, tympanic membrane rupture, confusion, and outdoor location . . . .

In assessing a lightning victim, the following features must be sought. Cardiovascular and pulmonary consequences Asystolic arrest is the main cardiac event in lightning injury. Electrocardiographic (ECG) findings can take many forms, with ischaemic and infarct forms. They almost invariably resolve completely over time. Alterations in QT interval and arrhythmias of many kinds are seen. ECG changes might not occur until late in the course, and so are poor diagnostic tools. Respiratory arrest is common. A person not suffering cardiopulmonary arrest is highly unlikely to die from lightning strike. Neurological consequences Direct neural injury can occur both centrally and peripherally. All forms of intracranial bleeding have been reported. Direct cerebral damage particularly affects the basal ganglia, cerebellum, and brainstem. Dural tears, scalp haematomata, and fractures are also seen. Seizures occur as a result of anoxia and injury. Peripheral nerve injury, including autonomic injury, can give prolonged and long-​lasting disability, which often develops late. Other late features include spinal cord atrophic paralysis, cerebellar ataxia, incoordination, paraesthesiae, and aphasia. Continuing complex regional pain syndromes may be seen. Keraunoparalysis and burns More than 70% of victims demonstrate keraunoparalysis. This is a syndrome of cold, pulseless, mottled, and asensory extremities.

Fig. 10.3.5.1  Example of keraunographic marking. Courtesy Dr Ajay Mahajan (Mahajan AL, Rajan R, et al. (2007). Lichtenberg figures: cutaneous manifestation of phone electrocution from lightning. J Plast Reconstr Aesthet Surg, 61(1),111–​13). Reprinted with permission from Elsevier.

The syndrome resembles a compartment syndrome and occurs in the line of passage of the strike current. It resolves spontaneously within 24 h with no sequelae, and requires no surgical intervention. Burns are of minor consequence in lightning injury, and again require little intervention. Entry and exit burns might be full thickness, though small. Arborescent (feathering) burns resemble fern-​like patterns on the skin (Fig. 10.3.5.1). Their aetiology has been convincingly shown to be due to an inflammatory response following field arcing across the skin. They fade within 24 h. Linear burns are due to the passage of hot plasma tongues over the skin. Eschar is simply allowed to separate without further treatment. Flash might be seen, like sunburn or welder’s flash, from the profound radiation of the strike. Sheet burns resulting from efflux of hot plasma can be a variant of linear burning, since both seem to follow moisture and sweat lines. There might be contact burns from metal such as buckles and coins. It is said that these are thermal, but doubt has been cast on this. Eye, ear, and explosive injuries The explosive force of the lightning insult blasts clothing apart (Fig. 10.3.5.2), and may cause percussive injury to the lungs and abdominal viscera. Tympanic membranes are usually ruptured, perhaps from the explosive force of the strike. Percussive eye injury, particularly retinal, has been reported. Cataracts can develop much later. Other injuries Renal and haematological damage have occasionally been reported. Several writers examining lightning strike during pregnancy suggest that outcome for a fetus is poor, independent of

10.3.5  Lightning and electrical injuries

(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 paraesthesiae 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

Fig. 10.3.5.2  Reconstruction of external result of a lightning strike. Courtesy Professor Mary Ann Cooper, University of Illinois, Chicago.

that for the mother. Menstrual and sexual difficulties have been reported, though the latter could be more of a psychological nature.

Electrical injury In contrast with lightning injury, victims might suffer prolonged attachment to the source of electrical current, making them dangerous to touch. Before resuscitation, they must be separated from the current source, and this usually means interrupting the current flow at the supply point. Burns are far more serious, and might merit intense surgical treatment. The likelihood of internal burning (remembering the possibility of electroporation) might require further surgical intervention. Cardiac and respiratory burns can also occur. Cardiovascular consequences Ventricular fibrillation is the most common fatal cardiac arrhythmia following electrical injury. Cardiopulmonary resuscitation is urgently required. Electricity suppliers have standard first aid/​resuscitation procedures. Cardiac dysfunction can persist for long periods, and ECG changes may not resolve. Recent studies indicate the importance of vascular channels for the passage of current. Alterations in vascular function have been documented, and further, similar alterations in vessels remote from the current passage have been demonstrated at the same time. These findings point to humoral factors in mediating electrical injury. The findings also cause us to question whether most of the damage is mediated by current passage through fluid channels, rather than previously claimed nerve conduction.

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 conductor 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 might be seen. Amputations are relatively common. Other aspects Widespread muscle damage generates myoglobin that must be cleared by the kidney with a severe risk of renal damage. Other metabolic and biochemical disturbances secondary to hypoxia might develop. Massive hyperkalaemia has implications for the use of depolarizing muscle relaxants. Eye damage includes retinal damage, with punctation and detachment, and thermal damage to other media. During follow-​up the possibility of ocular pareses and cataracts must be recognized. After shock during pregnancy, the prognosis for the fetus is poor. Non​focal injury is more likely in survivors.

Psychological consequences of electrical and lightning injuries Although electrical and lightning injuries are fundamentally different in nature and management, their psychological sequelae are similar. Sequelae (‘remote symptoms’, so-​called as they occur with no evidence of current passage through the brain) can be profoundly disabling. They most often come to attention via Worker’s Compensation and litigation, and if ignored, do a great disservice to a victim. They can persist for many years and might never resolve. The changes have the features of organic psychological consequences. This is the overall picture, though it might be suggested that a psychological reaction to the loss of function and continuing pain might be functionally generated, although many believe that findings from neuropsychological testing strongly suggest an organic basis. Indeed, recent research in depression indicates that the hippocampus is found to diminish in volume, implicating that such volume changes, together with changes in cortisol and

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Table 10.3.5.1  Proportions and enumeration of remote injuries Proportions

Memory disturbance

71%

Concentration disturbance

63%

Aggression and irritation

67%

Wariness and phobia

58%

Loss of mental powers

50%

Social isolation

38%

Sleep disorder

38%

and others including confusion, word finding disability, anxiety, depression, and learning disorders. Subdivisions of remote injuries

Memory and learning deficits Globally more specifically Visual Visuospatial Auditory

19%

Verbal learning deficit

54%

Verbal fluency deficit

46%

Concentration and attention deficit

46%/​42%

Executive function deficit

38%

Reduced executive speed

62%

35% 38% 62%

and others including general and verbal IQ decrease, dynamic coordination decrease, slowed information processing, deficit in fine motor skills, phobia, and anxiety and depression.

brain-​derived neurotrophic factor, are important in causing depressive syndromes. Research in the sequelae of electric shock also shows reduction in hippocampal volume as a direct consequence of peripheral shock. Several of these symptoms develop over time postinjury, and might not be present for some weeks after the initial examination where the emphasis is more on the physical symptoms. The state of the victim, in totality, deteriorates for 12–​18  months following the injury, then improves to achieve stability 18 months to 3 years from the injury though falling short of original premorbid function. The remote symptoms follow two major categories—​emotional, personality, and behavioural consequences on the one hand, versus cognitive and higher function consequences on the other, with effects on cognitive agility and speed. Table 10.3.5.1 is a summary of psychological findings. An important part of evaluating a victim is to submit them to neuropsychological testing. The aim of such testing, in part, is to objectify the dysfunctions that are seen, and if possible, subdivide them more specifically. It is unfortunate that in evaluating an electric shock victim or a lightning victim, too many examiners regard the psychological syndrome as either representing malingering, or of no consequence, to the victim’s severe detriment. It has been documented that assessment by those unfamiliar with the injury overlooks or wrongly diagnoses over 90% of the resulting syndrome features.

Treatment of the injuries First, urgent and life-​ saving treatment must be administered. Secondly, there must be surveillance for delayed sequelae, and thirdly, long-​term monitoring for morbidity, including cataract formation and psychological problems.

Lightning injury First, the casualty is resuscitated and evacuated. Cardiopulmonary resuscitation is continued until medical emergency help is obtained. Ventilation and cardiac support might be required. ECG monitoring must be used to detect subtle effects like QT prolongation. Associated trauma is treated. In the long term, patients are observed for development of pain syndromes. Ocular and auditory functions are monitored. Sensitivity to the psychological sequelae is required, and preventive interviewing might be useful. Carbamazepine, gabapentin, clonazepam, flecainide, and mexilitine are useful to control neurally derived pain and resulting weakness. An antidepressant is a useful adjunct to this.

Electrical injury Urgent life support is indicated. Ventilatory and inotropic support and correction of arrhythmias may be required together with correction of biochemical abnormalities, and attention to any myoglobinuria. For burns, progressive debridement and/​or amputation might be needed. Specialized rehabilitation may be required. Associated trauma is treated. Ocular and auditory functions are monitored, and psychological disturbances are reviewed. In the long term, surveillance is similar to lightning injury.

Psychological elements In all cases, the management of the psychological syndrome is paramount and might be the greatest determinant of long-​term functional capability. Awareness of the impact of the injury on employment and relationships and social networks is fundamental. Cognitive and computer aids are being developed, and cognitive support is important. Personality change, social withdrawal, sexual dysfunction, with loss of earning capacity, places a large strain on marital partnerships, and this requires special support. An antidepressant such as an SSRI/​SNRI (selective serotonin reuptake inhibitor/​serotonin and norepinephrine reuptake inhibitor), or a tricyclic such as clomipramine, may be useful. Agomelatine is showing some promise in this application. Early and continuing neuropsychological assessment and support is desirable.

Controversy The place of polaxamers in discovering the extent of electroporation and in delineating debridement levels is of great interest. A  polaxamer is a polymer with a central hydrophobic chain flanked by two hydrophilic chains. There are multiple variants of each of these elements. In this structure, however, they

10.3.6  Diseases of high terrestrial altitudes

resemble the structure of cell membranes, and they can be patched into cell membrane defects including those caused by electroporation. On the one hand they might offer a therapeutic restorative for damaged membranes, and on the other a radio-​ labelled polaxamer might be used for imaging the extent of damage. The mechanisms of the psychological disability and remote injury 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 if litigation or compensation is involved. The useful duration of monitoring of otherwise asymptomatic people has not been determined. A pressing need is the formulation of the psychological syndrome into a Diagnostic and Statistical Manual (DSM) formulation.

FURTHER READING Andrews CJ (2006). Further documentation of remote effects of electrical injury, with comments on the place of neuropsychological testing and functional scanning. IEEE Trans Biomed Eng, 53, 2102–​13. Andrews CJ, et  al. (1992). Lightning injuries:  electrical, medical and legal aspects. CRC Press, Boca Raton, FL. Andrews CJ, Reisner AD (2017). The neuropsychological consequences of lightning and electrical injury: review and hypotheses for causation. Neural Regen Res, 12, 677–​86. Cherington M, Cooper MA (eds) (1995). Seminars in Neurology, 15 (3, 4). Cooper MA (1980). Lightning injuries: prognostic signs for death. Ann Emerg Med, 9, 134. Cooper MA, Andrews C, Holle R (2005). Lightning injuries. In: Auerbach P (ed) Wilderness medicine, 4th edition, pp. 73–​111. Mosby, St Louis, MO. Cooper MA, Andrews CJ (2005). Disability, not death, is the issue in lightning injury. Proc Int Conf On Lightn Stat Elec, Boeing, Seattle, WA. Hendler N (2005). Overlooked diagnoses in chronic pain: analysis of survivors of electric shock and lightning strike. J Occup Env Med, 47, 796–​805. Kurtulus, A., Acar, K., Adiguzel, E., Boz, B. (2008). Hippocampal neuron loss due to electric injury in rats: a stereological study. Legal Medicine (Tokyo), 22, 2671–​5. Lee RC, Capelli-​Schellpfeffer M, Kelley K (eds) (1994). Electrical injury: a multidisciplinary approach to prevention, therapy & rehabilitation. Ann N Y Acad Sci, 720. Lee RC, Cravalho EG, Burke JF (1992). Electric trauma. Cambridge University Press, Cambridge. Morse MS, Berg JS, TenWolde RL (2004). Diffuse electrical injury: a study of 89 subjects reporting long-​term symptomatology that is remote to the theoretical current Pathway. IEEE Trans Biomed Eng, 51, 1449–​59. Park K, et al. (2012). Alterations in arterial function after high-​voltage electrical injury. Critical Care, 16, R25. Reisner A (2013). Possible mechanisms for delayed neurological damage in lightning and electrical injury. Brain Injury, 27, 565–​9.

10.3.6  Diseases of high terrestrial altitudes Tyler Albert, Erik R. Swenson, Andrew J. Pollard, Buddha Basnyat, and David R. Murdoch ESSENTIALS Ascent to altitudes above 2500 m leads to exposure to hypobaric hypoxia. This affects performance on first arrival at high altitude and disturbs sleep, but physiological changes occur over time to defend arterial and tissue oxygenation and allow the individual to adjust. This process of acclimatization includes (1) an increase in the rate and depth of breathing; and (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 at altitude. Risk is increased by ascent to higher altitudes, by more rapid gain in altitude, and (in some people) genetic predisposition; the condition may be avoided in most cases by slow, graded ascent. Clinical presentation occurs soon after arriving at a new altitude, most often manifest as one of three conditions:

Acute mountain sickness A common condition that presents with non​specific symptoms, including headache and anorexia. The victim is likely to be apathetic, but clinical examination is generally unremarkable. Mild cases usually resolve with rest and avoidance of further ascent. Those whose symptoms fail to resolve (or worsen) should descend immediately. Treatment with acetazolamide (which can also be used as prophylaxis) or dexamethasone is often given in severe cases.

High-​altitude cerebral oedema An uncommon condition that typically presents with worsening symptoms of acute mountain sickness and ataxia, with progressive neurological symptoms including behavioural changes, confusion, and impairment of consciousness. Papilloedema and focal neurological signs may be present. Treatment is urgent, with the most important measure being descent. Oxygen or simulated descent using a portable hyperbaric chamber can be helpful. Dexamethasone is widely recommended (and can be used as prophylaxis).

High-​altitude pulmonary oedema A relatively uncommon condition with significant mortality that typically presents with dyspnoea and cough. Signs include low-​grade fever, tachycardia, tachypnoea, basal crepitations, and (in late disease) cyanosis. Treatment is urgent, with the most important measure being descent. Oxygen should be given if available. Simulated descent using a portable hyperbaric chamber can be helpful. Nifedipine reduces pulmonary artery pressure, relieves symptoms, and is usually given (and can be used as prophylaxis).

Chronic mountain sickness and other medical problems Chronic mountain sickness (Monge’s disease) is a disease of adults who reside for prolonged periods at high altitude and develop polycythaemia and eventually cor pulmonale. Symptoms appear to

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resolve with descent, but treatment with venesection has been attempted in those who remain at altitude. High-​altitude pulmonary hypertension has been described in both infants and adults, predominantly native lowlanders who ascend to and reside at high altitude: this also appears to resolve on descent. Pre-​existing medical conditions are mostly little affected by ascent to altitude, but people particularly likely to be affected by hypoxia/​altitude include those with (1) coronary ischaemia and a strongly positive exercise treadmill test; (2) sickle cell disease or trait; (3)  chronic pulmonary disease, especially pre-​existing pulmonary hypertension from any cause.

Introduction High-​altitude regions of the world, once considered remote and accessible to only a few individuals, are in fact home to over 200 million people living permanently above 2500 m in Asia, South America, and North America. In South America, miners and astronomers work for long durations at altitudes over 4500 m, while an equal number of tourists spend time at these altitudes in such activities as trekking, skiing, and pilgrimages. Anyone at these altitudes is susceptible to high-​altitude illnesses which, if not recognized and appropriately treated, can spoil the experience of alpine environments, impair work ability, and in the worst scenarios cause death.

The high-​altitude environment Although the percentage of oxygen in ambient air remains constant at 21%, barometric pressure decreases with increasing altitude, leading to a corresponding fall in partial pressure of oxygen (Po2) (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 the maximum for permanent human habitation, Po2 is about half of the sea-​level value. On the summit of Mount Everest (8848 m), Po2 is about one-​third of the sea-​level value. In human physiology, the definitions of high altitude in Box 10.3.6.1 are commonly used.

800 Barometric pressure (mmHg)

1702

700 Mont Blanc 4807 m

600

Mount Everest 8848 m

500 400 300 200

0

2000

4000 6000 8000 Altitude (m) Barometric pressure falls as altitude increases

10000

Fig. 10.3.6.1  Change in barometric pressure with altitude. © Pollard, Andrew J. and Murdoch, David R., The High Altitude Medicine Handbook (3e). Oxford: Radcliffe Medical Press Ltd; 2003. Reproduced with the permission of the copyright holder.

Box 10.3.6.1  Altitude—​definitions Intermediate altitude (1500–​2500 m) Physiological changes due to hypobaric hypoxia (such as reduced exercise performance, increased ventilation, increased haematopoiesis) are detectable, but arterial oxygen saturation remains above 90%. Acute altitude illness is unlikely. High altitude (2500–​3500 m) Acute altitude illness is common following rapid ascent to this altitude. Very high altitude (3500–​5800 m) Arterial oxygen saturation falls below 90%. Acute altitude illness is common and marked hypoxaemia can occur during exercise and sleep. Extreme altitude (>5800 m) Further acclimatization cannot be achieved, progressive physiological deterioration occurs, and survival cannot be maintained permanently. Marked hypoxaemia occurs at rest.

In addition to hypoxia, several other characteristics of the high-​ altitude environment are important to understand. Temperature decreases approximately 1°C for every 150  m rise in altitude, irrespective of latitude, so that high-​altitude areas are considerably colder. Ultraviolet penetration increases by approximately 12% for each 1000 m altitude gain, increasing the risk of sunburn, ultraviolet keratitis, and other sun-​related problems. The low humidity at high altitude contributes greatly to fluid loss and dehydration, as does the increased 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 associated with unhealthy concentrations of irritating gases and particulates.

Effects of hypobaric hypoxia A reduction in exercise capacity is a major effect of ascent to high altitudes. Maximal oxygen consumption decreases by approximately 10% for each 1000-​m gain in altitude above 1500 m, and this does not recover appreciably with acclimatization. Reduced maximal 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 partly responsible for individual variations in exercise performance at high altitudes. For example, Tibetans, a population having resided at high altitude for more than 25 000 years, have a variant of the gene encoding a transcription factor (hypoxia inducible factor -​2, HIF-​2), and mountaineers who perform well at high altitudes have a higher expression of an angiotensin-​converting enzyme gene variant. Sleep can also be disturbed at high altitude. There is difficulty getting to sleep, frequent arousals, less rapid eye movement (REM) time, and a decrease in slow-​wave sleep. Periodic breathing, characterized by episodes of hyperpnoea followed by apnoea, is relatively common among travellers over 2500 m. It is thought to result from instability of the respiratory control system through enhanced hypoxic drive or response to CO2, and can be minimized by the use of acetazolamide. Hypoxaemia during apnoeic episodes during periodic breathing likely accounts for many of the arousals from sleep that are experienced at high altitude.

10.3.6  Diseases of high terrestrial altitudes

Neuropsychological changes at high altitude are often quite subtle, although various changes in mental performance have been documented. Attention span, short-​term memory, arithmetic ability, and decision-​making can all be impaired at altitudes over 4000 m.

redistribution of blood flow: coronary and cutaneous flow both fall, cerebral and retinal flow increase, and renal flow decreases initially although returns to normal with acclimatization.

Acclimatization

Central blood volume increases with ascent to high altitude due to peripheral venous constriction. This, in turn, can suppress antidiuretic hormone and aldosterone to induce a diuresis along with an independent action of peripheral chemoreceptors stimulated by hypoxia to reduce renal sodium and water reabsorption.

Acclimatization is the process of gradual adjustment to high altitude hypoxia. In general, it is a physiological process involving a series of adjustments that occur in both the short term (minutes to hours) and long term (days to weeks). These changes enhance oxygen delivery to cells and efficiency of oxygen use. In contrast, ‘altitude adaptation’ refers to physiological changes that occur over longer time periods (decades and generations) and confer advantages for life at high altitude. Acclimatization reduces the impact of high-​altitude hypoxia, but is insufficient to fully return the body to its sea-​level normoxic capacities. The principal steps involved in high altitude acclimatization can be summarized as follows: Ventilation Hyperventilation is the most important feature of acclimatization and serves to defend alveolar Po2 and thus arterial and tissue Po2. Increases in the rate and depth of breathing, termed the hypoxic ventilatory response, are mediated by hypoxic stimulation of peripheral chemoreceptors located mainly in the carotid bodies. Hyperventilation increases alveolar Po2 in the face of decreased inspired Po2, while also reducing alveolar Pco2 leading to a respiratory alkalosis. Although initially the alkalosis limits the full hypoxic ventilatory response, eventually it is somewhat compensated for by increased urinary bicarbonate excretion over several days and subsequently followed by a further increase in ventilation over the course of several weeks, reflecting an increase in intrinsic hypoxic sensitivity of the peripheral chemoreceptors. The degree of hyperventilation in response to high-​altitude hypoxia can be profound and, with exercise, it may be what subjectively causes a person to have to stop. Alveolar ventilation increases approximately fivefold on the summit of Mount Everest, where inspired Po2 is less than one-​third of its sea-​level value and arterial Pco2 values as low as 10 mmHg at rest have been recorded. Blood Although erythropoietin secretion is increased within 2 h of ascent to high altitude, it takes many days to weeks for an increase in red cell mass to occur. This ultimately increases the oxygen-​carrying capacity of the blood and permits greater oxygen transport to tissues. The shift in the oxyhaemoglobin dissociation curve to the right, which occurs on ascent and is due to an increase in red cell 2,3-​diphosphoglycerate, which favours unloading of oxygen in the tissues. However, this particular adjustment is offset by the shift to the left caused by the respiratory alkalosis mentioned previously, leaving the P50 essentially unchanged. Circulation Although there is an abrupt increase in cardiac output on ascent to high altitude, there follows a progressive decrease in stroke volume and maximal cardiac output is reduced at all levels of exercise, including maximal exercise. Although there is no evidence for insufficient myocardial oxygenation, there is disagreement about whether the myocardium is depressed by hypoxia. There is an immediate

Fluid balance

Extreme altitudes Acclimatization in adults seems to be possible up to about 5500 m. Above this height, there is a fine balance between adjustment to high altitude and deterioration as a result of chronic hypoxia. The term ‘high-​altitude deterioration’ refers to the general deterioration in physical condition that occurs after lengthy stays at extreme altitudes. Typical features include progressive weight loss (fat and muscle), worsening appetite, poor sleep, and increased lethargy. The most extreme altitudes, such as the summit of Mount Everest, are very close to the limit of human tolerance to hypoxia. Indeed, early estimates indicated that all available oxygen on the summit of Mount Everest would be required for basal oxygen uptake, with none left for physical exertion. Alveolar gas samples taken near the summit of Everest (8400 m; barometric pressure, 36.3 kPa) show an inspired Po2  = 6.27 kPa, and alveolar Po2  =  4.00 kPa. Mean arterial gas values at this altitude were:  Po2 3.3 kPa; Pco2 1.8 kPa; pH 7.5; oxygen saturation 54%. Consequently, it is extraordinary that some humans are able to climb to this height without using supplementary oxygen. Missing in our efforts to fully describe acclimatization and the profound altitudes that some individuals can attain are profound changes at the levels of the microcirculation and cellular metabolism. Many of these might involve the hundreds of genes that are up-​and down-regulated by gene transcription factors called hypoxia inducible factors 1 and 2 (HIF). Several reports have suggested mild, possibly permanent, defects in cognition in climbers who have ascended to extreme high altitudes.

Illnesses due to altitude Until high-​altitude acclimatization has occurred, lack of physiological compensation for hypobaric hypoxia can manifest as altitude illness. Acute mountain sickness, high-​altitude pulmonary oedema, and high-​altitude cerebral oedema are recognized distinct clinical syndromes of altitude illness. Acute mountain sickness is both the most common and the quickest to develop, and while it often precedes high-​altitude pulmonary oedema or high-​altitude cerebral oedema, either can occur in its absence. Development of altitude illness usually occurs after a rapid ascent, although there is considerable variation in susceptibility between individuals. Genetic factors are likely to be important in determining susceptibility, but several other factors are contributory and are discussed in the following paragraphs. Acute mountain sickness Incidence rates of acute mountain sickness vary with the absolute altitude gained and the speed of ascent. Some 30–​50% of those who ascend to 4500 m on a standard trek in the Himalayas develop acute mountain sickness. Its incidence is greater at higher altitudes and

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with greater gains in altitude, and might be precipitated by physical exertion, although this remains controversial. Some people have a history of recurrent acute mountain sickness, suggesting individual susceptibility. Typically, symptoms of acute mountain sickness begin 6–​12 h after ascent to altitudes over 2500 m. The familiar features are non​specific symptoms that are readily confused with many other illnesses and include: • headache •  nausea • vomiting • fatigue • anorexia • dizziness • sleep disturbance For practical purposes, people ascending to altitude with unexplained symptoms that include the above mentioned should be assumed to have acute mountain sickness. The headache is typically worse at night, upon lying down, and with a Valsalva manoeuvre. Anorexia is often pronounced. Clinical examination is typically unremarkable, although it might reveal some peripheral oedema. There might be tachycardia and elevated core temperature. Typically, the person with acute mountain sickness is apathetic and withdrawn, often seeking solitude (see Fig. 10.3.6.2). The aetiology of acute mountain sickness is unknown. It has been argued that it is a mild form of cerebral oedema since it often precedes development of high-​altitude cerebral oedema, and the symptoms of acute mountain sickness include symptoms of headache and nausea consistent with a mild increase in intracranial pressure. Brain imaging studies have not found increases in global brain volume or oedema in the first 6–​10 h after exposure to hypoxia despite symptoms of acute mountain sickness, but it might be

that these techniques lack sufficient sensitivity, particularly if the oedema is not global. However, brain volume does increase after longer exposure to hypoxia. Some recent evidence suggests that oxidative stress might be involved in the development of acute mountain sickness. Other theories include hypoxia-​mediated irritation of the trigeminal system from hypoxia-​mediated increase in radical oxygen species or nitrosative radicals. Mild acute mountain sickness usually resolves if the victim avoids further ascent and rests. Paracetamol (acetaminophen), non​ steroidal anti-​ inflammatory agents, and other analgesics might bring relief from headache. Those whose symptoms fail to resolve or worsen should descend immediately. More severe symptoms will also resolve with descent, but some people will require treatment to facilitate descent. Supplementary oxygen might be beneficial if available. Treatment with acetazolamide (250 mg orally, three times daily), or dexamethasone (4 mg orally, four times daily) can be useful in severe cases. Acetazolamide is a carbonic anhydrase inhibitor, which increases renal excretion of bicarbonate to induce a metabolic acidosis. The hyperventilation induced by the respiratory compensation improves oxygenation and helps relieve symptoms. Portable hyperbaric chambers are widely used on trekking routes and can be pressurized to simulate a 500–​700 m descent, temporarily relieving symptoms in order to facilitate a true descent. These chambers are inflated with a hand or foot pump to achieve the barometric pressure of a lower elevation. CO2 is removed by the airflow generated by the pumping action, and a CO2 scrubber is included in some models. Acute mountain sickness can be avoided or prevented in most cases by carefully graded ascent. Above 3000 m, a rate of ascent of 300–​600 m per day with a rest day every 1000 m will avoid symptoms for most people. However, there is considerable individual variation. For some destinations, itineraries are rapid enough to induce 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

of travellers. For this reason, prophylaxis with acetazolamide, started on the day before ascent over 3000 m (125–​250 mg twice daily or 250–​500 mg daily of the slow-​release preparation) is frequently recommended for prevention and can be quite effective. Since the side effects induced by this drug may be serious (allergic reactions), mimic acute mountain sickness in some respects (headache, nausea, anorexia), or be intolerable (paresthesiae), several test doses should be tried before it is used for prophylaxis during ascent. There is evidence that acetazolamide doses of 125 mg twice daily can be effective in some people. Dexamethasone can also be useful for prophylaxis, although its mechanism of action is unknown. One study found that the inhaled corticosteroid budesonide, in doses unable to generate significant blood levels to act at the brain, was as effective as oral dexamethasone. However, two subsequent studies could not confirm this efficacy. In recent trials, ginkgo biloba has been found to be ineffective and thus is not advised, particularly since it is not a regulated pharmaceutical and preparations can vary in content and contamination with other substances. Theophylline reduces periodic breathing during sleep, but not oxygenation, and probably has little utility in prophylaxis. High-​altitude cerebral oedema Unlike acute mountain sickness, which is quite common among travellers to high altitude, high-​ altitude cerebral oedema and high-​altitude pulmonary oedema are relatively uncommon. High-​ altitude cerebral oedema is more typical after ascent to altitudes over 4000 m, but cases have been described even at the modest elevation of 2100 m. As with acute mountain sickness, higher rates are found at the highest altitudes and after more rapid ascent. At 4000 to 5500 m, rates of 1% have been described amongst trekkers. High-​altitude cerebral oedema is usually preceded by acute mountain sickness and is frequently associated with high-​altitude pulmonary oedema since the greater hypoxemia occurring with high-​altitude pulmonary oedema is the equivalent to suddenly being at an even higher altitude (see following paragraphs). Symptoms of acute mountain sickness have usually been present for 1 to 2 days before the onset of high-​altitude cerebral oedema. Risk factors for the development of high-​altitude cerebral oedema are probably similar to those recognized for other forms of altitude illness. high-​altitude cerebral oedema might be more common in the presence of intracranial space-​occupying lesions such as cysts or tumours. Worsening symptoms of acute mountain sickness and ataxia are typical early signs of development of high-​altitude cerebral oedema. Behavioural changes (being irrational, withdrawn, or exuberant), confusion, and a change in conscious level leading to coma might ensue. Papilloedema might be present. Both focal neurological signs and cranial nerve lesions can occur. Brain imaging studies show typical signs of cerebral oedema, particularly in the splenium of the corpus callosum, with changes in white matter signal, compression of sulci, and blunting of gyri. Lumbar puncture, if undertaken, reveals elevated pressures but is otherwise normal. High-​altitude cerebral oedema is indistinguishable clinically from many other causes of compromised cerebral function. There is a very high mortality among those who develop coma. It is likely that high-​altitude cerebral oedema is a vasogenic oedema resulting from injury to the blood–​brain barrier, following disturbances in cerebral autoregulation. Cytotoxic oedema from

release of mediators in the central nervous system in response to hypoxia might also contribute. In view of the seriousness of high-​altitude cerebral oedema, treatment is urgently required, and the most important measure is immediate descent. Oxygen therapy or simulated descent using a portable hyperbaric chamber can improve oxygenation and symptoms and thus facilitate descent. Intravenous dexamethasone (8 mg followed by 4 mg, orally four times per day) might improve symptoms and is widely recommended. high-​altitude cerebral oedema tends to recover more slowly than other forms of altitude illness and ataxia is often the last sign to disappear. High-​altitude cerebral oedema is probably prevented by slow, graded ascent (as with acute mountain sickness described previously) and prophylaxis with dexamethasone might be beneficial for those with a risk of the condition. High-​altitude pulmonary oedema High-​altitude pulmonary oedema typically occurs within 4  days of ascent to altitudes over 2500 m and might be accompanied by symptoms of acute mountain sickness or high-​altitude cerebral oedema. It presents more frequently with increasing altitude:  1–​2% of people may be affected at 4500 m, but rates as high as 10% have been reported after rapid ascent at this altitude. Previous episodes of high-​altitude pulmonary oedema for an individual repeating the same ascent rate and altitude gain confer a 60–​70% likelihood of recurrence. It can also occur in those who have become acclimatized at one altitude and then make a further ascent. A form of high-​altitude pulmonary oedema, known as re-​entry high-​altitude pulmonary oedema, can occur in adults and often more in children living at high altitude after returning home from a lowland vacation. It is a serious form of altitude illness and is associated with fatality when not managed urgently and appropriately. High-​altitude pulmonary oedema is slightly more common in men than women. The risk of it developing is increased by cold, rapid ascent, exertion, coexistent viral infection, and possibly by drugs or ingestions that cause respiratory depression, such as alcohol. Individual susceptibility is well recognized and those who have previously suffered from it appear to be more susceptible in the future. There are various genetic associations described including pulmonary surfactant protein A, HLA DR6, HLA DQ4, epithelial sodium channel protein, and endothelial nitric oxide synthase. People with raised pulmonary blood flow or an exaggerated hypoxic pulmonary vascular response might also be more susceptible (i.e. those with atrial septal defect, unilateral absence of a pulmonary artery or a chronic respiratory condition). People with high-​altitude pulmonary oedema typically present with dyspnoea out of proportion to others in the group and cough. The breathlessness is made worse with exertion and can present with blood-​tinged frothy sputum and frank haemoptysis. Other symptoms include chest pain, orthopnoea, nausea, insomnia, headache, dizziness, and confusion. Low-​grade fever is a common finding together with tachycardia, tachypnoea, crackles on auscultation of the chest, and cyanosis in late disease. Signs of right ventricular enlargement can be present with an accentuated pulmonary second heart sound and right ventricular heave. Oxygen saturations are decreased from the prevailing levels of those acclimatizing well, the electrocardiogram shows right axis deviation, tachycardia, and peaked P-​waves, and the chest radiograph

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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 on the right. In patients who have been studied with cardiac catheterization during high-​altitude pulmonary oedema, pulmonary arterial pressure is often quite elevated, but pulmonary wedge pressures are normal, ruling out heart failure. Most people who are susceptible to high-​altitude pulmonary oedema show an abnormal rise in their pulmonary arterial pressure at sea level during exposure to hypoxia or on normoxic exercise. Hypoxic pulmonary vasoconstriction varies almost fivefold among healthy persons, and at sea level or low altitudes poses no problems. The clinical syndrome is not unique, and similar findings occur in other respiratory diseases, including acute bacterial or viral pneumonia and pulmonary embolism. High-​altitude cough (see following paragraph) might also cause diagnostic confusion. As described earlier, high-​altitude pulmonary oedema appears to result from an exaggerated hypoxic pulmonary vasoconstrictor response. Because there is regional unevenness in the response, this leads to downstream pressure increase in over-​perfused areas that lead to capillary leak, either from pressure induced changes in permeability or at the extreme capillary stress failure and frank bleeding into the alveolar space. Once high-​altitude pulmonary oedema is recognized, the victim must descend. Even descent of several hundred metres can be enough to raise the barometric pressure sufficiently to increase inspired oxygen tensions and reduce pulmonary artery pressure. Without appropriate management, it can be fatal, and further ascent should not be undertaken. In a mountain environment, immediate descent might be impossible because of weather or other circumstances. The patient might be so breathless that they cannot move and, as mentioned earlier, at a very high risk to develop high-​altitude cerebral oedema. Adjunctive therapies might improve symptoms and allow descent. The patient should be encouraged to sit up to prevent orthopnoea. Oxygen should be given if available. As a strong inhibitor of hypoxic pulmonary vasoconstriction, nifedipine (20 mg slow release preparation, four times daily) reduces pulmonary artery pressure and relieves symptoms. Side effects of nifedipine include headache, dizziness, and postural hypotension, but the drug is generally well tolerated. Other pulmonary vasodilators such as hydralazine, phentolamine, inhaled nitric oxide,

and sildenafil have been used and might be beneficial, but nifedipine is most widely used. Portable hyperbaric chambers are often available on commercial trekking routes (see Fig. 10.3.6.4). They can simulate descent, improve oxygenation, and relieve symptoms. Devices that help provide positive expiratory airway pressure might also improve oxygenation. The risk of high-​altitude pulmonary oedema is reduced by slow, graded ascent. Above 3000 m, a rate of ascent of 300–​600 m per day with a rest day every 1000 m is recommended. Nifedipine (20-​mg slow release preparation, three times daily) and other calcium channel blockers, dexamethasone (8 mg twice daily), inhaled salmeterol, a β2-​ andrenoceptor agonist, and phosphodiesterase-​ 5 inhibitors are effective for prophylaxis in those known to be susceptible. Acetazolamide, which inhibits hypoxic pulmonary vasoconstriction by a mechanism unrelated to its action as a carbonic anhydrase inhibitor, might also be effective in its prevention, although it has not been formally tested for this indication. Dexamethasone, while effective in prevention for high-​altitude pulmonary oedema-​susceptible persons, does not appear to be efficacious in treatment. This might stem from the fact that its action largely is dependent on changes in gene transcription that require many hours to become effective. High-​altitude retinal haemorrhage Retinal haemorrhages occur frequently at altitudes of 5000 m or higher, even in those without acute mountain sickness or high-​ altitude cerebral oedema. Although usually asymptomatic, they can cause visual problems if the macula is involved (Fig. 10.3.6.5). The causes of high-​altitude retinal haemorrhage can include increased cerebral blood flow, Valsalva manoeuvres (during exertion or coughing), polycythaemia, and hypoxia-​mediated capillary endothelial permeability. In most instances of high-​altitude retinal haemorrhage without altitude illness, descent might not be necessary. The haemorrhages usually resolve within days to weeks. If vision is compromised or there is concomitant altitude illness, descent is mandatory. Peripheral oedema Swelling of the hands, face, and ankles commonly occurs at high altitude and might not be related to acute mountain sick­ ness, high-​altitude cerebral oedema, or high-​altitude pulmonary

10.3.6  Diseases of high terrestrial altitudes

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 the oedema. High-​altitude cough Dry hacking cough is a common, bothersome problem at high altitude, and has caused rib fractures in some severe cases. High-​ altitude cough is probably multifactorial in origin: water loss from the airways due to hyperventilation of cold-​dry air, post nasal drip, acute mountain sickness, high-​altitude pulmonary oedema, and bronchoconstriction have all been invoked as possible causes of altitude related cough. Breathing through a silk scarf, throat lozenges, and steam inhalation might be helpful. If there is nasal congestion, a decongestant nasal spray is useful.

Effects of high altitude on pre-​existing medical conditions Hypertensive patients should continue their medications at high altitude, and the vast majority of hypertensive skiers and trekkers do very well despite a transient rise in the blood pressure. Some patients with labile hypertension might have a sudden, dangerous rise in their blood pressure at high altitude and, for them, blood pressure monitoring might be necessary. The exaggerated blood pressure response to high altitude is apparently mediated by increased α-​adrenergic activity. Hence an α-​blocker might be useful or, as shown recently in a well-​conducted randomized study, angiotensin receptor blockade with valsartan up to 3500 m is effective. People with stable coronary artery disease tolerate intermediate and high altitudes relatively well, even while exercising. This might be partly attributable to the marked reduction in maximal exercise at high altitude, which reduces myocardial oxygen demand and maximal heart rate. Animal experiments at high altitude have

also demonstrated down-​regulation of the β-​receptors of the heart. However, travel to high altitude can precipitate new-​ onset angina, although it is unclear whether this is related to exertion or to hypobaric hypoxia as such. People with cardiac risk factors or with previous myocardial ischaemia, coronary artery bypass surgery, or angioplasty are considered to be at high risk if they have a strongly positive exercise treadmill test. Although cold air and exercise are triggers for asthma, many asthmatics remain well at high altitude. This might be due to decreased density of the air, a lack of allergens, or the increase in steroid hormones produced under hypoxic stress. However, it is important for asthmatics going up to high altitude to carry their medicines (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 to high altitudes, but there remain some causes for concern. Hyperventilation leading to hypocapnia and hypoxia are themselves triggers for seizure activity. People with sickle cell disease or trait are at high risk of sickle crises above 2000 m, and should avoid staying at altitude. Diabetics might find that increased energy expenditure at high altitude alters carbohydrate and insulin requirements. Consequently, rapidly acting insulin, close monitoring, availability of oral and intravenous glucose, and knowledgeable companions are important. Loss of diabetic control due to intercurrent infections, like diarrhoea, is also possible. It is especially important that insulin preparations never freeze, and one option for prevention is by keeping them close to the body. Pre-​existing pulmonary hypertension from any cause can be a problem at high altitude and comes close to being an absolute contraindication to travel above very modest altitudes (20 tablets). Convulsions with mefenamic acid are unlikely to be persistent but, if they are, should be managed by diazepam 10–​20 mg intravenously or lorazepam ​4 mg intravenously.

Treatment Treatment is supportive. Methaemoglobin concentrations exceed­ ing 30% should be treated with intravenous methylthioninium chloride (methylene blue) 1–​2 mg/​kg.

Opiates and opioids 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 selec­ tive, agents are thought to inhibit the inducible form of cycloxygenase (COX-​2) more than the other forms of the enzyme. These drugs, therefore, all tend to inhibit prostaglandin synthesis, and the main toxicity seen in overdose is on the kidney. In very large doses, central nervous system effects may be seen but these are uncommon. Non​ steroidal anti-​ inflammatory drugs (NSAIDs) come in different chemical groupings:  oxicams (meloxicam, piroxicam, ­ tenoxicam) and phenylpropionic (arylpropionic) acid derivatives (e.g. fenbufen, ibuprofen, naproxen, tiaprofenic acid, mefenamic acid). The COX-​2 selective agents are also potentially nephrotoxic in overdose due to inhibition of renal prostaglandin synthesis.

Mechanisms of toxicity The toxicity of paracetamol is related to its metabolism (Fig. 10.4.1.1). In therapeutic doses, 60–​90% is metabolized by conjugation to form paracetamol glucuronide and sulphate. A much smaller amount (5–​10%) is oxidized by mixed function oxidase enzymes to form a highly reactive compound (N-​acetyl-​ p-​benzoquinoneimine, NAPQI), which is then immediately conjugated with glutathione and subsequently excreted as cysteine and mercapturate conjugates. Only 1–​4% of a therapeutic dose of the drug is excreted unchanged in urine. In overdose, larger amounts of paracetamol are metabolized by oxidation because of saturation of the sulphate conjugation pathway. As a result, liver glutathione stores become depleted so NHCOCH3

NHCOCH3

NHCOCH3

GSH δ+

OSO3H

NHCOCH3

Paracetamol sulphate NHCOCH3

OH Paracetamol

O

O

N-Acetyl-p-benzoquinoneimine (NAPQI) NHCOCH3

Paracetamol glucuronide

Glutathione conjugate

NHCOCH3 NHCOCH3

SCH2CHCO2H OC6H9O6

GSH

OH Paracetamol mercapturic acid

Fig. 10.4.1.1  Metabolism of paracetamol.

SCH2CHCO2H OH Cysteine conjugate

10.4.1  Poisoning by drugs and chemicals

that the liver is unable to deactivate the toxic metabolite. NAPQI is believed to have two separate but complementary effects. Firstly, it reacts with glutathione, thereby depleting the cell of its normal defence against oxidizing damage. Secondly, it is a potent oxidizing as well as arylating agent; it inactivates key sulphydryl groups in certain enzymes, particularly those controlling calcium homeostasis. Paracetamol-​ induced renal damage probably results from a mechanism similar to that causing for hepatotoxicity (i.e. by formation of NAPQI). As would be expected from the mechanism of toxicity, the severity 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, however, some variation in individual susceptibility to paracetamol-​ induced hepatotoxicity. Those with a high alcohol intake and poor nutrition, and those suffering from anorexia nervosa or acute starvation have glutathione depletion and are at higher risk. Individuals with HIV-​related disease also appear to be more susceptible to paracetamol-​induced hepatic damage. Those receiving enzyme-​ inducing drugs are also at greater risk. Clinical features The features of paracetamol poisoning are summarized in Table 10.4.1.5. Biochemical and haematological abnormalities may also occur (Table 10.4.1.6). Following the ingestion of an overdose of paracetamol, patients usually remain asymptomatic for the first 24 h, or at most develop anorexia, nausea, and vomiting. Paracetamol-​induced kaluresis may cause hypokalaemia. Liver damage is not usually detectable by routine liver function tests until at least 12 h after ingestion of the drug, and hepatic tenderness and abdominal pain are seldom exhibited before the second day. Liver damage reaches a peak, as assessed by plasma alanine or aspartate aminotransferase (ALT, AST) activity or prothrombin time (international normalized ratio, INR), 72–​96 h after ingestion. More often there is prolongation of the prothrombin time and a marked rise in aminotransferase activity (activities of several thousand are not uncommon) without the development of fulminant hepatic failure. Renal failure due to acute tubular necrosis develops in about 25% of patients with severe

Table 10.4.1.5  Clinical features of untreated paracetamol poisoning (>200 mg/​kg) Day 1

Day 2

Day 3

Asymptomatic

May become asymptomatic or develop symptoms de novo

(in severe untreated poisoning)

Nausea

Vomiting

Jaundice → liver failure → hepatic encephalopathy

Vomiting

Hepatic tenderness ± generalized abdominal tenderness

Back pain + renal angle tenderness → renal failure

Abdominal pain

Occasionally, mild jaundice

Cardiac arrhythmias

Anorexia

Disseminated intravascular coagulation Pancreatitis

Table 10.4.1.6  Biochemical and haematological abnormalities in paracetamol poisoning Biochemical abnormalities

Haematological abnormalities

AST/​ALT ↑↑

PT ↑

Bilirubin ↑

Platelets ↓

Blood sugar ↓

Clotting factors II ↓ V ↓ VII ↓

Creatinine ↑ Lactate ↑ Phosphate ↓ Amylase ↑ Potassium ↓ early due to kaluresis ↑ later in renal failure

hepatic damage and in a few without evidence of serious disturbance of liver function. Other features, including hypoglycaemia and hyperglycaemia, cardiac arrhythmias, pancreatitis, gastrointestinal haemorrhage, and cerebral oedema may all occur with hepatic failure due to any cause and are not direct consequences of paracetamol toxicity. Paracetamol can cause metabolic acidosis at two distinct periods after overdosage. Transient hyperlactataemia is frequently found within the first 15 h in all but minor overdoses and appears to be due to inhibition of mitochondrial respiration at the level of ubiquinone and increased lactate production. It is rarely of clinical consequence, although in very severe paracetamol poisoning (plasma paracetamol concentration >500 mg/​ litre at 4 h after ingestion) the acidosis may be very rarely associated with coma. The second phase of hyperlactataemia and acidosis occurs in those patients who present late and go on to develop hepatic damage; in this instance, decreased hepatic lactate clearance appears to be the major cause, compounded by poor peripheral perfusion and increased lactate production. Hypophosphataemia is a recognized complication of acute liver failure, including that due to paracetamol, and may contribute to morbidity and mortality by inducing mental confusion, irritability, coma, and abnormalities of platelet, white cell, and erythrocyte 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-​ induced renal tubular damage. Prediction of liver damage In the early stages following ingestion of a paracetamol overdose, most patients have few symptoms and no physical signs. There is thus a need for some form of assessment that estimates the risk of liver damage at a time when the liver function tests are still normal. Details of the dose ingested may be used but, in many cases, the history is unreliable and, even when the dose is known for certain, it does not take account of early vomiting and individual variation in response to the drug. However, a single measurement of the plasma paracetamol concentration is an accurate predictor of liver damage provided that it is taken not earlier than 4 h after ingestion of the overdose. Information gained from several studies has enabled the production of graphs which may be used for prediction of liver damage and which serve as

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SECTION 10  Environmental medicine, occupational medicine, and poisoning

a guide to the need for specific treatment (Fig. 10.4.1.2). These may not be accurate with slow-​release products. In patients who have taken several overdoses of paracetamol over a short period of time, the plasma paracetamol concentration will be meaningless in relation to the treatment graph. Such patients should be considered at risk and treated. Patients who regularly consume alcohol in excess of currently recommended limits (particularly those who are malnourished), those who regularly take enzyme-​inducing drugs (e.g. carbamazepine, phenytoin, phenobarbital, and rifampicin) and those with conditions causing glutathione depletion (e.g. malnutrition and HIV infection) may be at risk of liver damage. Studies in the early 1970s showed that 60% of patients whose plasma paracetamol concentration was above the line drawn between 200 mg/​litre (1.32 mmol/​litre) at 4 h and 50 mg/​litre (0.33 mmol/​ litre) at 12 h after the ingestion of the overdose were likely to sustain liver damage (ALT or AST >1000 u/​litre), unless specific protective treatment were given. There are now two approaches to risk management used worldwide. In the United Kingdom, following a decision by the MHRA in 2012 to abandon a detailed risk assessment in the decision to treat, it is deemed that patients with concentrations above a ‘treatment line’ starting at 100  mg/​litre (0.66  mmol/​litre 4 h after ingestion (Fig. 10.4.1.2) require therapy with antidote. In North America and Australasia, a parallel line starting at 150 mg/​litre 4 h after ingestion is used. The MHRA decision aims to prevent one death in the United Kingdom approximately every 2.1 years, and has been criticized as being too cautious and resulting in many unnecessary treatments. Patients who ingest multiple overdoses, or take repeated therapeutic excess, are at greater risk of liver damage and decisions to treat them are generally based on dose ingested. Current UK advice is very conservative with a treatment cut-​off of paracetamol dose above 75 mg per kilogram in 24 h.

Paracetamol nomograms 220

Original ‘200 mg’ Line International ‘150 mg’ Line UK ‘100 mg’ Line

200 180 160 140 120 100 80 60 40 20 0 0

2

4

6

8

10

12

14

16

18

20

22

Plasma paracetamol concentration (mmol/litre)

1.6 1.5 1.4 1.3 1.2 1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

240 Plasma paracetamol concentration (mg/litre)

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24

Time (hours)

Fig. 10.4.1.2  Paracetamol treatment nomograms. Those above the treatment lines are regarded at risk and treated with acetylcysteine. Thresholds differ in different countries, the ‘100 mg’ line being used in the United Kingdom. There is a scarcity of data after 15 h and the dotted lines show extrapolations used in clinical practice.

Prognostic factors The overall mortality of paracetamol poisoning in untreated patients is only of the order of 5%. A rise in transaminase (ALT/​AST) activity is usually the first liver function test to become abnormal, but a rise in INR is of particular value in assessing the prognosis of an individual patient. The more rapid the increase in ALT and INR, the worse the prognosis of the patient. A prothrombin time of more than 20 s at 24 h after ingestion indicates that significant hepatic damage has been sustained, and a peak prothrombin time of more than 180 s is associated with a chance of survival of less than 8%. Acid–​base disturbances are also a good guide to prognosis. Systemic acidosis developing more than 24 h after overdose indicates a poor prognosis; patients with a blood pH below 7.30 at this time have only a 15% chance of survival. In addition, a rise in the serum creatinine concentration is associated with poor survival; patients with a serum creatinine concentration above 300 µmol/​litre have only a 23% chance of survival. A study of prognostic indicators in patients who died of paracetamol-​ induced fulminant hepatic failure treated conventionally compared measurement of factors V and VIII with conventional tests. An admission pH below 7.30 with a serum creatinine concentration above 300 µmol/​litre and a prothrombin time above 100 s in patients with grade III–​IV encephalopathy had a sensitivity, predictive accuracy, positive prediction value, and specificity of 91, 86, 83, and 91%, respectively. However, a factor VIII/​V ratio above 30 had comparable values of 91, 95, 100, and 100%. Novel biomarkers (e.g. microRNAs) are now being studied which may give an earlier more accurate risk assessment than is possible with conventional approaches. 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. Patients who have taken staggered overdoses should be treated with an antidote irrespective of the plasma paracetamol concentrations. They can be discharged after antidotal treatment, provided they are asymptomatic and the INR, plasma creatinine concentration, and ALT activity are normal. Patients who present 15 h or more after overdose tend to be more severely poisoned and at greater risk of developing serious liver damage and should receive antidotal treatment as the plasma concentration alone may not be an accurate guide of severity; it may be non​detectable at the time of late presentation. The INR, venous pH, plasma creatinine concentration, and liver function tests are helpful in determining prognosis. Acetylcysteine Acetylcysteine acts by replenishing cellular glutathione stores and may also repair oxidation damage caused by NAPQI either directly or, more probably, through the generation of cysteine and/​or glutathione. It may also act as a source of sulphate and so ‘unsaturate’ sulphate conjugation. Two principal regimens for acetylcysteine have been employed. The most widely utilized worldwide is a 21-​h protocol (Table 10.4.1.7); the oral protocol previously used in the United

10.4.1  Poisoning by drugs and chemicals

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 States being replaced by IV therapy. An alternative 12 h IV protocol (100 mg/​kg over 2h, 200 mg/​kg over 10 h) that is associated with far fewer antidote-​induced adverse events is also being employed. Provided that acetylcysteine is administered within 8–​10 h of overdose, the development of hepatic damage is normally prevented; thereafter, the protective effects decline rapidly. Up to 10% of patients treated with intravenous acetylcysteine (20–​21 ​h regimen) develop rash, angioedema, hypotension, and bronchospasm. Far higher proportions (up to 70%) develop nausea and vomiting, with treatment required in up to 30%. These reactions, which are due to the initial bolus, cause very few fatalities but cause treatment interruption and patient distress. Anaphylactoid reactions are far more common at lower paracetamol concentrations, so more aggressive use of the antidote increases the incidence of these reactions. Antihistamines, such as chlorpheniramine and bronchodilators (e.g. salbutamol), may be given if such anaphylactoid reactions do occur, but discontinuing the infusion temporarily may be all that is required. Management of severe liver damage A 10% glucose solution should be administered to prevent the onset of hypoglycaemia. If fulminant hepatic failure supervenes, the use of a continued intravenous acetylcysteine (the 16-​h infusion is continued until recovery or death) will reduce morbidity and mortality. In one prospective study, the survival rate in 25 patients with paracetamol-​induced fulminant hepatic failure was 20%, with an incidence of cerebral oedema and of hypotension requiring inotropic support of 68 and 80%, respectively. With acetylcysteine, the comparable figures in 25 matched patients were 48% (survival rate), 40% (cerebral oedema), and 48% (hypotension). A proton pump inhibitor will reduce the risk of gastrointestinal bleeding from ‘stress’ ulceration/​erosion. There is no evidence that fresh frozen plasma prevents gastrointestinal haemorrhage in patients with severe coagulation abnormalities (prothrombin time >100 s). If acute renal failure supervenes, then this should be managed conventionally. Liver transplantation has been performed successfully in patients with paracetamol-​induced fulminant hepatic failure.

Salicylates Salicylate poisoning may result from overdose of aspirin tablets, percutaneous absorption of salicylic acid (used in keratolytic agents), and ingestion of methyl salicylate (‘oil of wintergreen’). In therapeutic doses, aspirin is absorbed rapidly from the stomach and small intestine, but in overdose, absorption may occur more slowly, and plasma salicylate concentrations may continue to rise for up to 24 h. The pharmacokinetics of elimination of aspirin are important determinants of salicylate toxicity. Biotransformation to both

Salicylic acid Conjugation with glycine

Hydroxylation

Salicyluric acid

Salicylacyl glucuronide

Conjugation with glucuronic acid

Gentisic acid

Salicylphenolic glucuronide

Fig. 10.4.1.3  Metabolism of aspirin.

salicyluric acid and salicylphenolic glucuronide (Fig. 10.4.1.3) is saturable with the following clinical consequences:  (1) the time needed to eliminate a given fraction of a dose increases with increasing dose; (2)  the steady state plasma concentration of salicylate, particularly that of the pharmacologically active non-​ protein-​bound fraction, increases more than proportionately with increasing dose; and (3) renal excretion of salicylic acid becomes increasingly important; a pathway which is extremely sensitive to changes in urinary pH. When ingested in overdose, salicylates directly stimulate the respiratory centre to produce both increased depth and rate of respiration, thereby causing a respiratory alkalosis (Fig. 10.4.1.4). At least part of this effect is due to local uncoupling of oxidative phosphorylation within the brainstem. In an attempt to compensate, bicarbonate, accompanied by sodium, potassium, and water, is excreted in the urine resulting in dehydration and hypokalaemia. More importantly, the loss of bicarbonate diminishes the buffering capacity of the body and allows an acidosis to develop more easily. Very high salicylate concentrations in the brain depress the respiratory centre and may further contribute to the development of acidaemia. Simultaneously, a variable degree of metabolic acidosis develops, not only because of the presence of salicylic acid itself, but also because of interference with carbohydrate, lipid, protein, and amino acid metabolism by salicylate ions (Fig. 10.4.1.4). Inhibition of citric acid cycle enzymes causes an increase in circulating lactic and pyruvic acids. Salicylates stimulate fat metabolism and cause increased production of the ketone bodies, β-​hydroxybutyric acid, acetoacetic acid, and acetone. Dehydration and lack of food intake, because of vomiting, further contribute to the development of ketosis. Protein catabolism is accelerated and synthesis diminished. Aminotransferases (responsible for the interconversion of amino acids) are inhibited. Increased circulating blood concentrations of amino acids result, together with aminoaciduria; inhibition of active tubular reabsorption of amino acids also contributes. Aminoaciduria increases the solute load on the kidneys and, thereby, increases water loss from the body. A primary toxic effect of salicylates in overdose is uncoupling of oxidative phosphorylation (Fig. 10.4.1.4). ATP-​dependent reactions are inhibited, and oxygen utilization and CO2 production are increased. Energy normally used for the conversion of inorganic phosphate to ATP is dissipated as heat. Hyperpyrexia and sweating result, causing further dehydration. Fluid loss is enhanced because

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SECTION 10  Environmental medicine, occupational medicine, and poisoning

Hyperglycaemia

Catecholamines Tissue glycolysis Glucocorticoids Uncoupling of oxidative phosphorylation

Hepatic glycogenolysis Stimulation of respiratory centre

O2 consumption CO2 production

Buffering capacity HCO3−(and Na+ K+and H2O) excretion Cardiac output

Stimulation of chemoreceptor trigger zone

Vomiting and decreased oral fluid intake

Neuroglycopenia

Stimulation of lipid metabolism

Hyperpyrexia and sweating

Respiratory rate Respiratory alkalosis

Hypoglycaemia

Depression of respiratory centre

Respiratory acidosis

Inhibition of Ketone body Krebs cycle formation enzymes Circulating pyruvic and lactic acid levels Circulating amino-acid Metabolic acidosis levels Inhibition of amino acid metabolism

Renal clearance of sulphuric and phosphoric acids

Dehydration and electrolyte imbalance

Aminoaciduria

Fig. 10.4.1.4  Pathophysiology of salicylate poisoning.

salicylates stimulate the chemoreceptor trigger zone and induce nausea and vomiting and, thereby, diminish oral fluid intake. If dehydration is sufficiently marked, low cardiac output and oliguria will aggravate the metabolic acidosis already present which, if severe, can itself diminish cardiac output. Glucose metabolism also suffers as a result of uncoupled oxidative phosphorylation because of increased tissue glycolysis and peripheral demand for glucose (Fig. 10.4.1.4). This is seen principally in skeletal muscle and may cause hypoglycaemia. The brain appears to be particularly sensitive to this effect and neuroglycopenia can occur in the presence of a normal blood sugar level when the rate of utilization exceeds the rate at which glucose can be supplied from the blood. Increased metabolism and peripheral demand for glucose activates hypothalamic centres, resulting in increased adrenocortical stimulation and release of adrenaline. Increased glucose 6-​phosphatase activity and hepatic glycogenolysis contribute to the hyperglycaemia, which is sometimes seen following ingestion of large amounts of salicylate. Increased circulating adrenocorticosteroids exacerbate fluid and electrolyte imbalance. Although this is rarely a practical problem, salicylate intoxication may be accompanied by hypoprothrombinaemia due to a warfarin-​like action of salicylates on the physiologically important vitamin K epoxide cycle. Vitamin K is converted to vitamin K 2,3-​epoxide and then reconverted to vitamin K by a liver membrane reductase enzyme, which is competitively inhibited by warfarin and salicylates. Clinical features and assessment of severity of salicylate intoxication The dose of salicylate ingested and the age of the patient are the principal determinants of the severity of an overdose. The plasma salicylate concentration should be determined on admission, but it is important to repeat it 2 h later to ensure that the concentration is not rising. If the concentration has risen, the level should be repeated after a further 2 h. Generally speaking, plasma salicylate

concentrations that lie between 300–​500 mg/​litre some 6 h after ingestion of an overdose are associated with only mild toxicity, concentrations between 500 and 700 mg/​litre are associated with moderate toxicity, and concentrations in excess of 700 mg/​litre confirm severe poisoning. Salicylate poisoning of any severity is associated with sweating, vomiting, epigastric pain, tinnitus, and deafness (Table 10.4.1.8). Young children quickly develop metabolic acidosis following the ingestion of aspirin in overdose, but by the age of 12 years the usual adult picture of a combined dominant respiratory alkalosis and mild metabolic acidosis is seen. To some extent, the presence of an alkalaemia protects against serious salicylate toxicity because salicylate remains ionized and unable to penetrate cell membranes easily. Development of acidaemia allows salicylates to penetrate tissues more readily and leads, in particular, to central nervous system toxicity characterized by excitement, tremor, delirium, convulsions, stupor, and coma. Very high plasma salicylate concentrations cause

Table 10.4.1.8  Clinical features of salicylate poisoning

• Nausea, vomiting, and epigastric discomfort • Irritability, tremor, tinnitus, deafness, blurring of vision • Hyperpyrexia, sweating, dehydration • Tachypnoea and hyperpnoea • Non​cardiogenic pulmonary oedema • Acute renal failure • Mixed respiratory alkalosis and metabolic acidosis (except in children who usually develop metabolic acidosis alone)

• Hypokalaemia, hypernatraemia, or hyponatraemia • Hyperglycaemia or hypoglycaemia • Hypoprothrombinaemia (rare) • Confusion, delirium, stupor, and coma (in severe cases)

10.4.1  Poisoning by drugs and chemicals

paralysis of the respiratory centre and cardiovascular collapse due to vasomotor depression. Pulmonary oedema is seen occasionally in salicylate poisoning and, although this is often due to fluid overload as a result of treatment, it may be non​cardiac and occur in the presence of hypovolaemia. In these circumstances, the pulmonary oedema fluid has the same protein and electrolyte composition as plasma, suggesting increased pulmonary vascular permeability. Although aspirin overdose may be complicated by inhibition of platelet aggregation and hypoprothrombinaemia, gastric erosions, and gastrointestinal bleeding are rare following acute salicylate overdose. Oliguria is sometimes seen in patients following the ingestion of salicylates in overdose. The most common cause is dehydration but, rarely, acute renal failure or inappropriate secretion of antidiuretic hormone may occur. Although the urine pH may be alkaline in the early stages of salicylate overdose, it soon becomes acidic. Measurement of arterial blood gases, pH, and standard bicarbonate may show a respiratory alkalosis in the early stages of salicylate intoxication accompanied by the development of a metabolic acidosis. The plasma potassium concentration is often low; rarely, the blood sugar may be high. Treatment The plasma salicylate concentration should be re-​measured 2–​3 h after the first measurement. Dehydration, electrolyte imbalance and, most importantly, metabolic acidosis should be corrected. The role of multiple-​dose activated charcoal in increasing salicylate elimination is controversial and it cannot be recommended on current evidence. As the relationship between renal clearance of salicylates and urine pH is logarithmic, urine alkalinization should be undertaken in patients with a plasma salicylate concentration greater than 500 mg/​litre, particularly if an acidosis is present. The therapeutic aim is to make the urine alkaline (ideally, pH 7.5–​8.5), and in adults this may be achieved by administration of sodium bicarbonate, 225 mmol (225 ml of 8.4%); further doses of bicarbonate are given as required. Hypokalaemia should be corrected before administration of sodium bicarbonate, because this lowers the serum potassium concentration further. In patients with severe poisoning (plasma salicylate concentration >700 mg/​litre or >5.1 mmol/​litre), haemodialysis should be considered, particularly when severe acid–​base abnormalities are present. Pulmonary oedema occasionally complicates salicylate toxicity. Fluid overload should be excluded as far as possible but, if increased pulmonary vascular permeability is suspected, measurement of the pulmonary artery wedge pressure may be needed both for confirmation of the diagnosis and to monitor subsequent fluid administration. Positive end-​expiratory pressure ventilation appears to be beneficial.

Clinical features Symptoms include nausea, vomiting, hyperventilation, haematemesis, abdominal pain, diarrhoea, sinus tachycardia, supraventricular, and ventricular arrhythmias, hypotension, restlessness, irritability, headache, hyperreflexia, tremor, and convulsions. Hypokalaemia results from Na+-​K+-​ATPase activation. A mixed respiratory alkalosis and metabolic acidosis is common. Most symptomatic patients have plasma theophylline concentrations in excess of 25 mg/​litre. Convulsions are seen more commonly when concentrations are greater than 50 mg/​litre. Treatment Multiple-​dose activated charcoal (e.g. 50 g 4-​hourly) enhances the systemic elimination of theophylline. Intractable vomiting may be alleviated by ondansetron, 8 mg intravenously in an adult. Gastrointestinal haemorrhage may require blood transfusion and the administration of a proton pump inhibitor intravenously. Tachyarrhythmias may be induced by the rapid flux of potassium across cell membranes and early correction of hypokalaemia may prevent their development. The plasma potassium concentration should therefore be measured on admission and at regular intervals thereafter while the patient is symptomatic. Potassium supplements will be needed in almost all cases and doses of up to 60 mmol/​h may be required at the outset in severe cases. Non​selective β-​adrenoceptor blocking drugs, such as propranolol, may also be useful in the treatment of tachyarrhythmias secondary to hypokalaemia. There may be a role for extracorporeal elimination techniques in very severe poisoning (plasma theophylline concentration >100 mg/​litre).

Thyroxine Clinical features Only a small percentage of patients who ingest large amounts of thyroid hormones develop features of toxicity. Symptoms develop within a few hours with triiodothyronine (T3) and after 3–​6  days with thyroxine (T4). They tend to resolve in about the same time as they take to develop. Sinus tachycardia, tremor, anxiety, irritability, insomnia, hyperactivity, sweating, diarrhoea, and fever are most common. Atrial fibrillation and convulsions have also been reported. Myocardial necrosis occurs rarely. Treatment Serum T4 and T3 concentrations should be measured approximately 12 h after ingestion (this need not be measured as an emergency). Those with high T4 concentrations should be reviewed for evidence of toxicity on the fourth or fifth day after ingestion. Patients who develop toxicity should be given propranolol 10–40 mg, 3–4 times a day for 5 days.

Drugs of abuse

Theophylline

Amfetamines and MDMA (ecstasy)

Poisoning may complicate therapeutic use, as well as being the result of deliberate self-​poisoning. If a sustained-​released formulation has been ingested, peak plasma concentrations of the drug are frequently not attained until 6–​12 h after overdose and the onset of toxic features is correspondingly delayed.

Amfetamines, particularly methamfetamine (‘crystal meth’, ‘ice’) and MDMA, are abused widely. Features of poisoning are related predominantly to stimulation of central and peripheral adrenergic receptors and, in addition, hyperthermia and hyponatraemia (secondary to inappropriate anti-diuretic hormone) may

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develop in severe MDMA toxicity. Poisoning is usually the result of recreational use. Clinical features These drugs cause increased alertness and self-​confidence, euphoria, extrovert behaviour, increased talkativeness with rapid speech, lack of desire to eat or sleep, tremor, dilated pupils, tachycardia, and hypertension. More severe intoxication is associated with excitability, agitation, paranoid delusions, hallucinations with violent behaviour, hypertonia, and hyperreflexia. Convulsions, rhabdomyolysis, hyperthermia, and cardiac arrhythmias can develop in the most severe cases. Rarely, intracerebral and subarachnoid haemorrhage and acute cardiomyopathy occur and may be fatal. In the case of MDMA, hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, acute renal failure, and hyponatraemia are observed commonly in severe cases, in addition to those features described earlier. Death occurred in 2 of 17 patients with serum sodium concentrations of 107–​128 mmol/​litre. Their clinical course was remarkably similar; initial vomiting and disturbed behaviour was followed by seizures, drowsiness, a mute state, and disorientation. Severe hepatic damage, including fulminant hepatic failure, has also been reported. The serotonin syndrome has been described. Treatment Intravenous fluids should be given for dehydration. Diazepam 10–​20 mg intravenously or haloperidol 2.5–​5.0 mg intramuscularly are effective in controlling agitation. The peripheral sympathomimetic actions of amfetamines may be antagonized by β-​adrenergic blocking drugs. Although acidification of the urine increases renal elimination of amfetamines, sedation is usually all that is required. Dantrolene 1 mg/​kg intravenous should be administered for hyperthermia that does not respond to conventional cooling methods. In most cases, hyponatraemia responds to fluid restriction alone. Transplantation may be indicated in patients who develop MDMA-​induced fulminant hepatic failure.

Cannabis Cannabis is obtained from the plant Cannabis sativa which contains over 400 compounds including over 60 cannabinoids. The most potent cannabinoid is Δ9-​tetrahydrocannabinol (THC), which is responsible for the psychoactive effects seen with use; other cannabinoids include Δ8-​tetrahydrocannabinol, cannabinol, and cannabidiol. Smoking is the usual route of use, but cannabis is occasionally ingested as a ‘cake’, made into a ‘tea’ or injected intravenously. Clinical features Acute use Features include euphoria, distorted and heightened images, colours, and sounds; altered tactile sensations, sinus tachycardia, hypotension, and ataxia. Visual and auditory hallucinations, depersonalization, and acute psychosis are particularly likely to occur after substantial ingestion in naïve cannabis users. Cannabis impairs all stages of memory including encoding, consolidation, and retrieval. Memory impairment following acute use may persist for months following abstinence.

Cannabis infusions injected intravenously may cause nausea, vomiting, and chills within minutes; after about 1 h, profuse watery diarrhoea, tachycardia, hypotension, and arthralgia may develop. Marked neutrophil leucocytosis is often present, and hypoglycaemia has been reported occasionally. Chronic use Heavy users suffer impairment of memory and attention and poor academic performance. There is an increased risk of anxiety and depression. Regular users are at risk of dependence. Cannabis use results in an overall increase in the relative risk for later schizophrenia and psychotic episodes. Cannabis smoke is probably carcinogenic. Treatment Most acutely intoxicated patients require no more than reassurance and supportive care. Sedation with diazepam, 10 mg intravenously, repeated as necessary, should be administered to patients who are disruptive or distressed. Haloperidol, 2.5–​5 mg intramuscularly repeated as necessary, is occasionally required.

Synthetic cannabinoid receptor agonists Synthetic cannabinoid receptor agonists (SCRAs) are full cannabinoid type 1 (CB1) receptor agonists and bind to these receptors with a higher affinity than Δ9-​tetrahydrocannabinol. Furthermore, unlike the metabolites of Δ9-​tetrahydrocannabinol, the metabolites of several synthetic cannabinoids retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2 receptors. Cannabinoids also bind non​specifically to cellular membranes and act on opioid and benzodiazepine receptors, prostaglandin synthetic pathways, and protein metabolism. These interactions have the potential for complex effects and are likely to contribute to toxicity. Clinical features Current third and fourth generation synthetic cannabinoid receptor agonists (SCRAs) produce more severe clinical features than earlier SCRAs. A reduced level of consciousness, tonic–​clonic convulsions, transient respiratory failure, and severe agitation, particularly on recovery, are typical. Treatment Treatment is symptomatic and supportive. As impaired ventilation is transient, supported ventilation is not usually necessary.

Cathinones, benzofurans, and related compounds Cathinones are derivates of cathionine, which occurs naturally in the herb Catha edulis (Khat). Structurally these are phenylethyla­ mines, similar in structure to catecholamines and amfetamines. Mephedrone (4-​methylmethcathinone) is one of the most widely abused cathinones, others include mexedrone, methylone, butylone, and fluoromethcathinone. Purity of these street drugs varies widely. These are usually insufflated (snorted) or swallowed. Other phenylethylamines, such as bromofurans (‘Benzofury’), have many similar effects to amfetamines, but some have more hallucinogenic effects due to the receptor specificity of the individual compounds. Methylenedioxypyrovalerone (MDPV, ‘ivory wave’) inhibits the reuptake of dopamine and norepinephrine centrally, and is a potent cause of psychiatric features.

10.4.1  Poisoning by drugs and chemicals

Clinical features These agents act as stimulants, causing agitation, hallucinations, increased muscle activity with bruxism (teeth grinding), hyperpyrexia, sweating, dilated pupils, tachycardia, and arrhythmias. Toxicity is increased if co-​ingested with other stimulants, or drugs affecting central amine mechanisms (e.g. antidepressants, tramadol). Metabolic complications include hypokalaemia, hyperglycaemia, and metabolic acidosis. Complications include seizures and rhabdomyolysis. Treatment Intravenous fluids should be given for dehydration. Diazepam, initially 10–​20 mg intravenously, is the drug of choice for agitation: this is also appropriate to control excess muscle activity. Large doses may be required. ECG and cardiovascular monitoring is necessary. Management of other features is symptomatic.

Cocaine In recent decades, there has been a considerable increase in the recreational use of cocaine. It is a powerful local anaesthetic and vasoconstrictor and may be abused by smoking, ingestion, injection or by ‘snorting’ it intranasally. Users, body packers, and those who swallow the drug to avoid being found in possession of it (‘stuffers’), are at risk of overdose. ‘Street’ cocaine is cocaine hydrochloride, which is water soluble, so can be injected or snorted. It may be dissolved in an alkaline solution from which the cocaine is extracted into ether, which is then evaporated to leave relatively pure (‘freebase’) cocaine. ‘Crack’ (cocaine also without the hydrochloride moiety) is extracted by using baking soda (sodium bicarbonate). Other drugs, such as ethanol, cannabis, and conventional hypnotics and sedatives, are frequently taken with cocaine to reduce the intensity of its less pleasant effects. Clinical features The features of cocaine poisoning are similar to those of amfetamine. In addition to euphoria, it also has sympathomimetic effects including agitation, tachycardia, hypertension, sweating, and hallucinations. Prolonged convulsions with metabolic acidosis, hyperthermia, rhabdomyolysis, ventricular arrhythmias, and cardiorespiratory arrest may follow in the most severe cases. Less common features include dissection of the aorta, myocarditis, myocardial infarction, dilated cardiomyopathy, subarachnoid haemorrhage, cerebral haemorrhage, and cerebral vasculitis. Several rare complications of the method of use of cocaine have been reported. These include pulmonary oedema after intravenous injection of freebase cocaine and pneumomediastinum and pneumothorax after sniffing it. In addition, chronic ‘snorting’ has caused perforation of the nasal septum, rhinorrhoea of cerebrospinal fluid due to thinning of the cribriform plate, and pulmonary granulomata. Treatment Users who are intoxicated may require sedation with diazepam to control agitation or convulsions; very large doses of diazepam may be required. Measures to prevent further absorption are not usually relevant. Hypertension and severe tachycardia may be controlled with a β-​blocker but, in one case at least, the use of propranolol

caused paradoxical hypertension. Accelerated idioventricular rhythm should not normally require treatment but ventricular fibrillation and asystole should be managed in the usual way.

Ethanol Ethanol is commonly ingested in beverages before, or concomitantly with, the deliberate ingestion of other substances in overdose. It is also used as a solvent and is found in many cosmetic and antiseptic preparations. It is rapidly absorbed through the gastric and intestinal mucosae. Gastric alcohol dehydrogenase isoenzyme has a role in metabolizing ethanol before absorption, thereby preventing ethanol entering the systemic circulation, particularly following ingestion of moderate amounts of alcohol. Absorbed ethanol is initially and principally converted to acetaldehyde by an NAD-​dependent hepatic alcohol dehydrogenase. A small proportion is oxidized by the microsomal ethanol oxidizing system and the catalase pathway. Acetaldehyde is removed by oxidation via the NAD-​dependent enzyme aldehyde dehydrogenase, to yield acetate and, subsequently, CO2 and water. About 95% of ingested ethanol is oxidized to acetaldehyde and acetate; the remainder is excreted unchanged in the urine, and, to a lesser extent, in the breath and through the skin. Ethanol is a central nervous system depressant that interferes with cortical processes in small doses and may depress medullary function in large doses. The effects of ethanol on the central nervous system are generally proportional to the blood ethanol concentration. Ethanol is also a peripheral vasodilator. In the severely intoxicated, it may cause hypothermia and hypotension. Ethanol metabolism results in accumulation of free NADH, with resulting increase in the NADH:NAD ratio and inhibition of hepatic gluconeogenesis, which may cause hypoglycaemia, particularly in children or when poisoning follows fasting, exercise, or chronic malnutrition. An increase in the lactate:pyruvate ratio may also ensue, with development of hyperlactataemia. Clinical features Ethanol exacerbates the effects of other central nervous system depressants, in particular, hypnotic agents. In those not tolerant, the fatal dose of ethanol alone is between 300 and 500 ml absolute alcohol, if this is ingested in less than 1 h. The features of ethanol poisoning are summarized in Table 10.4.1.9.

Table 10.4.1.9  Clinical features of ethanol poisoning Mild intoxication (500–​1500 mg/​litre)

Emotional lability, and slight impairment of visual acuity, muscular coordination, and reaction time Moderate intoxication (1500–​3000 mg/​litre)

Visual impairment, sensory loss, muscular incoordination, slowed reaction time, slurred speech Severe intoxication (3000–​5000 mg/​litre)

Marked muscular incoordination, blurred or double vision, sometimes stupor and hypothermia, occasionally hypoglycaemia and convulsions Coma (>5000 mg/​litre)

Depressed reflexes, respiratory depression, hypotension, and hypothermia. Death may occur from respiratory or circulatory failure or as the result of aspiration of stomach contents in the absence of a gag reflex

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Severe hypoglycaemia typically occurs within 6–​36 h of ingestion of a moderate to large amount of alcohol by either a previously malnourished individual or one who has fasted for the previous 24 h; it is common in children 5 years of age or less. The patient is often comatose, hypothermic, and convulsing, with conjugate deviation of the eyes, trismus, and extensor plantar reflexes; the usual features of hypoglycaemia (e.g. flushing, sweating, tachycardia) are often absent. Convulsions are the most common presenting sign in children with hypoglycaemia. Lactic acidosis (usually only mild) is an uncommon but potentially serious complication of acute ethanol intoxication and occurs particularly in patients with severe liver disease, pancreatitis, or sepsis. Hypovolaemia, which may accompany severe intoxication, predisposes to lactic acidosis. Treatment Supportive measures are all that are required for most patients with acute ethanol poisoning, even if the blood ethanol concentration is very high. Particular care should be taken to protect the airway. In more severe cases, acid–​base status should be determined. Lactic acidosis requires correction of hypoglycaemia, hypovolaemia, and circulatory insufficiency, if present. An infusion of sodium bicarbonate may be necessary in severely poisoned patients in whom a lactic acidosis persists. Blood sugar should be determined hourly in severe cases and the rate of intravenous glucose adjusted accordingly. If blood sugar concentrations decrease despite an infusion of 5–​10% dextrose, a 50% glucose solution, 50 ml intravenously, should be given because hypoglycaemia is usually unresponsive to glucagon. Haemodialysis may be considered if the blood ethanol concentration exceeds 7500 mg/​litre and if a severe metabolic acidosis is present, which has not been corrected by the measures outlined earlier. Fructose is of negligible clinical benefit in accelerating ethanol oxidation and may cause acidosis; it should not be used.

Treatment Supportive measures to maintain adequate ventilation and circulation should be employed, and this is often all that is required. GHB withdrawal should be managed as for acute alcohol withdrawal. Baclofen, a specific GABAB receptor agonist, has been used successfully in conjunction with benzodiazepines, to control withdrawal from GHB and GBL.

Ketamine Ketamine is a dissociative anaesthetic acting on NMDA-​R receptors. It is used as a drug of abuse for its hallucinogenic effects. In repeated doses it is toxic to the bladder causing irreversible bladder wall thickening and infiltration, with smaller capacity, muscle instability, and urothelial ulceration. Urinary frequency, incontinence, and hydronephrosis are complications. Several synthetic derivates are also abused in the hope they are ‘bladder safe’. Clinical features The main features are psychological with dissociative agitation, aggression, and paranoia. There is a risk of physical harm both to patient and carers. Hallucinations may result in injury from ‘flying’ or walking into traffic. Chronic use may result in dependency, GI symptoms and, most importantly, urological tract damage. Treatment Agitation should be managed supportively. Diazepam 10–​20 mg IV initially may be used for severe agitation. Patients should be counselled about the risks of abuse.

Lysergic acid diethylamide Lysergic acid diethylamide (LSD) acts as an antagonist at peripheral 5-​HT receptor subtypes, but as a 5-​HT2A receptor agonist in the central nervous system. LSD and MDMA (ecstasy) are sometimes 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-​ building agent (it stimulates growth hormone release) and as a sedative drug of abuse. It is a precursor of gamma-​aminobutyric acid (GABA) and acts as an agonist at GABAB receptors as well as at a GHB-​specific receptor in the brain. γ-​butyrolactone (GBL) and 1,4-​ butane-​diol (1,4-​BD) are GHB precursors, converted into it after ingestion. They are organic industrial solvents found in products such as acetone-​free nail polish removers and paint strippers. 1,4-​BD is also marketed as a dietary supplement.

The ability of LSD to distort reality is well known. Visual hallucinations, distortion of images, agitation, excitement, dilated pupils, tachycardia, hypertension, hyperreflexia, tremor, and hyperthermia are common; auditory hallucinations are rare. Time seems to pass very slowly, and behaviour may become disturbed with paranoid delusions. Panic attacks are relatively common, but frank psychotic episodes (which may result in homicide) are not. The psychoactive effects can last for 48 h. Episodic visual disturbances (‘flashbacks’; hallucinogen persisting perception disorder) occur in which the effects of LSD are re-​experienced without further exposure to the drug. The symptoms include false fleeting perceptions in the peripheral fields, flashes of colour, geometric pseudohallucinations, and positive afterimages. These disturbances may persist for several years but are often treatable with benzodiazepines and exacerbated by phenothiazines.

Clinical features Low doses cause mild agitation, excitement, nausea, and vomiting, with euphoria and hallucinations at higher doses. Coma, bradycardia, and respiratory depression occur in the most severely poisoned. The most unique aspect of GHB poisoning is its very brief duration. Patients may progress from deep coma, requiring intubation, to self-​extubation and full alertness over only a few hours. A GHB withdrawal syndrome can occur in chronic abusers with clinical features occurring within 6–​12 h of the last dose. Features include insomnia, tremor, and confusion, which may progress to delirium not dissimilar to the alcohol withdrawal syndrome.

Treatment Most patients will require little more than reassurance and sedation. Supportive measures are all that can be offered to those who are seriously ill.

10.4.1  Poisoning by drugs and chemicals

Opiates and opioids Opioids are a large group of drugs, which act on opioid receptors and are usually used as analgesics. Abuse of opiates, particularly heroin, causes many patients to present with unintentional overdose, which is normally from intravenous injection (needle marks visible) but may occur from inhalation (‘chasing the dragon’). Oral ingestion in addicts is less common. Many addicts abuse other drugs in addition to opioids, and the combination of benzodiazepines and opioids are particularly hazardous. Some opioids have other effects not mediated through opioid receptors. Methadone has been shown to inhibit potassium channels at high doses and is also associated with sudden death in susceptible patients due to QT prolongation and torsade de pointes. Buprenorphine, a partial agonist opioid, is now used as an alternative to methadone in replacement programmes. Fentanyl is a very potent opioid available in a range of formulations, particularly transdermal. Illicit extraction into an IV preparation has been reported. Tramadol is an opioid with serotonergic metabolites. It causes both convulsions and respiratory depression in overdose. Clinical features Cardinal signs of opiate overdose are pinpoint pupils, reduced respiratory rate, and coma. Vomiting may also occur, particularly after intravenous injection in naïve users, and complicates the clinical pattern due to aspiration pneumonia. Methadone acts slowly (peak effects usually 4–​6 h after ingestion), though its onset may be more rapid when given intravenously. Non​cardiogenic pulmonary oedema is seen in a proportion of severe opioid overdoses and is treated by positive pressure ventilation. Hypothermia may occur in patients lying outside. Rhabdomyolysis has also been associated with opioid ingestion. Buprenorphine is potentially seriously toxic if given intravenously, and in some countries, has been combined with naloxone to reduce the acute hazard. Treatment Naloxone is a pure opioid antagonist. It will reverse the central effects of all opioids if given in sufficient dose. In the event of veins not being accessible, intramuscular use is an alternative, but the onset will be slower. Use of naloxone by nebulizer has also been used in methadone poisoning. Failure of a suspected opioid poisoning to respond to an adequate dose of naloxone (at least 2.4 mg IV in an adult) should prompt reassessment of the diagnosis. It may indicate co-​ingestion of other central nervous system depressants, or ingestion of γ-​hydroxybutyrate, which also causes small pupils and loss of consciousness. Naloxone has a half-​life of approximately 45–​90 min so its duration of action is, therefore, much shorter than that of the opioids for which the patient is being treated. Naloxone may therefore be given by infusion; the normal advised dose is approximately two-​thirds of that required to fully wake a patient, every hour. This dose can be reassessed at regular intervals depending on the expected half-​life of the ingested product. Morphine has active metabolites (morphine 6-​ glucoronide), which may become relevant in large overdoses. This metabolite is renally excreted and more potent than the parent compound, thus poisoning may be prolonged in older people or in patients with renal impairment or renal damage following rhabdomyolysis. Other

supportive care should be administered as necessary, including respiratory support. Significant hypotension due to pure opioid effects will usually respond to naloxone; patients who are managed just by ventilation may therefore be treated unnecessarily aggressively with fluid replacement. In some patients, high concentrations of opioids, such as codeine, cause histamine release and whealing and itching of the skin, effects that should be treated conventionally with antihistamines.

Tryptamines—​synthetic and natural This group of drugs are hallucinogens and include the naturally occurring mushroom hallucinogenic alkaloids psilocin and psilocybin, and synthetic compounds such as dimethyltryptamine and α-​methyltryptamine; there are also 4-​and 5-​substituted derivates (e.g. 4-​hydroxy-​N,N,-​diethyltryptamine (4-​HO-​DET) and 5-​ methoxy-​N,N-​diisopropyltryptamine (5-​MeO-​DIPT)). Toxicity is related to stimulation of serotonin 2A receptors (5HT2A). Clinical features The features of toxicity are almost universally related to the hallucinogenic potential and psychosis induced by these agents. Additional features including dizziness, weakness, and tremor are common. In severe toxicity seizures, tachycardia, arrhythmias, abdominal symptoms, and renal injury are seen. Rarely vasospasm may occur. Treatment This is generally supportive, with reassurance the main approach. Agitation should be managed by diazepam (10–​20 mg IV). Severe vasospasm should be managed aggressively by intra-​arterial αadrenoceptor antagonists or nitrates.

Metals Aluminium Aluminium hydroxide is used as an antacid and occasionally as a phosphate binder in the management of chronic renal failure. Aluminium sulphate is employed in water purification and paper manufacture. Aluminium may be absorbed orally and by inhalation. More than 90% of absorbed aluminium is bound to transferrin. Though some accumulates in brain tissue, most body aluminium is stored in bone and the liver. It is excreted mainly via the kidneys so accumulation may occur in the presence of renal failure. Clinical features Acute poisoning Ingestion of a significant quantity of a soluble aluminium salt such as aluminium sulphate causes burning in the mouth and throat, nausea, vomiting, diarrhoea, abdominal pain, hypotension, seizures, haemolysis, haematuria and, rarely, hepatorenal failure. Topical aluminium sulphate may be irritant to the skin and eyes. By contrast, insoluble aluminium salts, such as aluminium oxide, do not produce an acute toxic response. Chronic poisoning Inhalation of ‘stamped aluminium powder’ can cause a persistent cough and breathlessness due to lung fibrosis or occupational asthma.

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Increased death rates from some types of cancer have been observed in aluminium production, but these effects are believed to be the result of exposure to other substances, such as benzopyrene, rather than exposure to aluminium. Aluminium may cause contact allergy. Aluminium encephalopathy is a potential, though now very unusual, complication in patients with chronic renal failure administered aluminium-​containing phosphate binders or dialysed using aluminium-​contaminated water. The latter is fortunately now very rare as a result of advancements in dialysis water filtration. The accumulation of aluminium in the brain produces cognitive decline, ataxia, dysarthria, myoclonic jerks, and seizures. Aluminium intoxication may also contribute to renal osteodystrophy and anaemia in patients with chronic renal impairment. Aluminium has been implicated in Alzheimer’s disease, but a definitive causative association has not been established. Treatment Deferoxamine forms a stable complex with aluminium which it mobilizes primarily from bone with subsequent urinary elimination of the chelate. Deferoxamine is absorbed poorly from the gastrointestinal tract and must be administered parenterally. The deferoxamine chelate is dialysable and all published clinical studies of aluminium chelation using deferoxamine have involved patients in renal failure undergoing either dialysis or haemofiltration. There is evidence that deferoxamine can improve aluminium-​induced encephalopathy, bone disease, and anaemia in dialysis patients. Specialist advice should be sought.

Arsenic Arsenic forms organic and inorganic compounds in trivalent and pentavalent states. Inorganic arsenical compounds may generate arsine gas (see ‘Arsine’, later in this chapter) when in contact with acids, reducing metals, sodium hydroxide, and aluminium. Common sources of exposure include fish consumption, traditional medicines, and groundwater contamination in Asian countries. In addition, arsenic trioxide has been used in the treatment of acute promyelocytic leukaemia. Most inorganic arsenicals are well absorbed following ingestion and skin absorption may occur from prolonged exposure. Soluble arsenic compounds can also be absorbed by inhalation. Arsenic crosses the placental and blood–​brain barriers rapidly. Following distribution arsenic accumulates in bone, hair, and nails. The half-​life is generally 2–​10 days and excretion is predominantly in the urine. Clinical features Acute poisoning This can follow accidental, or deliberate ingestion, the toxicity being largely dependent on the water solubility of the ingested compound. Within 2 h of substantial ingestion of a soluble arsenical compound, severe haemorrhagic gastroenteritis may ensue with collapse and death usually within four days. A  metallic taste, salivation, muscular cramps, facial oedema, difficulty in swallowing, hepatorenal dysfunction, convulsions, and encephalopathy are reported. A peripheral neuropathy (predominantly sensory), bone marrow depression, striate leukonychia (Mee’s lines), and hyperkeratotic, hyperpigmented skin lesions are common in those surviving a substantial ingestion. In moderate or severe arsenic poisoning, investigations may show anaemia, leucopenia, thrombocytopenia and disseminated intravascular coagulation. ECG abnormalities

have been reported and include QT prolongation and ventricular arrhythmias. Chronic poisoning The ingestion of arsenic in contaminated drinking water or ‘tonics’ leads to progressive weakness, anorexia, nausea, vomiting, stomatitis, colitis, increased salivation, epistaxis, bleeding gums, conjunctivitis, weight loss, and low-​grade fever. Characteristically, there is hyperkeratosis of the palms and soles of the feet, ‘raindrop’ pigmentation of the skin, and Mee’s lines on the nails. A symmetrical peripheral neuropathy is typical. Hearing loss, psychological impairment, and EEG changes have been reported. Other chronic effects include disturbances of liver function and ulceration and perforation of the nasal septum. In Taiwan, chronic arsenic exposure has been shown to cause blackfoot disease, a severe form of peripheral vascular disease, which leads to gangrenous changes. Arsenic is classified by the International Agency for Research on Cancer (IARC) as a class 1 (confirmed) carcinogen. Chronic exposure to arsenic in drinking water has been causally linked to lung, skin, kidney, and bladder cancer, while occupational exposure to arsenic is associated with lung cancer. Treatment The traditional chelator dimercaprol has been superseded by succimer (DMSA) and unithiol (DMPS). Both chelators are effective, but unithiol is thought to be superior. The intravenous dose of unithiol 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 unavailable. However, nausea and vomiting may limit oral unithiol administration. Convulsions, cardiovascular effects, and respiratory symptoms should be treated conventionally. Haemodialysis may be required to increase elimination if renal failure develops.

Cadmium If hygiene is poor, workers can be exposed to cadmium from the smelting and refining of metals, from soldering or welding metal that contains cadmium, or in plants that make cadmium products such as batteries, coatings, or plastics. Itai-​itai disease (literally ‘ouch-​ouch’ disease, so named because of the effects of severe pain in the joints), occurred in Toyama Prefecture, Japan, in 1950 and was due to mass cadmium poisoning as a result of mining. Clinical features Cadmium compounds are poorly absorbed orally but are well absorbed through the lungs. Cadmium is deposited in the liver and kidneys and very slowly excreted in the urine (half-​life 10–​30 years). Acute poisoning The ingestion of cadmium salts (>3 mg/​kg body weight) may lead to gastrointestinal disturbance which, in severe cases, may progress to circulatory collapse, acute renal failure, pulmonary oedema, and death. Inhalation of cadmium oxide fumes produced in welding or cutting has led to the development of severe lung damage and death. Often, there are no initial symptoms but after some 4–​10 h, there is increasing respiratory distress. Dyspnoea, cough, and chest pain are accompanied by chills and tremor. Severe pulmonary oedema may develop, or chemical pneumonitis in less severe cases. Recovery may be complicated by progressive pulmonary fibrosis.

10.4.1  Poisoning by drugs and chemicals

Repeated exposure to cadmium, such as occupationally, leads to renal tubular dysfunction with glycosuria, aminoaciduria, and hypercalciuria, an increased incidence of renal stones and osteomalacia. Less common features include anosmia, anaemia, teeth discoloration, and neuropsychological impairment. Later, emphysema may develop. Workers repeatedly exposed to high concentrations of cadmium have developed carcinoma of the prostate or lung.

Despite claims that topically applied ascorbic acid and sodium calcium edetate protect against dermal toxicity, there is insufficient evidence to advocate their use. Immediate surgical assessment is recommended in cases of severe ingestion, as resection of necrotic gastrointestinal tissue may be life-​saving. There is no evidence that any chelating agent improves outcome in cases of systemic poisoning. Haemodialysis removes chromium from the blood, but the 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 cadmium may be chelated by any currently available antidote.

Cobalt is an essential trace element and is a constituent of vitamin B12 (cyanocobalamin). Cobalt salts have been used as blue colourants for thousands of years. Cobalt composited with tungsten carbide (‘hard metal’) is a very durable and temperature-​resistant metal used in the manufacture of drills and other tools. Historically, cobalt salts were used in brewing to enhance the ‘head’ on beer and in the treatment of anaemia. In recent years, poorly functioning cobalt-​ containing hip prostheses have become an important further source of exposure. Cobalt exerts its toxicity through generating reactive oxygen species, inflicting DNA damage and disrupting ionic, enzymatic, and haematopoietic homeostasis. Cobalt can be absorbed orally and by inhalation and most undergoes renal excretion over 7 days, but a small proportion is retained with a biological half-​life of approximately 2 years.

Chronic poisoning

Chromium Chromium exists mainly in two oxidation states: trivalent (Cr3+) and hexavalent (Cr6+). Cr3+ exposure has limited toxicological relevance, due to its low absorption and inability to cross cell membranes. In contrast, Cr6+ compounds are highly reactive, powerful oxidizing agents that inflict severe local damage. They are also well absorbed through most routes of exposure and cross cell membranes readily. Somewhat paradoxically, Cr6+ induces its devastating systemic toxicity by intracellularly reducing to Cr3+, releasing highly reactive oxygen free radicals in the process. In addition, the Cr3+ formed is able to bind and damage nuclear DNA, inducing genotoxicity. Chromium exposure and absorption through inhalation, ingestion, and dermal routes is primarily occupational, with excretion occurring through the kidney. Clinical features Acute poisoning Soluble Cr6+ compounds include sodium and potassium chromate and dichromate and chromic acid (Cr6+ trioxide). Inhalation of these highly irritant compounds causes mucous membrane inflammation, cough, headache, chest pain, and dyspnoea; pulmonary oedema and respiratory failure may ensue. Ingestion of highly water-​soluble Cr6+ compounds causes a burning sensation in the mouth and throat, nausea, abdominal pain, diarrhoea, and a risk of gastrointestinal haemorrhage. Hypovolaemic shock may follow. Methaemoglobinaemia, haemolysis, coagulopathy, and renal and hepatic failure have been reported. Chromic acid splashes produce severe burns. Percutaneous absorption may lead to systemic toxicity; fatalities have occurred. Chronic poisoning Inhalation of Cr6+ compounds has led to atrophy, ulceration, and perforation of the nasal septum. Pharyngeal and laryngeal ulcers may also occur. Asthma may be precipitated by exposure to fumes. Lung fibrosis, bronchitis, emphysema, and renal proximal tubular damage result from occupational exposure. Cr6+ is classified by the IARC as a group I carcinogen and chronic occupational exposure is strongly associated with an increased incidence of lung cancer. ‘Chrome ulcers’ may develop after repeated topical exposure to Cr6+ compounds. Cr6+ compounds are also skin sensitizers and contribute to the development of cement dermatitis and contact dermatitis from paint primer, tanned leather, tattoo pigments, and matches. Treatment The principal management of chromium poisoning is avoidance of exposure. Inhalational exposure should be treated conventionally.

Clinical features Acute poisoning Acute poisoning is rare, though ingestion causes gastrointestinal irritation. Chronic poisoning Hard metal lung disease is a now rare form of interstitial lung disease that occurs in susceptible patients exposed to hard metal and in some diamond workers who use cobalt-​containing polishes. Patients usually present with exertional dyspnoea and cough. There may be associated constitutional symptoms of fever, weight loss, or malaise. Inspiratory crackles are the earliest physical sign, but finger clubbing, cyanosis, and eventually cor pulmonale can ensue. Interstitial fibrosis is seen on chest X-​ray (primarily the lower zones), and a restrictive ventilatory defect is often present. Cobalt is also a recognized cause of occupational asthma. Historically, those consuming large amounts of cobalt-​ contaminated beer developed ‘beer-​drinkers’ cardiomyopathy’ with heart failure often accompanied by a pericardial effusion and polycythaemia. Systemic cobalt toxicity also developed in patients receiving cobalt chloride as treatment for anaemia (cobalt stimulates erythropoietin release), with manifestations including hypothyroid goitre (cobalt inhibits the uptake of iodine by the thyroid gland), deafness, visual disturbances, and/​or peripheral neuropathy. More recently, systemic cobalt toxicity has been encountered occasionally in recipients of cobalt-​containing hip prostheses. This is far more likely in those with an ill-​fitting prosthesis where there is increased friction between metal surfaces, and in those who have a metal-​ containing hip as a revision of a damaged ceramic prosthesis (residual ceramic shards abrading the metal surface). Cobalt is classified as a group 2B carcinogen by the IARC, with limited evidence to suggest a causal relationship between cobalt and cancer.

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Treatment Hard metal pneumoconiosis may respond to steroid therapy. Systemic features are usually at least partly reversible providing the cobalt source is removed. There is no antidote for systemic poisoning.

Copper Copper is used for pipes and roofing materials, in alloys and as a pigment. It is a component of several endogenous enzymes, including tyrosinase and cytochrome oxidase, and is essential for the utilization of iron. Copper sulphate is used as a fungicide, an algicide, and in some fertilizers. Following ingestion, copper transport across the intestinal mucosa is facilitated by cytosolic metallothionein. In blood, copper is initially albumin-​bound and transported via the hepatic portal circulation to the liver where it is incorporated into caeruloplasmin. Ninety-​ eight (98%) per cent of copper in the systemic circulation is bound to caeruloplasmin and free copper is excreted via a lysosome-​to-​bile pathway. This process is essential to normal copper homeostasis and provides a protective mechanism in acute copper poisoning. An impaired or overloaded biliary copper excretion system results in hepatic copper accumulation, as occurs in Wilson’s disease (see Chapter 12.7.2) and copper poisoning. Free reduced Cu(I) can bind to sulfhydryl groups and inactivates enzymes such as glucose-​6-​phosphate dehydrogenase and glutathione reductase. In addition, copper may interact with oxygen species (e.g. superoxide anions and hydrogen peroxide) and catalyse the production of reactive toxic hydroxyl radicals. Copper(II) ions can oxidize haem iron to form methaemoglobin. Clinical features Acute poisoning Acute copper poisoning usually results from the ingestion of contaminated foods or from accidental or deliberate ingestion of copper salts. Copper salt ingestion causes profuse vomiting with abdominal pain, diarrhoea, headache, dizziness, and a metallic taste. Gastrointestinal haemorrhage, haemolysis, and hepatorenal failure may ensue and fatalities have occurred. Body secretions may be green or blue. Occupational exposure to copper fumes (during refining or welding) or to copper-​containing dust causes ‘metal fume fever’ with upper respiratory tract symptoms, headache, fever, and myalgia. Chronic poisoning Chronic copper poisoning has been reported predominantly as ‘vineyard sprayer’s lung’ in those spraying fungicides containing copper sulphate. Features include progressive dyspnoea, cough, wheeze, myalgia, malaise, anorexia, micronodular, and reticular opacities on chest X-​ray (which may coalesce), and a restrictive lung function defect. Lung biopsy may show pulmonary granulomata and fibrosis. Other features include hepatic copper-​ containing granulomas, hypergammaglobulinaemia, and hepatomegaly. There is no convincing evidence that copper is carcinogenic in humans. Treatment Blood copper concentrations correlate well with the severity of intoxication following acute ingestion. Serum caeruloplasmin concentrations will also be increased in acute copper salt poisoning. Supportive measures are paramount following copper salt ingestion. Early endoscopy or CT scan with contrast is recommended if

corrosive damage is suspected. An early surgical opinion should be sought if there are clinical signs of an acute abdomen or deep ulcers and/​or areas of necrosis on endoscopy or CT. Methaemoglobinaemia should be treated with intravenous methylthioninium chloride 1–​2  mg/​kg. Oral D-​penicillamine, 1.5–​2  g daily, enhances urinary copper elimination in patients with Wilson’s disease but confirmed benefit in acute copper salt poisoning has not been demonstrated. Experimental studies suggest unithiol (DMPS) may be the most effective antidote in copper poisoning but the presence of acute kidney injury in severely poisoned patients often limits the value of antidotes which enhance urine copper excretion. Extracorporeal elimination techniques do not enhance copper elimination significantly. Exchange transfusion has been undertaken successfully in patients with copper sulphate-​induced haemolysis.

Lead Occupational lead exposure occurs mainly by inhalation, for example, in the reclamation of lead from scrap metal, in the demolition and flame-​cutting of structures painted with lead-​containing paint, in the manufacture of storage batteries, ceramics, and pigments and in radiation shielding. Non​occupational lead exposure predominantly involves ingestion and important sources include ‘traditional’ remedies (particularly among ethnic minorities) and children with pica who pick at surfaces coated with lead-​containing paint or eat lead-​contaminated soil. Application of lead-​containing cosmetics such as ‘surma’ has also resulted in lead intoxication. Both ingested and inhaled lead are absorbed readily. Most (98.5%) 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 erythrocytes. Lead can cross both the blood–​brain and placental barriers. Elimination is predominantly renal. As the body accumulates lead over many years, even small doses can accumulate over time and cause toxicity. There are two principal mechanisms of lead toxicity. First, lead complexes with important functional chemical groups including –​ COOH, –​NH2, and –​SH, and so disrupts the function of enzymes and other biologically important molecules. Lead inhibits several enzymes involved in haem synthesis (including δ-​aminolaevulinate dehydratase and ferrochelatase) and erythrocyte maturation (erythrocyte pyrimidine 5’ nucleotidase), causing a microcytic or normocytic hypochromic anaemia. Secondly, lead substitutes for divalent ions, particularly calcium, which explains why lead accumulates in bone. The critical role of calcium in neuronal differentiation, myelination, and synapse development and functionality explains why lead poisoning can induce devastating neurotoxicity. The developing nervous system is particularly susceptible to irreversible damage. Lead substitution for calcium also causes widespread chemical interactions, disrupts second messenger cellular signalling and triggers calcium-​activated apoptosis. Clinical features Lead poisoning frequently presents with non​ specific features, including abdominal pain, anorexia, constipation, headache, and lethargy. Anaemia presents due to impaired haem synthesis and reduced erythrocyte lifespan. Classically, lead poisoning presents with peripheral neuropathy in the form of foot or wrist drop, although this manifestation is now uncommon. In moderate intoxication, reversible renal tubular dysfunction occurs (causing glycosuria, aminoaciduria, and phosphaturia), which progresses to irreversible

10.4.1  Poisoning by drugs and chemicals

interstitial fibrosis and progressive renal insufficiency in severe cases. Hypertension may result from renal toxicity. Lead encephalopathy (delirium, seizures, and coma) only occurs in very severe poisoning (blood lead concentrations >100 μg/​dl (4.8 micromol/​litre)) and is much more common in children than adults. Transplacental transfer of lead from mother to fetus results in reduced fetal viability, low birth weight, and premature birth. Despite unequivocal evidence that even low blood lead concentrations are detrimental to health, the current practice in the United Kingdom is to only enforce stopping work with lead when a worker’s blood lead concentration exceeds 60 µg/​dl (2.9  micromol/​litre); 30 µg/​dl (1.4 micromol/​litre) for a woman of reproductive capacity; 50 µg/​dl (2.4 micromol/​litre) for an employee aged under 18 years. There is no safe blood lead concentration for children, particularly those below the age of 5 years. Treatment Primary prevention aimed at eliminating lead hazards for children and workers is crucial. The importance of primary prevention in children is emphasized particularly by the observation that chelation does not improve scores on tests of cognition, behaviour, and neuropsychological function in children with moderate lead poisoning (blood lead concentrations of 22–​45 µg/​dl (1.0–​2.2 micromol/​litre)). The social dimension of the problem must also be recognized: simply giving children chelation therapy and then returning them to a contaminated home environment is of no value. Similarly, if an occupational source of lead exposure is implicated, a thorough evaluation of the workplace, other exposed workers and the systems for handling lead at work are appropriate. The decision to use chelation therapy is based on the symptoms present and the blood lead concentration. All symptomatic patients with blood lead concentrations of 50 µg/​dl (2.4 micromol/​litre) or higher should be considered for chelation therapy. Parenteral sodium calcium edetate, 75 mg/​kg per day, has been the chelating agent of choice for more than 50 years but oral succimer (DMSA) 30 mg/​kg per day is of similar efficacy.

Mercury Mercury is the only metal that is liquid at room temperature. It exists in three forms: metallic (Hg0), mercury(I) (mercurous), and mercury(II) (mercuric). Metallic mercury is very volatile and when spilt has a large surface area so that high atmospheric concentrations may be produced in enclosed spaces, particularly when environmental temperatures are high. In addition to simple salts, such as chloride, nitrate, and sulphate, mercury(II) forms organometallic compounds where mercury is covalently bound to carbon, such as methyl-​, ethyl-​, phenyl-​, and methoxyethyl mercury. Inorganic mercury is used extensively in industrial and pharmaceutical settings; exposure is predominantly occupational though minor non​occupational exposure occurs via dental amalgam. By contrast, exposure to organomercury compounds most commonly occurs from dietary intake, as organomercury can accumulate up the food chain of aquatic species. The absorption of mercury depends on its chemical form. Inhaled mercury vapour is absorbed rapidly and oxidized to mercury (II) in erythrocytes and other tissues. Prior to oxidation, absorbed mercury vapour can cross the blood–​brain barrier, but the divalent ion oxidation product serves to trap mercury in the brain. Mercury vapour is also absorbed via the skin. Less than 1% of an ingested dose of metallic mercury reaches the systemic circulation. Organic mercuric salts are

better absorbed following ingestion than are inorganic mercuric salts. Organic mercury compounds cross the blood–​brain barrier readily. In contrast, the kidney is the main storage organ for inorganic mercury compounds. In vivo mercury is bound to metallothionein, which serves a protective role, since renal damage is caused only by the unbound metal. Mercury is excreted mainly in urine and faeces although a small amount of absorbed inorganic mercury is exhaled as mercury vapour. The half-​life of most body mercury is 1–​2 months, but a small fraction has a half-​life of several years. The exact mechanism of toxicity of mercury remains unclear, but involves binding of the Hg2+ form to the sulfhydryl groups present on structural proteins, receptors, enzymes, intracellular organelles and DNA and to selenoproteins. The central nervous system is particularly susceptible. Clinical features Acute poisoning Acute mercury vapour inhalation causes headache, nausea, cough, chest pain and bronchitis/​pneumonitis. Repeated exposure to low mercury vapour concentrations presents typically with characteristic neurological features including fine tremor, lethargy, memory loss, insomnia, personality changes, and ataxia. Other features include stomatitis, gingivitis, hypersalivation, and renal tubular damage. Mixed motor and sensory peripheral neuropathy may develop. Ingestion of metallic mercury is usually without systemic effects as it is poorly absorbed from the gastrointestinal tract. However, ingestion of inorganic mercury (II) (mercuric) or aromatic mercuric salts causes an irritant gastroenteritis with corrosive ulceration, which may lead to circulatory collapse and shock. Inorganic mercury(I) (mercurous) compounds are less soluble, less corrosive, and less toxic than mercuric salts. Ingestion of mercurous chloride in teething powder has led to ‘pink disease’ or acrodynia in infants. This is a hypersensitivity reaction characterized by a desquamating erythematous rash of the extremities, irritability, profuse sweating, tachycardia, and hypertension. Systemic toxicity in the form of renal and neurological damage can present following exposure to mercury salts. There are reports of deliberate intravenous or subcutaneous metallic mercury injection. Accidental injection also has occurred after injury from broken thermometers. Intravascular mercury may result in pulmonary venous or peripheral arterial embolism. Subcutaneous mercury initiates a soft-​tissue inflammatory reaction with granuloma formation. Signs of systemic mercury toxicity are rare following metallic mercury injection. Chronic poisoning Chronic poisoning from inorganic mercury compounds or mercury vapour causes anorexia, insomnia, abnormal sweating, headache, lassitude, increased excitability, tremor, peripheral neuropathy, gingivitis, hypersalivation, personality changes, and memory or intellectual deterioration. Glomerular and tubular damage may occur, and renal tubular acidosis has been described in children. Most cases of human poisoning from alkyl mercury compounds result from ingestion of contaminated foods over a long period. There is often a latent period of several weeks between exposure and the development of symptoms which are predominantly neurological, with paraesthesiae of the lips, hands, and feet, ataxia, tremor, dysarthria, constriction of visual fields, and emotional and intellectual changes. Gastrointestinal disturbances may precede or

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accompany these features. Seizures, coma, and death have occurred. Chronic exposure to methylmercury has been associated with an increased incidence of liver cancer, cirrhosis, renal disease, and cerebral haemorrhage. Treatment Although there are no controlled clinical data to show that chelation therapy improves outcome in patients with neurological features of mercury poisoning, unithiol 30 mg/​kg/​day intravenously (or 77  mg/​kg/​day orally) increases urinary mercury elimination and reduces blood mercury concentrations. Where extracorporeal renal support is required for the treatment of renal failure, there is evidence that continuous veno–​venous haemodialfiltration is more effective than haemodialysis at removing unithiol–​mercury complexes. Substantial exposure to corrosive mercury salts may warrant immediate surgical assessment, as resection of necrotic gastrointestinal tissue may be life-​saving.

Nickel Nickel is a ubiquitous trace metal mined in the form of sulphide ore. It is used primarily for producing stainless steel and other alloys. Nickel forms inorganic soluble (sulphate, chloride) and insoluble (oxide, sulphide) salts, used in electroplating and battery manufacture. Nickel carbonyl (Ni(CO)4) is a colourless, volatile liquid used as a catalyst in the petroleum, plastic, and rubber industries. It is an intermediate compound in nickel purification and is released as fumes when nickel is thermally decomposed. Nickel metal and inorganic salts can be absorbed orally and by inhalation, though absorption is generally poor. By contrast, nickel carbonyl is highly lipophilic and rapidly absorbed. Nickel is principally bound to albumin in the blood and is concentrated in the kidneys, liver, and lungs prior to renal excretion. The mechanism of nickel toxicity is thought to involve the induction of oxidative stress through reactive oxygen species production. Clinical features Acute poisoning Nickel carbonyl inhalation leads within a few minutes to dizziness, headache, vertigo, nausea, vomiting, cough, and dyspnoea. In many cases these symptoms disappear and there follows a symptom-​free period lasting 12–​36 h before tachypnoea, dyspnoea, haemoptysis, cyanosis, chest pain, vomiting, tachycardia, weakness, and muscle fatigue supervene. Paraesthesiae, diarrhoea, abdominal distension, delirium, and convulsions have also been reported. Death from cardiorespiratory failure may occur 4 to 11 days after exposure. At high concentrations, soluble nickel salts are primary skin, gut, and eye irritants. Workers at an electroplating plant who drank water accidentally contaminated with nickel sulphate experienced nausea, vomiting, diarrhoea, abdominal pain, headache, cough, and breathlessness, which persisted for up to 2 days. A 2-​year-​old child died 4 h after ingesting 15 g nickel sulphate crystals. Chronic poisoning Chronic exposure to aerosols of nickel salts may lead to chronic rhinitis and sinusitis and, in rare cases, anosmia and perforation of the nasal septum. Inhaled nickel can produce a type I hypersensitivity reaction, manifest as bronchial asthma with circulating IgE antibodies to nickel. Pulmonary eosinophilia (Loeffler’s syndrome) due to a type III hypersensitivity reaction to nickel has also been described.

A significant increase in deaths from non​malignant respiratory disease or pneumoconiosis has been observed in nickel refinery workers. Nickel compounds are classified by the IARC as class I carcinogens, with evidence that occupational exposure increases the risk of cancer of the lung and nasal sinuses. Metallic nickel and nickel salts cause allergic contact dermatitis in up to 10% of females and 1% of males and is due to a type IV delayed hypersensitivity. Treatment Blood nickel concentrations immediately following exposure to nickel carbonyl provide a guide to severity of exposure and the need for chelation therapy. Unithiol (DMPS) enhances the urinary excretion of nickel in nickel-​intoxicated animals. Diethyldithiocarbamate and disulfiram (which is metabolized to diethyldithiocarbamate) are effective agents in the treatment of nickel dermatitis, but their role in the treatment of acute severe nickel carbonyl poisoning has not been confirmed in a controlled clinical study.

Phosphorus Elemental phosphorus exists in several crystalline forms (allotropes), of which yellow phosphorus (sometimes referred to as white) is the most important toxicologically. Phosphorus oxidizes spontaneously in contact with air to form phosphorus pentoxide which, by an exothermic reaction, forms phosphoric acid on contact with water. Hence, dermal and gastrointestinal exposures to phosphorus rapidly become exposures to phosphoric acid. Clinical features Typically, patients who have ingested phosphorus present with either gastrointestinal features (most commonly) or central nervous system features; 20% have a combination of both. Features generally begin within minutes of ingestion and include nausea, vomiting, abdominal pain, burns of the pharynx, oesophagus, and stomach, which may lead to gastrointestinal haemorrhage. Shock in part due to fluid loss and GI haemorrhage follows. In other cases, central nervous system features (restlessness, irritability, delirium, coma, convulsions, and cerebral oedema) predominate. Metabolic complications (metabolic acidosis, hypoglycaemia, hyperphosphataemia and hypocalcaemia) and hepatorenal failure ensue. Cardiovascular collapse and arrhythmias are the most common cause of death following ingestion, but in other cases cerebral oedema and haemorrhage complicating fulminant hepatic failure are responsible. Treatment Treatment is supportive. Hypotension/​shock should be corrected vigorously with intravenous fluid and inotropes. If metabolic acidosis is not responsive to fluid resuscitation, give intravenous sodium bicarbonate. Early fibreoptic endoscopy and CT is indicated to grade the severity of the injury in any patient who is symptomatic or has evidence of oropharyngeal burns.

Thallium Thallium sulphate was previously used as a rodenticide but is now banned for this use in many countries. Thallium salts have also been employed in the manufacture of optical and electrical equipment, as catalysts in organic synthesis, and in isotopic form for medical imaging of the myocardium.

10.4.1  Poisoning by drugs and chemicals

Clinical features Initial symptoms (if ingested) include nausea, vomiting, abdominal pain, and, less commonly, gastrointestinal bleeding. Constipation follows in most patients. After a few days (usually between two and five), paraesthesiae develop, which start in the feet and progress to the hands and fingers; painful and tender extremities (‘burning feet syndrome’) and ascending sensory neuropathy then supervene. In severe cases confusion, delirium, convulsions, renal failure, respiratory failure, heart failure, and coma occur; the mortality is high. If death does not occur within the first week, tremor, ataxia, and (usually lower limb) muscle weakness develops, due to the onset of motor neuropathy, which is usually distal. Ocular features include nystagmus, ptosis, and abnormalities of gaze due to involvement of the third, fourth, and sixth cranial nerves. Retrobulbar neuritis, facial paralysis, decreased visual acuity, optic atrophy, and defective colour vision may develop. Characteristically, alopecia develops within 1–​3 weeks and it is often this sign which leads to the diagnosis being made. If the patient survives, the hair usually regrows, but is often abnormally fine and unpigmented. Nail growth is impaired with the development of ridges, Mees’ lines, and erosion of the proximal parts of the nails. Treatment As thallium ions are excreted into the gastrointestinal tract via the saliva, the bile, and through the intestinal mucosa, it is possible to sequester thallium ions in the gut and prevent reabsorption by the oral administration of colloidally soluble Prussian blue (potassium ferric hexacyanoferrate (II)) 250–​300  mg/​kg/​day (approximately 10 g twice daily for an adult). Thallium ions are exchanged for potassium ions in the lattice of the Prussian blue molecule and are subsequently excreted in faeces. During treatment with Prussian blue, plasma concentrations of thallium fall and urine excretion declines exponentially. In contrast, faecal excretion of thallium is detectable even when urine excretion of the metal has ceased and, therefore, administration of Prussian blue should be continued until thallium can no longer be detected in the faeces.

Zinc Zinc oxide fumes are emitted in any process involving molten zinc and are the most common cause of metal fume fever. Exposure to zinc chloride occurs in soldering; in the manufacture of dyes, paper, and deodorants; and on military exercises when it is used as a smoke screen. Poisoning has followed the accidental or deliberate ingestion of elemental zinc and zinc chloride and fatal intoxication has followed inadvertent intravenous administration. Inhalation of zinc chloride and oxide may lead to nasopharyngeal and respiratory toxicity. Zinc may be absorbed through broken skin when zinc oxide paste is used to treat wounds and burns. Clinical features Zinc sulphate ingestion causes gastrointestinal irritation, sometimes in association with headache and dizziness. Zinc chloride is highly corrosive, and ingestion has led to erosive pharyngitis, oesophagitis, and haematemesis. Acute renal failure and pancreatitis have also been recorded after ingestion of zinc salts. Topical exposure to zinc chloride causes ulceration and dermatitis of the exposed skin. Zinc chloride is highly irritant to the eye.

In contrast to the relatively mild clinical course after zinc oxide inhalation, exposure to zinc chloride ammunition bombs (hexite) produces a chemical pneumonitis with marked dyspnoea, a productive cough, fever, chest pain, and cyanosis. The acute respiratory distress syndrome may ensue. Metal fume fever occurs most commonly in individuals who perform welding involving zinc. It presents generally with influenza-​like symptoms, fever, shaking chills, arthralgias, myalgias, headache, and malaise, some 4–​10 h following exposure. In patients with ongoing metal fume exposure over the course of a workweek, tachyphylaxis occurs resulting in improvement in symptoms over the course of the workweek and maximal symptoms occurring after an exposure-​free period such as a weekend. Treatment Management is supportive. Endoscopy and CT should be performed following zinc chloride ingestion to assess the severity of oesophageal or gastric burns.

Pesticides Aluminium and zinc phosphides Aluminium and zinc phosphides are highly effective insecticides and rodenticides, which are used to protect grain during transport and storage. The phosphide interacts with moisture in the surrounding air to liberate phosphine, which is the active pesticide. Acute poisoning, therefore, results either from the ingestion of the salts themselves or inhalation of the phosphine generated during their use; the latter is discussed later on in this chapter. In cases of poisoning by phosphide ingestion, toxic effects are due to phosphine release when the phosphide comes into contact with gut fluids. Phosphine is absorbed through the alimentary mucosa and widely distributed to tissues. Clinical features Early features include nausea, vomiting, retrosternal, and epigastric pain, gastric, or duodenal erosions causing haematemesis and dyspnoea. Diarrhoea is less common. Shock and circulatory failure occurring early in the course of poisoning are of ominous prognostic importance, as circulatory failure is a common and frequent cause of death. Impaired myocardial contractility and global dyskinesia are frequent in those severely poisoned. This group of patients is characterized by severe hypotension, reduced cardiac output, raised systemic venous pressure, normal pulmonary artery wedge pressure and inadequate systemic vasoconstriction. Severe metabolic acidosis, renal failure, and disseminated intravascular coagulation are common accompaniments. Treatment Treatment is symptomatic and supportive. Gastric lavage should be avoided as it might increase the rate of disintegration of the product ingested and increase toxicity. Activated charcoal does not bind metal phosphides.

Anticoagulant rodenticides Warfarin was widely used as a rodenticide until target species developed resistance to it. The newer anticoagulant rodenticides

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(sometimes termed ‘super warfarins’), such as brodifacoum, bromodialone, chlorophacinone, coumatetralyl, difenacoum, diphacinone and flocoumafen, are more potent and longer-​acting antagonists of vitamin K1 than warfarin. While accidental ingestion of small amounts rarely results in altered coagulation, deliberate ingestion may result in prolongation of the INR for several weeks or months and fatal haemorrhage has occurred. These anticoagulants inhibit vitamin K1-​2,3-​epoxide reductase and thus the synthesis of vitamin K and subsequently clotting factors II, VII, IX, and X. There is no anticoagulant effect until existing stores of vitamin K and clotting factors are depleted. The greater potency and duration of action of long-​acting anticoagulant rodenticides compared to warfarin is attributed to their greater affinity for vitamin K1-​2,3-​epoxide reductase, their ability to disrupt the vitamin K1-​epoxide cycle at more than one point, hepatic accumulation, and unusually long biological half-​lives due to high lipid solubility and enterohepatic circulation. Clinical features Gastrointestinal bleeding, haematuria, and bruising are the most common features, though the most common site of fatal haemorrhage is intracranial. The onset of bleeding may be delayed for several days since the peak anticoagulant effect does not occur until some 72–​96 h after ingestion. Treatment Routine measurement of the INR is generally not indicated in children as the amounts they ingest are almost invariably small. In all other cases, the INR should be measured on presentation and 36 to 48 h after exposure. If the INR is normal at this time, no further action is required. If a patient presents within 1 h of a large ingestion, the administration of activated charcoal (50 g for adults; 10–​15 g for children) should be considered, as it is known that warfarin is adsorbed to charcoal. In patients with severe poisoning who have ingested a long-​acting formulation, oral cholestyramine 4 g three times daily for an adult should be considered in order to shorten the plasma half-​life of the rodenticide. If active bleeding occurs, dried prothrombin complex (which contains factors II, VII, IX, and X) 25–​50 units/​kg, or fresh frozen plasma 15 ml/​kg (if no concentrate is available) should be given, together with phytomenadione 5 mg by slow intravenous injection (100 µg/​kg body weight for a child). If active bleeding occurs in a patient who is being prescribed an anticoagulant, warfarin (or another anticoagulant) should be discontinued. If there is no active bleeding and the INR is less than 4.0, treatment with phytomenadione is not required. If the INR is more than 4, phytomenadione 5 mg by slow intravenous injection (100 µg/​kg body weight for a child) should be administered, unless the patient is anticoagulated for therapeutic reasons. If the patient is prescribed anticoagulants, the INR is more than 8, and there is no active bleeding or only minor bleeding, stop warfarin (restart when the INR 75 mm Hg). The atropine dose should be titrated to control rhinorrhoea and bronchorrhoea. If the initial dose produces only a partial response, it should be doubled and doubled again if there is only a limited clinical response. If these measures fail, the patient should be intubated and mechanical ventilation instituted. At present there is insufficient evidence to either recommend or advise against the use of pralidoxime in severe poisoning with carbamate insecticides. Pralidoxime seldom should need to be administered in less severe cases since carbamates have a relative short duration of action. However, if intoxication is life-​threatening and unresponsive to atropine and supportive measures, pralidoxime chloride 30  mg/​kg body weight by intravenous injection over 20 minutes should be given.

Chloralose Chloralose is marketed for amateur use as cereal or paste baits containing 2 to 4% rodenticide. Technical α-​chloralose (c. 90% pure) is used by professionals against bird pests and rodents. Clinical features Toxic amounts of chloralose cause severe central nervous system excitation with hypersalivation, increased muscle tone, hyperreflexia, opisthotonus, myoclonic jerks, and convulsions. Rhabdomyolysis is a potential complication. Coma, generalized flaccidity, and respiratory depression may follow. Treatment Children who ingest small amounts of baits (amateur formulations) containing chloralose are unlikely to develop symptoms. In contrast, 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.

features include nausea, vomiting, diarrhoea, abdominal pain, and cyanosis secondary to methaemoglobinaemia. The combination of methaemoglobinaemia and haemolysis results in varying degrees of hypoxaemia and symptoms such as general weakness, fatigue, dizziness, agitation, anxiety, confusion, and headache. Chest pain and dyspnoea may also be experienced. Intravascular haemolysis causes hyperkalaemia and jaundice. Poisoning with chlorate is also commonly complicated by acute renal failure, though the underlying mechanisms are not fully understood. Treatment Methaemoglobinaemia can be corrected by slow intravenous injection of methylthioninium chloride (methylene blue) 1–2 mg/​kg body weight as a 1% solution, although this treatment is less effective in the presence of major intravascular haemolysis. Blood transfusion may be required. Plasma potassium concentrations should be monitored and reduced if necessary. Haemodialysis/​haemodialfiltration may remove chlorate and will also be required for the management of renal failure and hyperkalaemia. Plasmapheresis and plasma exchange or exchange transfusion have also been employed to remove chlorate, circulating free haemoglobin, and red cell stroma, but data are too limited to make a firm recommendation.

Chlorophenoxy herbicides Chlorophenoxy (phenoxyacetate) herbicides are weed killers that act as synthetic auxins (plant ‘hormones’) and cause plant death by disrupting nutrient transport and growth. They comprise an aliphatic carboxylic acid moiety attached to a chlorine-​or methyl-​substituted aromatic ring. Important examples are listed in Table 10.4.1.10. These herbicides are usually formulated as salts or esters of the active compound and sometimes coformulated with the chemically related herbicides ioxynil, bromoxynil and/​or dicamba. Most instances of serious poisoning have been due to deliberate ingestion, mainly in the developing world. Mechanisms of toxicity include dose-​dependent cell membrane damage, chemical mimicry of acetyl coenzyme A and uncoupling of oxidative phosphorylation. Clinical features Ingestion causes nausea and vomiting which may be accompanied by burning in the mouth and throat and abdominal pain. Severe corrosive injury to the gastrointestinal tract is rare. Hypotension, which is common, is due predominantly to intravascular volume loss, although vasodilation and direct myocardial toxicity may also contribute. Coma, hypertonia, hyperreflexia, ataxia, nystagmus, miosis, hallucinations, convulsions, fasciculation, and paralysis may then ensue. Hypoventilation is commonly secondary to central nervous system

Table 10.4.1.10  Chlorophenoxy herbicides

Chlorates

Chemical name

Other names

Sodium and potassium chlorates are non​ selective herbicides. Potassium chlorate is also used in matchstick heads, explosives, and fireworks. Sodium chlorate and potassium chlorate are powerful oxidizing agents that induce methaemoglobinaemia and haemolysis.

2,4-​Dichlorophenoxy acetic acid

2,4-​D

4-​(2,4-​Dichlorophenoxy) butyric acid

2,4-​DB

2-​(2,4-​Dichlorophenoxy) propionic acid

2,4-​DP, dichlorprop

4-​Chloro-​2-​methylphenoxyacetic acid

MCPA

Clinical features

4-​(4-​Chloro-​2-​methylphenoxy) butyric acid

MCPB

2-​(4-​Chloro-​2-​methylphenoxy) propionic acid

Mecoprop

2-​(2, 4-​Dichloro-​m-​tolyoxy) propionanilide

Clomeprop

Features of chlorate toxicity may develop within as little as two hours of ingestion and are usually due to gastrointestinal irritation. Early

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depression, but respiratory muscle weakness is a factor in the development of respiratory failure in some patients. Myopathic symptoms, including limb muscle weakness, loss of tendon reflexes, myotonia, and increased creatine kinase activity, have been observed. Metabolic acidosis, rhabdomyolysis, renal failure, increased aminotransferase activities, pyrexia, and hyperventilation have been reported. Treatment

including jaw clenching in the absence of overt seizures, superior lateral gaze fixation, and opisthotonus have all been described. This increase in motor activity, in turn, results in raised creatine kinase activity, rhabdomyolysis, hyperpyrexia, and metabolic acidosis in some cases. Less frequent complications include hyperventilation, respiratory alkalosis, minor elevation of transaminase activities, upper gastrointestinal bleeding, and mildly deranged coagulation.

In addition to supportive care, urine alkalinization with high-​flow urine output will enhance herbicide elimination and should be considered in all seriously poisoned patients. Haemodialysis produces similar herbicide clearances to urine alkalinization and should be considered if high-​flow urine alkalinization cannot be performed for clinical reasons.

Treatment

Glyphosate

Methyl bromide

Glyphosate-​containing herbicides are very popular because their mode of action is plant-​specific (by inhibition of an enzyme pathway not present in mammals), they act only on contact with plant foliage and are inactivated on contact with soil. Formulations usually contain the isopropylamine salt of glyphosate, together with a surfactant. The latter is often an animal fat derivative (a tallow amine) polyoxyethylene amine (POEA), which contributes substantially to the toxicity of the formulation. Dilute, ready-​to-​use glyphosate/​POEA preparations are rarely associated with systemic toxicity, which usually requires the deliberate ingestion of a concentrate (typically 41% glyphosate/​15% POEA).

The uses of methyl bromide (bromomethane) have gradually become restricted as it is an ozone-​depleting chemical. It is currently used to fumigate mills, warehouses, shipping containers, stored products, and soil in greenhouses to eradicate pests such as woodworm and rodents that damage crops and buildings. In most countries application is now restricted to trained and licensed personnel. Methyl bromide is absorbed readily through the lungs and is excreted largely unchanged by the same route.

Clinical features Ingestion of more than 85 ml of the concentrated glyphosate/​POEA formulation is likely to cause significant toxicity in adults. Fatal ingestions have usually involved more than 200 ml. The most prominent effects are on the alimentary tract with burning in the mouth, throat, nausea, vomiting, dysphagia, and diarrhoea. Upper gastrointestinal haemorrhage is a much less common complication. Renal and hepatic impairment are also frequent and usually reflect reduced organ perfusion. Respiratory distress, impaired consciousness, pulmonary oedema, infiltration on chest radiograph, shock, arrhythmias, renal failure requiring haemodialysis, metabolic acidosis, and hyperkalaemia may supervene in severe cases and, together with advancing age and late presentation, are poor prognostic indicators. Treatment Management is symptomatic and supportive. Intravenous fluids or blood transfusion may be required. Respiratory and renal failure should be managed conventionally. The fatality rate in case series of glyphosate concentrate ingestion is approximately 6%. Death most frequently ensues within 72 h and is related to refractory cardiovascular collapse.

Metaldehyde Metaldehyde in the form of pellets is used widely for killing slugs and in some countries as a solid fuel. Clinical features Nausea, vomiting, diarrhoea, abdominal pain, agitation, dizziness, and tachycardia are common, but it is central nervous system and skeletal muscle complications that characterize the most severe toxicity. Convulsions may develop within 3 h of ingestion and recur frequently, and over days. Consciousness is impaired. Tremor, hypertonia, exaggerated limb reflexes, muscle twitching or spasms,

Treatment is supportive. Intravenous diazepam 10  mg IV or lorazepam 4 mg IV in an adult should be given to suppress convulsions and a clear airway and adequate ventilation ensured, using endotracheal intubation if necessary. Rhabdomyolysis and its complications should be managed conventionally.

Clinical features Inhalation causes respiratory tract irritation with shortness of breath, cough, and varying degrees of pulmonary oedema. Hypoxaemia and respiratory failure are inevitable consequences. Neurotoxicity manifests hours or days later with agitation, delirium, ataxia, intention tremor, nystagmus, dysdiadochokinesis, and hyperreflexia. Abnormal movements of the limbs are common and convulsions occur frequently. Consciousness may be impaired to the point of coma in severe cases. Proteinuria, oliguria (due to renal tubular and cortical necrosis), and jaundice have been described. Treatment The casualty should be removed promptly from the contaminated atmosphere and undressed, as methyl bromide can penetrate clothing and rubber gloves. Contaminated skin should be washed with water. Treatment is supportive. Systemic uptake can be quantified by measuring serum and urine bromide concentrations.

Neonicotinoids Neonicotinoids are now employed widely as systemic insecticides and some (imidacloprid, dinotefuran, thiamethoxam, nitenpyram) are used as flea control agents for dogs and cats. They block postsynaptic nicotinic receptors (nAChRs), particularly the α4ß2 subtype. The high specificity of neonicotinoids for insect nicotinic receptors, their low affinity for human nAChRs and relatively poor penetration of the human blood–​brain barrier should result in much lower toxicity to humans than nicotine-​containing pesticides. Human poisoning with neonicotinoids is well recognized and may be severe and fatal, though the solvents and surfactants present in many formulations may also contribute to toxicity. Clinical features Poisoning with neonicotinoids is characterized by the rapid onset of symptoms including nausea and vomiting, fever, sweating, increased

10.4.1  Poisoning by drugs and chemicals

salivation, bronchorrhoea, agitation, lack of coordination, disorientation, muscle weakness, seizures, and coma. Breathlessness, depressed respiration, cyanosis, and respiratory arrest have been reported. Bradycardia is sometimes present, but tachycardia is observed more frequently; ventricular tachycardia/​fibrillation has occurred occasionally, as has cardiac arrest. Severe hypotension and shock supervene in those severely poisoned. Miosis is present in some cases but not the majority. Metabolic acidosis and renal failure have been observed. Treatment In patients who are unconscious a clear airway should be established and, if ventilation is impaired, assisted ventilation should be commenced. Hypotension and cardiac dysrhythmias should be managed conventionally and acid–​base and electrolyte balance corrected. Since the clinically important features, notably bronchorrhoea, are caused by cholinergic overactivity, atropine sulphate 2 mg intravenously (in an adult) should be given and the dose repeated until the signs of atropinization are present (dry skin and sinus tachycardia). There is some evidence that activated charcoal can bind neonicotinoids and if administered within 1 h of ingestion may reduce absorption; gastric lavage is contraindicated because of the presence of solvents unless it can be performed with a cuffed endotracheal tube in situ.

Organophosphorus insecticides Organophosphorus insecticides are among the most widely used pesticides throughout the world. They inhibit acetylcholinesterase causing accumulation of acetylcholine at central and peripheral cholinergic nerve endings, including neuromuscular junctions. The clinical presentation and severity of OP poisoning depends not only on the pesticide and the magnitude of exposure but also on several other factors, including the route of exposure, the age of the patient, whether exposure was a suicidal attempt (when a substantial ingestion is more likely), and the presence of a solvent in the formulation. Not only may skin absorption of the OP itself be enhanced by the presence of the solvent, but also ingestion of a solvent may induce vomiting with risk of aspiration; depressed consciousness may follow. In addition, there is increasing evidence that the solvents in formulations are responsible for the high morbidity and mortality. Clinical features The first symptom of mild poisoning, particularly in individuals occupationally exposed, is often a feeling of exhaustion and weakness. Vomiting, cramping abdominal pain, sweating, and hypersalivation may follow. Constriction of one or both pupils and a sensation of tightness in the chest during inspiration also may occur at an early stage, but these signs are not reliable indices of the severity of systemic poisoning because they may be caused by local anticholinesterase effects of spray mist on the eye or bronchi. In cases of more severe poisoning, the nicotinic features tend to appear first, but a combination of muscarinic, nicotinic, and central nervous system symptoms is apparent in many severe cases. Muscle twitching may affect the eyelids, tongue, face muscles, and calf muscles; respiratory muscles then become involved, and general muscle weakness ensues. Convulsions may occur, though OPs vary in their potency to induce seizures. Bronchial hypersecretion/​ bronchorrhoea, with bronchoconstriction, is followed in severe cases by cyanosis, respiratory depression, and coma. Death may follow from respiratory failure. Coma is usually due to direct central

nervous system depression by the pesticide and solvents in the commercial formulation. Aspiration pneumonia is common. Though bradycardia would be expected from the mode of action of organophosphorus insecticides, it is present in only about 20% of cases; sinus tachycardia is more common. Rarely, complete heart block and arrhythmias occur. Relapse after apparent resolution of cholinergic symptoms has been reported, particularly in patients who have ingested highly lipophilic insecticides, and is termed the intermediate syndrome. This involves the onset syndrome of muscle paralysis affecting particularly upper limb muscles, neck flexors, and cranial nerves some 24–​96 h after exposure, though there are reports of paralysis occurring before 24 h and even after 96 h. It is often associated with the development of respiratory failure. Delayed neuropathy is a rare complication of acute exposure to some insecticides. It results from phosphorylation and subsequent ageing of at least 70% of neuropathy target esterase (NTE). Only a small number of marketed insecticides, for example methamidophos, are capable of causing this syndrome. The features resulting from distal degeneration of some axons in both the peripheral and central nervous systems occur 1–​4 weeks after exposure. Cramping muscle pain in the lower limbs, distal numbness, and paraesthesiae are followed by progressive weakness, depression of deep tendon reflexes in the lower limbs and, in severe cases, in the upper limbs. Signs include a high-​stepping gait from bilateral foot drop and, in severe cases, quadriplegia with foot and wrist drop, as well as pyramidal signs. In time, there might be significant recovery of peripheral nerve function but, depending on the degree of pyramidal involvement, spastic ataxia may be permanent The diagnosis is confirmed by measuring erythrocyte acetylcholinesterase activity; plasma butyrylcholinesterase activity is a less preferable alternative. Treatment Management involves supportive measures and judicious administration of antidotes. Bronchorrhoea requires prompt relief with intravenous atropine 2 mg (0.02–​0.1 mg/​kg in a child). The atropine dose should be titrated to control rhinorrhoea and bronchorrhoea, to 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 response, it should be doubled and doubled again if there is only a limited clinical response. In addition, supplemental oxygen should be given to maintain PaO2 greater than 10 kPa (75 mm Hg). If necessary, the patient should be intubated and mechanical ventilation (with positive end-​expiratory pressure) should be instituted. There are consistent animal data supporting the effectiveness of oximes, when given early. While there are also some clinical studies which support the benefit of oxime therapy, others do not. Recent studies indicate that solvents in the formulations play a crucial role in toxicity, which could explain why oximes seem to be less effective clinically than in experimental studies where pure insecticide is often employed. Pralidoxime chloride 30 mg/​kg by intravenous injection over 20 min, repeated at 4–​6 h intervals, should be administered as soon as possible in any patient requiring atropine; alternatively, an intravenous infusion of 8–​10 mg/​kg/​h in an adult may be employed after the bolus injection. Administration of pralidoxime should continue for as long as atropine is required, that is, until clear, irreversible clinical improvement is achieved, which may take many days while residual insecticide is cleared from the body stores.

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The use of diazepam 5–​10 mg intravenously in an adult will reduce anxiety and restlessness, but larger doses may be required to control convulsions; diazepam also reduces morbidity and mortality.

Phosphine Phosphine is used extensively as a fumigant to control rodents and a wide variety of insects in sealed containers or structures. It is also used in the semiconductor industry. Clinical features The initial symptoms are often alimentary rather than respiratory. Indeed, the nausea, vomiting, diarrhoea, and epigastric pain may be so striking that physicians are misled into making a diagnosis of acute gastroenteritis. However, respiratory complaints do occur. Chest tightness, breathlessness, chest pain or soreness, and palpitations are commonly reported. Inhaled phosphine is as cardiotoxic as ingested metal phosphides (see earlier). Acute heart failure, pulmonary oedema (which may be both cardiogenic and non​cardiogenic) and cardiac arrhythmias have been observed, particularly in children. Convulsions, ataxia, and intention tremor have also been reported. Treatment The casualty should be removed from exposure as soon as possible. Thereafter, treatment is supportive and symptomatic.

Pyrethroids Pyrethroids are used widely as insecticides both in the home and commercially, and in medicine for the topical treatment of scabies and head lice. In tropical countries, mosquito nets are commonly soaked in pyrethroid solutions as part of antimalarial strategies. Pyrethroid sprays are used to ‘disinsect’ the interiors of aircraft. Despite their extensive worldwide use, severe poisoning with pyrethroids is extremely rare. The most important mechanism of toxicity is modification of the gating characteristics of voltage-​sensitive sodium channels, causing delayed closure. A protracted sodium influx ensues, which, if it is sufficiently large and/​or long, lowers the action potential threshold and causes repetitive firing which manifests as paraesthesiae. Clinical features Pyrethroids are best known for their ability to cause facial paraesthesiae following occupational cutaneous exposure; these symptoms last only a few hours at most. Inhalation of pyrethroid-​containing dust or aerosol droplets may cause respiratory tract irritation, but systemic toxicity is unusual. Ingestion causes irritation of the gastrointestinal tract with nausea and vomiting, increased salivation, and mouth ulceration. Coma, convulsions, and pulmonary oedema may ensue in the most severe cases and fatalities have occurred rarely. Treatment Symptomatic and supportive measures should be employed, and reassurance given that facial paraesthesiae will not be a long-​term problem.

Other chemicals Acetone Acetone is a clear liquid with a characteristic pungent odour and sweet taste, used widely in industrial and household products including

paints, nail polish, and nail polish removers. It is absorbed rapidly through the lungs and gut and metabolized in the liver to pyruvate. Metabolism is saturable with elimination of the parent compound in expired air (it can be smelt on the breath) and urine at high doses. Clinical features There is irritation of mucous membranes of eyes, nose, and throat. Systemic toxicity causes headache, excitement, restlessness, chest tightness, incoherent speech, nausea and vomiting and, occasionally, gastrointestinal bleeding, coma, convulsions, and hyperglycaemia (resulting from the metabolism of pyruvate to glucose). Treatment If toxicity has followed inhalation, remove from exposure, give supportive treatment, and correct hyperglycaemia. Since acetone is a small molecule, there may be a role for dialysis in the management of seriously poisoned patients, particularly if plasma acetone concentrations are high.

Acids Acids commonly involved in cases of poisoning include the inorganic acids hydrochloric, hydrofluoric (see ‘Hydrogen fluoride/​ hydrofluoric acid’, further on in this chapter), nitric, phosphoric, and sulphuric acids; and organic acids such as acetic, formic, lactic, and trichloroacetic acids. Car battery acid typically contains 28% sulphuric acid. Proprietary cleaning agents and antirust compounds often comprise a mixture of hydrochloric and phosphoric acids. Inorganic acids generally are of concentrations more likely to be corrosive at the normally available solution. Clinical features Acid burns of the skin cause erythema, blistering and, in severe cases, ulceration and necrosis. In the eyes, intense pain and blepharospasm are common, and corneal burns may occur. When ingested, acids tend to damage the stomach more than the oesophagus, but oropharyngeal and oesophageal injuries may also occur. Immediate pain is followed by vomiting and/​or haematemesis. Severe injury results in inability to swallow saliva with drooling. Gastric and oesophageal perforation may occur, resulting in chemical peritonitis and shock. Other effects include hoarseness, stridor, and respiratory distress secondary to laryngeal and epiglottic oedema, metabolic acidosis leucocytosis, acute tubular necrosis, renal failure, hypoxaemia, respiratory failure, intravascular coagulation, and haemolysis. Treatment Acid burns to the skin should be irrigated liberally with water or saline and managed as a thermal burn. Skin grafting may be necessary and specialist advice should be sought. After ocular exposure with acid, the eye should be irrigated, preferably with saline for 15–​30 min. Topical local anaesthetic is usually required to relieve pain and to overcome blepharospasm. Specialist advice should be sought. After ingestion, a clear airway should be established. Opioids are often necessary for analgesia. Dilution and/​or neutralization is contraindicated. Features of severe tissue injury (severe abdominal pain, abdominal distension, circulatory collapse, or lactic acidosis) may indicate the presence of bowel necrosis or perforation. Immediate surgical assessment is recommended because early resection of necrotic tissue and intraluminal stenting has been shown

10.4.1  Poisoning by drugs and chemicals

to improve survival and reduce the risk of oesophageal stricture formation. Both CT scan and fibreoptic endoscopy have been shown to be useful in assessing the severity of injury, risk of mortality, and risk of subsequent stricture formation. These two imaging modalities are complimentary and when combined provide the best understanding of the injury and risk. If there are severe clinical features, then endoscopy is best performed by a surgeon capable of undertaking definitive treatment. Corticosteroids confer no benefit and may mask abdominal signs of perforation; antibiotics should be given for established infection only. Acid ingestion may result in antral, pyloric, or jejunal strictures, achlorhydria, protein-​losing enteropathy, and gastric carcinoma.

cases of severe haemolysis. If renal failure ensues, haemodialysis/​ haemodialfiltration should be undertaken. Antidotes to remove arsenic are of no value.

Alkalis

Acute exposure

Alkalis are commonly found in the home and those encountered in cases of poisoning include sodium hydroxide (drain, lavatory, pipe cleaners), sodium carbonate, sodium silicate, sodium perborate, sodium phosphate, sodium carbonate (denture cleaning tablets), sodium dichloroisocyanurate (water sterilizing tablets), sodium hypochlorite (a bleaching agent), and alkaline batteries.

Following inhalation or ingestion, euphoria, dizziness, weakness, headache, blurred vision, mucous membrane irritation, tremor, ataxia, chest tightness, respiratory depression, cardiac arrhythmias, coma, and convulsions occur. Direct skin contact with liquid benzene may produce marked irritation.

Clinical features The features of eye, skin and laryngeal contamination with alkalis are similar to those produced by acids (see ‘Acids’) though when ingested, alkalis are more likely to damage the oesophagus. Oropharyngeal pain, together with epigastric pain are followed by vomiting and diarrhoea. Oesophageal ulceration with or without perforation may be complicated by mediastinitis or pneumonitis. Oesophageal perforation may result in catastrophic aorto-​enteric fistula formation. Treatment The treatment of corrosive injuries caused by alkalis is largely the same as for those produced by acids (see ‘Acids’). In severe cases, following resuscitation and stabilization, early assessment by endoscopy and/​or CT imaging is the priority. Alkali ingestion may result in stricture formation and there is a risk of malignancy. The mean latent period for development of carcinoma of the oesophagus following alkali ingestion is more than 40 years.

Benzene Benzene is a colourless, volatile liquid with a pleasant odour. It is an ingredient in many paints and varnish removers, and in some petrols. About 10% of inhaled benzene is excreted unchanged in the breath. The remainder is metabolized by mixed function oxidase enzymes predominantly in the liver, but also in the bone marrow, the target organ of benzene toxicity. Benzene is a human carcinogen. Clinical features

Chronic exposure The toxic effects of chronic poisoning may not become apparent for months or years after initial contact and may develop after all exposure has ceased. Anorexia, headache, drowsiness, nervousness, and irritability are well described. Anaemia (including aplastic anaemia), leucopenia, thrombocytopenia, pancytopenia, leukaemia, lymphomas, chromosomal abnormalities, and cerebral atrophy have been reported. There is also an association between occupational benzene exposure and non-​Hodgkin’s lymphoma. Patients have recovered after as long as a year of almost complete absence of formation of new blood cells. A dry, scaly dermatitis may develop on prolonged or repeated skin exposure to liquid benzene. Treatment Following removal from the contaminated atmosphere, treatment should be directed towards symptomatic and supportive measures. Gastric lavage is hazardous as aspiration is likely to occur.

Arsine

Benzyl alcohol

Arsine is a colourless, non​irritating gas. Arsine binds with oxidized haemoglobin causing massive intravascular haemolysis.

Benzyl alcohol has been used as a preservative in intravascular flush solutions and in drug formulations, which has led to severe toxicity in neonates. Benzyl alcohol is metabolized to benzoic acid, which is then conjugated with glycine in the liver and excreted as hippuric acid. The immature liver’s capacity to metabolize benzoic acid is limited and, when exceeded, leads to accumulation of this metabolite and metabolic acidosis.

Clinical features There is usually a delay of some 2–​24 h after exposure before the onset of headache, malaise, weakness, dizziness, breathlessness, migratory abdominal pain, fever, tachycardia, tachypnoea, nausea, and vomiting. A bronze skin colour is noted in some patients, but most have the typical appearance of a jaundiced patient. Acute renal failure is observed by the third day after substantial exposure, and the urine is dark red, then brown (from haemoglobinuria), before anuria (due to acute renal tubular necrosis) ensues. Investigations will show leucocytosis, reticulocytosis, elevated plasma haemoglobin, and haemoglobinuria. Treatment If haemolysis is severe, the use of red cell exchange and plasma exchange may be more beneficial than red cell exchange alone, though plasma exchange alone is also effective in the treatment of intravascular haemolysis. Blood transfusion will be required in

Clinical features In 1982, a syndrome consisting of metabolic acidosis, convulsions, neurological deterioration (due to intraventricular haemorrhage), gasping respirations, hepatic and renal abnormalities, cardiovascular collapse, and death was described in small premature infants between 2 to 14 days of age. This was due to IV solutions containing benzyl alcohol. In contrast, healthy adult humans are able to tolerate as much as 30 ml of 0.9% benzyl alcohol by rapid intravenous infusion without signs of toxicity. However, a 5-year-old girl developed hypernatraemia and metabolic acidosis due to the infusion of

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diazepam for 36 hours to control status epilepticus. The presence of benzyl alcohol has been used as marker of toluene exposure. Treatment Metabolic acidosis, hepatic and renal failure should be treated conventionally and administration of fluids or drugs containing benzyl alcohol should be discontinued.

Carbon dioxide Carbon dioxide is a colourless gas that is also available commercially as a solid for refrigeration purposes (‘dry ice’). High concentrations may accumulate in wells, silos, manholes, mines, and in several volcanic lakes in Africa. In 1986, Lake Nyos in Cameroon emitted a cloud of carbon dioxide that killed 1700 villagers and 3500 of their livestock. Clinical features Dyspnoea, cough, headache, dizziness, sweating, restlessness, paraesthesiae, and sinus tachycardia are features after modest exposure. Higher concentrations (>10%) produce psychomotor agitation, myoclonic twitches, eye flickering, coma, and convulsions. Death occurs from acute cardiorespiratory depression, typically at concentrations exceeding 17%. Skin contact with solid carbon dioxide (dry ice) may result in frostbite and local blistering. Treatment The casualty should be removed from the contaminated environment and oxygen administered. Thereafter, care is supportive. Dry ice burns are treated similarly to other cryogenic burns, with thawing of the affected tissue and suitable analgesia.

Carbon disulphide Carbon disulphide is used as a fumigant for grain and as a solvent, particularly in the rayon industry. It is a clear, colourless, volatile liquid with an odour like that of decaying cabbage. Clinical features Acute exposure Acute poisoning is rare. Absorption occurs through the skin as well as by inhalation. Because of its potent defatting activity, carbon disulphide causes reddening, cracking, and peeling of the skin, and a burn may occur if contact continues for several minutes. Splashes in the eye cause immediate and severe irritation. Acute inhalation may result in irritation of the mucous membranes, blurred vision, nausea and vomiting, headache, delirium, hallucinations, coma, tremor, convulsions, and cardiac and respiratory arrest. Chronic exposure There is an increased incidence of cardiovascular disease (hypertension, arteriosclerosis, ischaemic heart disease, elevated cholesterol) among workers exposed to carbon disulphide. In addition, sleep disturbances, fatigue, anorexia, and weight loss are common complaints. Intellectual impairment, cerebellar signs, diffuse vascular encephalopathy, parkinsonism, peripheral polyneuropathy, hepatic damage, and permanent impairment of reproductive performance have been described.

Treatment Treatment involves removal from exposure, washing contaminated skin, irrigation of the eyes with water and supportive measures. In most cases, however, preventive measures to keep carbon disulphide concentrations in the workplace as low as possible are more important.

Carbon monoxide Carbon monoxide is a tasteless, odourless, colourless, non​irritating gas produced by incomplete combustion of organic materials. Normal endogenous carbon monoxide production is sufficient to maintain a resting carboxyhaemoglobin concentration of 1 to 3% in urban non​smokers and 5–​6% in smokers. Common sources of carbon monoxide are car exhaust fumes (in the absence of a catalytic converter), improperly maintained and ventilated heating systems, and smoke from all types of fire, typically charcoal barbecues used indoors. Carbon monoxide derived from domestic heating systems is a major cause of accidental death in the developing world. Inhalation of methylene chloride (from paint strippers) may lead to carbon monoxide poisoning due to breakdown of the parent compound. Symptoms and signs that follow inhalation of carbon monoxide are the result of tissue hypoxia. The affinity of haemoglobin for carbon monoxide is approximately 240 times greater than that for oxygen. Carbon monoxide combines with haemoglobin to form carboxyhaemoglobin, reducing the total oxygen-​carrying capacity of the blood. In addition, the oxygen dissociation curve shifts to the left due to modification of oxygen-​binding sites. As a result, the affinity of the remaining haem groups for oxygen is increased, the oxygen dissociation curve is distorted as well as being shifted and the resulting tissue hypoxia is thus far greater than that which would result from simple loss of oxygen-​carrying capacity. Carbon monoxide may also inhibit cellular respiration as a result of reversible binding to cytochrome oxidase a3. At higher concentrations, carbon monoxide causes brain lipid peroxidation and it has been suggested this may be relevant to the development of delayed neuropsychiatric sequelae. Clinical features The clinical features of carbon monoxide poisoning may be divided into those caused acutely, predominantly due to hypoxia, and those that result from tissue damage by the mechanisms detailed earlier. These later toxicities are therefore related to the initial amounts of carbon monoxide inhaled and length of time before rescue and treatment. In acute poisoning, organs with high oxygen demand are at special risk of damage and this includes, in particular, the heart and brain. The symptoms of mild to moderate exposure are non​specific and include headache, nausea, and confusion. These non​specific symptoms require a high degree of suspicion in patients at potential risk of poisoning with the gas. As concentrations increase, metabolic acidosis ensues from interference with metabolic processes, and central nervous system features progress to cause loss of consciousness with hypertonia and hypereflexia, extensor plantar responses, papilloedema, and convulsions. Cardiovascular changes include arrhythmias and ischaemic myocardial damage. Other complications tend to be detected later and include persistent neurological damage in any part of the brain, which may

10.4.1  Poisoning by drugs and chemicals

result in either paralysis or midbrain damage causing parkinsonism or akinetic mutism, deafness due to central ischaemia of the brain stem nuclei and cochlea, muscle necrosis causing rhabdomyolysis and renal failure and skin changes (bullae) due to prolonged unconsciousness. The degree of intoxication is correlated to some extent with carboxyhaemoglobin concentrations but, by the time patients arrive in hospital, they will often have received oxygen in an ambulance, which may lower carbon monoxide concentrations from those present at the scene of the injury. Very severe features are to be expected with carboxyhaemoglobin above 60%, but significant features would not generally be expected at concentrations below 30%. Neuropsychiatric problems may occur after recovery from carbon monoxide intoxication and are said to develop insidiously over several weeks. Defining limits of these changes may be difficult in patients with relatively mild exposure, and ascribing causation is particularly difficult in low-​level exposures where formal studies suggest no effect. Treatment Removal from exposure and administration of 100% oxygen using a tightly fitting facemask are essential. If patients are unconscious, endotracheal intubation and mechanical ventilation is required. Prolonged administration of oxygen is necessary to ensure carbon monoxide bound in tissues is released. Traditionally, hyperbaric oxygen has been used in carbon monoxide poisoning, although there remains significant controversy about its efficacy. A trial in the United States of America has shown some suggestion of benefit, but commentators are divided about the relevance of the relatively small changes noted, and the wider application of these results. In part, this is because patients were brought for treatment for quite some distance, and the debate remains as to whether any potential small therapeutic benefit warrants transfer to a distant treatment facility.

Cyanide Hydrogen cyanide and its derivatives are used widely in industry and are released during the thermal decomposition of polyurethane foams. Cyanide poisoning may also result from the ingestion of the cyanogenic glycoside amygdalin, which is found in the kernels of almonds, apples, apricots, cherries, peaches, plums, and other fruits. Cyanide reversibly inhibits cellular enzymes which contain ferric iron notably cytochrome oxidase a3 so that electron transfer is blocked, the tricarboxylic acid cycle is paralysed, and cellular respiration ceases. Clinical features Acute poisoning The ingestion by an adult of 50 ml of (liquid) hydrogen cyanide or 200–​300 mg of one of its salts is likely to prove fatal. Inhalation of hydrogen cyanide gas may produce symptoms within seconds and death within minutes. Acute poisoning is characterized by dizziness, headache, palpitation, anxiety, a feeling of constriction in the chest, dyspnoea, pulmonary oedema, confusion, vertigo, ataxia, coma, and paralysis. Cardiovascular collapse, respiratory arrest, convulsions, and metabolic acidosis are seen in severe cases. Cyanosis may occur, and the classical ‘brick red’ colour of the skin is noted occasionally. There is sometimes an odour of bitter almonds on the breath, but the ability to detect this is genetically determined and some 40% of the population are unable to do so.

Chronic exposure Chronic exposure results predominantly in neurological damage which can include ataxia, peripheral neuropathies, amblyopia, optic atrophy, and nerve deafness. Treatment The immediate administration of oxygen is of paramount importance, as there is evidence that it prevents inhibition of cytochrome oxidase a3 and accelerates its reactivation. Treatment thereafter depends on the severity and type of exposure. If hydrogen cyanide has been inhaled and the patient remains conscious 10 min after exposure has ceased, no antidotal treatment is required. In more severe cases an antidote is invariably necessary. Methaemoglobin binds cyanide, forming cyanmethaemoglobin. Methaemoglobinaemia may be induced efficiently by the administration of intravenous sodium nitrite 300 mg over 5 min. Because the effect of sodium nitrite is relatively rapid and methaemoglobin formation slower, the benefit of sodium nitrite may also be from its vasodilator action and the consequent improved tissue perfusion. Intravenous sodium nitrite is usually given with intravenous sodium thiosulfate; they have been shown to act synergistically in experimental cyanide poisoning by providing sulphane sulphur to enhance endogenous metabolism. Sodium thiosulfate is administered intravenously in a dose of 12.5 g over 10 min. Dicobalt edetate solutions contain free cobalt, which complexes six times more cyanide than dicobalt edetate. Cobalt is toxic, however, and use of this formulation in the absence of cyanide poisoning may cause cobalt toxicity. Dicobalt edetate should, therefore, be given only when the diagnosis is certain. Dicobalt edetate is administered intravenously in a dose of 300 mg over 1 min, with a further 300 mg being given if recovery does not occur. One mole of hydroxocobalamin inactivates one mole of cyanide, but, on a weight-​for-​weight basis, 50 times more hydroxocobalamin is needed than cyanide because hydroxocobalamin is a far larger molecule. If available, hydroxocobalamin 5 g is given intravenously over 30 min; a second dose (5 g) may be required in severe cases.

Diethylene glycol Diethylene glycol is used as a coolant, as a building block in organic synthesis and as a solvent. It can be also found in some hydraulic fluids and brake fluids. Occupational exposure is by the dermal route, but the most common route of exposure is ingestion, often unintentionally as a result of contamination of medicines. Diethylene glycol has been responsible for several mass poisonings in Australia, Bangladesh, Haiti, India, Nigeria, South Africa, and the United States of America. Diethylene glycol is metabolized by alcohol dehydrogenase to 2-​hydroxyethoxyacetaldehyde and by aldehyde dehydrogenase to 2-​hydroxyethoxyacetate and a small amount of diglycolic acid. The metabolic acidosis observed in diethylene glycol poisoning is primarily due to 2-​hydroxyethoxyacetate, but lactate also plays a part in severe poisoning. Diglycolic acid is the metabolite responsible for the development of proximal tubular necrosis. Clinical features Nausea and vomiting, headache, abdominal pain, coma, seizures, metabolic acidosis, and acute renal failure have most commonly been reported. Renal dysfunction in those who do not develop dialysis dependence often improves over several months. Pancreatitis and hepatitis have been observed, together with cranial neuropathies, such as

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facial nerve motor deficits, and demyelinating peripheral neuropathy, demonstrated clinically as bilateral lower extremity numbness.

Table 10.4.1.11  Clinical features of ethylene glycol poisoning 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 instituted promptly. If the patient presents early after ingestion, the priority is to inhibit metabolism using either intravenous fomepizole or ethanol. Fomepizole requires less monitoring, but is more expensive than ethanol. After a loading dose of fomepizole 15 mg/​kg over 30 min, four 12-​hourly doses of 10 mg/​kg should be given, followed by 15 mg/​ kg 12-​hourly until the glycol concentration is not detectable. If haemodialysis is used, the frequency of dosing should be increased to 4-​hourly as fomepizole is dialysable. Alternatively, a loading dose of intravenous ethanol 50 g for an adult (50 ml of absolute ethanol in 1 L 5% dextrose, i.e. a 5% ethanol solution) should be given, followed by an intravenous infusion of 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 approximately 1000 mg/​litre. Administration of ethanol should be continued until the glycol is undetectable in the blood. If haemodialysis/​ haemodialfiltration is used, greater amounts of ethanol (17–​22 g/​h) must be given, because ethanol is readily dialysable. Haemodialysis/​haemodialfiltration will remove diethylene glycol, but it is not known whether the metabolites are also removed.

• Nausea, vomiting, haematemesis

Ethylene glycol Ethylene glycol has a variety of commercial applications and is commonly used as an antifreeze fluid in car radiators. Its sweet taste and ready availability have contributed to its popularity as a suicide agent and as a poor man’s substitute for alcohol. It is thought that the minimum lethal dose of ethylene glycol is about 100 ml for an adult, although recovery after treatment has been reported following the ingestion of up to 1 L. The toxicity of ethylene glycol depends predominantly on its metabolites (Fig. 10.4.1.5) though the initial inebriation is due to ethylene glycol itself. Central nervous system symptoms coincide with the peak production of glycolaldehyde; aldehydes inhibit many aspects of cellular metabolism. Glycolate is largely responsible for the marked acidosis seen in severe cases; lactate concentrations are generally not very high. Lactate is produced as a result of the large amount of NADH formed by the oxidation of ethylene glycol and by inhibition of the tricarboxylic acid cycle by the condensation products of glyoxylate. There is increasing evidence that calcium oxalate monohydrate crystals are the cause of renal failure and cerebral oedema. Clinical features The clinical features of ethylene glycol poisoning may be divided into three stages depending on the time after ingestion (Table 10.4.1.11). Although the three stages are useful theoretical descriptions of Ethylene glycol

ADH

Glycoaldehyde

ALDH AO

• Coma and convulsions (often focal) • Nystagmus, ataxia, ophthalmoplegias, papilloedema, depressed reflexes, myoclonic jerks, tetanic contractions

• Cranial nerve II, V, VII, VIII, IX, X, XII palsies Stage 2 (12–​24 h): cardiorespiratory involvement

• Tachypnoea, tachycardia • Mild hypertension • Metabolic acidosis • Myocarditis • Pulmonary oedema • Congestive cardiac failure Stage 3 (24–​72 h): renal involvement

• Flank pain, renal angle tenderness • Hypocalcaemia • Acute tubular necrosis • Calcium oxalate crystalluria ethylene glycol poisoning, the onset and progression of the clinical course is frequently not as consistent or predictable. After a brief period of inebriation due to the intoxicating effect of ethylene glycol itself, metabolic acidosis develops, followed by tachypnoea, coma, seizures, hypertension, and hypocalcaemia, together with calcium oxalate crystalluria, the appearance of pulmonary infiltrates, and oliguric renal failure. If untreated, death from multiorgan failure usually occurs 24–​36 h after ingestion. Severe acidosis, hyperkalaemia, seizures, and coma carry a poor prognosis. A serum ethylene glycol concentration more than 500 mg/​litre indicates severe poisoning. Treatment Supportive measures to combat cardiorespiratory depression should be employed and metabolic acidosis, hypocalcaemia, and renal failure should be treated conventionally. (For further information on treatment with fomepizole or ethanol, please see the section ‘Diethylene glycol’.) If admission plasma concentrations show that the ethylene glycol ingested has already been metabolized, fomepizole or ethanol administration will not be of benefit and ethanol might exacerbate the acidosis. Haemodialysis/​ haemodialfiltration removes ethylene glycol, glycolaldehyde, and glycolate (but not oxalate), and will also correct acid–​base disturbances. Dialysis should be employed particularly if presentation is late and marked metabolic acidosis is present. It should be continued until the glycol and glycolate are no longer detectable in the blood.

Glycolate

GO

Glyoxylate

LDH or GO

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.

Oxalate

10.4.1  Poisoning by drugs and chemicals

Formaldehyde Formaldehyde is a flammable, colourless gas with a pungent odour. It is most commonly available commercially as a 30–​50% w/​w aqueous solution and is an important raw material in the synthesis of organic compounds such as plastics and resins. It is added to cosmetics and foodstuffs as a preservative and antimicrobial agent and is used in embalming. Formaldehyde also occurs naturally in the environment. It is released during the combustion of organic materials (e.g. in forest fires, wood-​burning stoves, and waste incinerators), and is a product of incomplete petrol combustion in internal combustion engines. Absorption may follow ingestion, inhalation, or dermal contact. Once absorbed, formaldehyde is oxidized rapidly to formate then converted more slowly to carbon dioxide and water. Clinical features Severe irritation of the mucous membranes of the eyes, nose, and upper airways occurs after minimal exposure to low (1250  mm), higher vegetation index, and population density. Similar approaches have been used on a smaller scale to investigate associations between specific mineral constituents of soil and disease, with phyllosilicate materials (smectite clays and mica), quartz, iron oxide, and zirconium associated with podoconiosis prevalence. Not everyone exposed to these soils develops podoconiosis, but family clustering has long been observed. Recent genetic studies demonstrated high heritability of the trait and segregation analysis suggests the presence of an autosomal codominant major gene conferring susceptibility to podoconiosis. A genome-​wide association study demonstrated association between variants in HLA class  II

loci and podoconiosis, suggesting that the disease may be a T-​cell-​ mediated inflammatory disease. The best evidence to date suggests that podoconiosis is the result of an abnormal inflammatory reaction to mineral particles that penetrate the skin and accumulate in the lower leg. Colloid-​sized particles of elements common in irritant clays (aluminium, silicon, magnesium, and iron) have been demonstrated in the lower limb lymph node macrophages of both patients and non​patients living barefoot on the clays. Electron microscopy of lymph nodes shows evidence of follicular hyperplasia, with an increased number of proliferative germinal centres. An exaggerated lymphocyte population (predominantly CD4+ T lymphocytes) is seen in the paracortex sinuses of some of the nodes.

Epidemiology 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, Cameroon, Rwanda, Uganda and Kenya, and were previously reported in Tanzania, Equatorial Guinea, the islands of Bioko, São Tomé, and Principe, and Cabo Verde. Recent nationwide mapping of podoconiosis in Ethiopia, the most heavily endemic country in the world, suggests that 1.54 million individuals, or 4% of the adult population, live with podoconiosis, and almost half the population (47.8%) live in areas environmentally suitable for the development of podoconiosis. The condition has been reported in the Central American highlands from Mexico, south to Ecuador, but recent work suggests very few new cases in these areas. Podoconiosis has also been reported in north-​west India, Sri Lanka, and Indonesia. Large-​scale population studies in Ethiopia indicate that being female, older, unmarried, washing the feet less frequently than daily, and being semi-​skilled or unemployed are all associated with increased risk of podoconiosis. All major community-​based studies have shown onset in the first or second decade and a progressive increase in prevalence up to the sixth decade.

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Average Prevalence (%) based on available data 0.21–0.30

1.00–2.51

Case report

0.31–0.99

2.52–4.62

Reported Presence

Not reporting

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.

Clinical, economic, and social burdens Studies have documented that 77.4% to 97% of patients have experienced ‘acute attacks’ (acute dermatolymphangioadenitis or ADLA) at least once per year. These are episodes of inflammatory swelling of lymphoedematous legs that may be triggered by bacterial, viral, or fungal superinfection. They are characterized by hot, painful, and reddened swelling and lead to loss of productivity. According to a study in southern Ethiopia in an area with 1.7 million 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 productive 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 misconceptions 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 excluded 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.

exacerbation of symptoms when they try to walk long distances or do hard physical work. Early changes include spreading or ‘splaying’ of the forefoot, swelling of the sole of the foot, leakage of colourless ‘lymph’ fluid from the foot, and changes in the skin so that it looks like moss or velvet (Fig. 10.5.2). The affected person may report limb aches, heaviness of the lower leg and foot, and odour from the lymph leak, which may attract flies. As the lymphoedema progresses, both legs and feet will be affected, though one is usually more severely affected than the other.

Clinical features The disease process is usually described in three phases: prodromal, early, and advanced. Prodromal symptoms include itching of the skin of the forefoot, a burning sensation in the foot and lower leg, ‘chills’, or generalized joint pains. The affected person may describe

Fig. 10.5.2  Early changes—​oedema, block toes, changes in skin colour (here related to the pattern of the open sandal worn), lymph ooze, and early mossy changes around interdigital clefts.

10.5  Podoconiosis (nonfilarial elephantiasis)

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

Fig. 10.5.3  ‘Water-​bag’ type swelling: patient in her early 20s.

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 developed for mapping studies. Each foot should be assessed for mossy changes, interdigital maceration, wounds, and stage of disease 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 successfully used in endemic areas to provide information about the causes of podoconiosis and to encourage preventive behavioural changes.

Treatment

Fig. 10.5.4  ‘Leathery’ type advanced podoconiosis in patient aged 14.

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 package of self-​care measures including foot hygiene, ointment,

Table 10.5.1  Distinguishing podoconiosis from lymphatic filariasis Characteristic

LF

Podoconiosis

Area of residence

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 Mass Drug Administration (MDA)

Protective footwear Floor coverings Foot washing

Treatment

2 drugs (albendazole + DEC) Foot hygiene

Foot hygiene, bandages, exercises, socks and shoes

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bandages, elevation, exercises, and use of socks and shoes has recently been shown to reduce the incidence and duration of acute attacks. Charles’s operation (removal of skin, subcutaneous tissue, and deep fascia to lay the muscles and tendons bare, followed by 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 healing postnodulectomy to be good.

Prognosis Recent follow-​up during a community-​based trial suggests excess mortality associated with podoconiosis. Untreated patients have severely reduced mobility and work capacity by their mid-​40s, chiefly due to episodes of acute dermatolymphangioadenitis.

Global awareness Podoconiosis was included in the WHO list of ‘Other Neglected Tropical Conditions’ in February 2011, and is currently addressed under the lymphatic filariasis programme of the Department for Control of Neglected Tropical Diseases (NTDs). Elimination of podoconiosis as a public health problem is achievable because no biological agent or vector involved in podoconiosis has been identified, the global scale of the problem is relatively small, and the strategies for podoconiosis prevention and control are safe. A national network, the National Podoconiosis Action Network, and a global initiative, Footwork, the International Podoconiosis Initiative (https://​podo.org), were launched in 2012. These aim to advocate for and coordinate integration of podoconiosis interventions into NTD control strategies at national and international

levels. Together with non​government partners, Footwork has coordinated training of health workers in podoconiosis management in Cameroon and Uganda and will provide similar training in Rwanda and Burundi.

Likely research developments The Global Atlas of Podoconiosis project was launched in 2017 to further understanding of the geographical distribution and spatial epidemiology of the disease. Studies examining host immunological and inflammatory responses are currently underway. A  range of devices to enable better diagnosis and volume measurement are being developed and tested, while a trial examining the effectiveness of doxycycline has recently been launched in Cameroon. Implementation research exploring optimal integration of podoconiosis care into existing health systems is also underway.

FURTHER READING Deribe K, Cano J, Trueba ML, Newport MJ, Davey G. (2018). Global epidemiology of podoconiosis: a systematic review. PLoS Negl Trop Dis, 12(3), e0006324. Deribe K, et al. (2015). The feasibility of elimination of podoconiosis. Bull WHO, 93, 712–​18. Negussie H, et  al. (2018). Lymphoedema management to prevent acute dermatolymphangioadenitis in podoconiosis in northern Ethiopia (GoLBet): a pragmatic randomised controlled trial. The Lancet Global Health, 6(7), e795–​e803. Tekola F, et  al. (2006). Economic costs of podoconiosis (endemic non-​filarial elephantiasis) in Wolaita Zone, Ethiopia. Trop Med Int Health, 11, 1136–​44. Tekola F, et al. (2012). The HLA class II locus confers susceptibility to podoconiosis. N Engl J Med, 388, 1200–​8.

SECTION 11

Nutrition Section editor: Katherine Younger

11.1 Nutrition: Macronutrient metabolism  1839 Keith N. Frayn and Rhys D. Evans 11.2 Vitamins  1855 Tom R. Hill and David A. Bender 11.3 Minerals and trace elements  1871 Katherine Younger 11.4 Severe malnutrition  1880 Alan A. Jackson

11.5 Diseases of affluent societies and the need for dietary change  1891 J.I. Mann and A.S. Truswell 11.6 Obesity  1903 I. Sadaf Farooqi 11.7 Artificial nutrition support  1914 Jeremy Woodward

11.1

Nutrition: Macronutrient metabolism Keith N. Frayn and Rhys D. Evans

ESSENTIALS Food intake is sporadic and, in many cultures, occurs in three daily boluses. At the same time, energy expenditure is continuous and can vary to a large extent independently of the pattern of energy intake, although fixed or predictable demands (e.g. through occupation) means that in most persons food intake and energy expenditure are soon balanced. The body has developed complex systems that direct excess nutrients into storage pools; as they are needed, they also regulate the mobilization of nutrients from these pools. Analogous to the fuel tank of a car and the throttle that regulates fuel oxidation, supply and need are closely linked, except that in the vehicle there is just one fuel and just one engine. In contrast, in humans there are three major nutrients and a variety of tissues and organs, each of which may have its own preferences for fuels that vary with time. Carbohydrate, lipid, and protein (the latter a source of amino acids) are the three types of energy supply that are stored variably and assimilated from food each day. That we can carry on our daily lives without thinking about whether to store or mobilize fuels, and which to use, attests to the remarkable efficiency and refinement of these systems of metabolic control.

Overview of metabolism The body requires energy for chemical and mechanical work in order to maintain homeostasis; functions including maintenance of ionic gradients, transport, biosynthesis, heat generation, and locomotion. This energy is derived from three groups of energy-​rich substrates: carbohydrates, lipids, and amino acids. Multiple groups are utilized because they all have chemical and thermodynamic advantages and disadvantages, and together they provide energy under widely varying conditions and demands. All three nutrient groups exist in large, energy-​rich macromolecular storage forms. The principal macronutrient stores are listed in Table 11.1.1 and are related to daily fluxes of energy substrates in the body. For energy mobilization these are sequentially broken down into less energy-​rich metabolites, the energy liberated being captured by

intermediary reduction-​oxidation molecules which carry the energy to a common pathway of oxidation linked to the phosphorylation of ADP to ATP. Hence, the energy is used to synthesize ATP, the common energy carrier to which most energy-​requiring biological processes are linked. At a whole-​body level, this process is termed ‘catabolism’. Conversely, in energy-​rich states when energy intake exceeds expenditure, these metabolic pathways can be reversed, whereby ingested nutrients from all three groups are assembled into large storage macromolecules (‘anabolism’) (Fig. 11.1.1). Lipids (fats) are the most energy-​dense metabolic fuels (c.37 kJ/​g). The storage form of lipids for energy provision is triacylglycerol (TAG), which comprises three fatty acids esterified to a glycerol backbone. Being highly hydrophobic and reduced, TAGs are very energy dense and a highly efficient energy store. However, TAGs are relatively slow to mobilize, must be oxidized to yield energy and cannot provide energy anaerobically, and the non​esterified fatty acids (NEFAs) from which they are assembled are amphipathic (detergent-​like) and hence potentially toxic in high concentrations. Furthermore, fatty acids cannot be converted into carbohydrates or proteins, limiting their metabolic flexibility. Carbohydrates such as glucose are less reduced and more soluble than lipids and 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 three times its own weight), so its low energy density makes this an inefficient energy store, and only limited amounts are synthesized (Table 11.1.1). Carbohydrates are able to supply intermediary metabolites to maintain pathway integrity (anaplerosis) in contrast to lipids, oxidation of which leads to depletion of intermediary metabolites (cataplerosis): hence some carbohydrate is always required for metabolism to proceed efficiently (captured in the old aphorism ‘fat burns in the fire of carbohydrate’). Proteins (polymers of amino acids) have similar energy content to carbohydrates (c.17 kJ/​g), but each protein has a specific function and they are not used as dedicated energy stores. In catabolic states of carbohydrate depletion (e.g. starvation), however, proteins are broken down to their constituent amino acids for conversion into glucose for energy and anaplerosis—​hence proteins constitute a virtual carbohydrate store.

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Table 11.1.1  The principal macronutrient stores Macronutrient

Total amount in body

Energy equivalent (MJ)

Days’ supply if the only energy source

Daily intake (g)

Daily intake as percentage of store

Carbohydrate

0.6 kg

8.5

3  years) and European Medicines Agency in 2017 for patients at any age. At the time of writing in the United Kingdom, NICE has given provisional

12.8 Lysosomal disease

approval for Brienura with limited reimbursement from the National Health Service in England under a managed access programme. Anecdotal reports and post-​marketing information provides some reassurance that this intensive and laborious intervention provides clinically useful benefit and stabilization of disease in otherwise stricken children. It is not yet known whether the therapy will delay the onset of blindness. Two small-​scale early-​phase clinical trials of gene therapy have been conducted in infants with CLN2 using recombinant adeno-​associated vectors delivered intracranially. Two distinct vector serotypes with potentially different cellular tropisms have been used. At the time of writing no beneficial outcomes have been reported from either trial. Papillon–​Lefèvre syndrome This is an unusual syndrome, inherited as an autosomal recessive trait, resulting in periodontal disease with tooth loss and palmoplantar keratosis that is associated with a selective deficiency of cathepsin C activity within the azurophil granules of neutrophilic polymorphonuclear leucocytes. Several mutations have been identified within the gene encoding cathepsin C, which is an exo-​cysteine protease, also known as dipeptidyl peptidase I, that serves as a multifaceted scaffold on which numerous chymotrypsin-​like proteases are activated during neutrophil maturation. These include granule serine peptidases such as elastase, cathepsin G and proteinase 3 in neutrophils, and chymase and tryptase in mast cells; a partial role in the activation of granzyme B, a key effector system of natural killer cells, has been suspected from animal studies but only described in one affected human pedigree. Deficiency of antimicrobial peptides released during the normal inflammatory process has also been shown. A more severe allelic variant known as Haim–​Munk syndrome, originally reported from Cochin in Southern India, is associated with onychogryphosis, pes planus, arachnodactyly, and osteolysis involving the distal phalanges (acro-​osteolysis). It appears that the enzyme deficiency leads to the failure of bacterial clearance in the gums, thereby causing destructive periodontitis and tooth loss. The corresponding role of cathepsin C within the dermal epithelium is not known, but a failure of cathepsin C activity reproducibly leads to epithelial abnormalities and thickening of the skin, particularly on the soles of the feet. Some patients with disabling skin manifestations have obtained benefit by the use of retinoids, with or without antimicrobial therapy. These agents are, however, unlikely to improve early-​onset destructive periodontal disease which leads to loss of primary and secondary dentition. Recurrent oral infection with Aggregatibacter actinomycetemcomitans infection has been reported. The importance of the Papillon–​Lefèvre syndrome rests not only on the identification of lysosomal cathepsin C as an important component of immune defences against bacteria that preferentially invade the privileged periodontal site, but also on the involvement of this enzyme in the normal turnover of keratinized skin as well as defence against microbial invasion. Spondyloenchondrodysplasia with immune dysregulation This autosomal recessive skeletal dysplasia with intracranial calcification had been long recognized, but association with deficiency of the lysosomal tartrate-​resistant iron-​containing purple (type 5) acid phosphatase and diverse clinical manifestations of autoimmunity, including lupus erythematosus, has been recent.

The type 5 acid phosphatase is a readily measured lysosomal enzyme expressed in osteoclasts and pathological macrophages. In healthy persons, the enzyme is also abundant in Langerhans and dendritic cells. Apart from its ability to degrade skeletal phosphoproteins, including osteopontin, it probably modulates the effector pathways of phagocytic activation or antigen presentation. There is little or no evidence of ‘storage’: the disease illustrates the extraordinary diversity of lysosomal functions in the whole animal and how genetic disturbances can induce wide-​ranging clinical effects. Enchondromatous lesions are seen in long bones with sclerosis and irregularity of the metaphyseal plate. Lateral spine radiographs reveal platyspondyly and irregularity of the vertebral endplates. There is intracranial calcification in the basal ganglia, thalami and deep cerebral gyri. The manifestations of autoimmunity are characterized by elevated antinuclear antibody and anti-​double-​stranded DNA antibody titres with hypocomplementaemia. The clinical course in patients is varied but generally florid, with hypothyroidism, vitiligo, thrombocytopenia requiring splenectomy, autoimmune haemolytic anaemia, hepatosplenomegaly, nonerosive arthropathy, and vasculitic skin eruptions. Defects of organelle assembly: Chédiak–​Higashi, Griscelli’s, and Hermansky–​Pudlak syndromes Inherited defects of protein complexes that participate in the biogenesis of lysosomes and their related secretory organelles such as melanosomes are increasingly being recognized. The organelles with specialized functions that closely resemble lysosomes are termed lysosome-​related organelles and include δ-​granules in platelets; Weibel–​Palade bodies of endothelial cells; lytic granules and vesicles implicated in the immune ‘synapse’ in lymphocytes; basophil and azurophil granules in polymorphonuclear leucocytes; lamellar bodies in type 2 pneumocytes; neuromelanin granules in the catecholaminergic neurones of the nigro-​strial pathway, and the melanosomes of the iris, choroid, and skin. Most of these organelles maintain an acidic intra-​organellar milieu, but while they often employ the lysosomal recognition marker, mannose 6-​phosphate, they do not necessarily have a full complement of lysosomal membrane proteins such as LAMP1 and LAMP2 and other characteristics. Chédiak–​Higashi, Griscelli’s, and Hermansky–​Pudlak syndromes are rare conditions inherited as autosomal recessive traits. All cause oculocutaneous albinism, often in association with abnormal platelet granules and melanosomes in the skin and eyes: partial albinism is frequent. Chédiak–​Higashi and Griscelli’s syndromes Chédiak–​Higashi syndrome is caused by mutations in the lysosomal trafficking regulator gene located on chromosome 1q44. It predisposes to microbial infection and there are giant lysosomal granules in peripheral blood granulocytes; ceroid storage occurs in the nervous system and lungs. The clinical phenotype results from a complex set of immune defects affecting natural killer cells and neutrophilic leucocytes. Natural killer cell cytotoxicity is absent. Neutrophils, melanocytes, neurons, muscle cells, and Schwann cells show giant inclusion bodies. Recurrent cutaneous and systemic pyogenic infections occur with defective neutrophil and monocyte migration. Neurodegeneration is a prominent feature in young adults, but death often results from a rapidly progressive lymphoproliferative disorder.

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The Griscelli’s syndrome(s) are three unusual variants: one (type III) is a simple form of albinism, and the others combine albinism with defective immunity (type II) or neurological deficits (type I). Griscelli’s syndrome type II with immunological defects is caused by mutations in Rab27a, a soluble GTPase, which regulates the flow of melanosomes in melanocytes and regulates exocytosis of lytic granules at the point of the ‘immune synapse’ in cytotoxic T lymphocytes. Deficient Rab27a thus causes dysfunctional T lymphocytes and pigmentary abnormalities. The Griscelli’s syndrome type I, which also has neurological symptoms, is caused by mutations in the motor protein, myosin Va, which may cooperate with Rab27a to transport melanosomes along actin filaments but apparently does not participate in the exocytosis of lytic T cell granules. Hermansky–​Pudlak syndrome Nine genetically distinct Hermansky–​Pudlak disorders are known. Hermansky–​Pudlak syndrome type 2 is caused by mutations in the β-​3A adaptin gene which is associated with altered trafficking 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 very rare, one of the Hermansky–​Pudlak syndromes occurs at a high frequency in the Swiss Alps and the Puerto-​Rican population where it is the most common single-​gene defect. Clinical features include a bleeding tendency due to abnormal platelets; diminished pigmentation of the skin, iris, and hair; and diverse inflammatory complications including granulomatous colitis, cardiomyopathy, and severe pulmonary fibrosis. The pulmonary disease appears to be related to defective release of surfactant by type 2 pneumocytes. Hermansky–​Pudlak syndrome type 2 causes a mild bleeding diathesis and platelet dense bodies are absent; the patients are susceptible to bacterial infection due to congenital neutropenia. There are clear similarities between Hermansky–​ Pudlak and Chédiak–​Higashi syndromes, and further functional studies of their respective cognate proteins should refine our knowledge about the regulation of synthesis and coordinated assembly of lysosomes and related organelles. Treatment of biogenesis defects These disorders are often very severe. For example, patients with Chédiak–​Higashi disease and Griscelli’s syndrome type 2 occasionally develop a life-​threatening syndrome with fever, jaundice, and pancytopenia—​haemophagocytic lymphohistiocytosis—​which is related to impaired natural killer and cytotoxic T-​cell function and failure to resolve of lymphocyte and macrophage activation. These cells proliferate, releasing inflammatory cytokines that induce fever. Jaundice, hepatosplenomegaly, and pancytopenia are present in a hyperacute illness which is usually triggered by infection with Epstein–​Barr virus or other viruses. High-​dose corticosteroids and immunomodulatory agents are needed to suppress the inflammation. Rituximab and ciclosporin have been successful where the response to corticosteroids, ciclosporin, and etoposide was inadequate. When this accelerated lymphohistiocytic phase of the illness is resolved, transplantation with haematopoietic stem cells which replace the defective components of immune system with normal effector cells reduces the risk that this potentially fatal syndrome will recur.

Oculocutaneous albinism may require aids for poor vision due to retinal photoinjury, especially at school, and protection against high-​intensity ultraviolet and visible light-​induced damage, with skin carcinoma, should be offered. Haemorrhagic manifestations may require platelet transfusions and parenteral desmopressin (DDAVP—​1-​desamino-​8-​d-​arginine vasopressin) to improve platelet function in the short term. Aspirin and other nonsteroidal drugs should be avoided if possible. Serious microbial infections with bacteria are common in affected children and fungal infections due to Candida or Aspergillus also occur. Immunization for common viral and bacterial infections, including influenza, Haemophilus influenzae, and pneumococci, should be given, and appropriate antimicrobial drugs used promptly where infection is likely. Established pulmonary fibrosis proceeds rapidly and may require treatment with domiciliary supplemental oxygen in the home, and lung transplantation may be successful in selected cases. A smoke-​ free environment is likely to be advantageous.

FURTHER READING The study of lysosomal diseases is burgeoning: critical cellular functions carried out in the lysosomal compartment place the study of this organelle at the heart of contemporary molecular cell biology. The sheer pace of discovery and involvement of the lysosome in many pathological conditions and processes, with or without an overt genetic basis, means that comprehensive sources of up-​to-​date information are hard to find. Here we principally identify references of immediate application in the clinical field.

Books Alberts B, et  al. (2007). Molecular biology of the cell, 5th edition. Garland Science (Taylor & Francis Group), New York. Barranger JA, Cabrera-​Salazar MA (eds) (2007). Lysosomal storage disorders. Springer Science, New York. Mehta A, Winchester B (eds) (2012). Lysosomal storage diseases: a practical guide. Wiley-​Blackwell, London. Mole S, Williams R, Goebel H (eds) (2011). The neuronal ceroid lipofuscinoses (Batten disease), 2nd edition. Oxford University Press, Oxford. Nyhan WL, Barshop BA, Ozand PT (eds) (2005). Atlas of metabolic diseases, 2nd edition. Hodder Education, London. Saftig P (ed) (2005). Lysosomes. Springer Science, New York.

Reviews of diagnosis and treatment of lysosomal diseases Anderson G, et  al. (2005). Blood film examination for vacuolated lymphocytes in the diagnosis of metabolic disorders; retrospective experience of more than 2,500 cases from a single centre. J Clin Pathol, 58, 1305–​10. Baldo BA (2015). Enzymes approved for human therapy: indications, mechanisms and adverse effects. BioDrugs, 29,  31–​55. Cox TM (2016). Lysosomal diseases. In: Bond JD (ed) Encyclopedia of Cell Biology, Vol. I, pp. 763–​88. Elsevier, Waltham. De Duve C (1964). From cytases to lysosomes. Fed Proc, 23, 1045–​9. Hocquemiller M, et  al. (2016). Adeno-​associated virus-​based gene therapy for CNS diseases. Hum Gene Ther, 27, 478–​96. Kornfeld S, Mellman I (1989). The biogenesis of lysosomes. Annu Rev Cell Biol, 5, 483–​525. Mindell JA (2012). Lysosomal acidification mechanisms. Annu Rev Physiol, 74,  69–​86.

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Neufeld EF (2011). From serendipity to therapy. Annu Rev Biochem, 80,  1–​15. Pineda M, Walterfang M, Patterson MC (2018). Miglustat in Niemann–​ Pick disease type C patients: a review. Orphanet J Rare Dis, 13, 140. Piper RC, Luzio JP (2001). Late endosomes: sorting and partitioning in multivesicular bodies. Traffic, 2, 612–​21. Platt FM, d’Azzo A, Davidson BL, Neufeld EF, Tifft CJ (2018). Lysosomal storage diseases, Nat Rev Dis Primers, 4, 27. Popovic D, et  al. (2012). Rab GTPase-​ activating proteins in autophagy:  regulation of endocytic and autophagy pathways by direct binding to human ATG8 modifiers. Mol Cell Biol, 32, 1733–​44. Ravikumar B, et  al. (2010). Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev, 90, 1383–​435. Saftig P, Klumperman J (2009). Lysosome biogenesis and lysosomal membrane proteins:  trafficking meets function. Nat Rev Mol Cell Biol, 10, 623–​35. Schulz A, et al. (2013). NCL diseases—​clinical perspectives. Biochim Biophys Acta, 1832, 1801–​6. Sengupta S, Peterson TR, Sabatini DM (2010). Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell, 40, 310–​22. Von Figura K (1991). Molecular recognition and targeting of lysosomal proteins Curr Opin Cell Biol, 3,  642–​6. Walkely SU, Xu H, Ren D (2015). Lysosomal physiology. Annu Rev Physiol, 77,  57–​80. Yang Z, Klionsky DI (2010). Eaten alive: a history of macroautophagy. Nat Cell Biol, 12, 814–​22.

Journal articles Aerts JM, et  al. (2008). Biomarkers for lysosomal storage disorders: identification and application as exemplified by chitotriosidase in Gaucher disease. Acta Paediatr, 97 Suppl 457, 7–​14. Baldo G, Giugliani R, Matte U (2014). Gene delivery strategies for the treatment of mucopolysaccharidoses. Expert Opin Drug Deliv, 11, 449–​59. Barton NW, et al. (1991). Replacement therapy for inherited enzyme deficiency macrophage-​targeted glucocerebrosidase for Gaucher’s disease. N Engl J Med, 324, 1464–​70. Ben Turkia H, et  al. (2013). Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease. Am J Hematol, 88, 179–​84. Biffi A, et al. (2013). Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science, 341, 1233158. Briggs TA, et al. (2011). Tartrate-​resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat Genet, 43, 127–​31. Burton BK, et al. (2015). A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency. N Engl J Med, 373, 1010–​20. Cartier N, Aubourg P (2008). Hematopoietic stem cell gene therapy in Hurler syndrome, globoid cell leukodystrophy, metachromatic leukodystrophy and X-​adrenoleukodystrophy. Curr Opin Mol Ther, 10,  471–​8. Cherqui S, Courtoy PJ (2017). The renal Fanconi syndrome in cystinosis:  pathogenic insights and therapeutic perspectives. Nat Rev Nephrol, 13, 115–​31. Chtarto A, et al. (2013). A next step in adeno-​associated virus-​mediated gene therapy for neurological diseases: regulation and targeting. Br J Clin Pharmacol, 76, 217–​32. Cheng SH (2014). Gene therapy for the neurological manifestations in lysosomal storage disorders. J. Lipid Res, 55, 1827–​38. Chien YH, et al. (2013). Long-​term efficacy of miglustat in paediatric patients with Niemann–​Pick disease type C. J Inherit Metab Dis, 36, 129–​37.

Cox TM, Schofield JP (1997). Gaucher’s disease: clinical features and natural history. Ballières Clin Haematol, 10, 657–​89. Cox TM, et al. (2008). Management of non-​neuronopathic Gaucher disease with special reference to pregnancy, splenectomy, bisphosphonate therapy, use of biomarkers and bone disease monitoring. J Inherit Metab Dis, 31, 319–​36. Cox TM, et  al. (2012). Evaluation of miglustat as maintenance therapy after enzyme therapy in adults with stable type 1 Gaucher disease: a prospective, open-​label non-​inferiority study. Orphanet J Rare Dis, 7, 102. Cox TM et  al. (2017). Eliglustat maintains long-​term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy. Blood, 129, 2375–​83. Deegan PB, Cox TM (2012). Imiglucerase in the treatment of Gaucher disease: a history and perspective. Drug Des Devel Ther, 6, 81–​106. Eng CM, et  al. (2001). Safety and efficacy of recombinant human alpha-​galactosidase A-​replacement therapy in Fabry’s disease. N Engl J Med, 345,  9–​16. Eng CM, et al. (2007). Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis, 30, 184–​92. Escolar ML, et al. (2005). Transplantation of umbilical-​cord blood in babies with infantile Krabbe’s disease. N Engl J Med, 352, 2069–​81. Fratantoni JC, et  al. (1969). The defect in Hurler and Hunter syndromes. II. Deficiency of specific factors involved in mucopolysaccharide degradation. Proc Natl Acad Sci USA, 6,  360–​6. Huizing M, et al. (2008). Disorders of lysosome-​related organelle biogenesis: clinical and molecular genetics. Annu Rev Genomics Hum Genet, 9, 359–​86. Kamath RS, et  al. (2014). Skeletal improvement in patients with Gaucher disease type 1:  a phase 2 trial of oral eliglustat. Skeletal Radiol, 43, 1353–​60. Kaplan P (2014). Clinical potential of eliglustat tartrate in the treatment of type 1 Gaucher disease. Res Rep Endocrine Disord, 4,  1–​8. Kishnani PS, et al. (2007). Recombinant human acid-​glucosidase: major clinical benefits in infantile-​onset Pompe’s disease. Neurology, 68, 99–​109. Kohlschutter A, Schulz A, Denecke J (2014). Epilepsy in neuronal ceroid lipofuscinoses. J Pediatr Epilepsy, 3, 199–​206. Lukina E, et al. (2014). Eliglustat, an investigational oral therapy for Gaucher disease type 1: phase 2 trial results after 4 years of treatment. Blood Cells Mol Dis, 53,  274–​6. Maegawa GH, et al. (2006). The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported. Pediatrics, 118, e1550–​62. Maegawa GH, et al. (2007). Pyrimethamine as a potential pharmacological chaperone for late-​onset forms of GM2 gangliosidosis. J Biol Chem, 282, 9150–​61. McEachern KA, et  al. (2007). A specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy of Gaucher disease. Mol Genet Metab, 91, 259–​67. Meikle PJ, et  al. (1999). Prevalence of lysosomal storage disorders. JAMA, 281, 249–​54. Mindell JA (2012). Lysosomal acidification mechanisms. Annu Rev Physiol, 74,  69–​86. Mistry PK, et al. (2015). Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial. JAMA, 313, 695–​706. Mole SE (2014). Development of new treatments for Batten disease. Lancet Neurol, 13, 749–​51.

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Musolino PL, et  al. (2014). Hematopoietic stem cell transplantation in the leukodystrophies:  a systematic review of the literature. Neuropediatrics, 45, 169–​74. Nair S, et al. (2016). Clonal immunoglobulin against lysolipids in the origin of myeloma. N Engl J Med, 374, 555–​61. Nair S, et al. (2018). Antigen-mediated regulation in monoclonal gammopathies and myeloma. JCI Insight, 3(8), pii: 98259. Neudorfer GM, et  al. (2005). Late-​onset Tay–​Sachs disease:  phenotypic characterization and genotypic correlations in 21 affected patients. Genet Med, 7, 119–​23. Pavlova EV, et al. (2019). The lysosomal disease caused by mutant VPS33A. Hum Mol Genet, 28, 2514–30. Pellegrini N, et al. (2005). Respiratory and limb muscle weakness in adults with Pompe disease. Eur Respir J, 26, 1024–​31. Porto AF (2014). Lysosomal acid lipase deficiency:  diagnosis and treatment of Wolman and cholesteryl ester storage diseases. Pediatr Endocrinol Rev, 12 Suppl 1, 125–​32. Robertson PL, Maas M, Goldblatt J (2007). Semiquantitative assessment of skeletal response to enzyme replacement therapy for Gaucher’s disease using the bone marrow burden score. Am J Roentgenol, 188, 1521–​8. Rosenbloom BE, et al. (2005). Gaucher disease and cancer incidence: a study from the Gaucher Registry. Blood, 105, 4569–​72. Saftig P, et al. (2001). Disease model: LAMP-​2 enlightens Danon disease. Trends Mol Med, 7,  37–​9. Sardiello M, et al. (2009). A gene network regulating lysosomal biogenesis and function. Science, 325,  473–​7. Schiffmann R, et al. (2001). Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA, 285, 2743–​9. Schiffmann R, et al. (2008). Randomized, controlled trial of miglustat in Gaucher’s disease type 3. Ann Neurol, 64, 514–​22. Schulz A, et al. (2018). Study of intraventricular cerliponase alfa for CLN2 disease. N Engl J Med, 378, 1898–​907. Settembre C, et al. (2011). TFEB links autophagy to lysosomal biogenesis. Science, 332, 1429–​33.

Shayman, JA (2013). The design and clinical development of inhibitors of glycosphingolipid synthesis: will invention be the mother of necessity? Trans Am Clin Climatol Assoc, 124,  46–​60. Sidransky E (2012). Gaucher disease: insights from a rare Mendelian disorder. Discov Med, 14, 273–​81. Sidransky E, et al. (2009). Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med, 361, 1651–​61. Tardieu M, et  al. (2014). Intracerebral administration of adeno-​ associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/​II trial. Hum Gene Ther, 25, 506–​16. Tardieu M, et al. (2017). Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/​2 clinical trial. Lancet Neurol, 16, 712–​20. Van Capelle CI, et al. (2008). Eight years experience with enzyme replacement therapy in two children and one adult with Pompe disease. Neuromuscul Disord, 18, 447–​52. Van den Hout HM, et  al. (2003). The natural course of infantile Pompe’s disease: 20 original cases compared with 133 cases from the Literature. Pediatrics, 112, 332–​40. Weinreb NJ, et  al. (2013). Long-​term clinical outcomes in type 1 Gaucher disease following 10  years of imiglucerase treatment. J Inherit Metab Dis, 36, 543–​53. Winchester B (2012). Classification of lysosomal storage diseases. In:  Mehta A, Winchester B (eds) Lysosomal storage disorders:  a practical guide, pp. 37–​ 48. Wiley-​ Blackwell, Hoboken, New Jersey.

Websites Online Mendelian Inheritance in Man: http://​www.ncbi.nlm.nih.gov. Scriver CR, et al. (2004). Metabolic and Molecular Bases of Inherited Disease, 8th edition. Part 16: Lysosomal disorders, Chapters 134–​54. McGraw-​Hill, New York. http://​www.ommbid.com.

12.9

Disorders of peroxisomal metabolism in adults Anthony S. Wierzbicki

ESSENTIALS The peroxisome is a specialized organelle which employs molecular 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 pathway for isoprenoid lipids derived from chlorophyll, such as phytanic acid, utilizes α-​oxidation, but a default mechanism involving ω-​oxidation may also metabolize phytanic acid and its derivatives. The biochemical manifestations, molecular pathology, and diverse clinical features of many peroxisomal disorders have now been clarified, offering the promise of prompt diagnosis, better management, and useful means to provide appropriate genetic counselling for affected families. At the same time, specific treatments including rigorous dietary interventions and plasmapheresis to remove undegraded toxic metabolites offer credible hope of improvement and prevention of disease in affected individuals. Inborn errors of peroxisomal metabolism usually present in infancy and childhood, but some disorders typically become manifest later in life and in adults, in whom the progress is often slow.

Particular adult peroxisomal disorders X-​linked adrenoleukodystrophy (X-​ALD)—​due to mutation in the gene for an ATP-​binding cassette (ABC) protein of unknown function and characterized by accumulation of unbranched saturated VLCFAs, particularly hexacosanoate (C26), in the cholesterol esters of brain white matter, adrenal cortex, and certain sphingolipids of the brain. The disease has multiple phenotypes: it may present in adolescence with slowly progressive stiffness, clumsiness, weakness, weight loss, and skin pigmentation typical of Addison’s disease; it may present in adults with primarily psychiatric manifestations. Most cases develop increasing handicap; management is palliative and supportive in most instances. Adult Refsum’s disease—​due in most cases to mutations in the gene for phytanoyl-​CoA hydroxylase (PHYH) such that patients are unable to detoxify phytanic acid by α-​oxidation and have greatly elevated levels of this in their plasma. Usually presents in late childhood with progressive deterioration of night vision, the occurrence of progressive retinitis pigmentosa, and anosmia; late features include

deafness, ataxia, polyneuropathy, ichthyosis, and cardiac arrhythmias. Treatment is by restriction of dietary phytanic acid, with or without its elimination by plasmapheresis or apheresis.

Neuropsychiatric adult peroxisomal disorders Historical perspective The likely first description of X-​linked adrenoleukodystrophy (X-​ ALD; OMIM 300100) was in 1910 when a 6-​year-​old child developed abnormal eye movements, apathy, and mental deterioration. His gait then deteriorated and skin darkening was noted prior to his death a few months later. Examination of the brain by Schilder showed central demyelination, perivascular lymphocytes, foam cells, and gliosis which he termed encephalitis periaxalis diffusa. Other cases he later described are likely due to other leukodystrophies. Adrenoleukodystrophy was defined in 1970, with its characteristic adrenal changes of excess very long-​chain fatty acids (VLCFAs) and cholesterol esters present in cell inclusion bodies. These VLCFAs were later recognized as pathognomonic and identifiable in plasma samples and the primary defect was identified as an inability to metabolize them. The gene was mapped to Xq18 and identified as a member of the ATP-​binding cassette (ABC) transporter family. X-​ ALD was localized to the peroxisome. Subsequently, mouse models have been developed which show some clinical features of human disease such as adrenomyeloneuropathy but typically lack the cerebral changes seen in man.

Aetiology Adrenoleukodystrophy is characterized by the accumulation of unbranched saturated VLCFAs with a chain length of 24 to 30 carbons, particularly hexacosanoate (C26), in the cholesterol esters of brain white matter, in the adrenal cortex, and in certain sphingolipids of the brain. The disorder shows X-​linked inheritance with expression in female heterozygotes. The disruptive effects of the accumulation of VLCFAs, especially hexacosanoic acid (C26:0), on cell membrane structure and function may explain the neurological manifestations seen in adrenoleukodystrophy patients. VLCFAs cause alterations in membrane fluidity and affect cortisol secretion from cultured cells

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of adrenal cortical origin. In addition, albumin has only one C26 binding site compared with more than six for shorter fatty acids, so limiting its efficacy as a reverse transport protein for excess VLCFAs.

Clinical features X-​ALD is heterogeneous: seven phenotypes occur in males and five are recognized in females. Childhood cerebral adrenoleukodystrophy presents between the ages of 5 and 10 years with emotional lability, hyperactivity/​withdrawal, and mental deterioration, mimicking attention deficit disorder which evolves to parietal lobe dysfunction with apraxia, astereognosis, and later dementia. MRI shows a characteristic pattern of symmetric involvement of the posterior parieto-​ occipital white matter in 85% of patients, frontal involvement in 10%, and an asymmetric pattern in the rest. The clinical phenotype of X-​ALD shows a variable progression which may be interrupted by periods of arrest on MRI sometimes lasting 5 to 10 years. The adolescent form is adrenomyeloneuropathy which presents with slowly progressive stiffness, clumsiness, weakness, weight loss, and skin pigmentation typical of Addison’s disease. Autonomic function including micturition and erectile function are affected later. Somatosensory, auditory, and brainstem evoked potential are abnormal with some cases of abnormal visual and peripheral nerve conduction abnormalities. Brain MRI scans are abnormal in 50% of men and 80% of women, usually affecting corticospinal tracts with later parenchymal changes. Depression and emotional lability are common. Adult cerebral adrenoleukodystrophy is a variant of adrenomyeloneuropathy occurring after age 20 without spinal cord symptoms. The primary signs are psychiatric with a presentation of psychotic mania and may include schizophrenia or dementia. Some cases show a pure initial Addisonian picture with no neurological involvement; all are autoantibody negative. The onset of Addison’s disease is usually in childhood but the neurological changes follow in 20 to 30 years. Subtle hyper-​reflexia or impaired vibration sense and subtle MRI or neurophysiological signs may be detected earlier in these cases. It had been considered that neurological changes were mild or absent in carriers of X-​ALD, but up to 20% are symptomatic. Women who are X-​ALD heterozygotes usually present with adrenomyeloneuropathy at age 30 to 40. Subtle signs are often detected prior to presentation but eventually the full picture occurs, with late-​onset dementia. A  recent prospective study of 46 female carriers found an age-​dependent phenotype of myelopathy occurring in 63% and faecal incontinence in 28% independent of X-​inactivation status. These were associated with abnormalities in plasma VLCFAs and decreased fibroblast β-​oxidation of VLCFAs. In female adrenoleukodystrophy heterozygotes, adrenal cortical insufficiency rarely develops, although isolated mineralocorticoid insufficiency may occur but may be difficult to diagnose. Furthermore, adrenoleukodystrophy heterozygotes are predisposed to hypoaldosteronism related to the use of nonsteroidal anti-​inflammatory drugs (NSAIDs). A subclinical decrease in glucocorticoid reserve, as measured by synthetic ovine corticotropin-​ releasing hormone testing, may be present in most of these women. Aldosterone levels should be included in ACTH stimulation testing done to detect adrenal insufficiency in affected women. NSAIDs should be considered a risk factor for the development of hypoaldosteronism in women who are heterozygous for adrenoleukodystrophy.

Rare presentations include olivopontocerebellar atrophy which has been described as X-​ALD ataxia in Japanese. Other uncommon presentations include unilateral masses which can mimic brain tumours and cases of spontaneous remission of neurological symptoms. A clinical syndrome that mimics features of ALD is acyl-​coenzyme A (CoA) oxidase deficiency but most cases present with severe neonatal disease.

Neuropathology There are two distinct forms of neuropathology associated with X-​ ALD. Pure adrenomyeloneuropathy is a distal axonic neuropathy while the cerebral forms are associated with inflammation. In cerebral X-​ALD, brain pathology is often grossly normal though with signs of cerebral atherosclerosis. Grey matter is unaffected but white matter disease occurs in a rostrocaudal direction with demyelination prominent in the parieto-​occipital cortex and the cerebellum. The detailed pathology shows oligodendroglial cell loss, astrocytosis, and a perivascular inflammatory infiltrate. In the noncerebral form, demyelination is seen in the corticospinal tracts with no obvious inflammation and only mild gliosis and occasional macrophages. In the adrenal cortex, cells are filled with lamellar deposits of cholesterol esters with primary cortical atrophy and no evidence of inflammation or antibodies, with milder changes in the adrenomyeloneuropathy form. In men with X-​ALD, the testes show Leydig cell alterations, again with lamellar deposits. It has been estimated that at least 10% of males with Addison’s disease (adrenocortical failure) have X-​linked adrenomyeloneuropathy or unrecognized X-​ALD.

Metabolism of VLCFAs VLCFAs are derived from the diet and endogenous synthesis, with between 20 and 80% derived from synthesis depending on the study. The synthetic pathway occurs in brain microsomes with repeated additions of malonyl-​CoA units to palmitic (C16:0) or stearic (C18:0) acid precursors. There are probably separate pathways for C20:0 and C22:0 (behenic) fatty acids with the C22:0 pathway also elongating C22:1 (erucic) acid. Synthesis of VLCFAs starts with use of a specific activator protein SLC27A4—​the fatty acid transport protein 4 (FATP4). The synthesis of saturated VLCFA, monounsaturated VLCFA (MUFA), and polyunsaturated fatty acids (PUFAs) occurs in the endoplasmic reticulum by four distinct enzymes; elongation of very long-​chain fatty acids ligase (ELOVL), 3-​ketoacyl-​CoA reductase (HSD17B12), 3-​ hydroxyacyl dehydratase (HACD3), and trans-​2,3,-​enoyl-​CoA reductase (TECR). The initial condensation reaction catalysed by ELOVL is usually rate limiting. Mammals have seven different ELOVL enzymes (ELOVL1–​7) but only a single enzyme has been identified so far for each synthetic pathway. ELOVL1, ELOVL3, ELOVL4, and ELOVL6 are involved in the synthesis of saturated and monounsaturated fatty acids and ELOVL2, ELOVL4, ELOVL5, and ELOVL7 are essential for PUFA metabolism. The synthesis of C24:0 and C26:0 VLCFAs is carried out by the concerted action of ELOVL6 (C18:0–​C22:0) and ELOVL1 (C24:0–​C26:0) of which the latter is the key rate-​limiting step. Degradation of VLCFAs occurs by β-​oxidation within peroxisomes after activation by specific acyl-​CoA ligases which are chain-​ length specific. Again, FATP4 plays a key role in activating the fatty acid.

12.9  Disorders of peroxisomal metabolism in adults

Molecular genetics: the X-​ALD protein and its homologues The X-​ALD gene was mapped to a region of the X-​chromosome close to the glucose-​6-​phosphate dehydrogenase gene. The gene was established to code for an ABC protein of still unknown function but likely to involve the translocation of a variety of substrates across extra-​and intracellular membranes, including lipids, sterols, and drugs. The ABCD1 protein (adrenoleukodystrophy protein) maps to Xq28 and is mutated in X-​ALD. ABCD1 is a member of the ABC transporter superfamily. It expresses a half transporter which is located in the peroxisome. The gene has an open reading frame of 2235 bases which encodes a 745-​ amino acid protein with 38.5% amino acid identity and 78.9% similarity to another peroxisomal protein (ABCD3). Mutations in ABCD1 result in X-​ALD in animal models, with elevated VLCFAs. ABCD1 is one of four related peroxisomal transporters that are found in the human genome, the others being ABCD2 (adrenoleukodystrophy related protein) (OMIM 601081), ABCD3 (peroxisomal membrane protein 70) (OMIM 170995), and ABCD4 (P70R/​PMP69) (OMIM 603214). The adrenoleukodystrophy protein and the adrenoleukodystrophy-​related protein are expressed on oligodendroglia, while the adrenoleukodystrophy-​related protein and peroxisomal membrane protein 70 are found in neurons of the central nervous system. These genes are highly conserved in evolution, and two homologous genes are present in the yeast genome, PXA1 and PXA2, which also transport long-​chain fatty acids. The 80-​kDa protein encoded by this gene is absent in patients with X-​ ALD, in whom X-​ALD mRNA was undetectable. Most of the ABCD1 mutations (>450) in X-​ALD are point mutations, but large deletions have been described. There is no correlation between genotype and phenotype. In 15 to 20% of obligate female heterozygotes, false-​ negative results occur for plasma VLCFAs. Mutation analysis is the only reliable method for the identification of heterozygotes. Overexpression of the adrenoleukodystrophy protein and its homologue, the adrenoleukodystrophy-​related protein (ABCD2), can restore the impaired peroxisomal β-​oxidation in the fibroblasts of adrenoleukodystrophy patients. However, it seems that functional replacement of the adrenoleukodystrophy protein by adrenoleukodystrophy-​ related protein is not due to stabilization of the mutated adrenoleukodystrophy protein. Similarly, the adrenoleukodystrophy-​related protein and peroxisomal membrane protein 70 could restore the peroxisomal β-​oxidation defect in the liver of adrenoleukodystrophy protein-​deficient mice by stimulating Aldr and Pmp70 gene expression through a dietary treatment with the peroxisome proliferator fenofibrate. These results suggested that a correction of the biochemical defect in adrenoleukodystrophy might be possible by drug-​induced overexpression or ectopic expression of the adrenoleukodystrophy-​related gene. The adrenoleukodystrophy protein transporter may facilitate the interaction between peroxisomes and mitochondria, the two sites within the cells where β-​ oxidation of VLCFAs occurs. The phenotype of X-​ ALD was thought to be based on microglial activation for cerebral effects, while inflammation is less involved in adrenomyeloneuropathy but transcriptome studies show that a combination of effects of the deficiency on oxidative phosphorylation and adipocytokine and insulin signalling are responsible for the phenotypes. Many papers have described mutations in the ABCD1 gene in X-​ ALD patients, indeed more than 600 different mutations have now

been described (http://​www.x-​ald.nl) of which 51% are missense, 28% frame-​shift, and 12% nonsense mutations; 6% are small insertions/​deletions and 13% are exon deletions. About 75% of all nonrecurrent ABCD1 mutations result in the absence of ABCD1 protein (http://​www.x-​ald.nl). Nonsense and frame-​shift mutations as well as large deletions lead to a truncated protein. Many missense mutations result in unstable protein whose detection is likely to be dependent on the specificity and sensitivity of the method used. The lack of anti-​ABCD1 immunofluorescence (IF) using microscopy in cultured fibroblasts is commonly used to assess ABCD1 protein expression. However, fibroblasts express relatively low levels of ABCD1 and so this method may miss ABCD1 expression detectable by the more sensitive western blot methods. Re-​investigation of ‘IF negative’ cell lines using improved techniques has confirmed this supposition, hence some previously suspected cases may require re-​analysis. Disease-​associated missense mutations are not equally distributed over the ABCD1 protein. Analysis of 300 missense mutations showed clustering in two major regions (Fig. 12.9.1).

Epidemiology Screening and diagnostic records suggest that the prevalence is a minimum of 1 in 22 500 to 1 in 62 000. In contrast, the use of the Hardy–​Weinberg approach and genetic frequency data suggests a combined male to female frequency of 1 in 18 000 similar to phenylketonuria (1 in 12 000).

Differential diagnosis The differential diagnosis of neuropsychiatric abnormalities is shown in Table 12.9.1. X-​ALD can mimic attention deficit disorder, multiple sclerosis, organic dementias, and psychoses among neurological diseases, and Addison’s disease and hypogonadism among endocrine disorders (Table 12.9.2). The critical clinical differential element is the finding of abnormal ACTH concentrations and skin pigmentation with neurological signs, however subtle.

Clinical investigation Clinical biochemistry The primary abnormality in X-​ALD is an accumulation of VLCFAs (>C22) which occur in myelin. C26:0 can account for up to 5% of brain cerebrosides and sulphatides. In X-​ALD, both saturated and unsaturated forms of C26:0 (cerotic) and C24:0 (lignoceric) acids accumulate with reductions in C24:1(n-​9) (nervonic) acid. Normally, shorter fatty acids accumulate in brain cholesterol esters, but in X-​ALD, by contrast, these are mostly C26:0 and are enriched in myelin and in areas of demyelination. Similarly, C26:0 accumulates in white matter phosphatidylcholine phospholipids, C24:0 and C24:1 in gangliosides. Erythrocytes, plasma, and cultured fibroblasts all contain a 2-​to 10-​fold excess of VLCFAs. The diagnostic test relies on measurement of C26:0 levels and the ratios of C26 to C22:0 (docosahexaenoic acid) and C26:0 to C24:0 (tetracosanoic acid). Some neonatal paediatric screening programmes have begun to implement screening for C26:0 phosphatidylcholine as a marker of X-​ALD in their dried blood spot analysis programmes. Results can be confirmed by fibroblast studies or by the use of sequencing techniques. Highly elevated VLCFA levels are also found in peroxisomal biogenesis disorders but these show a different clinical presentation to X-​ALD or transiently with ketogenic diets for seizures. False-​negative results may occur in patients consuming excess C22:1;

2159

10

100

8

80

6

60

4

40

2

20

0

Evolutionary conservation (% AA identity per block of 10 amino acids)

section 12 Metabolic disorders

Number of disease-causing mutations per block of 10 amino acids

2160

0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750

N

C

Transmembrane domain 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 retardation

Behavioural disturbance

Catatonia

Visual hallucination

Psychosis

Depression

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

Table 12.9.2  Differential diagnosis of X-​ALD Presentation

Differential diagnosis

Childhood neurological with normal endocrinology

Hyperactivity, attention deficit disorder Epilepsy/​seizures Brain tumour Metachromatic/​globoid leukodystrophy Postencephalitic syndromes, e.g. subacute sclerosing panencephalitis Myelinoclastic diffuse sclerosis

Childhood neurological with hypoadrenalism

Addison’s disease with post-​hypoglycaemic damage

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 transplantation. The presence of demyelination and gadolinium enhancement are used to differentiate stable from likely progressive inflammatory changes on MRI scanning (Fig. 12.9.2c). Proton magnetic resonance spectroscopy shows only mild reduction in N-​acetyl aspartate, normal choline and myo-​inositol, and normal lactate in patients

(a) (A)

(B)

(C)

(D)

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

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 oils. A few affected males (0.1%) have borderline normal C26:0 levels and 15% of obligate female carriers have normal results. Effective mutation detection in these families is therefore fundamental to the unambiguous determination of genetic status. Of particular concern are female members of kinships with segregating X-​ALD mutations, because normal levels of VLCFA do not guarantee a lack of carrier status. Prenatal diagnosis is possible from cultured amniocytes or chorionic villus cells. Abnormal liver function tests are a common finding in adrenoluekodystrophies and occur secondary to disturbances in di-​ and trihydroxycholestanoic acid (DHCA and THCA) metabolism. Radiology A MRI scan often reveals biochemical changes before the development of clinical symptoms. Eighty per cent of childhood cerebral adrenoleukodystrophy patients have symmetric periventricular white matter changes in the posterior parietal and occipital lobes with a dorsocaudal progression with time (Fig. 12.9.2a). Patients with adrenomyeloneuropathy typically have abnormalities in the pyramidal tracts (Fig 12.9.2b). Contrast studies show up areas of active demyelination, inflammation with breakdown of the blood–​brain barrier, and gliosis. The Loes score (34-​point X-​ALD severity score) based on

Fig. 12.9.2  (a) MRI of the brain in a case of childhood cerebral adrenoleukodystrophy (ALD) showing characteristic extensive white matter changes in the parieto-​occipital region and internal capsules on FLAIR sequences (A). This area is initially affected in about 80% of cases of cerebral ALD. The rim enhances after administration of gadolinium on T1 sequences (B). In about 20% of cases the site of initial involvement in cerebral ALD is the frontal white matter as shown on this FLAIR image of a different patient with cerebral ALD (C), with prominent rim enhancement after administration of gadolinium on a T1-​weighted image (D). (b) MRI of the brain in a patient with adrenomyeloneuropathy showing increased signal in the pyramidal tracts on T2-​weighed coronal (A) and axial (B) images indicative of Wallerian degeneration. (c) MRI of the brain (T2 (A) and FLAIR (C) images; T1 with gadolinium (B, D)) of a patient with adrenomyeloneuropathy who rapidly deteriorated clinically with new symptoms of cognitive decline. On MRI, extensive white matter changes were seen in the parieto-​occipital white matter and corpus callosum (A), but no enhancement of the lesion after administration of gadolinium (B). A follow-​up MRI about 3 months later shows progression of the white matter lesion (C) and there is now faint enhancement of the rim of the lesion after gadolinium administration (D). Reproduced with permission from Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, Aubourg P, Poll-​The BT. X-​linked adrenoleukodystrophy (X-​ALD): clinical presentation and guidelines for diagnosis, follow-​up and management. Orphanet J Rare Dis. 2012 Aug 13;7:51. doi: 10.1186/​1750-​1172-​7-​51. Copyright © 2012 Engelen et al.; licensee BioMed Central Ltd.

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section 12  Metabolic disorders

Endocrinology

(b)

(A)

(B)

(c) (A)

(C)

(B)

(D)

Overt hypoadrenalism occurs in 40% of patients with childhood 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 responses. Clinical Addison’s disease is found in 1% of female heterozygotes. In adrenoleukodystrophy heterozygotes, adrenal cortical insufficiency rarely develops, although hypoaldosteronism may occur, especially if NSAIDs are being used. ACTH levels are increased 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. 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 cerebral 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 affecting 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 processing.

Treatment

Fig. 12.9.2 Continued

with arrested as compared with progressing disease where N-​acetyl aspartate levels are significantly reduced while choline compounds, myo-​inositol, and lactate are raised. 18Fluorodeoxyglucose positron emission tomography shows increased glucose uptake in the frontal lobes with decreased activity in the temporal lobes and cerebellum in patients with X-​ALD. The increase in frontal activity correlated with scores from psychological evaluations. Proton spectroscopy using N-​acetyl aspartate shows up neuronal loss, while choline compound studies assaying phosphocholine and glycerophosphocholine indicate membrane turnover and demyelination, and myo-​inositol compounds seem to be indices of gliosis. The presence of lactate indicates the anaerobic metabolism of the inflammatory cell infiltrate. In the adrenomyeloneuropathy brain, MRIs may be normal in 50% of men and 80% of women but diffuse spinal cord atrophy is present.

The progressive nature of X-​ ALD means that comprehensive family and professional management support services are required. Leukodystrophies are associated with progressive learning difficulties, 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 MRI scanning at approximately 3–​6-​month intervals depending on the rate of progression. Endocrine assessment is performed at baseline and repeated if the clinical syndrome includes features of hypoadrenalism. Dietary therapy was based on the restriction of the intake of C26:0 to less than 15% of normal intake, but early trials showed no effect of this on levels of VLCFA levels. Addition of oleic acid normalized VLCFA levels in fibroblasts and oral glyceryl trioleate reduced VLCFA levels by 50% with an improvement in nerve conduction measures. A  4:1 combination of glyceryl trioleate and trierucate (Lorenzo’s oil) normalized VLCFA levels within 1 month and prompted mass use of this intervention. No evidence of a clinically relevant benefit from dietary treatment with Lorenzo’s oil has been seen in many studies of patients with neurological involvement and X-​ALD, and asymptomatic thrombocytopenia was noted in 30% of patients. The fatty acid composition of the plasma and liver, but not that of the brain, improves with this therapy, suggesting that

12.9  Disorders of peroxisomal metabolism in adults

little erucic acid crossed the blood–​brain barrier. Thus, dietary supplementation with Lorenzo’s oil is of limited value in correcting the accumulation of saturated VLCFAs in the brain of patients with established neurological adrenoleukodystrophy. In a study of 89 asymptomatic boys with X-​ALD who had normal MRI scans, Lorenzo’s oil and moderate fat restriction were prescribed for 6.9 ± 2.7  years. Plasma fatty acids and clinical status were followed as measures of outcome. Twenty-​four per cent developed MRI abnormalities and 11% developed neurological and MRI abnormalities. The trial concluded that the reduction of C26:0 by Lorenzo’s oil was associated with a reduced risk of developing MRI abnormalities. Lorenzo’s oil therapy is indicated in asymptomatic boys with X-​ALD who have normal brain MRI scans. Experience with other adrenoleukodystrophy patients indicated that total fat intake in excess of 30 to 35% of total calories may counteract or nullify the C26:0-​reducing effect of Lorenzo’s oil. Patients who develop progressive MRI abnormalities should be considered for haematopoietic stem cell transplantation, but the 5-​year mortality is 38% and survival is increased by 8 months on average. Results in 283 boys with X-​ALD who received haematopoietic cell bone marrow transplantation showed that the estimated 5-​ year survival was 66%. The leading cause of death was disease progression. Donor-​derived engraftment occurred in 86% of patients. Demyelination involved parietal–​occipital lobes in 90%, leading to visual and auditory processing deficits in many boys. Bone marrow transplantation must be considered very early, even in a child without symptoms but with signs of demyelination on MRI, if a suitable donor is available. There are few data on the usefulness of bone marrow transplantation in adrenomyeloneuropathy. Adrenal function must be monitored since 80% of asymptomatic patients with adrenoleukodystrophy develop evidence of adrenal insufficiency and adrenal hormone replacement therapy should be provided when indicated by laboratory findings. Given the inflammation associated with X-​ALD, a number of immunosuppressive regimens have been investigated. Studies of cyclophosphamide, immunoglobulin, and interferon-​β have been unsuccessful.

Prognosis The prognosis in X-​ALD depends on the presentation. As yet, there are no methods of determining which type of disease will result from a given mutation as genotype–​phenotype correlation is poor. Once leukodystrophy begins, the prognosis is poor as progression is inevitable. Data from inherited error bone marrow transplant registries shows prolongations in life with transplantation in X-​ALD but do not record improvements in quality of life.

Future developments Other potential therapeutic approaches to X-​ALD include the use of lipid-​lowering drugs. Lowering cholesterol activates human ABCD2 in cultured cells. In mice, a sterol regulatory element exists in the Abcd2 promoter and overlaps sites for liver X receptor/​retinoid X receptor heterodimers. Adipose Abcd2 is induced by SREBP1c, whereas hepatic Abcd2 expression is down-​regulated by concurrent activation of liver X receptor-​α and SREBP1c. Hepatic Abcd2 expression in liver X receptor-​α/​β mice is inducible to levels vastly exceeding wild type.

Statins (3-​HMG-​CoA reductase inhibitors) are capable of normalizing VLCFA levels in primary skin fibroblasts derived from X-​ALD patients. They block the induction of proinflammatory cytokines through effects on rho kinase. Twelve patients with X-​ALD were treated with lovastatin for up to 12 months. Levels of C26:0 declined from pretreatment values and stabilized at various levels during a period of observation of up to 12 months, which does not correlate with the type of adrenoleukodystrophy gene mutation. In six patients, erythrocyte C26:0 levels fell by 50%. All patients with adrenomyeloneuropathy remained neurologically stable. However, follow-​up trials have been unsuccessful. The PPAR-​α agonist-​mediated induction of ABCD2 expression seems to be indirect and possibly mediated by the sterol-​responsive element-​binding protein 2 in mice. In addition PPAR-​α is involved in the regulation of ELOVL1, a key step in VLCFA synthesis. In vitro CoA esters of both bezafibrate and gemfibrozil inhibit ELOVL1 and could form starting points for novel drug development. However, a study of the pan-​PPAR agonist bezafibrate in 10 male patients failed to show any effects of plasma or erythrocyte VCLFA concentrations despite reducing plasma triglyceride levels as predicted. Studies in animal models have suggested that the PPAR-​γ (with some PPAR-​α activity) agonist pioglitazone may reduce axonal degeneration but there have been no studies in humans. Sodium 4-​phenylbutyrate reduces VLCFA levels through its effects on peroxisomal function and increases adrenoleukodystrophy-​ related protein levels. However, human studies have failed to show consistent beneficial effects. ω-​Oxidation is an alternative oxidation route for VLCFAs. These fatty acids are substrates for the ω-​oxidation system in human liver microsomes and are converted into ω-​hydroxy fatty acids and further oxidized to dicarboxylic acids via cytochrome P450 (CYP)-​mediated reactions. The high sensitivity towards the specific CYP inhibitor 17-​octadecynoic acid suggested that ω-​hydroxylation of VLCFAs is catalysed by the CYP4A/​F subfamilies, particularly CYP4F2 and CYP4F3B, and that therapies capable of increasing ω-​oxidation may have the potential to reduce the progression of the disease. Previously gene therapy has been attempted for X-​ALD using lentivirus transformation of white cells and 9 to 14% of cells showed reconstitution of ABCD1 expression over 24 months. A more modern gene therapy approach using an adeno-​associated virus construct AAV-​9/​ABCD1 shows appropriate neurological tropism following intracerebroventricular or intravenous injection and reduces plasma and brain VLCFA levels in Abcd1-​deficient  mice. Given the extensive oxidative stress associated with demyelination in X-​ALD there has been interest in antioxidant therapies in the treatment of X-​ALD. A combination of the antioxidants α-​ tocopherol, N-​acetyl-​cysteine, and α-​lipoic acid reduced demyelination in Abcd1-​deficient mice. There are no studies of this approach in humans. There has been an explosion of interest in novel therapeutic strategies for inherited errors of metabolism. Classical enzyme replacement therapy for X-​ALD is impossible given the need to replace a peroxisomal transporter molecule, but other strategies utilizing technologies such as stabilized mRNA technology combined with liposome or other shielded delivery technologies allied with various methods of delivering tissue specificity may be more successful. These show promise in cell culture models but no studies have yet been performed in human X-​ALD. None of these technologies

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section 12 Metabolic disorders

have reached animal models let alone human trials in peroxisomal diseases.

Neuro-​ophthalmic adult peroxisomal disorders Introduction Though survival is improving for peroxisomal biogenesis disorders and more subtle defects are now diagnosed, most still present in the neonatal period or in infancy. This is also true for most single enzyme peroxisomal deficiencies. Only one group of disorders presents later, with the onset of symptoms often in early teenage years but, due to delays in diagnosis, many are not identified until they reach adulthood. In contrast to the neuropsychiatric or endocrine presentation associated with adrenoleukodystrophy, these peroxisomal disorders present as central and peripheral neuropathies—​a neuro-​ ophthalmic picture. They are often termed Refsum’s disease though, given the multiple underlying genetic defects, it would be better to refer to them as Refsum’s syndrome. The syndrome comprises three genetic disorders:  phytanoyl-​ CoA hydroxylase deficiency (classical adult Refsum’s disease), atypical rhizomelic chondrodysplasia punctata type 1, and the newly described α-​methylacyl-​CoA racemase deficiency.

Historical perspective Adult Refsum’s disease (OMIM 266510), also called heredopathia atactica polyneuritiformis, is a hereditary sensory motor neuropathy type IV. It was first described in 1947, but only recognized as a syndrome by Refsum in 1962. He described a constellation of signs comprised of retinitis pigmentosa, anosmia, deafness, ataxia, and polyneuropathy allied with raised levels of protein in the cerebrospinal fluid. The biochemical defect was identified in 1963 when phytanic acid was noted in the plasma of affected patients and defective α-​oxidation was later suggested as the cause of adult Refsum’s disease. This disease was thought to be unifactorial with admittedly some rare aberrant complementation studies until 1995 when, after the localization of the gene for phytanoyl-​CoA hydroxylase, up to

50% of cases in one series were shown not to be linked to chromosome 10 but to chromosome 6. Eventually, the novel defect was identified as a variant of rhizomelic chondrodysplasia punctata type 1 and caused by mutations in peroxin 7. In parallel with this discovery, three patients were described in 1997 with a phenotype of sensory neuropathy and a subtle bile acid disorder but whose families included siblings with a Refsum’s-​like syndrome which was identified as due to a deficiency in α-​methylacyl-​CoA racemase. A  clinical phenocopy associated with polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) (OMIM 612674) has recently been described. In contrast to other Refsum-​like syndromes, phytanic acid levels are normal in this condition.

Clinical features In contrast to Zellweger’s syndrome (OMIM 214100), neonatal adrenoleukodystrophy (OMIM 202370), infantile Refsum’s disease (OMIM 266500), and rhizomelic chondrodysplasia (OMIM 601757), adult Refsum’s disease usually presents in late childhood with progressive deterioration of night vision, the occurrence of progressive retinitis pigmentosa, and anosmia (Table 12.9.3). Anosmia, contrary to early reports, is a constant feature of adult Refsum’s disease. After 10 to 15  years, deafness, ataxia, polyneuropathy, ichthyosis, and cardiac arrhythmias can occur. Short metacarpals or metatarsals are found in about one-​third of patients. Rare findings include psychiatric disturbance and proteinuria. Premature death may result from cardiac arrhythmias. α-​ Methylacyl-​ CoA racemase (OMIM 604489)  presents with adult-​onset sensorimotor neuropathy (Table 12.9.3). It may be accompanied by retinitis pigmentosa, visual field restriction and loss of acuity, axonal sensorimotor neuropathy, and myopathy-​like adult Refsum’s disease. Other features described have included primary hypogonadism, hypothyroidism, spastic paraparesis, epileptic seizures, and mild developmental delay. More severe childhood-​onset cases have shown a phenotype of defects in bile acid synthesis allied with fat-​ soluble vitamin deficiencies, coagulopathy, and cholestatic liver disease and a resemblance to a Niemann–​Pick type C phenotype.

Table 12.9.3  Comparison of clinical features of underlying metabolic defects associated with adult Refsum’s disease Adult Refsum’s disease (n c. 300)

Rhizomelic chondrodysplasia (n c.5)

α-​Methylacyl-​CoA racemase (n c.6)

PHARC (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 PA dependent

Age >20 PA dependent

Age >30 Axonal/​ demyelinating

Age >30 Variable progressive

Ataxia

Age >20 PA dependent

Age >20 PA dependent

Variable

Progressive

Cholestasis

No

No

Yes

No

Biochemistry: Phytanic acid Pristanic acid (μmol/​L)

>300 100 295 mOsm/​litre with inappropriately hypotonic urine (urine osmolality/​plasma osmolality 800 mOsm/​kg in cases of central diabetes insipidus and 38.5ºC), delirium or coma, seizures, vomiting, diarrhoea, and jaundice. Management requires (1)  supportive treatment; (2) identification and treatment of any precipitating condition, including infection; (3) antithyroid treatment (e.g. loading dose of carbimazole or propylthiouracil), followed 1 h later by stable iodine (e.g. Lugol’s iodine).

Other conditions Acute thyroiditis—​usually caused by bacterial infection; presents with severe thyroid pain, fever, and malaise; thyroid function is rarely disturbed. Subacute (or de Quervain’s) thyroiditis—​due to viral infection and commonly presents with thyroid pain; there may be transient thyrotoxicosis, followed by hypothyroidism, before restoration of normal thyroid function; diagnosis depends on demonstration of raised inflammatory markers and low/​absent radio-​iodine uptake by the thyroid. Amiodarone—​inhibits T4 deiodination and hence leads to free T4 levels that are in the upper half of the reference range or mildly elevated; may cause hypothyroidism or hyperthyroidism, the latter being difficult to treat.

Structure of the thyroid gland Development The human thyroid develops as a diverticulum in the pharyngeal floor at around 3 weeks of gestation. This median anlage moves caudally and remains connected to the pharynx via the thyroglossal duct, which is subsequently obliterated when the thyroid begins to expand as two distinct lobes at around 2 months of gestation. The foramen caecum marks the point in the tongue where the thyroid develops and there is sometimes an upward extension of thyroid tissue from the isthmus, the pyramidal lobe, arising from the lower part of the thyroglossal duct. At the same time, the lateral anlage ultimobranchial bodies, derived from the fifth branchial pouches, fuse with the developing thyroid to which they contribute the parafollicular calcitonin-​secreting clear cells. Synthesis of thyroid hormone begins at week 12, at the same time as TSH production by

Fig. 13.3.1.1  Histology of a normal thyroid. Thyroid epithelial cells are arranged in follicles containing colloid. Original magnification ×200. Photomicrograph by courtesy of Dr K. Suvarna.

the pituitary. There is significant maternal-​to-​fetal T4 transfer so that babies with no endogenous thyroid hormone production are nonetheless protected from the adverse effects of fetal hypothyroidism on development of the brain, lung, and skeleton. Preterm infants may have transient hypothyroxinaemia in the first weeks of life but trials of thyroid hormone supplementation have been inconclusive.

Anatomy and histology The adult thyroid weighs 15 to 20 g; each lobe is around 4 cm long and 2 cm wide, although the right lobe is often larger than the left. The isthmus connecting the two lobes lies just below the cricoid cartilage. The blood supply on each side is derived from the external carotid artery via the superior thyroid artery and from the subclavian artery via the inferior thyroid artery. There is adrenergic and cholinergic innervation which regulates blood flow. The thyroid is attached to the trachea by connective tissue, and the recurrent laryngeal nerves lie between the trachea and the posterior aspect of the lobes. The gland is made up of lobules each comprising 20 to 40 spherical follicles. The follicles vary considerably in size, but average 200 µm in diameter, and are made up of a single layer of thyroid follicular epithelial cells (Fig. 13.3.1.1). The cells are cuboidal when quiescent and columnar when active, and have a microvillous apical membrane. The follicular lumen contains colloid, the principal constituent of which is the glycoprotein thyroglobulin secreted by the thyroid cells. Each follicle is surrounded by a rich capillary network. Clear cells lie scattered between follicular epithelial cells or in the interstitium, and account for around 1% of the epithelial mass.

Thyroid hormone synthesis and metabolism Synthesis and secretion Thyroid hormone synthesis requires iodide uptake and oxidation, iodination of certain tyrosine molecules on thyroglobulin, and coupling of the iodotyrosines to form the thyroid hormones T3 and T4 (Fig. 13.3.1.2). Iodide is actively transported into the thyroid cell by the Na+/​I− symporter, which is also expressed in breast tissue and the salivary glands. Perchlorate, thiocyanate, and pertechnetate are also transported by the same symporter and these anions can

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Follicular lumen Apical membrane containing TPO, catalysing steps 2–4

Thyroid epithelial cell

I−

2

MIT DIT T3 TG

TG 3

T4 TG

4 5

I−

TG synthesis 7

6 MIT DIT

T3

8

1 Iodide trapping 2 Oxidation 3 TG iodination 4 Coupling 5 Colloid resorption 6 TG hydrolysis 7 Deiodination of MIT+ DIT 8 Deiodination of T4 9 T3 and T4 secretion

T4

1 I−

9 T3 T4

Fig. 13.3.1.2  Steps in the synthesis of thyroid hormones. DIT, di-​iodotyrosine; MIT, monoiodotyrosine; TG, thyroglobulin; TPO, thyroid peroxidase.

competitively inhibit iodide uptake. The World Health Organization (WHO) recommended daily intake of iodine is 150 µg for adults (250 µg during pregnancy and lactation) but there is wide variation in actual intake with many countries having borderline or frankly deficient intakes of less than 50 to 100 µg. In some parts of western Europe and North America intake has been excessive (up to 750 µg/​ day), although there is recent evidence that an increasing number of individuals in these countries remain at risk of iodine deficiency, especially during pregnancy. Iodide is oxidized by thyroid peroxidase, a haem-​containing enzyme located at the apical border of the thyroid cell, using hydrogen peroxide generated by dual oxidase (DUOX) and DUOX maturation factor 2, and is then rapidly incorporated into tyrosine residues to form monoiodotyrosine and di-​ iodotyrosine. Thyroid peroxidase is also responsible for the coupling of these iodotyrosines, with different sites in the thyroglobulin molecule being responsible for the formation of T3 or T4. Normally, each thyroglobulin molecule contains three or four T4 molecules, but only 20% of thyroglobulin molecules contain a T3 molecule. Thyroglobulin acts as slow turnover reservoir for thyroid hormone, thus ensuring maximum use is made of often scarce dietary iodine. Around a 7-​week supply of T4 is contained in the normal thyroid. Thyroid hormone is released from the gland after endocytosis of colloid and lysosomal hydrolysis of the thyroglobulin to yield T4 and T3, which are secreted from the basal membrane into the capillaries in a molar ratio of 14:1. Released iodotyrosines are deiodinated for iodide recycling.

thyroid hormone levels (Table 13.3.1.1). Several transporters mediate thyroid hormone uptake by cells; monocarboxylate transporter 8 is particularly important in the uptake of T3 by brain, and mutations in this gene cause severe psychomotor Table 13.3.1.1  Conditions in which there is altered binding of thyroid hormones to binding proteins TBG

Increased binding

Genetic variation in TBG Oestrogens (pregnancy, oral contraception, hormone replacement therapy, tamoxifen) Other drugs (perphenazine, opiates, 5-​fluorouracil, clofibrate, mitotane) Hepatitis, cirrhosis Acute intermittent porphyria

Decreased binding

Genetic variation in TBG Steroids (testosterone, anabolic steroids, glucocorticoids) Acromegaly Nephrotic syndrome Protein malnutrition Acute severe illness L-​asparaginase

Albumin Decreased binding

Any cause of hypoalbuminaemia

Thyroid hormone transport

Increased binding

Genetic variation

Up to 90% of the total T3 in the circulation is derived from peripheral conversion of T4 to T3 by deiodinase enzymes (see next) rather than thyroid secretion. Only 0.03% of T4 and 0.3% of T3 in the circulation exist as free hormone that is able to diffuse into tissues; the remainder is protein bound. T4 binds predominantly to T4-​binding globulin, and to a lesser extent to transthyretin (or prealbumin); a little is bound to albumin. T3 binds to T4-​binding globulin and albumin, with little bound to transthyretin. Alteration in the concentration or binding capacity of thyroid hormone-​ binding proteins can produce major changes in total but not free

Transthyretin Increased binding

Genetic variation

Competition for binding sites Drugs

Phenytoin Carbamazepine Salicylates and non​steroidal anti-​inflammatory drugs

Non​esterified fatty acids TBG, thyroid-​binding globulin.

13.3.1  The thyroid gland and disorders of thyroid function

I(5)

I(5′) T4

HO

NH2

O I(3′)

CH2 I(3)

T3

HO

O I

I

NH2 CH2

CH

COOH

DI3,(DI1)

DI1,DI2 I

CH

NH2

HO

COOH

O

I

I

DI3,(DI1)

DI1,DI2

CH2

CH

COOH

reverse T3

I

NH2 di-iodothyronine (T2)

HO

O I

CH2

CH

COOH

I

Fig. 13.3.1.3  Main deiodination pathway for thyroid hormones. DI, deiodinase enzyme; parentheses denote a minor contribution. Deiodination of T3 also yields 3,5-​T2 and deiodination of reverse T3 also yields 3′,5′-​T2. T2 is further deiodinated to monoiodothyronine and thyronine.

retardation and hypotonia due to brain-​specific hypothyroidism during development.

Metabolism of thyroid hormone The half-​life of T4 in the circulation is 7  days, contrasting with the much shorter half-​life of T3 of 24 h. The most important metabolic pathway for T4 is outer ring (5′) deiodination to T3 (Fig. 13.3.1.3). This is catalysed by type 1 and type 2 deiodinase (EC 1.97.1.10), while type 3 deiodinase (EC 1.97.1.11) catalyses inner ring (5) deiodination leading to hormone inactivation. Type 1 deiodinase can also catalyse inner ring deiodination of T3 and T4. All three enzymes have a selenocysteine moiety as the active catalytic site. Type 1 deiodinase is expressed predominantly in the liver, kidney, thyroid, and brain, type 2 in the pituitary, brain, placenta, skeletal muscle, and heart (tissues critically dependent on thyroid hormone for development or function), and type 3 in the brain, placenta, and skin. The type 1 deiodinase is largely responsible for the generation of circulating T3 from T4, whereas T3 generated by the type 2 enzyme mainly provides intracellular T3 at specific sites. Around 40% of T4 is metabolized to T3 and 40% is converted to reverse T3 by the type 3 deiodinase. This same enzyme is responsible for the main metabolic pathway for T3 which is converted to 3,3′-​ di-​iodothyronine. Starvation, trauma, and drugs (propylthiouracil, amiodarone, glucocorticoids, propranolol) impair T4 to T3 conversion and must be borne in mind when interpreting tests of thyroid function (see next). In addition to deiodination, a small proportion of thyroid hormone is metabolized by conjugation of the phenolic hydroxyl group with sulphate or glucuronic acid, which increases water solubility and allows urinary and biliary excretion. Biliary iodothyronine glucuronides can be reabsorbed, constituting an enterohepatic cycle.

Thyroid hormone action Thyroid hormone acts primarily as a transcription regulatory factor, mediated by T3 binding to nuclear receptor isoforms that belong to

the same superfamily as steroid and retinoic acid receptors. All such receptors possess a conserved DNA-​binding domain containing two zinc fingers, which interact with specific DNA response elements, and a hormone-​binding domain. Alternative splicing results in two pairs of thyroid hormone receptors (Fig. 13.3.1.4) whose tissue expression varies during development. Thyroid hormone receptors bind to DNA as homodimers or heterodimers (with the retinoid X receptor). Without ligand, basal gene transcription is inhibited by a corepressor. When T3 binds, homodimers dissociate releasing corepressor and allowing gene transcription; the stable heterodimer binds coactivators in the presence of T3 with the same outcome. The α2 thyroid hormone receptor does not bind T3 and may act as a natural inhibitor of receptor activity. A cell surface receptor for T3, involving integrin αvβ3 and leading to protein kinase signal transduction, has been delineated and there are further pathways for thyroid hormone action involving cytoplasmic and mitochondrial receptors.

Tissue distribution

1

410

2

492

461

1

514

2

Brain, muscle fat Brain, testis

Liver, kidney Pituitary, hypothalamus

DNA T3 binding binding domain domain

Fig. 13.3.1.4  Structure of the thyroid hormone receptors. The numbers indicate the amino acid content. Homologous areas are shaded; the lack of homology in the T3-​binding domain of the α2 receptor (hatched area) prevents T3 binding and the function of this receptor is unknown.

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Regulation of thyroid function The main regulator of thyroid function is TSH (thyrotropin), secreted by thyrotrophs in the anterior pituitary gland in response to the tripeptide thyrotropin-​releasing hormone derived from the hypothalamic supraoptic and paraventricular nuclei. Thyroid hormones exert a classic negative feedback effect on thyrotrophs; the acute effect is mediated by T3 in the pituitary which is derived from T4 by type 2 deiodination. Thyroid hormones also inhibit hypothalamic thyrotropin-​releasing hormone synthesis. TSH secretion stimulated by thyrotropin-​releasing hormone is inhibited by dopamine and somatostatin, while α-​adrenergic activation stimulates TSH release. Cytokines, particularly interleukin-​1, interleukin-​6, and tumour necrosis factor, inhibit TSH synthesis and may be responsible for the suppression of TSH seen in severe illness. Within the thyroid, TSH binds to the G protein-​coupled TSH receptor, leading to intracellular signalling predominantly via cAMP. TSH increases iodide transport and organification, endocytosis of colloid, and thyroid hormone secretion, as well as thyroid follicular epithelial cell division. Autoregulatory mechanisms can modulate thyroid function when TSH levels are constant. The most important is iodine intake. Increased iodide transport transiently decreases organification and reduces thyroid hormone synthesis (the Wolff–​ Chaikoff effect); after several weeks under normal conditions, the thyroid escapes and resumes hormone production. Sudden increases in iodine intake can also acutely block thyroid hormone release. In iodine deficiency, thyroid hormone production is switched to preferential T3 synthesis, but this effect is largely TSH-​mediated rather than autoregulatory.

Laboratory investigation of thyroid function Determining thyroid status The introduction of sensitive immunoradiometric assays for circulating TSH, with a detection level of 0.1 mU/​litre or less, has transformed the evaluation of thyroid status. A normal TSH level rules out primary thyroid dysfunction. Low levels of thyroid hormones elevate TSH as a result of negative feedback, while excessive thyroid hormone suppresses TSH. The thyrotropin-​releasing hormone test for detecting low TSH levels is now redundant. As well as primary thyroid disorders, other conditions may alter TSH levels and must be borne in mind when using TSH as a screening test for thyroid dysfunction (Table 13.3.1.2), as must the possibility of secondary (pituitary or hypothalamic) disturbances of thyroid function. It is, therefore, essential to confirm thyroid status when TSH levels are abnormal, or when pituitary or hypothalamic abnormalities are possible, by measuring circulating thyroid hormone levels. Methods which measure total T3 or T4 are prone to artefacts caused by abnormal thyroid hormone binding (Table 13.3.1.1), although in the absence of such abnormalities these tests are reliable. When altered binding is suspected or found, compensation can be made by calculation of the free T3 or free T4 index. These indices are derived from the total hormone levels and measurement of the differential distribution of radiolabelled T3 between unoccupied protein binding sites in the sample and an absorbent resin (hence the term ‘resin uptake test’). T4-​binding globulin levels can also be measured directly.

Table 13.3.1.2  Causes of abnormal serum TSH concentrations TSH level

Cause

Free thyroid hormone levels

Raised

Overt hypothyroidism

↓

Subclinical hypothyroidism

N

Sick euthyroid syndrome

↓ or N

Dopamine antagonists (acute effect)

N

TSH-​secreting pituitary adenoma

↑

Thyroid hormone resistance syndrome

↑

Adrenal insufficiency

↓ or N

Overt thyrotoxicosis

↑

Subclinical thyrotoxicosis

N

Recently treated hyperthyroidism

N

Thyroid-​associated ophthalmopathy without Graves’ disease

N

Excessive thyroxine treatment

N or ↑

Sick euthyroid syndrome

↓ or N

First trimester of pregnancy

N or ↑

Pituitary or hypothalamic disease

N or ↓

Anorexia nervosa

N or ↓

Dopamine, somatostatin (acute effect)

N

Glucocorticoids

N

Lowered

N, normal; TSH, thyroid-​stimulating hormone; ↑, increased; ↓, decreased.

However, the ready availability of immunoassays for free T3 and free T4 has generally supplanted these methods. The immunoassays rely on the ability of a radiolabelled thyroid hormone analogue to bind to thyroid hormone antibody but not to plasma binding proteins. The analogue then competes for antibody binding with the free thyroid hormone in the sample. Despite initial concerns about the theoretical basis and performance of such assays, recent improvements allow generally reliable estimation of free thyroid hormones. In cases of doubt, free hormone levels can be measured by physical separation from bound hormone using ultracentrifugation or equilibrium dialysis. Several indirect methods can be used to determine thyroid status. The thyroidal uptake of radio-​iodine (123I, 131I) or 99mTc pertechnetate is increased in hyperthyroidism and decreased in hypothyroidism, but can be affected by excessive dietary iodine and destructive processes in the thyroid so that uptake is low when the patient is thyrotoxic (see ‘Destructive thyroiditis’). Serum thyroglobulin is raised in hyperthyroidism of all types but is also raised in destructive thyroiditis and thyroid cancer. Its main role in investigation is follow-​up of treated thyroid cancer (see Chapter 13.3.2). Several non-​specific tests have also been used to determine end-​ organ responses to thyroid hormones, including basal metabolic rate, tendon relaxation time, and serum levels of cholesterol, ferritin, sex hormone-​binding globulin, and liver enzymes although these should not be used routinely to determine thyroid status.

Thyroid function in non​thyroidal illness and pregnancy Assessing thyroid function in severely ill patients often reveals abnormalities termed the ‘sick euthyroid syndrome’. Many of the changes are due to cytokine release, but therapeutic agents such as dopamine

13.3.1  The thyroid gland and disorders of thyroid function

and glucocorticoids also contribute, as do unknown factors. Any major, acute illness or starvation can result in a decrease in circulating T3 (total and free) with normal levels of T4 and TSH. Reverse T3 levels rise. The severity of the illness correlates with the magnitude of the fall in T3, and in very sick patients total T4 levels also fall. Analogue-​based free T4 assays generally produce normal results but sometimes high or low values occur. In 10 to 15% of sick individuals, TSH levels are abnormal (raised or lowered). Psychiatric illness can be associated with raised total and free T4 levels with normal T3. There is no proven benefit from thyroid hormone administration in the sick euthyroid syndrome and the hormone changes may be protective by limiting catabolism (although this view is regularly challenged). The importance of these alterations lies in their potential to cause diagnostic confusion. Thyroid function tests should only be requested in ill patients when thyroid disease is genuinely suspected. Abnormal thyroid function tests due to the sick euthyroid syndrome return to normal after recovery and, therefore, repetition of testing is the simplest way to confirm the reason for unusual results. Pregnancy also affects thyroid function testing. The most obvious change is the rise in T4-​binding globulin secondary to high oestrogen concentrations, which elevates total but not free T3 and T4 levels. In addition, the reference ranges for free T3 and T4 are higher than normal in the first half of pregnancy because placental human chorionic gonadotropin, at high levels, acts as a weak stimulator of the TSH receptor. There is a reciprocal fall in TSH levels during the first trimester, but TSH returns to normal in the second trimester as human chorionic gonadotropin levels decline. Current guidelines advise the use of population and trimester-​specific reference ranges during pregnancy. Occasionally, the changes in circulating hormone concentrations are sufficiently pronounced to cause transient ‘gestational’ hyperthyroidism associated with high circulating HCG (human chorionic gonadotrophin) concentrations (e.g. in those with hyperemesis) during pregnancy. Antithyroid drugs are usually unnecessary in this condition, and attention should be directed to controlling the vomiting and giving parenteral fluids. Renal clearance of iodine is increased in pregnancy, leading to maternal and neonatal goitre and mild hypothyroidism in areas where iodine intake is marginal (50 µg/​day). These complications can be prevented by ensuring an adequate iodine intake of 250 µg/​day during pregnancy.

Determining the cause of thyroid dysfunction The most frequent cause of thyroid dysfunction in iodine-​sufficient areas is autoimmunity, and the simplest test for this is measurement of thyroid autoantibodies, particularly those directed against thyroid peroxidase. Antibodies against thyroglobulin are also easily measured but are usually accompanied by thyroid peroxidase antibodies, so testing for the latter alone is usually adequate. Different methods, including haemagglutination, immunofluorescence, radioimmunoassay, and enzyme-​ linked immunosorbent assay, give different prevalence rates for thyroid autoantibodies. Almost all patients with autoimmune hypothyroidism and around 75% with Graves’ disease have thyroid peroxidase antibodies. Generally lower levels are found in 5 to 15% of healthy women and 2% of men, and in slightly higher proportions of patients with nodular goitre and thyroid cancer, and results therefore need to be interpreted carefully. Individuals with positive thyroid autoantibodies but normal thyroid function are at increased risk of developing autoimmune hypothyroidism (c.2% per year). Measurement of antibodies to the TSH receptor may be useful

Fig. 13.3.1.5  CT scan of the chest of a patient with a large retrosternal goitre causing tracheal compression.

to confirm an underlying diagnosis of Graves’ disease and reliable assays to perform this test are now widely available. Thyroid imaging by scintiscanning is useful in determining the aetiology of thyroid disease when this is not obvious clinically, particularly in hyperthyroidism and ectopic thyroid tissue. Its role in the evaluation of a solitary thyroid nodule is considered in Chapter 13.3.2. 99Tcm pertechnetate is usually used as it has a short half-​life (6 h) which allows safe administration of high activity and rapid scanning. 123I is not as readily available but is preferable to 131I, especially in children, as it too has a short half-​life and does not emit β-​radiation. Thyroid ultrasound is being increasingly used as an alternative to scintiscanning. The technique allows accurate determination of thyroid size, which may be useful in follow-​up of goitre, and can help to determine the nature of an atypical neck mass. Its role in evaluating nodular thyroid disease is considered in Chapter 13.3.2. CT scanning is particularly valuable in determining the extent of a retrosternal goitre and assessing tracheal compression (Fig. 13.3.1.5). In contrast, a standard chest radiograph can be misleading in evaluating tracheal compression, particularly in the anterior–​posterior plane.

Goitre The distribution of thyroid size in any population forms a continuous, positively skewed curve, whose shape depends on the age, sex, and country of residence of the individuals assessed. Hence a precise definition of goitre is impossible. Ultrasound is the most accurate method to assess thyroid size, and estimates of goitre prevalence based on inspection and palpation underestimate the true frequency. However, simple schemes, such as that shown in Box 13.3.1.1, are useful in field studies of goitre prevalence. Box 13.3.1.1  WHO/​UNICEF grading of goitre Grade 0 = no visible or palpable thyroid Grade 1 = thyroid enlargement that is palpable but not visible when the neck is in the neutral position Grade 2 = thyroid enlargement that is both visible and palpable when the neck is in the neutral position Grade 3 = goitre visible at a considerable distance

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Box 13.3.1.2  Causes of goitre Endemic goitre Iodine deficiency Goitrogens, including drugs with an antithyroid action Sporadic goitre Simple, non​toxic goitre: diffuse or multinodular (colloid goitre) Toxic multinodular goitre Hashimoto’s thyroiditis Graves’ disease Destructive thyroiditis Postpartum thyroiditis Silent thyroiditis Subacute thyroiditis Amiodarone Genetic disorders Dyshormonogenesis Thyroid hormone resistance syndrome McCune–​Albright syndrome TSH receptor mutation Infiltration Riedel’s thyroiditis Amyloidosis Sarcoidosis Secondary TSH-​secreting pituitary tumour Excessive stimulation from human chorionic gonadotropin in pregnancy or choriocarcinoma

Of the many causes of goitre (Box 13.3.1.2), those associated with disturbances of thyroid function are considered later. The remainder can be classified broadly as endemic and sporadic non​toxic goitres.

Endemic goitre Prevalence Goitre is said to be endemic when the prevalence exceeds 10% in children aged 6 to 12 years, although this figure is arbitrary and it has recently been suggested that a prevalence of more than 5% should be used. Over 200 million people are affected worldwide, especially in the Himalayas, Andes, and parts of Africa, although Eastern and Southern Europe are also involved. Aetiology The main cause is iodine deficiency, with goitre prevalence exceeding 30% in areas with very low iodine intakes (800 MBq). Recombinant TSH administration may allow lower 131I doses to be given, increasing the potential for outpatient treatment. Goitre size is usually reduced by more than 50% at 2  years, and most of the improvement occurs within 2 to 3 months. Long-​term follow-​up data are not yet available, although hypothyroidism certainly occurs in 20 to 40% by 5 years. Tracheal compression by a goitre can be treated with 131I despite theoretical concerns over acute worsening due to a radiation thyroiditis. Surgery is used in other centres and is particularly indicated for stridor, severe tracheal compression, or retrosternal goitres and if there is any suspicion of malignancy. Thyroidectomy is the most effective treatment available for goitre, but there may be a recurrence in around 20% of patients within 10 years and is not avoidable by giving T4 replacement. Complications, including recurrent laryngeal nerve damage, hypoparathyroidism, and hypothyroidism, are more likely with the biggest goitres, near-​total thyroidectomy, and reoperation.

Hypothyroidism Impaired production of thyroid hormones is usually due to a primary abnormality of thyroid gland or iodine deficiency; occasionally it is secondary to pituitary or hypothalamic disorders, dealt with in Chapters 13.2.1 and 13.2.2. The onset of primary hypothyroidism is gradual and may be detected when the TSH is elevated (to compensate for impaired thyroid output) but the free thyroid hormone levels are normal. This state is subclinical hypothyroidism (diagnosis depends on ensuring that the TSH elevation is not due to a sick euthyroid syndrome by repeat measurement after 3 months). As thyroid damage continues, TSH levels rise further but free T4 levels fall. When serum TSH concentrations rise above 10 mU/​litre, symptoms usually become apparent, and the patient is said to have overt or clinical hypothyroidism.

Aetiology The causes of hypothyroidism are listed in Box 13.3.1.3. The commonest cause worldwide is iodine deficiency, discussed earlier. In iodine-​sufficient areas, autoimmune hypothyroidism and thyroid damage after radio-​iodine or surgical treatment for hyperthyroidism are the major causes.

Epidemiology The prevalence of overt hypothyroidism in white populations is around 2% in women and 0.2% in men, with a mean age of 60 at diagnosis: rates are lower among black and Asian/​Pacific Islander populations. Subclinical hypothyroidism is even more common (6–​8% of women and 3% of men). Around 4% of these individuals progress to overt hypothyroidism annually if thyroid peroxidase antibodies accompany the elevated TSH. Half this number progress in the absence of thyroid peroxidase antibodies. Focal lymphocytic infiltration of thyroid associated with thyroid autoantibody

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Box 13.3.1.3  Causes of hypothyroidism Primary Iodine deficiency Autoimmune hypothyroidism Hashimoto’s thyroiditis Primary myxoedema Iatrogenic 131 I treatment Subtotal or total thyroidectomy External irradiation for lymphoma or cancer involving the neck Drugs Iodine-​containing contrast media Amiodarone Lithium Antithyroid drugs p-​Aminosalicylic  acid Interferon-​α and other cytokines Aminoglutethimide Tyrosine kinase inhibitors (e.g. sunitinib) Congenital hypothyroidism Absent or ectopic thyroid gland Dyshormonogenesisa TSH receptor mutation Destructive thyroiditis Postpartum thyroiditis Silent thyroiditis Subacute thyroiditis Infiltrative disorders Amyloidosis Sarcoidosis Haemochromatosis Scleroderma Cystinosis Riedel’s thyroiditis Consumptive hypothyroidism due to increased type 3 deiodinase expression (e.g. infantile haemangiomas) Secondary Hypopituitarism Pituitary tumours Trauma (head injury) Pituitary surgery or irradiation Infiltrative disorders Infarction Isolated TSH deficiency or inactivity Hypothalamic disease Idiopathic Drugs Bexarotene a

The following types of dyshormonogenesis are due to mutations in the genes encoding the proteins given in parentheses: iodide transport defect (Na+/​I− symporter), defective iodide organification (thyroid peroxidase, dual oxidase 2, pendrin), loss of iodide reutilization (dehalogenase), deficient thyroid hormone synthesis (thyroglobulin). Defects in monoiodotyrosine coupling also occur but are, so far, poorly characterized.

positivity occurs in up to 15% of healthy women and 2% of men without an elevated TSH level, representing the earliest manifestation of thyroid autoimmunity; 2% of these people progress to overt hypothyroidism annually. Congenital hypothyroidism occurs

in about 1 in 3000 births and this high frequency has led to the widespread introduction of neonatal screening; recent increases in prevalence are likely to be due to the inclusion of milder cases.

Pathogenesis Autoimmune hypothyroidism is primarily the result of auto­ reactive T-​ cell-​ mediated cytotoxicity directed against thyroid follicular cells. Cytokines derived from the locally infiltrating T cells, macrophages, and dendritic cells impair thyroid cell function and enhance T-​cell-​mediated cytotoxicity. The role of thyroid autoantibodies in thyroid cell destruction is unclear, but thyroid peroxidase antibodies fix complement and may cause secondary damage. In 10 to 20% of patients, antibodies which block the TSH receptor are partially or wholly responsible for hypothyroidism, and transplacental passage of these antibodies (but not thyroid peroxidase antibodies) occasionally causes transient neonatal hypothyroidism. Genetic and environmental factors are involved in the aetiology but, as with most autoimmune disorders, the complex interaction of these factors has so far prevented a full understanding. Polymorphisms in HLA-​DR, CTLA4 and other immunoregulatory genes are associated with autoimmune hypothyroidism, and a high iodine intake may be an important environmental factor in some cases. Congenital hypothyroidism is caused by thyroid aplasia or hypoplasia in 60% of cases and in 30% there is an ectopic gland. Mutations in thyroid-​specific transcription factors have been found in some of these cases. In the remaining 10%, hypothyroidism is due to dyshormonogenesis (see Box 13.3.1.3).

Clinical features The cardinal features in adults with hypothyroidism are shown in Box 13.3.1.4. However, the ready availability of reliable screening tests for hypothyroidism, especially TSH assays, has led to the recognition of many patients in whom there are only vague or non​specific symptoms, such as tiredness, weight gain, and poor concentration. The differential diagnosis is accordingly vast, but the high frequency of hypothyroidism should prompt its exclusion when any suggestive features are present, particular in middle-​aged women with chronic fatigue or depression. Autoimmune hypothyroidism may present with a goitre (Hashimoto’s thyroiditis) or without (atrophic thyroiditis or primary myxoedema); these entities represent the ends of a spectrum of progressive thyroid destruction. When present, the goitre is of variable size but is often hard and irregular, sometimes giving rise to a suspicion of malignancy, which then requires exclusion by fine needle aspiration biopsy. Primary lymphoma of the thyroid is a rare but important association (Chapter 13.3.2). Thyroid pain due to autoimmune thyroiditis is also a rare complication. Patients may notice a Hashimoto goitre before any thyroid dysfunction has developed and annual follow-​up is then needed. The most dramatic presentation of hypothyroidism is myxoedema coma, which is fortunately rare. In addition to the usual features, there is hypothermia (as low as 23 °C) and coma, sometimes with seizures. Mortality is 30–​50% even with intensive treatment. Patients are typically older and either previously undiagnosed or poorly compliant with medication. There is generally an additional precipitant, such as respiratory depression due to drugs, chest infection, heart failure, stroke, blood loss, or exposure to cold.

13.3.1  The thyroid gland and disorders of thyroid function

Autoimmune hypothyroidism is frequently associated with other autoimmune conditions. In the type 2 autoimmune polyglandular syndrome, autoimmune thyroid disease (hypothyroidism or Graves’ disease) is associated with type 1 diabetes and/​or Addison’s disease. This syndrome is autosomal dominant with variable penetrance. In the rare, autosomal recessive type 1 autoimmune polyglandular syndrome (chronic mucocutaneous candidiasis, Addison’s disease, and hypoparathyroidism), autoimmune hypothyroidism is found in 5 to 10% of patients. Other commoner associations include pernicious anaemia, vitiligo, and alopecia areata, and there is a significant excess of autoimmune hypothyroidism in coeliac disease, dermatitis herpetiformis, chronic active hepatitis, premature ovarian failure, rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome. Breast cancer patients and individuals with Down’s and Turner’s syndromes have a higher than expected frequency of thyroid autoimmunity. Around 5% of patients with thyroid-​associated ophthalmopathy, discussed later in this chapter, have autoimmune hypothyroidism and 15% of patients with Graves’ disease successfully treated with antithyroid drugs develop hypothyroidism 10 to 20 years later. This relationship with Graves’ disease is further emphasized by rare patients who oscillate between hyperthyroidism and hypothyroidism over a period of months. The likely explanation is fluctuation in the relative levels of TSH receptor stimulating and blocking antibodies, but the cause of these changes is unknown. Juvenile hypothyroidism is uncommon. The features of adult hypothyroidism (Box 13.3.1.4) may be present, but the diagnosis is usually suggested by retarded growth and dentition, and an infantile face. Myopathy with muscle enlargement is common. Puberty is Box 13.3.1.4  Clinical features of hypothyroidism Symptoms Tiredness, weakness Dry skin Altered facial appearance Feeling cold Hair dry, unmanageable, and thinning Poor memory and concentration Constipation Weight gain with poor appetite Dyspnoea Hoarse voice Menorrhagia (later, oligomenorrhoea or amenorrhoea), decreased libido Paraesthesias Deafness Signs Dry coarse skin Cool peripheries Puffy face, hands, and feet Yellow skin due to carotene accumulation Diffuse alopecia Bradycardia Peripheral oedema Slow-​relaxing tendon reflexes Carpal tunnel syndrome Serous cavity effusions Galactorrhoea (raised prolactin) Enlarged salivary glands Rarely: ataxia, dementia, psychosis, coma

usually delayed, although sometimes it is precocious. Congenital hypothyroidism is typically unrecognizable at birth but, if not identified by screening, gives rise to prolonged jaundice, failure to thrive, impaired growth, feeding difficulties, constipation, and hypotonia. Left untreated, even for a few weeks after birth, there is permanent neurological damage resulting in intellectual impairment.

Pathology In Hashimoto’s thyroiditis there is a prominent diffuse and focal lymphocytic infiltrate with germinal centre formation. The thyroid follicles show varying degrees of destruction and little or no colloid. The remaining thyroid follicular cells have an increased number of mitochondria, giving rise to oxyphil metaplasia (Askanazy or Hürthle cells). There is a variable degree of fibrosis. In atrophic thyroiditis, fibrosis is the most prominent feature, with a less obvious lymphocytic infiltrate than in Hashimoto’s thyroiditis. Thyroid follicles are usually sparse, reflecting the later stage at which this form of autoimmune hypothyroidism is diagnosed. Whether there is a natural progression from Hashimoto’s to atrophic thyroiditis is unclear, although the goitre usually decreases with T4 replacement.

Laboratory diagnosis Measuring serum TSH is the first step in diagnosing hypothyroidism, with the important caveat that this approach will miss most cases of secondary hypothyroidism in which the serum TSH measured by immunoassays may be low, normal, or even slightly raised, due to the secretion of bioinactive forms of the hormone. If secondary hypothyroidism is suspected, for instance in the follow-​up of a patient with treated pituitary disease, it is essential to check the free T4 level. The TSH is elevated in other settings besides primary overt hypothyroidism (Table 13.3.1.2). It is therefore important to confirm the diagnosis by measuring the free T4 in all samples in which the TSH is elevated. Measurement of free T3 adds nothing to the diagnosis, especially as values may be within the reference range in a quarter of hypothyroid patients due to extrathyroidal conversion of T4. If myxoedema coma is expected, it is essential that treatment is initiated immediately without awaiting confirmation of the diagnosis. These patients often have dilutional hyponatraemia, hypoglycaemia, and electrocardiography changes (low voltage, prolonged QT interval, flat or inverted T waves, and heart block). Other non​specific features which may be found in any patient with hypothyroidism are elevation in serum liver and muscle enzymes (raised creatine phosphokinase concentrations particularly may cause unnecessary concern), raised cholesterol, and anaemia. The anaemia is usually normocytic or macrocytic, but microcytosis occurs when hypothyroidism is accompanied by menorrhagia. The aetiology is usually easily established. In the absence of a history of treated hyperthyroidism or iodine exposure, most juvenile or adult onset primary hypothyroidism in iodine-​sufficient countries is due to autoimmune hypothyroidism. Transient hypothyroidism due to destructive thyroiditis is considered later. The diagnosis of autoimmune hypothyroidism is confirmed by the presence of thyroid peroxidase antibodies, usually at high levels, although occasionally these antibodies are absent. Cytological diagnosis of Hashimoto’s thyroiditis is possible using fine needle aspiration biopsy, but is only necessary if there is uncertainty over the cause of a nodular goitre. Once congenital hypothyroidism is diagnosed by routine testing after birth, it is usual to initiate T4 immediately. The aetiology can be

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established by scintiscanning and/​or ultrasound: if the exact cause is not established at birth, treatment can be stopped without neurological consequences at age 3 to 4 years to repeat imaging and establish whether life-​long T4 replacement is necessary. Dyshormonogenesis, suspected when there is detectable thyroid tissue and a family history, requires specialized investigation to establish the diagnosis and increasingly this is possible by direct analysis of gene mutations. The commonest of these defects is Pendred’s syndrome in which there are mutations in the pendrin gene (SLC26A4) encoding a chloride/​ iodide transporter present in the thyroid and cochlea, leading to goitre, mild hypothyroidism, and deafness. The thyroid abnormalities usually appear in the second or third decade, rather than at birth. The diagnosis can be made easily by the perchlorate discharge test, which shows an excessive decline of radioactivity in the thyroid when potassium perchlorate is given 2 to 3 h after allowing the thyroid to take up a tracer dose of radio-​iodine.

Treatment In adult patients without heart disease and below the age of 65, treatment can begin with the estimated replacement dose of T4. If there is no remaining thyroid tissue (indicated by a very high TSH level and very low or undetectable free T4), the daily replacement dose is 1.6 µg T4/​kg body weight, which is around 100 to 150 µg/​day. In practice, the typical starting dose is 50 to 100 µg T4 daily, the lower dose being reserved for patients with mild to moderate biochemical abnormalities and those with significant cardiac disease. Dosage changes should be based on TSH levels measured 2 to 3 months after starting treatment, the main goal of treatment being to normalize the TSH. A  similar period is required to assess the effect of any change to the dosage, made as 25 or 50 µg increments or decrements depending on the degree of abnormality of the TSH. Treatment is usually straightforward, although if there is only partial thyroid failure when treatment is begun, the dose of T4 may require adjustment over many months. Once on a full replacement dose, TSH levels should be checked annually. Fluctuating or elevated TSH levels in a previously stable patient, or T4 requirements in excess of 200 µg/​day, usually indicate adherence problems. It is important to rule out malabsorption, including coeliac disease, Helicobacter pylori infection, excessive soya intake, or interactions with drugs: cholestyramine, ferrous sulphate, lovastatin, aluminium hydroxide, rifampicin, amiodarone, carbamazepine, and phenytoin all alter the absorption or clearance of T4. A common cause for poor adherence is worsening angina. Optimization of antianginal treatment is then required, although some patients may simply prove intolerant of full T4 replacement if their coronary artery disease is extensive and irremediable. It is important to remind poorly adherent patients that, because of the long half-​life of T4, missed tablets should always be taken and that this is safe. It should be emphasized that, in the absence of coronary artery disease, T4 has no adverse effects when given at doses that return TSH levels to normal. In older patients or in individuals with heart disease, the usual starting dose is 25 µg T4 daily (or on alternate days when there is severe angina), although in the elderly person without any cardiac comorbidity such caution is probably unnecessary. Dosage should be increased slowly with increments of 12.5 to 25 µg T4. Proportionately higher doses of T4 are needed during the first year of life than in adults, and the starting daily dose of T4 for congenital hypothyroidism is 8–​15 µg/​kg body weight. There is a continuing debate on the benefit of T4 in subclinical hypothyroidism.

It is reasonable to commence T4 when (i) the TSH levels are above 10 mU/​litre or (ii) above 5 mU/​litre prior to and during pregnancy. When TSH levels are below 10 mU/​litre, routine treatment is not indicated, but this could be considered if patients have symptoms suggestive of hypothyroidism or positive TPO antibodies. Modest improvements in mental function and lipid levels occur when T4 is given to some patients with subclinical hypothyroidism, but conclusive long-​term studies on the benefits of treatment have not been conducted. All patients with subclinical hypothyroidism or positive thyroid peroxidase antibodies should be offered annual testing for the development of overt hypothyroidism if T4 is not given. Another problem is posed by the occasional patient with overt hypothyroidism who continues to feel unwell or who fails to lose weight after the TSH is normalized with T4 replacement. It can take around 3 months from achieving full replacement for all symptoms to disappear, and weight gained during hypothyroidism will generally only be lost by following an appropriate diet. It is sensible to ensure that the TSH level is in the lower half of the reference range and sometimes a small increment of T4 can achieve this, improving symptoms but not suppressing the TSH. Higher doses of T4 that suppress the TSH should be avoided, as there is an increased risk of atrial fibrillation due to subclinical thyrotoxicosis. The other recognized adverse effect of excessive T4 is a decrease in bone mineral density, particularly in postmenopausal women who have previously had hyperthyroidism and therefore already have a low skeletal mass. Changes in bone mineral density are modest but an increase in fracture rate has been reported as a result of T4 given at supraphysiological doses in those aged over 65. There has some recent interest in the concept that thyroid hormone replacement should consist of both T4 and T3, based on the observation that deiodinase activity varies between tissues, suggesting that in some organs the level of the active thyroid hormone, T3, is insufficient when only T4 is given. The short half-​life of current T3 preparations makes T3 alone unsuitable for replacement and there is no evidence of any consistent benefit from trials of combined T4 and T3 treatment. Treatment of myxoedema coma is a medical emergency (see Box 13.3.1.5).

Prognosis T4 treatment is usually life-​long and, properly taken, restores normal health and lifespan. Occasional patients may discontinue T4 and remain euthyroid. Errors in initial diagnosis account for some of these; in others, a spontaneous decline in TSH receptor blocking antibody levels may be responsible. There is no easy means of ascertaining whether a patient continues to need T4, short of stopping it and measuring the TSH 6 weeks later. Because remission is uncommon and of uncertain duration, few endocrinologists attempt T4 withdrawal once started.

Special problems in pregnant women Untreated hypothyroidism impairs fertility and increases the risk of miscarriage. Children born to such mothers have varying degrees of intellectual impairment. It is therefore essential that T4 replacement is monitored closely in women with hypothyroidism who intend to become or who are pregnant. Ideally TSH and free T4 should be checked prior to conception, and then every 4 weeks once pregnancy is confirmed up to mid-​pregnancy. The requirement for T4 can increase by up to 50% during pregnancy but reverts to normal

13.3.1  The thyroid gland and disorders of thyroid function

Box 13.3.1.5  Treatment of myxoedema coma • Thyroid hormone replacement — A single intravenous bolus of 200–​400 µg T4; thereafter 50–​100 µg T4 daily — Some centres add a supplementary bolus of T3 5–​20 µg, followed by 2.5–​10 µg T3 every 8 h, with lower doses in older people or those with heart disease • Supportive treatment — Ventilation usually required — Space blankets for hypothermia — Intravenous infusion of hypertonic saline or glucose as required — Parenteral hydrocortisone 50 mg every 6 h • Identify and treat underlying precipitant (including any cause of respiratory depression, infection, cardiac and renal failure, and myocardial infarction) • Broad-​spectrum antibiotics if infection suspected

after delivery. Women can be advised to anticipate this by taking two extra doses of T4 each week as soon as pregnancy is confirmed. The TSH should be maintained below 2.5 mU/​litre during the first trimester. There are no implications for breastfeeding.

Areas of uncertainty or needing further research Although present combination regimens of T3 and T4 have shown no additional benefit compared to T4 alone, development of a sustained release preparation of T3 would be worth assessment. Because hypothyroidism is frequent, routine screening of certain groups or even the entire population has been advocated (Box 13.3.1.6), but the cost–​benefit of setting up new screening programmes is unclear.

If widely adopted, screening will turn up many individuals with subclinical hypothyroidism for whom the benefits of early treatment with T4 have not yet been fully established. Recent data show that there is an increased risk of miscarriage in thyroid peroxidase antibody-​positive women who are euthyroid and this may be reduced by T4 treatment, but more work is needed to confirm whether this is due to a subtle defect in thyroid hormone levels or a consequence of autoimmunity.

Thyrotoxicosis Thyrotoxicosis is defined as the state produced by excessive thyroid hormone. Hyperthyroidism exists when thyrotoxicosis is caused by thyroid overactivity but there are several types of thyrotoxicosis that are not due to hyperthyroidism, the most obvious being administration of excessive T4.

Aetiology The causes of thyrotoxicosis are shown in Box 13.3.1.7. Graves’ disease is responsible for 60 to 80% of cases and nodular thyroid disease (toxic multinodular goitre and toxic adenoma) accounts for most of the rest. Destructive thyrotoxicosis is dealt with in the next section.

Epidemiology The prevalence of thyrotoxicosis in white people is 2 to 3% in women and 0.2 to 0.3% in men and higher still in black and Asian/​Pacific Islander people. The peak age of onset for Graves’ disease is between 20 and 50  years of age, whereas toxic multinodular goitre occurs more often in later life.

Box 13.3.1.6  Indications for screening for hypothyroidism Established Congenital hypothyroidism Previous treatment for hyperthyroidism Previous neck irradiation (e.g. for lymphoma) Pituitary tumours, including follow-​up after surgery or irradiation Treatment with lithium or amiodarone Subclinical hypothyroidism Worthwhile Antepartuma in type 1 diabetes Three months postpartum after a prior episode of postpartum thyroiditis Unexplained infertility Non​specific symptoms in women over 40 years of age Refractory depression or bipolar affective disorder with rapid cycling Turner’s syndrome Down’s syndrome Autoimmune Addison’s disease Uncertain Patients with a family history of thyroid autoimmunity Dementia or obesity without other evidence of thyroid disease Antepartum to detect unsuspected hypothyroidismb Breast cancer a

Also measure thyroid peroxidase antibodies; screen euthyroid antibody-​ positive women 3 months postpartum for postpartum thyroiditis. b

It is also uncertain whether all pregnant women should be checked for thyroid peroxidase antibodies as predictors of postpartum thyroiditis.

Box 13.3.1.7  Causes of thyrotoxicosis Primary hyperthyroidism Graves’ disease Toxic multinodular goitre Toxic adenoma Drugs: iodine excess ( Jod–​Basedow phenomenon), lithium, amiodarone (type 1 amiodarone-​induced thyrotoxicosis) Thyroid carcinoma or functioning metastases Activating mutation of the TSH receptor Activating mutation of the Gsα protein (McCune–​Albright syndrome) Struma ovarii (ectopic thyroid tissue) Thyrotoxicosis without hyperthyroidism Ingestion of excess thyroid hormone (factitious thyrotoxicosis) Subacute thyroiditis Silent thyroiditis Other causes of thyroid destruction: amiodarone (type 2 amiodarone-​ induced thyrotoxicosis), 131I or external irradiation (acute effect), infarction of an adenoma Secondary hyperthyroidism TSH-​secreting pituitary tumour Chorionic gonadotropin-​secreting tumours Gestational thyrotoxicosis Thyroid hormone resistance (usually euthyroid)

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Pathogenesis Graves’ disease is caused by TSH receptor stimulating antibodies, clearly demonstrated by the occurrence of transient, neonatal thyrotoxicosis in babies born to mothers with Graves’ disease whose antibody levels are high enough for transplacental transfer to affect the fetus. As with autoimmune hypothyroidism, genetic factors, including HLA-​DR, CTLA4, and TSHR gene polymorphisms, are associated with the disease; the concordance rate in monozygotic twins is about 20% and much less in dizygotic twins. A high iodine intake, smoking, and stress have all been identified as environmental factors, but in many patients the genetic and environmental triggers remain elusive. Immune reconstitution after alemtuzumab and highly active antiretroviral therapy are associated with Graves’ disease. Smoking is a major risk factor for the development of thyroid-​ associated ophthalmopathy. These eye signs are due primarily to swelling of the extraocular muscles, the result of fibroblast activation by cytokines released by infiltrating T cells and macrophages, leading to glycosaminoglycan accumulation, oedema, and fibrosis. The close correlation between ophthalmopathy and thyroid disease is best explained by a shared orbital and thyroid autoantigen (probably the TSH receptor). Toxic multinodular goitre evolves from a non​toxic sporadic goitre (see earlier) and is particularly likely when iodine intake increases, either gradually as a result of changes in the diet, or acutely when iodine-​ containing agents (amiodarone, some contrast media) are given. More than 50% of toxic adenomas are due to a somatic activating mutation in the genes encoding the TSH receptor or the associated Gsα protein, and a similar but unknown mechanism leading to constitutive activation of a clone of thyroid cells must underlie the remainder.

Clinical features

of disease and the age of the patient. Occasionally there are paradoxical manifestations, such as the weight gain that can occur in up to 10% of patients when the increase in appetite exceeds the effects of increased metabolism, and apathetic or masked thyrotoxicosis in older patients which mimics depression. The most dramatic but rare presentation is thyrotoxic crisis or storm, with a mortality rate of 10 to 30% even with treatment. Patients typically are previously undiagnosed or partially treated and have an acute exacerbation of thyrotoxicosis precipitated by acute illness (infection, stroke, diabetic ketoacidosis) or trauma, especially directly to the thyroid (surgery or radio-​iodine). Exact diagnostic criteria for thyrotoxic crisis are not agreed and its frequency is sometimes exaggerated. There is marked fever (>38.5 °C), delirium or coma, seizures, vomiting, diarrhoea, and jaundice, with death being caused by arrhythmias, heart failure, or hyperthermia. The differential diagnosis of thyrotoxicosis includes any cause of weight loss, anxiety, and phaeochromocytoma, but simple biochemical testing can readily distinguish thyrotoxicosis from these conditions. Once the diagnosis of thyrotoxicosis is made, it is essential to determine the cause (see Box 13.3.1.7), as this determines treatment. Graves’ disease is usually clinically distinctive; there is a small to moderate, diffuse, firm goitre and around one-​half of these patients have signs of thyroid-​associated ophthalmopathy (Fig. 13.3.1.6 and Table 13.3.1.3). There may be evidence of another autoimmune disorder, in the patient or his/​her family, with the same associations as autoimmune hypothyroidism just described. Less than 1% of patients have pretibial myxoedema, which is better called thyroid dermopathy as it can occur anywhere, especially after trauma

(a)

The typical features of thyrotoxicosis from any cause are shown in Box 13.3.1.8, but their presence and severity depend on the duration

Box 13.3.1.8  Clinical features of thyrotoxicosis of any cause Symptoms Hyperactivity, irritability, altered mood Heat intolerance, sweating Palpitations Fatigue, weakness Weight loss with increased appetite Diarrhoea, steatorrhoea Polyuria Oligomenorrhoea, amenorrhoea, loss of libido Signs Sinus tachycardia, atrial fibrillation in older patients Fine tremor Warm, moist skin Goitre Palmar erythema, onycholysis, pruritus, urticaria, diffuse pigmentation Diffuse alopecia Muscle weakness and wasting, proximal myopathy, hyperreflexia Eyelid retraction or lag Gynaecomastia Rarely: chorea, periodic paralysis (usually in Asian men), psychosis, impaired consciousness

(b)

Fig. 13.3.1.6  Thyroid-​associated ophthalmopathy. (a) Upper lid retraction, periorbital oedema, and scleral injection. (b) Chemosis (conjunctival oedema) and proptosis.

13.3.1  The thyroid gland and disorders of thyroid function

Table 13.3.1.3  Clinical features of thyroid-​associated ophthalmopathy

a

Signs and symptoms

Assessment

Approximate frequencya (%)

Lid lag, lid retraction

Measure lid fissure width

50–​60

Grittiness, discomfort, excessive tearing, retrobulbar pain, periorbital oedema

Self-​assessment score by patient; activity score by clinician

40

Proptosis

Exophthalmometry or CT/​MRI-​based measurement

20

Extraocular muscle dysfunction (typically causing diplopia looking up and out)

Hess chart or similar; CT/​MRI scan to detect muscle size

10

Corneal involvement, causing exposure keratitis

Rose bengal or fluorescein staining

0.1 mU/​litre) and if they are less than 65 and in otherwise good health, electing to treat when overt hyperthyroidism is shown by an abnormal free T3 level (T3 usually increases before T4). However, in older patients, those with known cardiac disease or those who are symptomatic with a persistent TSH value less than 0.1 mU/​litre, there is an increasing shift to the use radio-​iodine for subclinical hyperthyroidism.

Destructive thyroiditis Acute thyroiditis is rare and is usually caused by bacterial infection of the thyroid via a pyriform sinus connecting the gland with the oropharynx. Most such patients are children or young adults. There is severe thyroid pain with fever and malaise, but thyroid function is rarely disturbed. Diagnosis is made by fine needle aspiration biopsy with culture of the specimen, and treatment consists of antibiotics, surgical drainage of any abscess, and excision of the sinus which is identified by barium swallow. Immunocompromised patients may also develop acute thyroiditis. Subacute (or de Quervain’s) thyroiditis is due to thyroid infection by any of several viruses, especially mumps, Coxsackie, influenza, adenoviruses, and echoviruses. The most prominent symptom is pain in the thyroid, often radiating to the ears. A small, tender goitre can be palpated which is usually diffuse, but there can be asymmetrical involvement. Systemic upset with fever is variable but sometimes profound, and symptoms of a prodromal viral infection several weeks earlier may be recalled. Serum C-​reactive protein levels and the erythrocyte sedimentation rate are elevated. There is a granulomatous thyroid inflammation with follicular destruction and the release of thyroid hormones often results in a transient thyrotoxicosis lasting 1 to 4 weeks. Continuing thyroid destruction then leads to a phase of hypothyroidism once stored hormone is depleted. This lasts 4 to 12 weeks before euthyroidism is restored, but relapses occur in 10 to 20% of patients. Sometimes only one phase of thyroid disturbance is seen. Confirmation of the clinical diagnosis is made by finding an elevated erythrocyte sedimentation rate and low or absent radio-​iodine uptake by the thyroid. Thyroid function requires continuous monitoring as the disease evolves. Mild cases

13.3.1  The thyroid gland and disorders of thyroid function

may resolve spontaneously with paracetamol or a non​steroidal anti-​ inflammatory drug as symptomatic treatment, but most patients benefit from prednisolone 15–40 mg daily as this rapidly alleviates the pain. The dose is tapered over 6 to 8 weeks depending largely on symptoms. Propranolol may be useful for thyrotoxic symptoms, and temporary T4 replacement is sometimes needed during the hypothyroid phase. Permanent late-​onset hypothyroidism may develop in around 15% of patients. Silent thyroiditis is an autoimmune disorder in which there is a transient but painless thyroid destruction, giving rise to the same kind of thyroid function disturbances as subacute thyroiditis. As well as the absence of thyroid pain, there is no sign of a systemic inflammatory response (including normal C-​reactive protein levels and erythrocyte sedimentation rate) and the two conditions are therefore readily distinguished. The commonest setting for silent thyroiditis is in the postpartum period in women with pre-​existing thyroid peroxidase antibodies and a mild autoimmune thyroiditis, exacerbated for unknown reasons at this time. Such postpartum thyroiditis is common, being detectable in up to 5% of women 3 to 6 months after delivery when repeated biochemical testing is done, although in many of these women the changes in thyroid function are mild and asymptomatic. Postpartum thyroiditis is three times more common in type 1 diabetes. Thyroid uptake tests are useful in the postpartum period to distinguish thyrotoxicosis due to postpartum thyroiditis from Graves’ disease. 99mTc pertechnetate is used in preference to 131I and only requires cessation of breastfeeding for a day. Treatment is with propranolol for thyrotoxic symptoms and T4 for hypothyroidism. As 90% of women recover normal thyroid function, T4 should be withdrawn 1 year after delivery and thyroid function tested 6 weeks later. However, annual follow-​up is needed as around 20% of these women have permanent hypothyroidism 5 years later. The condition usually recurs in subsequent pregnancies. Riedel’s thyroiditis is a rare disorder which, in some patients, may be with associated with IgG4-​related systemic disease causing multifocal fibrosclerosis (retroperitoneum, mediastinum, biliary tree, orbit). The typical presentation is a hard, painless goitre suggestive of malignancy, often with symptoms due to compression of the oesophagus, trachea, neck veins, or recurrent laryngeal nerves. Some cases respond to corticosteroids or tamoxifen, and surgery can relieve compressive symptoms. Amiodarone inhibits T4 deiodination, and in all amiodarone-​ treated patients free T4 levels are in the upper half of the reference range or mildly elevated. Several months to years after starting amiodarone, however, effects on the thyroid may become manifest. In patients with mild thyroid dysfunction, especially autoimmune thyroiditis and positive thyroid peroxidase antibodies, the excessive iodine released from the drug causes hypothyroidism. This is treated as usual with levothyroxine. Paradoxically, the high level of iodine causes hyperthyroidism in other subjects who are predisposed to this because of an underlying multinodular goitre or incipient Graves’ disease (Jod–​Basedow phenomenon). This is called type 1 amiodarone-​induced thyrotoxicosis; type 2 amiodarone-​induced thyrotoxicosis is due to thyroid destruction via drug-​induced lysosomal activation. Colour-​flow Doppler thyroid scanning shows an increase in vascularity in type 1 but not type 2 amiodarone-​induced thyrotoxicosis, but mixed forms sometimes make an exact diagnosis impossible. Treatment of amiodarone-​induced thyrotoxicosis can be difficult and biochemical changes are often out of proportion to the

symptoms. Amiodarone should be stopped if possible, but often this cannot be done and in any case the drug has a very long half-​ life. Antithyroid drugs alone can be very slow to take effect in type 1 amiodarone-​induced thyrotoxicosis; High doses are often required and potassium perchlorate may need to be added, 200 mg 4 or 5 times daily. There is a high frequency of agranulocytosis (up to 1%) with this drug. Prednisolone can also be used at doses of 40 to 60 mg daily and is particularly helpful in type 2 amiodarone-​ induced thyrotoxicosis. Thyroidectomy is another alternative in severe cases.

Thyroid hormone resistance syndrome Mutations in one allele of the β thyroid hormone receptor gene (Fig. 13.3.1.4) cause thyroid hormone resistance. The mutations affect the hormone-​binding domain and the mutant receptor inhibits the activity of normally encoded receptors, so-​called dominant negative inhibition, resulting in an autosomal dominant pattern of inheritance. The condition is usually discovered during screening for a goitre, but children may sometimes present with short stature, hyperactivity, or mild learning difficulties. Thyrotoxic features in some patients were originally ascribed to selective pituitary resistance to thyroid hormone, leading to increased thyroid hormone secretion and therefore thyrotoxicosis in the peripheral tissues. However, the same receptor mutations occur in generalized and pituitary resistance syndromes, and although differential tissue expression of receptor subtypes presumably underlies the occasional expression of thyrotoxic signs and symptoms, the exact molecular basis is unknown. The diagnosis is suggested by the presence of a normal or elevated TSH level with elevated free T3 and T4 levels. Biochemical changes of thyrotoxicosis such as elevated ferritin, sex hormone-​binding globulin, and liver enzymes are absent. The main differential diagnosis is a TSH-​secreting adenoma. Thyroid hormone resistance can be confirmed by direct mutational analysis. Treatment is usually not required as reducing thyroid hormone levels to normal causes hypothyroidism. If thyrotoxic symptoms do occur, treatment is with β-​blockers or thyroid hormone analogues (e.g. tri-​ iodothyroacetic acid) aimed at lowering TSH secretion. Recently, mutations in the α thyroid hormone receptor gene have been identified; patients have early-​onset severe hypothyroidism with a normal TSH level, low or normal T4 levels and normal or elevated T3 levels.

FURTHER READING Akamizu T, et al. (2012). Diagnostic criteria, clinical features, and incidence of thyroid storm based on nationwide surveys. Thyroid, 22, 661–​74. Alexander EK, et al. (2017). 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid, 27, 315–89. Bahn RS (2010). Graves’ ophthalmopathy. N Engl J Med, 366, 726–​38. Beck-​Peccoz P, et  al. (2013). 2013 European Thyroid Association guidelines for the diagnosis and treatment of thyrotropin-​secreting pituitary tumors. Eur Thyroid J, 2,  76–​82.

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Bernal J, Guadaño-​ Ferraz A, Morte B (2015). Thyroid hormone transporters—​functions and clinical implications. Nat Rev Endocrinol, 11, 406–​17. Biondi B, Wartofsky L (2014). Treatment with thyroid hormone. Endocr Rev, 35, 433–​512. Bonnema SJ, Fast S, Hegedüs L (2014). The role of radioiodine therapy in benign nodular goitre. Best Pract Res Clin Endocrinol Metab, 28, 619–​31. Braverman LE, Cooper D (eds) (2012). Werner and Ingbar’s the thyroid, 10th edition. Lippincott Williams & Wilkins, Philadelphia. Chen AY, et al. (2014). American Thyroid Association statement on optimal surgical management of goiter. Thyroid, 24,  181–​9. DeGroot LJ, et  al. (2019). Thyroid Disease Manager. https://​www. thyroidmanager.org de Vries EM, Fliers E, Boelen A (2015). The molecular basis of the non-​thyroidal illness syndrome. J Endocrinol, 225, R67–​81. Fagman H, Nilsson M (2010). Morphogenesis of the thyroid gland. Mol Cell Endocrinol, 323,  35–​54. Franklyn JA, Boelaert K (2012). Thyrotoxicosis. Lancet, 379, 1155–​66. Jonklaas J. et  al. (2014). Guidelines for the treatment of hypothyroidism:  prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid, 24, 1670–​751. Kahaly GJ, et al. (2018). 2018 European Thyroid Association guideline for the management of Graves’ hyperthyroidism. Eur Thyroid J, 7, 167–86. Koulouri O, et al. (2013). Pitfalls in the measurement and interpretation of thyroid function tests. Best Pract Res Clin Endocrinol Metab, 27, 745–​62. Lazarus J, et al. (2014). 2014 European Thyroid Association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J, 3,  76–​94. Léger J, et al. (2014). European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. J Clin Endocrinol Metab, 99, 363–​84. Marcocci C, Marinò M (2012). Treatment of mild, moderate-​to-​severe and very severe Graves’ orbitopathy. Best Pract Res Clin Endocrinol Metab, 26, 325–​37. Mullur R, Liu YY, Brent GA (2014). Thyroid hormone regulation of metabolism. Physiol Rev, 94, 355–​82. Okosieme O, et al. (2016). Management of primary hypothyroidism: statement by the British Thyroid Association Executive Committee. Clin Endocrinol (Oxf), 84, 799–​808. Paes JE, et al. (2010). Acute bacterial suppurative thyroiditis: a clinical review and expert opinion. Thyroid, 20, 247–​55. Papini E, Pacella CM, Hegedüs L (2014). Thyroid ultrasound (US) and US-​assisted procedures: from the shadows into an array of applications. Eur J Endocrinol, 170, R133–​46. Persani L, et al. (2018). 2018 European Thyroid Association (ETA) guidelines on the diagnosis and management of central hypothyroidism. Eur Thyroid J, 7, 225–37. Ross DS, et al. (2016). 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid, 26, 1343–421. Szinnai G (2014). Genetics of normal and abnormal thyroid development in humans. Best Pract Res Clin Endocrinol Metab, 28, 133–​50. Verloop H, et al. (2014). Genetics in endocrinology: genetic variation in deiodinases: a systematic review of potential clinical effects in humans. Eur J Endocrinol, 171, R123–​35. Weetman AP (2011). Diseases associated with thyroid autoimmunity: explanations for the expanding spectrum. Clin Endocrinol (Oxf), 74,  411–​8. Zimmermann MB, Boelaert K (2015). Iodine deficiency and thyroid disorders. Lancet Diabetes Endocrinol, 3, 286–​95.

13.3.2 Thyroid cancer Kristien Boelaert and Anthony P. Weetman ESSENTIALS Thyroid cancers are the most common endocrine malignancies and their incidence is rising globally, largely due to significant increases in small, incidentally detected low-​risk tumours. Follicular epithelial cell cancer—​the commonest type; usually well differentiated tumours with an excellent prognosis but occasionally highly undifferentiated; may be induced by exposure to ionizing radiation; typically present with asymptomatic thyroid enlargement; usually diagnosed by ultrasonography and fine needle aspiration biopsy; treatment is typically by hemi-​or total thyroidectomy, followed by radio-​iodine ablation (administered to remove any remaining thyroid tissue) and short-​to longer-​term thyroid-​stimulating hormone suppression depending on clinical risk stratification Medullary thyroid carcinoma—​arises from parafollicular C cells; comprises 3–​5% of all thyroid cancers; hereditary autosomal dominant forms associated with germline point mutations in the RET proto-​ oncogene; occurs in 20% as part of multiple endocrine neoplasia (MEN) type 2A or 2B, or as isolated familial medullary carcinoma; typically presents with a solitary thyroid nodule, accompanied in 50% of cases by cervical lymphadenopathy; can be associated with unusual hormonal effects, including secretory diarrhoea; diagnosis often made by fine needle aspiration biopsy and by raised serum calcitonin concentration; treatment is by total thyroidectomy (requiring long-​term thyroid hormone replacement) and neck dissection (if required), followed by monitoring of serum calcitonin levels and tyrosine kinase inhibitors in advanced cases; Genetic testing for the presence of RET mutations allows family testing, with prophylactic thyroidectomy recommended for affected individuals. Rare thyroid tumours—​include (1) anaplastic carcinomas—​present as a rapidly enlarging and fixed thyroid masses, sometimes with local pain; rapidly fatal; (2) sarcomas; and (3) primary lymphomas—​usually present as a rapidly enlarging thyroid mass in a patient with Hashimoto’s thyroiditis.

Primary thyroid follicular epithelial tumours Aetiology Differentiated thyroid cancers are the most common tumours arising from thyroid follicular epithelial cells and account for 95% of all thyroid carcinomas (Table 13.3.2.1). Papillary carcinomas Around 85% of all thyroid cancers are papillary carcinomas, and these carry the best prognosis. Most of these tumours are indolent and harbour mutually exclusive mutations of genes encoding effectors that signal through the mitogen-​activated protein kinase (MAPK) pathway. BRAF V600E accounts for 60% of these mutations, followed by RAS (15%) and chromosomal rearrangements (12%) including RET, NTRK, and ALK resulting in aberrant expression of BRAF or of receptor tyrosine kinases. The remaining 13% have no known driver mutations. Different mutations are associated

13.3.2  Thyroid cancer

Table 13.3.2.1  Classification of thyroid malignancies Primary thyroid follicular epithelial tumours

Differentiated (papillary, follicular, Hürthle cell) Poorly differentiated Undifferentiated (anaplastic)

C-​cell epithelial tumours (medullary carcinoma) Primary non​epithelial tumours

Lymphoid origin (lymphoma, plasmacytoma) Mesenchymal cell origin (sarcoma) Other (teratoma)

Secondary non​thyroidal tumours

Metastases Extension of tumour from adjacent structures

with varying histological subtypes of papillary thyroid cancers and confer distinct patterns of gene expression, signalling, and clinical characteristics. BRAF-​mutated papillary thyroid cancers tend to be more aggressive with high frequency of lymph node metastases and recurrence rates. Exposure to ionizing radiation is a risk factor for the development of papillary thyroid cancer and sharp increases in the incidence of these tumours, especially in young children, were observed following the nuclear reactor accident in Chernobyl in 1986 and following the atomic bomb explosions in Hiroshima and Nagasaki in 1945. Radiation-​induced papillary cancers have a high prevalence of fusion oncogenes activating RET or NTRK and RET/​ PTC3 is particularly linked to radiation. Low-​dose external beam radiation (10–​1500 cGy) to the head and neck increases the risk of papillary thyroid cancer over 10 to 30 years. Higher thyroid radiation doses, including those arising from radio-​iodine given for treatment of hyperthyroidism, are not associated with an increased risk of malignancy because thyroid cells are destroyed rather than transformed. Mutations in the TERT gene have been identified in more aggressive subsets of papillary cancers. Follicular carcinomas Follicular thyroid cancers account for 2–​5% of thyroid cancers and usually harbour mutations of either RAS or the PAX8-​PPARG fusion oncogene. These tumours are also more prevalent in areas of iodine-​deficiency and excessive stimulation of thyroid cell growth by thyrotropin (TSH) plays a role in their pathogenesis. Rarely follicular carcinomas are associated with activating mutations of the genes encoding the TSH receptor or Gsα protein, similar to those found in toxic adenoma, and it is thought that some follicular carcinomas arise from adenomas. The prognosis of patients with follicular cancers depends on the size of the tumour, the patient’s age, and the degree of angioinvasion which predicts the risk of distant metastases. Hürthle cell cancers These are classified as a variant of follicular carcinomas and are genetically distinct. They may be widely invasive and may behave aggressively, with lung and bone metastases and refractoriness to radio-​iodine.

Anaplastic carcinomas These may arise from and can coexist with differentiated cancers but can also occur de novo. They have been linked to mutations in TP53 (p53 tumour suppressor gene), the TERT promoter, effectors of the phosphatidylinositol 3-​kinase (PI3K)-​AKT, mammalian target of rapamycin (mTOR), and genes involved in epigenetic regulation. Germline mutations Several germline variations in chromosomes 9q22.23 and 14q13.3 have been linked with high risk of differentiated thyroid cancers, due to their proximity to genes encoding proteins involved in regulating thyroid development and differentiation including FOXE1 and NKX2-​1. Familial forms of papillary and follicular carcinomas exist but are unusual (3–​9% of cases), including Cowden’s disease (multiple hamartoma syndrome associated with PTEN mutations OMIM 158350), familial adenomatosis polyposis, including the Gardner syndrome variant (associated with loss of function mutations in the APC gene OMIM 175100), and Werner’s syndrome (adult progeria associated with mutation in the WRN gene). Other familial forms may be found in Peutz–​Jeghers syndrome (OMIM 175200), the Carney complex (OMIM 160980), and ataxia–​telangiectasia (OMIM 208900).

Epidemiology Thyroid cancer incidence rates have increased dramatically in most Westernized countries and between 2014–2016 there were an average of 3527 new diagnoses annually in the United Kingdom, representing more than 155% rise since the early 1990s. In the United States, the incidence of thyroid cancer has more than tripled from 1975 through to 2015, and it is estimated that there will be 52 070 new thyroid cancer cases and 2170 deaths from the disease in 2019. Thyroid cancer is about three times more common in women than in men, and the peak incidence is between 30 and 50 years of age. Most of the recent increase in disease burden is due to the incidental detection of small, low-​risk tumours, although there is some evidence that other factors including ionizing radiation, obesity, and environmental pollutants may be contributing factors. Papillary microcarcinomas, defined as tumours less than 1 cm in diameter, occur in up to 36% of autopsy specimens and up to 24% of surgical thyroidectomies. Clearly most of these do not significantly impact on long-​term outcomes and life expectancy.

Clinical features Most patients present with thyroid enlargement in the form of a thyroid nodule, which is often asymptomatic. This may be noticed by the patient or their relatives, or sometimes the abnormality is detected during physical examination for another complaint. The difficulty for diagnosis arises because thyroid nodules are frequent, and only about 5% of palpable thyroid nodules are malignant. Diffuse or multinodular thyroid enlargement occurs in around 10% of the population and is four times more common in women than in men. Between 4 and 7% of adults have visible thyroid nodules and these are usually hyperplastic or colloid nodules. Overall, the prevalence of malignancy in thyroid nodules is estimated between 4 and 6.5%. There are usually no symptoms or signs to distinguish benign from malignant nodules because most cancers progress slowly and

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present before disease is advanced. Clinical parameters associated with increased risk of malignancy include male sex and being at the extremes of age (less than 20 or over 60 years). Previous exposure to radiation and a family history of thyroid cancer should also arouse suspicion. A  carcinoma is more likely if thyroid enlargement has grown recently or is hard, irregular, or fixed on palpation. Clinical assessment should include careful examination of the cervical, submental, and supraclavicular lymph nodes. Late-​presenting features include hoarseness, dysphagia, or dyspnoea which may indicate local invasion, but these symptoms can occasionally occur with an enlarging benign goitre. Rarely the diagnosis only becomes apparent when metastatic disease is detected in bone or lung. The relatively indolent presentation of papillary and follicular thyroid carcinoma contrasts with that of anaplastic carcinoma, in which a rapidly enlarging and fixed thyroid mass occurs, sometimes with local pain. Extension to the oesophagus, trachea, and/​or recurrent laryngeal nerves is frequent, and the overlying skin may also be infiltrated.

(a)

(b)

Pathology Papillary carcinomas There are several variants of papillary thyroid carcinoma united by their characteristic cytological features. The nuclei are large, clear (‘Orphan Annie’, after the eyes of the cartoon character), and have longitudinal grooves and invaginations of cytoplasm causing a papillary growth pattern (Fig.  13.3.2.1a). One-​half of papillary carcinomas contain degenerate calcified papillae, termed psammoma bodies. The tumour is multicentric in up to 80% of cases if the resected thyroid is examined carefully. Metastasis is via the lymphatics and local lymph nodes are infiltrated in 40 to 50% of cases (more in young patients). Distant metastases are found in less than 5% of patients at presentation, with the lung being the most common site. There are more than 10 different variants of papillary thyroid cancer and those with a less favourable outcome include tall cell, columnar cell, and hobnail variants. These tumours generally present at a later age and more advanced stage than classical-​type papillary thyroid cancer. Data regarding outcomes of solid variant and sclerosing (including diffuse sclerosing) variants remain controversial. The follicular variant of papillary thyroid carcinoma is a tumour composed of neoplastic follicles rather than papillae, but with follicular cells showing nuclear features characteristic of papillary thyroid cancer. There are two main subtypes:  infiltrative (non-​ encapsulated) and encapsulated. The latter form has increased in incidence by an estimated 2-​to 3-​fold over the past two to three decades and makes up 10–​20% of all thyroid cancers currently diagnosed in Europe and North America. These tumours have a very low risk of adverse outcomes and are now termed non​invasive follicular thyroid neoplasm with papillary-​like nuclear features (NIFTP). No additional treatment with surgery or radio-​iodine ablation is required for these tumours, and no further pathological staging is needed. Follicular carcinomas Follicular carcinoma is characterized by follicular differentiation with a solid growth pattern and without the nuclear features of papillary carcinoma. The tumour is encapsulated, but there is invasion of the capsule and vessels, thereby distinguishing it from a follicular

(c)

Fig. 13.3.2.1  Histopathological features of thyroid follicular epithelial carcinoma. (a) Papillary carcinoma, with psammoma bodies and typical nuclear appearance. (b) Metastatic follicular carcinoma, eroding vertebral bone. (c) Anaplastic carcinoma showing pleomorphic spindle cells. All sections, original magnification ×200. Photomicrographs by courtesy of Dr K. Suvarna.

adenoma (Fig.  13.3.2.1b). They may be minimally invasive when there is only microscopic capsular invasion, or angioinvasive when there is vascular invasion. The former are indolent tumours with 10-​year mortality rates of less than 5%, whereas the latter are associated with mortality rates of 5–​30% depending on the number of invaded blood vessels.

13.3.2  Thyroid cancer

Hürthle cell cancers Oncocytic (Hürthle cells) cells are characterized by oxyphilic staining due to mitochondrial accumulation, resulting in abundant eosinophilic granular cytoplasm and hyperchromatic nuclei. They are classified into Hürthle cell adenomas or Hürthle cell carcinomas, depending on the presence or absence of capsular and vascular invasion. Poorly differentiated and anaplastic carcinomas Poorly differentiated thyroid cancers are aggressive tumours with partial loss of features of thyroid differentiation occupying a position between well-​differentiated thyroid tumours and completely dedifferentiated anaplastic cancers. They are associated with poor outcomes and 10-​year survival rates are around 50%. In anaplastic carcinoma there is no capsule, the cells are atypical, including spindle, multinuclear, and squamoid forms, and mitoses are frequent (Fig. 13.3.2.1c).

Investigation and diagnosis Blood tests Thyroid epithelial cancers generally fail to affect thyroid function, but this should be evaluated in all patients presenting with a thyroid nodule; a low circulating TSH concentration strongly suggests an autonomous benign nodule. Anaplastic carcinoma may occasionally cause hypothyroidism, but the most frequent cause of an elevated TSH concentration with a hard, nodular thyroid is Hashimoto’s thyroiditis. Some of the glands in these cases are so irregular that the presence of malignancy may be suspected. Differentiated thyroid cancer is more common in patients with autoimmune thyroid disease—​ both Graves’ disease and Hashimoto thyroiditis—​ and thyroid lymphoma almost always occurs in association with autoimmune thyroiditis. Any dominant or atypical area in a Hashimoto’s goitre therefore requires careful evaluation. Thyroid peroxidase and/​or thyroglobulin antibodies are raised in about one-​quarter of patients with thyroid follicular epithelial carcinoma, coincident with the presence of a lymphocytic infiltrate which, in turn, is associated with a slightly more favourable prognosis. Although measurement of serum thyroglobulin concentrations is extremely useful in follow-​up, as discussed next, this investigation is unhelpful in diagnosing thyroid cancer; levels may not be elevated in some patients and, even when elevated, cannot be causally distinguished from those that occur in benign adenoma, multinodular goitre, Graves’ disease, destructive thyroiditis, or Hashimoto’s.

Fig. 13.3.2.2  Ultrasound appearances of a cystic thyroid nodule with tiny echogenic foci with subtle ‘ring-​down’ or ‘comet tail’ artefact (arrow) due to inspissated colloid. From Scoutt LM, Hamper UM, Angtuaco TL (eds) (2016). Ultrasound. By permission of Oxford University Press, USA.

Ultrasonography High-​resolution ultrasonography is a very sensitive tool to diagnose thyroid malignancy and may be specific for the identification of papillary thyroid cancer. Most current guidelines recommend ultrasonography, performed by a competent operator, as the first line imaging tool in patients presenting with thyroid enlargement (Figs. 13.3.2.2 and 13.3.2.3). Ultrasonographic features associated with a higher risk of malignancy are illustrated in Table 13.3.2.2. Ultrasonographic features should be used in summation to identify thyroid lesions that may be malignant and warrant fine needle aspiration biopsy (FNAB). Ultrasonography also increases the yield of FNAB. The presence or absence of abnormal cervical lymph nodes should be documented when undertaking thyroid ultrasonography.

Imaging Thyroid nodules may be detected in up to 60% of adults when using high resolution ultrasonography, and they are found incidentally in 16% of cross-​sectional CT or MRI scans, 10% of carotid Doppler investigations, and 2–​3% of positron emission tomography (PET) scans. FDG-​PET positive nodules carry a higher risk of malignancy and require further evaluation. Several ultrasonographic criteria are associated with a higher suspicion for malignancy: current guidelines combine these into algorithms guiding practitioners regarding the selection of thyroid nodules that warrant further evaluation with fine needle aspiration biopsy.

Fig. 13.3.2.3  Ultrasound appearances of papillary thyroid carcinoma. There is a large, solid nodule in the inferior pole of the right lobe of the thyroid with punctate echogenic, non​shadowing microcalcifications (arrows); T, normal thyroid parenchyma. From Scoutt LM, Hamper UM, Angtuaco TL (eds) (2016). Ultrasound. By permission of Oxford University Press, USA.

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Table 13.3.2.2  Ultrasonographic features of benign and malignant thyroid nodules Benign nodule

Malignant nodule

Follicular lesion

Spongiform/​ honeycomb

Solid and hypoechoic

Hyperechoic/​ homogeneous halo benign

Purely cystic

Irregular margin

Hypoechogenicity/​loss of halo suspicious

Egg shell calcification

Intranodular vascularity

Iso/​hyperechoic (hypoechoic halo)

Absence of halo

Peripheral vascularity

Taller than wide Microcalcifications

In the United Kingdom, a scoring system of U1-​5 is recommended to classify thyroid nodules based on ultrasound findings: U1: normal thyroid; U2: benign thyroid lesion; U3: indeterminate thyroid lesion (likely follicular lesion); U4:  suspicious thyroid lesion; U5:  diagnostic for thyroid cancer. Nodules graded as U3-​5 warrant further cytological evaluation. The US guidelines recommend use of similar system classifying thyroid nodules as benign, very low, low, intermediate, or high risk of malignancy, and also take nodule size into account when selecting nodules that warrant FNAB. Radionuclide scanning Radionuclide scanning with 99mTc pertechnetate or radio-​iodine (123I or 131I) may be indicated if patients have thyroid enlargement and a low serum TSH concentration. The presence of a ‘hot’ nodule taking up significant amounts of radionuclide with failure of the surrounding tissue to take up the tracer is consistent with the presence of an autonomous nodule which is almost invariably benign. Most thyroid cancers fail to take up radionuclide (‘cold’ nodules), but benign lesions may behave in a similar way. Overall radionuclide scanning is not routinely recommended to diagnose thyroid cancer. Fine needle aspiration biopsy Fine needle aspiration biopsy and subsequent cytological evaluation remains the gold standard for the diagnosis of thyroid cancer, with sensitivity and specificity rates of more than 90%. This is now usually performed under ultrasound guidance. In the United Kingdom, the use of the ‘THY classification’ is recommended:  THY1:  non​ diagnostic (insufficient cells sampled); THY2: non​neoplastic; THY3: neoplasm possible, which is further subdivided into THY3a:  atypical features present, and THY3f:  follicular neoplasm; THY4: suspicious of malignancy and THY5: diagnostic of thyroid cancer. US guidelines recommend the use of the Bethesda classification, which is very similar to the United Kingdom system. Surgery is usually required for lesions classified as THY3f, THY4, and THY5 and repeat biopsy should be undertaken for THY1 and THY3a nodules. In all cases the clinical, ultrasonographic, and cytological findings should be considered together and where appropriate should be discussed in a multidisciplinary team (MDT) setting, especially if there is non​concordance between findings. Papillary carcinoma is readily diagnosed by fine needle aspiration biopsy, and medullary carcinoma and lymphoma can also be

detected by the use of immunohistochemical staining, although lymphoma frequently requires core or open biopsy for confirmation. Follicular carcinomas cannot be distinguished cytologically from follicular adenomas and are usually labelled as THY3F. Many patients with these lesions will undergo diagnostic hemithyroidectomy. However, there is a rapidly growing body of literature describing the use of gene expression classifiers, mutation analysis panels, and protein expression chips to distinguish benign from malignant follicular lesions. Some centres, especially in the United States, use molecular analysis of FNAB specimens routinely in decision-​making processes regarding the recommendation of surgery for these indeterminate lesions, although this is not common practice in the United Kingdom and most European countries. Thyroid cysts are usually benign and may be aspirated during biopsy, although reaccumulation of fluid is common and may indicate presence of malignancy; if this occurs, surgery is usually required for definitive diagnosis.

Management of differentiated thyroid cancer Surgical excision The initial form of treatment is surgery, which should be performed by a surgeon with the required training and expertise who is a core member of the multidisciplinary team. Assessment of extrathyroidal extension and presence (or absence) of central compartment and lateral neck lymph node disease through ultrasonography and cross-​ sectional imaging with CT or MRI is recommended. Thyroid lobectomy is recommended for patients with unifocal papillary microcarcinoma (2 cm but ≤4 cm limited to the thyroid

T3

Tumour >4 cm limited to the thyroid or any tumour with minimal extrathyroidal extension

All macroscopic tumour resected (R0/​R1)

Cervical lymph node metastases N1a/​N1b

Incomplete tumour resection (R2)

T4a

Tumour of any size beyond the thyroid capsule and invading surrounding tissues

T4b

Tumour invades prevertebral fascia or encases carotid artery or mediastinal vessels

Aggressive histology, e.g. Tall cell, insular or angioinvasion

Distant metastases (M1)

No locoregional tumour invasion No aggressive histological features

Regional lymph nodes (cervical and upper mediastinal)—​N Nx

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastases

N1

Regional lymph node metastases

N1a

Metastases to Level VI (pretracheal, paratracheal, and prelaryngeal/​ Delphian lymph nodes)

N1b

Metastases to unilateral, bilateral, or contralateral cervical (levels I, II, III, IV, or V) or retropharyngeal or superior mediastinal lymph nodes (level VII)

Distant metastases—​M M0

No distant metastases

M1

Distant metastases

Residual tumour—​R Rx

Cannot assess presence of residual primary tumour

R0

No residual primary tumour

R1

Microscopic residual primary tumour

R2

Macroscopic residual primary tumour

Based on the TNM classification tumours are then staged as follows (AJCC/​UICC staging system, Table 13.3.2.4).

Radio-​iodine remnant ablation and therapy for differentiated thyroid cancer After surgery, radio-​iodine is usually administered to remove any remaining thyroid tissue, which then allows thyroglobulin or 131I total body scanning to be used in follow-​up to detect metastases. This treatment may also destroy occult carcinoma and, by scanning after ablation, metastatic disease is revealed. Similar to the Table 13.3.2.4  Staging of differentiated (papillary and follicular) thyroid carcinomas (adapted from 2014 BTA guidelines for the management of thyroid cancer) Patients aged ≥55 y

Patients aged 30 mU/​litre) are required to produce maximum uptake of 131I. This may be achieved by levothyroxine withdrawal for 4 weeks, resulting in development of severe hypothyroid symptoms, or by the administration of recombinant human TSH (rhTSH) for 48 hours prior to administration of radio-​iodine, thereby avoiding the need for cessation of thyroid hormone replacement. If thyroid hormone withdrawal is used, patients are usually switched to the shorter-​acting liothyronine (20 µg three times daily) as replacement therapy 28 days before 131-​I ablation and this treatment is then discontinued 14 days before radio-​ iodine administration. Randomized controlled trials have shown

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equal efficacy of 131-​I remnant ablation when using thyroid hormone withdrawal and rhTSH, with improved quality of life in the rhTSH group due to absence of troublesome hypothyroid symptoms. The use of rhTSH is therefore recommended in patients with low to intermediate risk tumours (pT1 to pT3, pN0 or Nx, or N1 and M0 and R0). Radio-​iodine-​avid thyroid cancer metastases may be treated with further radio-​iodine therapy; doses between 3.7 and 5.5 GBq are usually administered. Dynamic risk stratification Patients who have undergone total thyroidectomy and remnant ablation with radio-​iodine should undergo dynamic risk stratification to define the response to initial therapy. This is usually done 9–​12 months following treatment, when patients are recommended to have a neck ultrasound and measurement of rhTSH stimulated thyroglobulin (Tg). Subsequent intensity and duration of follow-​up, as well as targets for TSH suppression, is then based on the assignment of patients to different response groups:  excellent, indeterminate, or incomplete response (Table 13.3.2.6). Long-​term levothyroxine replacement therapy Following thyroidectomy, it is necessary to maintain euthyroidism through lifelong levothyroxine replacement in all patients who have undergone a total thyroidectomy and, in some patients, following lobectomy. Suppression of serum TSH is required in intermediate and high-​risk patients since thyrotropin is a growth factor for thyroid cells. Following initial treatment with surgery and radio-​iodine remnant ablation, and before dynamic risk stratification, serum TSH should be suppressed below 0.1 mIU/​litre. It is unnecessary to suppress serum TSH in subjects who have undergone less than total thyroidectomy and in those who have not undergone remnant ablation. In patients who are stratified into the excellent response category following dynamic risk stratification, serum TSH can be maintained in the lower half of the normal reference range (0.3–​2.0 mIU/​litre). For historic patients who have not undergone dynamic risk stratification, it is appropriate to keep serum TSH suppressed below 0.1 mIU/​litre for 5–​10  years and then to allow serum TSH to rise to the lower half of the normal reference range if there is no evidence of recurrence either biochemically or structurally. The long-​term consequences of serum TSH concentrations suppressed below 0.1 mIU/​litre include cardiovascular morbidity and mortality as well as osteoporosis, and evaluation of probability of osteoporotic fragility fracture risk may be required.

Systemic therapies for metastatic radio-​iodine-​refractory thyroid cancer Metastatic thyroid cancer occurs in less than 10% of patients, about two-​thirds of whom ultimately present with radio-​iodine refractory disease. If patients have radio-​iodine avid disease, repeated administration of radio-​iodine therapy every 4–​6 months may be beneficial, especially if lung metastases are present. There is little benefit above a cumulative dose of 18.5 GBq. Bone metastases may respond to 131I or external beam radiotherapy, and orthopaedic intervention may be required to stabilize pathological fractures. Palliative external beam radiotherapy has a limited role in controlling locoregional disease when further surgery is ineffective or impractical. Radiotherapy can be used alone or in combination with low-​dose chemotherapy. Targeted therapies Improved understanding of the molecular pathogenesis of thyroid cancer has resulted in an explosion of targeted therapies in patients with advanced metastatic thyroid cancer. Two multikinase inhibitors, sorafenib and lenvatinib, have been approved for the treatment of radio-​iodine refractory tumours on the basis of prospective, double-​ blind randomized placebo-​ controlled trials that showed longer progression-​free survival. Lenvatinib appears to have the greatest efficacy. Significant adverse effects of both drugs often make the maintenance of full dose therapy a challenge. Common adverse effects include hypertension, hand–​foot skin reactions, diarrhoea, rash, fatigue, weight loss, and stomatitis. Longer-​term effects on quality of life and cumulative toxic effects of these agents remain to be determined. Phase 2 trials using several other multikinase inhibitors have commenced, including sunitinib, pazopanib, axitinib, cabozantinib, and motesanib, all of which have multifunctional actions including antiangiogenic properties. Targeted therapies including RAF-​kinase inhibitors used alone or in combination with MEK inhibitors are also being explored in several combination trials. Treatment with selumetinib, a MAPK kinase (MEK) 1 and MEK2 inhibitor, has been shown to produce a clinically meaningful increase in radio-​ iodine uptake in tumours previously refractory to radio-​iodine treatment through loss of the sodium iodide symporter, particularly those with a RAS mutation. This is a rapidly developing field and more trials will help address how best to stratify patients for treatment.

Follow-​up Lifelong follow-​up is necessary for papillary and follicular cancer because they may recur many years after apparent cure. As well as monitoring the concentration of serum TSH and performing

Table 13.3.2.6  Dynamic risk stratification determining response to treatment (adapted from 2014 BTA Guidelines for the management of thyroid cancer) Excellent response

Indeterminate response

Incomplete response

All the following: Suppressed and stimulated Tg 7.8) mmol/​litre. Diabetes affects fertilization, implantation, embryogenesis, organogenesis, fetal growth and development, and neonatal and perinatal morbidity and mortality. Preconception counselling is associated with improved pregnancy outcomes. Key aspects of periconceptional and pregnancy management include optimization of glycaemic control, stopping of medications contra-​indicated in pregnancy, avoidance of hypoglycaemia and diabetic ketoacidosis, and screening and management of diabetic complications. Risks to the fetus of maternal diabetes include congenital malformations, fetal macrosomia, intrauterine growth restriction, and those from the increased incidence of maternal pre-​eclampsia. Long-​term adverse effects such as increased susceptibility to metabolic disease later in life are also recognized. Once pregnancy is confirmed, women with pre-​existing diabetes should be encouraged to book early in the pregnancy for management by a hospital-​based multidisciplinary team. Optimal blood glucose targets are a fasting capillary glucose of 5.3 mmol/​litre, a one hour after meal value below 7.8  mmol/​litre, or a two-​hours after meal value below 6.4 mmol/​litre. In some women with gestational diabetes this may be achieved with diet and exercise, but oral hypoglycaemic agents (typically metformin or glibenclamide) and/​or insulin are often required. Women with diabetes should give birth in hospitals where 24 hour-​ a-​ day advanced neonatal resuscitation skills are available. Induction of labour or an elective caesarean section before 38 + 6 weeks of pregnancy is recommended if spontaneous labour has not occurred before then because of the increased risk of stillbirth.

The effect of pregnancy on maternal glycaemic control ceases very quickly post-​partum, hence women with pre-​existing diabetes taking insulin should immediately revert to their pre-​pregnancy regimen after birth, but with a lower insulin dose.

Introduction Diabetes mellitus (DM), whether pre-​existing, or new onset in pregnancy has major long-​term implications for both maternal and fetal health. The overall incidence of diabetes in women of childbearing age has increased over the last decade and is anticipated to continue to rise. One of the underlying causes of this is the rising prevalence of obesity, and this is impacting on the type of diabetes as well as the demographic factors of pregnant women with diabetes. Understanding the type of diabetes a woman has and the associated risk factors is key to the management of diabetes in pregnancy, as well as the implication for success or failure of potential intervention strategies. In addition, as the number of pregnant women with diabetes rises, there is a substantial impact on healthcare costs and resource utilization, emphasizing the need for the implementation of the best evidence-​based cost-​efficient treatment strategies.

The physiology of glucose homeostasis during pregnancy In normal early pregnancy there is an increase in insulin sensitivity and a fall in fasting plasma glucose in non​obese women. This increase in insulin sensitivity accounts for the fall in insulin requirements seen in women with type 1 DM and their susceptibility to hypoglycaemia during the first trimester. Insulin sensitivity continues to increase at the beginning of the second trimester, after which there is a progressive reduction in insulin sensitivity until term, and by late pregnancy insulin sensitivity will have fallen by 40–​60%. The underlying mechanisms for these changes are complex and due in part to maternal and placental adipokines and cytokines, as well as to the upregulation of the growth hormone/​insulin-​like growth factor axis by high circulating concentration of placental

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Section 14  Medical disorders in pregnancy

growth hormone. The contributions of the early increase in corpus luteal and then placental progesterone and 17β-​oestrogen by 10-​and 30-​fold, respectively, on insulin resistance is unclear. The physiological reduction in insulin sensitivity in later pregnancy facilitates the maternal-​fetal transfer of glucose and other nutrients across the placenta. Decreased insulin sensitivity decreases the glucose uptake in maternal muscle, the principal site of whole-​body glucose disposal, thereby redirecting glucose to the fetus where it is the principal fetal substrate. This transfer of glucose is facilitated by GLUT-​1, a specific placental glucose transporter protein, and by the maternal-​fetal glucose concentration gradient. By late pregnancy the degree of maternal hepatic and peripheral insulin resistance results in an increased hepatic glucose output and free fatty acid release from maternal adipose stores that increase during early pregnancy due to the relative insulin resistance. This normal physiological fall in insulin sensitivity in pregnancy is greater in obese women and those with gestational diabetes mellitus (GDM). Maternal insulin secretion increases in response to the fall in insulin sensitivity, such that post-​prandial insulin secretion is increased 200–​250% from baseline levels by late pregnancy. This is accompanied by an adaptive increase in the numbers of β cells in small islets, implying β-​cell neogenesis rather than duplication of β cells in existing islets. The increase in maternal insulin secretion helps promote maternal lipogenesis in early pregnancy and the deposition of adipose stores. If the maternal insulin response to pregnancy is inadequate, maternal hyperglycaemia will develop, leading to the development of gestational diabetes mellitus. While most women who become hyperglycaemic are at risk of future type 2 DM, and start pregnancy with increased insulin resistance such that their insulin demands to maintain euglycaemia in pregnancy are extremely high, a smaller proportion of women are in the early preclinical phases of type 1 DM. The increased insulin demands of pregnancy account for the observation that there is a threefold increase in the new presentation of type 1 DM in pregnancy. Identifying this small group of women is important as early insulin treatment and close antenatal surveillance is important.

Epidemiology and classification Diabetes in pregnancy is predominantly either pre-​existing type 1 or type 2 diabetes mellitus, or gestational diabetes, the latter defined as diabetes or glucose intolerance first diagnosed during the pregnancy. There are other rarer forms of pre-​existing diabetes, including monogenetic diabetes, recognition of which in pregnancy will increase as awareness and the ability to diagnose them increases. While the overall incidence of women with diabetes of any type is increasing, the largest proportional rise is seen in women with pre-​existing type 2 diabetes mellitus and gestational diabetes. In 2012, overall prevalence of gestational diabetes across Europe was reported as between 2 to 6%, but this is dependent on the diagnostic criteria used and the ethnic and demographic mix of the antenatal population, and higher values will be reported as more universal screening and testing for gestational diabetes is introduced (see later).

Maternal gestational diabetes and obesity are both independently associated with adverse pregnancy outcomes, and their combination has a greater impact than either one alone. Obesity and gestational diabetes are also associated with adverse long-​term cardiovascular health in both the mother and the child in later life. In 2015 it was estimated that in England and Wales around 35 000 pregnant women annually would have either pre-​existing diabetes (20%) or gestational diabetes mellitus (80%). Gestational diabetes usually arises in the late second trimester as a consequence of the pregnancy-​induced changes in maternal carbohydrate metabolism. However, undiagnosed type 2 diabetes mellitus is increasingly seen, and it is essential to identify these women as their clinical management needs to be similar to those with pre-​ existing recognized type 2 and optimized as early in pregnancy as possible.

The diagnosis of diabetes and type of diabetes in pregnancy The criteria for the diagnosis of diabetes outside of pregnancy can be made by any of the following; • a fasting plasma glucose of 7.0 mmol/​litre or above; • a two-​hour plasma glucose of 11.1 mmol/​litre or above during a 75 g oral glucose tolerance test taken as anhydrous glucose dissolved in water; • a glycosylated haemoglobin (HbA1c) of 6.5% (48  mmol/​mol) or above; • a random plasma glucose of 11.1 mmol/​litre or above in the presence of hyperglycaemic symptoms. The distinction between type 1 and type 2 diabetes mellitus can usually be made on the basis of clinical risk factors. Both types 1 and 2 are heterogeneous diseases in which the clinical presentation and disease progression in adults may vary considerably and can appear to overlap. The diagnosis of type 1 diabetes mellitus, an autoimmune disease characterized by β-​cell destruction, can if necessary usually be confirmed by the presence of islet specific autoantibodies and low circulating or undetectable concentration of serum C-​peptide, a measure of endogenous insulin secretion. These islet cell autoantibodies include those directed against insulin, glutamic acid decarboxylase (GAD) (GAD65), the tyrosine phosphatases IA-​2 and IA-​2b, and ZnT8. The diagnosis of type 2 diabetes mellitus remains a clinical diagnosis. Other than hyperglycaemia, including elevated HbA1c levels, there are no specific clinical diagnostic tests for type 2 diabetes mellitus. The lack of β-​cell autoimmunity, other autoimmune diseases, or other known causes for hyperglycaemia all favour a diagnosis of type 2. Most, but not all, patients with type 2 are overweight or obese, and many will have a family history of type 2 diabetes mellitus or other metabolic risk factors. See Chapter  13.9.1 for further discussion. In pregnancy, if the diagnosis of pre-​existing type 1 diabetes mellitus is uncertain, the presence of GAD antibodies would be expected to confirm the diagnosis in around 80% of cases, and the decision to undertake further testing for antibodies will depend on risk assessment (Fig. 14.10.1).

14.10  Diabetes in pregnancy

Test for Type 1 DM using GAD* antibodies

No need to test for type 1 DM

Strong fam

ily history

No risk fact

of type 2 D

M

Two or mo re ri BMI > 27kg 2sk factors for type 2 DM/m , family history of DM, age > type 2 40 yrs., no nwhite, pre vious GDM

ors for typ

e 2 DM

1 st or 2 nd degree rela tive DM or oth er autoimm with type 1 une disease s Autoimmu ne thyroid disease disease, A ddison’s vi , coeliac ti myasthen ia gravis, p ligo, ernicious anaemia. au toimmune hepatitis,

Fig. 14.10.1  Factors affecting the decision to test for GAD antibodies in a patient with diabetes in pregnancy.

Gestational diabetes mellitus Definition and diagnosis Gestational diabetes mellitus is defined as a new diagnosis of diabetes during pregnancy. There remains some controversy as how best to diagnose it. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study was designed to establish internationally agreed diagnostic criteria. In this landmark observational study more than 25 000 non​diabetic pregnant women were recruited between 2000 and 2006 from nine different countries. All women underwent a 75 gram, two-​hour OGTT between 24 and 32 weeks’ gestation, with healthcare providers blinded to the results unless suggestive of overt diabetes (fasting plasma glucose above 5.8 mmol/​l (105 mg/​dl), or the 2-​hour value above 11.1 mmol/​l (200 mg/​dl), or a random plasma glucose at 34–​37 weeks above 8.9 mmol/​l (160 mg/​ dl)). The fasting, 1-​and 2-​hour plasma glucose results of the OGTT were analysed from 23 316 mother-​newborn pairs for their association with four primary outcomes: macrosomia (corrected birth weight >90th centile), primary caesarean delivery, clinical neonatal hypoglycaemia, and hyperinsulinemia (as assessed by cord serum c-​peptide >90th centile for the study group as a whole). The analysis of the data showed the associations between the OGTT results at different time points and the four primary outcomes were continuous, with no clear inflection points. The results of the HAPO analysis formed the basis of the International Association of the Diabetes and Pregnancy Study Groups (IAPDSG) 2014 criteria for gestational diabetes. The new criteria for gestational diabetes were based on the threshold of glucose value at each time point that gave a 1.75 likelihood of an adverse outcome when compared with the mean reference value at the three separate time points. The American Diabetes Association (ADA), World Health Organization, and International Diabetes Federation

all subsequently endorsed the IAPDSG diagnostic criteria for gestational diabetes, which included a 75 gm OGTT performed between 24 to 28 weeks. In contrast to the HAPO-​ derived criteria, following a cost-​ effectiveness analysis of published intervention studies the National Institute for Health and Care Excellence (NICE) 2015 Diabetes and Pregnancy update proposed a higher fasting value and a lower two-​ hour oral glucose tolerance test value, with no one-​hour value for the diagnosis of gestational diabetes (Table 14.10.1). The NICE criteria also advocate the use of universal screening of five risk factors identified at the initial antenatal visit, with a 75 gm OGTT between 26 to 28 weeks performed on only those women with one or more risk factors, these being a body mass index (BMI) above 30 kg/​m2, a previous macrosomic baby weighing 4.5 kg or above, previous gestational diabetes, a first-​degree relative with diabetes, and belonging to an ethnic family origin with a high background prevalence of diabetes. An earlier diagnostic OGTT (at 16 weeks) is recommended for women with a history of previous gestational diabetes, with repeat at 24–​28 weeks if the first test was normal. The five risk factors recommended by NICE is not exhaustive and leaves out other recognized risk factors, including increasing age and a history of polycystic ovary syndrome. The NICE-​recommended screening at booking potentially may miss up to 25% of women with gestational diabetes. Applying the new IAPDSG criteria to the original HAPO cohort diagnosed between 15 to 20% of parturients as having gestational diabetes, depending on country of origin. Gestational diabetes mellitus in early pregnancy There is currently no agreed strategy for identifying women not known to have diabetes who have significant hyperglycaemia in early pregnancy. Glycosylated haemoglobin (HbA1c) is less reliable

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Table 14.10.1  Recommendations for screening and oral glucose tolerance testing in pregnancy IAPDSG criteria

NICE 2015 criteria

Screening

None

Risk factors at 1st antenatal clinic 1. BMI >30 kg/​m2 2. Previous history of GDM 3. Previous macrosomic birth, ≥ 4.5 kg 4. Family history 5. Minority ethnic family origin with a high prevalence of diabetes

75 gm OGTT

Universal at 24–​28 weeks

Selective testing 26–​28 weeks Based on the presence of risk factors

Plasma glucose

IAPDSG criteria one or more of the following thresholds be met or exceeded:

NICE 2015 criteria one or more of the following thresholds be met or exceeded

0 minute

5.1 mmol/​litre (92 mg/​dl)

5.6 mmol/litre (100 mg/​dl)

60 minute

10 mmol/​litre (180 mg/​dl)

120 minute

8.5 mmol/​litre (153 mg/​dl)

7.8 mmol/​litre (140 mg/​dl)

GDM, gestational diabetes mellitus.

in pregnancy due to the higher turnover of erythrocytes, and fasting blood glucose falls in early pregnancy. However, an HbA1c measurement of ≥5.9% (≥41 mmol/​mol) at the initial antenatal clinic appears to be a good discriminator for women who have significant glucose intolerance on a subsequent OGTT performed at around 20 weeks’ gestation, and with an increased risk of adverse pregnancy outcomes. This HbA1c value is lower than the diagnostic value for diabetes outside pregnancy (HbA1c 6.5% (48 mmol/​mol). Aetiology As described, pregnancy induces a state of relative decreased insulin sensitivity due to both maternal and placental factors. High circulating levels of maternal free fatty acids, adipokines, and cytokines may be factors contributing to this. Women who are obese and those who have gestational diabetes have increased levels of many of the adipokines and inflammatory cytokines associated with decreased insulin sensitivity, including leptin, tumour necrosis factor-​α (TNF​α) and interleukin-​6, while the insulin sensitizing adipocyte cytokine adiponectin is reduced. The placenta is a major source of these cytokines, hormones, and inflammatory mediators, as well as of human placental lactogen and placental growth hormone. Pregnancy is a physiologically leptin-​resistant state and results in a significant upregulation of leptin, which in turn leads to hyperglycaemia. The human growth hormone (GH) gene cluster contains a single gene expressed solely in the anterior pituitary (GH1), plus four genes expressed in the placenta (SHL1, CSH1, GH2, CSH2). GH1 encodes solely pituitary GH, which is also a ligand for the maternal GH receptor and stimulates the insulin-​like growth factor (IGF)-​1 axis. In pregnancy the 6–​8-​fold increase in placental growth hormone increases and replaces normal circulating pituitary growth hormone by 20 weeks’ gestation, and this is thought to decrease insulin sensitivity by inhibiting key components of the insulin-​signalling pathway.

The other members of the GH gene cluster, CSH1 and CSH2, encode for human placental lactogen which is a ligand for the maternal prolactin receptors. This can be detected in the maternal circulation by six weeks’ gestation and has been implemented in augmenting maternal insulin resistance and promoting the supply of fatty acids and glucose to the placenta. Changes in the placental microcirculation and placental dysfunction leading to increased fetal complications have been attributed to the adverse diabetic metabolic milieu resulting from hyperglycaemia, hyperinsulinism, dyslipidaemia, and secretion of adipokines and inflammatory cytokines, causing increased oxidative stress and protein glycosylation.

Rarer forms of diabetes Monogenic β-​cell diabetes is thought to be responsible for approximately 2% of all diabetes diagnosed before the age of 45 years, about 80% of such patients being misdiagnosed as either type 1 or type 2 diabetes, reflecting lack of clinical awareness and limited clinical access to genetic testing. Clues to the diagnosis of monogenic forms of diabetes include lack of typical characteristics of type 1 diabetes (no islet cell autoantibodies, low or no insulin requirement five years after diagnosis, persistence of measurable stimulated C-​peptide, absence of diabetic ketoacidosis), or type 2 diabetes (lack of obesity, hypertension, dyslipidaemia), in the presence of a strong family history of diabetes. An autosomal dominant family history of diabetes may be caused by monogenic disruption of glucokinase (GCK), hepatic nuclear factor (HNF)-​1A, HNF-​4A, or HNF-​1B gene expression. The molecular diagnosis of such forms of diabetes is important because it enables genetic counselling, predictive genetic testing in affected families, personalized tailoring of medication, and provides patient information regarding prognosis. GCK-​related diabetes Making the diagnosis of GCK-​related diabetes is important as it allows patients to be reassured that they have an inherited tendency to mild hyperglycaemia, which requires no specific glucose-​lowering treatment or self-​monitoring of blood glucose (outside of pregnancy), because the condition is not associated with microvascular or macrovascular complications. It also has important implications for management of pregnancy, because in parturients with GCK-​ related diabetes the risk of fetal macrosomia depends upon the fetal GCK genotype. If the fetus has not inherited the GCK mutation it will respond to maternal hyperglycaemia with increased insulin production, leading to excess fetal growth (adding an additional approximately 550–​700 g by term). Alternatively, if the fetus does inherit the GCK abnormality, it will sense the maternal hyperglycaemia as normal, produce normal amounts of insulin and have normal growth, and in this context the aggressive lowering of maternal glucose into the normal range may adversely affect fetal growth. As it is not currently possible to determine the fetal genotype non​invasively during pregnancy, the decision on whether to treat maternal hyperglycaemia in parturients with GCK-​related diabetes is made on the basis of monitoring fetal abdominal circumference, with a reading above the 75th percentile being the recommended threshold to start insulin and normalize maternal glycaemia. In the future, fetal genotyping using cell-​free fetal DNA from maternal plasma sampling during early pregnancy may assist in this context.

14.10  Diabetes in pregnancy

The impact of diabetes on the mother and fetus during pregnancy Diabetes affects all aspects of a woman’s reproductive life, including pregnancy. Diabetes, specifically maternal hyperglycaemia, affects fertilization, implantation, embryogenesis, organogenesis, fetal growth, and development and neonatal and perinatal morbidity and mortality. Women with pre-​existing diabetes or those who develop diabetes during the pregnancy are at added risk of maternal and fetal complications during pregnancy. Maternal diabetes and obesity also influence the risk of future obesity and diabetes in the child, through epigenetic factors and fetal programming in utero. Preconception planning, surveillance, and screening throughout pregnancy by a multidisciplinary specialist team can lessen the risks for both mother and fetus.

Preconception counselling for women with diabetes Preconception counselling is associated with improved pregnancy outcomes. Uptake is highly dependent on sociodemographic factors, and women with the greatest social deprivation scores, those with type 2 diabetes mellitus, and those from ethnic minority groups are less likely to access these services. As half of all pregnancies are unplanned, counselling women about pregnancy should form part of the ongoing care pathway for all women of childbearing age with diabetes. When any potentially teratogenic medication is prescribed as part of a woman’s routine diabetes care (such as an angiotensin converting enzyme (ACE)-​ inhibitor or a statin (HMG-​CoA reductase inhibitor)) women need to be counselled on the need to stop this prior to or as soon as pregnancy is confirmed in an unplanned pregnancy. In addition, advice should be given on the need to take high dose folic acid (5 mg daily) three months prior to pregnancy and continued for the first 12 weeks in pregnancy to reduce the risk of fetal neural tube defects. The key elements of preconception counselling and assessment are shown in Table 14.10.2.

Table 14.10.2  Key elements of preconception counselling Optimizing glycaemic control Medication review Screening and management of diabetes complications Advice regarding diet and weight Information on pregnancy risk to the mother, including particular risks of hypoglycaemia and DKA Increased risk of hypertensive disease in pregnancy Information on pregnancy risk to the baby—​risk of congenital abnormalities, preterm birth, and risk of macrosomia and growth restriction Importance of pregnancy planning and accessing multidisciplinary care in early pregnancy DKA, diabetic ketoacidosis.

Management of diabetes peri-​conceptionally and in pregnancy Optimizing glycaemic control Women need to be supported to achieve optimal glycaemic control peri-​conceptionally and throughout pregnancy to reduce the risk of miscarriage, congenital malformation, stillbirth, and neonatal death. Improved control prior to pregnancy also reduces the risk of deterioration of diabetic retinopathy and nephropathy during the pregnancy. Providing women with structured education around insulin management and dose adjustment of their rapid acting insulin to match their carbohydrate intake improves glycaemic control and lessens the risk of hypoglycaemia. Meta-​analysis of large data sets shows that congenital malformations, preterm delivery and maternal hyperglycaemia in the first trimester of pregnancy are all reduced in women who receive preconception counselling. There is a strong positive association of fasting glucose or glycated haemoglobin in women with type 1 diabetes mellitus and type 2 diabetes mellitus and major fetal anomalies, with multiple organ anomalies associated with the poorest glycaemic control. This association is so strong that 2015 NICE guidance is that women with an HbA1c above 86 mmol/​mol (10%) be strongly advised not to get pregnant. 2015 NICE guidance is to aim for an HbA1c below 48 mmol/​mol (6.5%) if this is achievable without causing problematic hypoglycaemia. Plasma glucose targets are fasting levels of 5–​7 mmol/​l on waking for women with type 1 diabetes mellitus and a plasma glucose level of 4–​7 mmol/​l before meals at other times of the day. To achieve this level of glycaemic control women with type 1 diabetes mellitus will require the use of a multiple dose insulin regime consisting of 4 or 5 insulin injections a day given as 1 or 2 basal insulin injections and 3 bolus rapid acting insulin injections to cover the main meals, or a continuous subcutaneous insulin infusion (CSII) pump. Recent technological advances around insulin pumps, continuous glucose monitoring, and automated bolus insulin calculators that help calculate pre-​meal insulin dosing depending on the amount of carbohydrate eaten, are all available to help women to achieve these targets. In the future, closed-​loop insulin delivery technologies, combining real-​time continuous glucose monitoring with CSII using a computer algorithm, will also be available, and early work in this field holds great promise that lower HbA1c levels will be achievable with less risk of hypoglycaemia. For women with type 2 diabetes mellitus, achieving an HbA1c below 48  mmol/​mol (6.5%) prior to pregnancy is easier, as these women will be at less risk of hypoglycaemia due to their relatively short history of diabetes and less dependency on insulin therapies. However, many such women will need to be started on an insulin prior to a planned pregnancy as all oral agents other than metformin will need to be stopped.

Medication review Some antihypertensive and lipid lowering agents routinely used in the management of diabetes have been associated with an increased risk of congenital malformations when used in the first trimester. These include ACE-​inhibitors, angiotensin II receptor blockers, and the HMG-​CoA reductase inhibitors known collectively as statins. NICE guidance cautions against the use of thiazides and related

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Section 14  Medical disorders in pregnancy

diuretics in pregnancy. Daily 5  mg of folic acid is recommended three months prior to any planned pregnancy.

Screening and management of diabetic complications During preconception counselling women need to be informed of how a pregnancy may affect their own health, including the impact on pre-​existing micro and macrovascular disease. It is important to ensure that a retinal and renal assessment has been performed within the previous year, and to seek information on symptoms of peripheral and autonomic neuropathy, and all cardiovascular risk factors including hypertension and hypercholesterolaemia. Retinopathy Pregnancy can lead to new onset diabetic retinopathy or worsening of pre-​existing disease. Sight-​threatening diabetic retinopathy in pregnancy is rare, but proliferative diabetic retinopathy which accelerates during pregnancy may not regress post-​partum. Screening for retinopathy is therefore recommended prior to pregnancy, during early pregnancy, and again at 28 weeks’ gestation. Any retinopathy detected requires treatment as it may deteriorate during pregnancy, and ongoing follow-​up during pregnancy and postnatally will be required. Diabetic retinopathy is not a contraindication to rapid optimization of blood glucose control in women who present with a high HbA1c, nor is it a contraindication to pregnancy or vaginal birth. Renal function Physiological changes occur in renal function in pregnancy. Glomerular filtration rate, creatinine clearance, and protein excretion all increase. Renal function is usually preserved in women with diabetes who start pregnancy with normal renal function. Women with diabetic nephropathy (serum creatinine >1.5  mg/​dl or proteinuria of more than 3 g protein/​24 hours) have an increased risk of preeclampsia, preterm delivery, fetal growth restriction, perinatal death, and a permanent deterioration in renal function (see Chapter 14.5). Assessment of renal function at the outset of pregnancy is important as optimization of blood glucose as well as blood

pressure before pregnancy may improve maternal and fetal outcomes. Furthermore, knowing baseline renal function (serum creatinine and urinary microalbumin excretion or urinary albumin/​ protein creatinine ratio) is essential for later comparison in case preeclampsia is suspected. Autonomic neuropathy Pre-​existing autonomic neuropathy is an important risk factor for poor glucose control, increased glucose variability and hypoglycaemia. It is also associated with gastroparesis. Although pregnancy does not worsen autonomic neuropathy, it can worsen the symptoms of gastroparesis due to the hormonal and mechanical effects of pregnancy that independently slow intestinal motility. Patients with gastroparesis may develop severe nausea and vomiting, as well as malabsorption, that complicate the timing of insulin administration and contribute to high levels of glucose variability and post-​prandial hypoglycaemia. Women with autonomic neuropathy should have an anaesthetic assessment in the third trimester of pregnancy due to the associated increased anaesthetic risk.

Maternal complications of diabetes in pregnancy Hypoglycaemia Hypoglycaemia in pregnancy is a significant problem, affecting up to 70% of women with pre-​existing diabetes and associated with excess mortality. Undoubtedly the strict glycaemic targets women are expected to achieve before and during pregnancy are an important factor. Awareness of hypoglycaemic symptoms is reduced in pregnancy and women require assessment and education around hypoglycaemia avoidance. This is particularly important for those with initial poor glycaemic control who undergo rapid intensification of their insulin management. Hypoglycaemia is particularly prevalent in the first half of pregnancy, when insulin requirements actually fall, and the first few weeks post-​partum (Fig. 14.10.2). Women who have frequent

16 14 12 Number of events

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10 8 6 4 2

4

6

8

10

12

14

16

18

20

22

24

26

28

30

32

34

36

38

Gestational week

Fig. 14.10.2  Hypoglycaemic episodes during pregnancy in women with type 1 diabetes. Reproduced from Nielsen LR et al. (2008). Hypoglycemia in pregnant women with type I diabetes. Diabetes Care, 31(1), 9–​14. Copyright © 2008, American Diabetes Association.

14.10  Diabetes in pregnancy

hypoglycaemic events may benefit from “smart” diabetes technologies, including insulin pumps with continuous glucose monitoring that allows the glucose monitor to temporarily switch off the insulin pump.

Diabetic ketoacidosis Diabetic ketoacidosis is a rare but serious complication in pregnancy and has an associated fetal mortality of up to 10%. All women with type 1 diabetes mellitus should be provided with blood ketone testing strips and a meter, instructed on their use, and advised to test for ketonaemia if they become hyperglycaemic or unwell, and be aware of the indications to seek urgent medical advice. Diabetic ketoacidosis can occur at near normal blood glucose levels during pregnancy, hence it should be excluded in any pregnant woman with pre-​gestational diabetes and persistent nausea and vomiting. The risk of diabetic ketoacidosis increases in late pregnancy due to increased insulin demands and enhanced lipolysis. The treatment of diabetic ketoacidosis in pregnancy is the same as for non​pregnant patients. Fetal assessment should occur following maternal stabilization, noting that fetal heart rate abnormalities usually correct with maternal treatment.

and neuropathy, both peripheral and autonomic, are all more common in women with type 1 diabetes mellitus. Women with type 2 diabetes mellitus are more likely to have a duration of diabetes of less than 10 years and usually less than 5 years, but this may change in the future due to the increasing prevalence of type 2 diabetes mellitus among younger women. All women with diabetes, particularly those with longstanding type 1diabetes mellitus and older obese women with type 2 diabetes mellitus and gestational diabetes, are at an increased risk of diabetic macrovascular disease, including coronary heart disease. Diabetic macrovascular disease remains uncommon in pregnancy, but when it precedes or occurs for the first time in pregnancy, both maternal and fetal outcomes are poor. As the prevalence of macrovascular complications increases with duration of diabetes mellitus, and the numbers of women choosing to delay childbirth into their thirties and forties increases, the prevalence of macrovascular complications in the pregnant population are likely to increase.

Other maternal complications The potential maternal complications from conception to the post-​ partum period are listed in Table 14.10.3.

Pre-​existing diabetic complications Pre-​existing complications differ in women with type 1 or type 2 diabetes mellitus, or gestational diabetes. Women with type 1 diabetes mellitus are likely to have had diabetes for longer than those with type 2 diabetes mellitus, and established diabetic microvascular disease increases with diabetes duration. Retinopathy, nephropathy,

Risks to the fetus Although maternal glucose crosses the placental barrier, insulin does not and, consequently, increases in maternal glucose stimulate fetal insulin production and result in hyperplasia of fetal insulin

Table 14.10.3  Maternal complications of diabetes from conception to the post-​partum period Time

Issue

Type 1 DM

Type 2 DM

GDM

Conception

Fertility

Subfertility due to poor control Delayed menarche Early menopause Autoimmune ovarian failure Increased prevalence of weight related amenorrhoea (anorexia)

Subfertility if associated with polycystic ovarian syndrome

1st trimester 0–​12 wks

Miscarriage

Increased Poor glycaemic control

Hypoglycaemia

High risk of severe recurrent hypoglycaemia

Increased if due to PCO

Loss of hypoglycaemic awareness 2nd trimester 13–​28 wks

Retinopathy

Worsening retinopathy

Hypoglycaemia

High risk of severe recurrent hypoglycaemia

Autonomic neuropathy

Gastroparesis

Nephropathy

Worsening renal function Increased proteinuria

3rd trimester 29–​40 wks

Preeclampsia Pregnancy-​induced hypertension Operative birth Birth trauma

Failed induction of labour Operative birth including caesarean section Birth trauma

Post-​partum

Post-​partum haemorrhage

Increased risk

Long term, 1–​10 years

Expected improvement of any pregnancy related deterioration in retinopathy and nephropathy

CVD, cardiovascular disease; DM, diabetes mellitus; GDM, gestational diabetes mellitus.

Long-​term risk of coronary vascular disease, and diabetic microvascular complications

Recurrent GDM Future type 2 DM Increased risk of CVD

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Section 14  Medical disorders in pregnancy

sensitive tissues. Maternal hyperglycaemia also enhances production of hPG, fetal IGF, and TNF​α. Like insulin, these act as fetal growth factors and result in accelerated fetal growth, macrosomia, and enlargement of the heart and liver.

Congenital malformations As previously discussed, diabetes mellitus is also associated with an increased risk of congenital malformation which is dependent upon glycaemic control (Fig. 14.10.3). When women with diabetes have a normal HbA1c in early pregnancy, congenital malformation rates approach that of the background population (risk of around 2%), but as HbA1c values increase from two to eight standard deviations above the normal range the malformation risk rises from 3 to 10% respectively. Diabetes mellitus is associated with a wide variety of malformations involving the cardiovascular system (e.g. transposition of the great vessels, ventricular septal defect), the central nervous system (e.g. anencephaly, spina bifida, hydrocephaly and holoprosencephaly), the genitourinary system, and the skeleton. The exact mechanism of the embryopathy remains uncertain, but there is evidence for contributions from increased oxidative stress due to elevated superoxide dismutase activity, reduced levels of myoinositol and arachidonic acid, and inhibition of the pentose phosphate shunt pathway.

Fetal macrosomia Maternal weight gain, even without diabetes, predisposes to fetal macrosomia, hence obese pregnant women are advised to avoid unnecessary weight gain during pregnancy. The causes of macrosomia are not fully understood. The Freinkel hypothesis attributes excessive fetal insulin to increased transport of maternal fuel to the conceptus as the predominant cause of fetal macrosomia. However, fetal growth is complex and influenced by maternal, paternal, and fetal genes and factors, uterine environment, and maternal and fetal hormonal status. Infants of diabetic mothers have an additional influence of maternal fluctuations in glycaemia, as a hyperinsulinized fetus can cause a glucose steal phenomenon in late pregnancy, reducing maternal insulin requirements and precipitating maternal hypoglycaemia. Macrosomia is associated with risks for birth for both the fetus and the mother. It is a risk factor for shoulder dystocia which can be difficult to predict but may occur more commonly in fetuses of 30 Congenital malformation (%)

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25 20 15 10 5 0

Women without diabetes

6.1–7.7

7.8–10.0

>10.0

HbA1c (%)

Fig. 14.10.3  Risk of congenital malformation dependent upon glycaemic control. Reproduced from BMJ, Taylor and Davison, 334: 742–​745, copyright © 2007, with permission from BMJ Publishing Group Ltd.

diabetic mothers with an estimated weight of more than 4 kg, and up to 50% in fetuses weighing 4.5 kg or more. Operative delivery and caesarean section are increased in both preexisting and gestational diabetes, independent of the effect of birth weight, potentially related to placental dysfunction leading to fetal distress in labour.

Intrauterine growth restriction Pre-​existing diabetes is also associated with intrauterine growth restriction (IUGR), which is diagnosed when ultrasound-​estimated fetal weight is below the 10th percentile for gestational age, implying a possible pathological process causing the low fetal weight. IUGR in pregnancy complicated by pre-​existing diabetes is usually caused by placental dysfunction related to maternal vasculopathy. Prevention of IUGR should ideally start before pregnancy. Strict glycaemic control and intensive treatment of nephropathy and hypertension are essential. Low-​dose aspirin initiated before 16 gestational weeks may also reduce IUGR risk in women with vasculopathy. Umbilical and other fetal Doppler studies can guide diagnosis and surveillance of fetuses with IUGR as these may reflect placental resistance and function.

Pre-​eclampsia There is an increased risk of pre-​eclampsia in women with pre-​ existing diabetes, especially in those with diabetic nephropathy. Preterm delivery may be required, balancing the risks of delivery and neonatal short term and long-​ term effects of prematurity. Delivery management and the timing of delivery is made according to maternal well-​being, the degree of glycaemic control, the presence of diabetic complications, growth of the fetus, evidence of uteroplacental insufficiency, and the results of fetal surveillance. Perinatal mortality remains high among infants of mothers with type 1 and type 2 diabetes mellitus. Although high glucose levels have been implicated, the exact mechanism remains unclear.

Neonatal and longer-​term effects The impact of maternal hyperglycaemia persists into the neonatal period with an increased risk of neonatal hypoglycaemia, respiratory distress, polycythaemia, hypocalcaemia, and hyperbilirubinaemia. The severity of these fetal metabolic problems correlates with levels of C-​peptide, insulin, and erthyropoietin in amniotic fluid and fetal cord blood, but these are not measured routinely. There is also a growing body of evidence suggesting a longer-​term effect of poor glycaemic control on neonatal outcome. Fetal pancreatic islet cells subjected to hyperglycaemia in utero appear to contribute to an increased susceptibility to metabolic disease later in life, such as obesity, type 2 diabetes mellitus, and the metabolic syndrome. The risks of developing type 2 diabetes mellitus are complex and poorly understood, but infants with both decreased and increased birth weight are at increased risk of developing type 2 diabetes mellitus when compared to those born with a normal birth weight.

Management of diabetes in pregnancy Pre-​existing diabetes Once pregnancy is confirmed, women with pre-​existing diabetes should be encouraged to book early in the pregnancy with an early dating scan at 11–13 weeks. Multidisciplinary, consultant-​ led,

14.10  Diabetes in pregnancy

hospital-​based care is usually the most appropriate level of care, with the multidisciplinary team (MDT) comprising of endocrinologists, diabetes nurses, dieticians, specialist midwives, and obstetricians. In addition to routine antenatal care and screening tests, regular surveillance (usually every two weeks) is suggested to assess blood glucose levels, screen for fetal anomaly, and assess fetal growth (Table 14.10.4). All women should have contact details and telephone access between clinic visits with a member of the MDT team. The optimal blood glucose targets remain the same throughout pregnancy and are similar regardless of the type of diabetes, namely a fasting capillary glucose of 5.3 mmol/​litre, a one hour after meal value below 7.8 mmol/​litre, or a two-​hours after meal value below 6.4 mmol/​litre. However, these targets may need to be individualized and increased for women at risk of hypoglycaemia. Women with type 1, type 2, or gestational diabetes on multiple dose insulin regimen or pump therapy are advised to perform home glucose monitoring fasting, one hour pre-​meals, one to two hours post-​meal, and before bed. Women with gestational diabetes managed with diet and exercise alone, or oral therapy, only need to test fasting and one to two hours post-​meals.

Gestational diabetes Women with gestational diabetes should be taught home glucose monitoring to ensure that their glycaemic targets are met throughout the duration of pregnancy. The aim of treatment is to achieve euglycaemia (while avoiding hypoglycaemia), as this has been shown to benefit both maternal and fetal outcomes. The primary intervention for women diagnosed with gestational diabetes but with a fasting blood glucose below 6 mmol/​l is dietary counselling in combination with physical activity and self-​ monitoring of blood glucose. In women who have a fasting blood

glucose on OGTT above 7.0 mmol/​l, diet and exercise alone would not be expected to lower this value to 5.3 mmol/​litre within an acceptable time period, and therefore the prompt initiation of insulin therapy, with or without metformin, is advised. For women with a fasting blood glucose on OGTT between 6.0 to 7.0 mmol/​l, immediate treatment with insulin therapy, with or without metformin, should be considered if there is clinical evidence of macrosomia or polyhydramnios. Dietary advice All patients with gestational diabetes should be referred to specialist dieticians, the key elements of dietary advice being to substitute complex for simple carbohydrates and increase dietary fibre. The need for pharmacological therapy for gestational diabetes depends entirely on the severity of the glucose intolerance, in addition to fetal growth as assessed on prenatal ultrasound. Diet alone will maintain the fasting and postprandial blood glucose values within the target range in approximately half of women with gestational diabetes. Exercise The role of exercise in gestational diabetes may be even more important than in women with pre-​existing diabetes, given that exercise in some women may lessen the need for medical therapy. Moderate exercise in women with gestational diabetes is well tolerated and has been shown to lower maternal glucose levels. Using exercise after a meal in the form of a brisk walk may blunt the postprandial glucose excursions sufficiently to avoid the need of medical therapy. Establishing a regular routine of modest exercise during pregnancy may also have long-​lasting benefits for women with gestational diabetes due to their appreciable risk of developing type 2 diabetes in the future. Pharmacological treatments

Table 14.10.4  Management plan for diabetes in pregnancy Early pregnancy 8–​9 weeks

Booking visit Dating scan at 11–13 weeks HbA1C, renal profile, assessment of proteinuria Baseline BP Referral for retinopathy screen

12 weeks

Diabetes review First trimester ultrasound scan

14–​16 weeks

Routine antenatal care

18–​20 weeks

Anomaly scan including fetal echocardiography

22 weeks

Diabetes review

24 weeks

Ultrasound fetal growth

26 weeks 28 weeks

Ultrasound fetal growth

30 weeks 32 weeks

Ultrasound fetal growth

34 weeks 36 weeks

Ultrasound fetal growth

37 weeks 38 weeks

Aim for delivery of women with pre-​existing diabetes Consider delivery of women with complex gestational diabetes

40 weeks

Offer induction of labour in women with gestational diabetes

If diet and exercise are insufficient, oral hypoglycaemic agents and/​ or insulin will be required. Insulin does not cross the placenta, but is more difficult to administer, and the risk of hypoglycaemia and weight gain is greater than with oral hypoglycaemic agents. Oral hypoglycaemics, particularly metformin and glibenclamide, have been demonstrated to be safe and efficacious in pregnancy. The advantages of metformin include ease of use, low risk of hypoglycaemia, and limitation of maternal weight gain and weight retention post-​partum. Although there is a theoretical concern that metformin crosses the placenta, recent evidence has demonstrated acceptable short-​term outcomes, with longer term outcomes yet to be clearly defined. Use of metformin was recommended by NICE in 2015, but it does not currently have a UK licence for use in diabetes in pregnancy. Glibenclamide is the only sulfonylurea that has been studied in a large randomized control trial performed in women with gestational diabetes. Maternal glycaemic control, macrosomia, neonatal hypoglycaemia, and neonatal outcomes were not different between women managed with glibenclamide or insulin. There is either very limited or no safety or outcome data on women with gestational diabetes being treated with other oral agents, including pioglitazone, metglitinides, acarbose, and incretins. If blood glucose control remains above target following treatment with the oral agents, then a recombinant human insulin should be considered. It is common to add a short and medium duration acting insulin to achieve better 24-​hour control while continuing the

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Section 14  Medical disorders in pregnancy

metformin therapy. Glibenclamide is usually discontinued once insulin is required. There is evidence suggesting an association between vitamin D deficiency/​insufficiency and gestational diabetes, although the molecular or cellular mechanisms for this association is unclear. It is currently not known whether vitamin D supplementation can reduce the risk of developing gestational diabetes and/​or improve glycaemic control in diabetic pregnant women with vitamin D deficiency/​insufficiency.

Obstetric matters Timing, mode, and place of birth Women with diabetes should give birth in hospitals where 24 hours-​ a-​day advanced neonatal resuscitation skills are available. Women with type 1 or type 2 diabetes mellitus and no other complications should be advised that birth between 37 + 0 weeks and 38 + 6 weeks of pregnancy lessens their heightened risk of stillbirth. Induction of labour or an elective caesarean section before 38 + 6 weeks of pregnancy is recommended if spontaneous labour has not occurred before then. Birth before 37 + 0 weeks may be advisable if there are metabolic or maternal or fetal indications. Antenatal steroids for fetal lung maturation can be used if a preterm delivery is anticipated, but close glycaemic monitoring is required alongside careful insulin titration.

Management of diabetes in labour During labour and delivery, most women with pre-​existing diabetes should be managed with a sliding scale of intravenous insulin and dextrose infusion to maintain capillary plasma glucose between 4 and 7  mmol/​litre to lessen the risk of neonatal hypoglycaemia. Hourly capillary plasma glucose should be performed. Women with gestational diabetes using diet, oral hypoglycaemic agents, or small doses of insulin can cease the medications in labour, with continued regular assessment of maternal capillary glucose. Women with gestational diabetes requiring large doses of insulin may require an insulin sliding scale in labour.

Post-​partum care The effect of pregnancy on maternal glycaemic control ceases very quickly post-​partum, hence women with pre-​existing diabetes taking insulin should immediately revert to their pre-​pregnancy regimen after birth, but with a lower insulin dose. It is important for women and healthcare staff to be prepared for the potential increased risk of hypoglycaemia in the immediate post-​partum period. Breastfeeding, lack of sleep, and the need for maternal adjustment to not requiring ‘tight glycaemic’ control as during the pregnancy, all contribute to this increased risk, which can be reduced if post-​partum women take 25–​30% less than their pre-​pregnancy insulin dose. Women taking insulin who breastfeed should test their blood glucose before and after breastfeeding and be encouraged to have a snack before and have one available when feeding. Due to the heightened risk of hypoglycaemia when breastfeeding, women need

to be warned of the potential dangers to the newborn when breastfeeding in bed. Healthcare staff and patients should be trained to monitor for both neonatal and maternal hypoglycaemia. Women with type 2 diabetes mellitus on metformin prior to and during pregnancy can safely continue this post-​partum and during breastfeeding. The concentration of metformin in breast milk is low, and infant exposure to metformin has been reported to range between 0.3 to 1.1% of the weight-​normalized maternal dose. Breastfeeding appears to confer an advantage to all women, reducing incidence of developing type 2 diabetes mellitus in those with and those without gestational diabetes. Breastfeeding has also been linked to a decreased risk of the infant developing obesity and impaired glucose tolerance in later life. Women with gestational diabetes can usually cease all diabetes medication post-​partum, with most reverting to normal glucose levels soon after birth, although 5–​10% will fulfil the criteria for type 2 diabetes. Although screening women with prior gestational diabetes for subsequent type 2 is accepted, there is a lack of consensus as to how and when this should be done. The ADA recommends using a 75 gm OGTT to screen for persistent diabetes 6–​12 weeks’ post-​partum, and lifelong screening for development of diabetes or pre-​diabetes at least every three years. In the United Kingdom, the 2015 NICE guidelines recommend a laboratory glucose prior to discharge, and a fasting glucose 6–​13 weeks post-​partum or a HbA1C after 13 weeks, with an annual fasting plasma glucose or HbA1C thereafter. All women with prior gestational diabetes remain at risk of diabetes in the future, with up to half developing type 2 diabetes mellitus within 10 years. A programme of diet and exercise can improve this risk, hence dietary and lifestyle modifications, including regular exercise, should be advocated in the long term. Post-​partum care should include advise on family planning and the need for contraception that allows women time to optimize their health prior to any future pregnancy.

Areas of uncertainty, controversy, and future developments The maternal and neonatal obstetric outcomes in women with pre-​ existing diabetes have the potential to improve with continuing advances in diabetes management, fetal surveillance, and neonatal care. However, a significant improvement in pregnancy outcomes will require more women with pre-​existing diabetes to plan their pregnancy and participate in preconception counselling to optimize their glycaemic control and identify and manage proactively any diabetic complications prior to pregnancy. Preconception counselling improves both maternal and fetal short-​and long-​term outcomes. It will become increasingly important to identify women with gestational diabetes, not only to minimize the impact of gestational diabetes on the pregnancy, but also for the future health of the child. Women with gestational diabetes represent the future population of parous women with diabetes, mostly type 2. This potential provides an opportunity for targeted prevention strategies to curb the current rise in obesity and type 2 diabetes. The association

14.10  Diabetes in pregnancy

of obesity and glucose intolerance in the offspring of women with pre-​ existing diabetes mellitus or gestational diabetes provides an opportunity for intergenerational risk prevention for future obesity and diabetes.

FURTHER READING Bellamy L, et al. (2009). Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-​analysis. Lancet, 373, 1773–​9. Confidential Enquiry into Maternal and Child Health (2005). Pregnancy in women with type 1 and type 2 diabetes in 2002–​03, England, Wales and Northern Ireland. London, CEMACH. Crowther CA, et al. (2005). Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med, 352, 2477–​86. Garcia-​Patterson A, et  al. (2010). Insulin requirements throughout pregnancy in women with type 1 diabetes mellitus: three changes of direction. Diabetologia, 53, 446–​51. Guerin A, Nisenbaum R, Ray JG (2007). Use of maternal GHb concentration to estimate the risk of congenital anomalies in the offspring of women with prepregnancy diabetes. Diabetes Care, 30, 1920–​5. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study Group (2008). Hyperglycemia and adverse pregnancy outcomes. N Engl J Med, 358, 1991–​2002. International association of diabetes and pregnancy study groups (2010). International association of diabetes and pregnancy study

groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care, 33, 676–​82. Macintosh MC, et  al. (2006). Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland:  population-​based study. BMJ, 333, 177. National Institute for Health and Care Excellence (NICE) (2015). Diabetes in Pregnancy:  Management from Preconception to the Postnatal Period. https://​www.nice.org.uk/​guidance/​ng3 Rowan JA, et al. (2008). Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med, 358, 2003–​15. Secher AL, et  al. (2013). The effect of real-​time continuous glucose monitoring in pregnant women with diabetes: a randomized controlled trial. Diabetes Care, 36, 1877–​83. Stewart ZA, et al. (2016). Closed-​loop insulin delivery during pregnancy in women with type 1 diabetes. N Engl J Med, 375, 644–​54. Tennant PW, et  al. (2014). Pre-​existing diabetes, maternal glycated haemoglobin, and the risks of fetal and infant death: a population-​ based study. Diabetologia, 57, 285–​94. Tripathi, A., et al. (2010). Preconception counseling in women with diabetes: a population-​based study in the north of England. Diabetes Care, 33, 586–​8. Zhao P, et  al. (2016). Maternal gestational diabetes and childhood obesity at age 9–​11: results of a multinational study. Diabetologia, 59, 2339–​48.

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14.11

Endocrine disease in pregnancy David Carty

ESSENTIALS Thyroid Many pregnant women will develop goitre. Gestational thyrotoxicosis needs to be differentiated from Graves’ disease, which requires treatment with propylthiouracil in early pregnancy and carbimazole in later pregnancy. Overt hypothyroidism is associated with adverse maternal and fetal outcomes and should be treated to maintain thyroid-​ stimulating hormone within the trimester-​ specific reference range.

Adrenal The diagnosis of both Addison’s disease and Cushing’s syndrome can be challenging in pregnancy. Patients with adrenal insufficiency may require higher replacement steroid doses, particularly in the third trimester.

Pituitary Prolactinomas are commonly encountered in pregnancy. Women with macroprolactinomas should have visual field monitoring throughout pregnancy. Lymphocytic hypophysitis is increasingly recognized as a cause of hypopituitarism arising in late pregnancy and in the post-​partum period.

Thyroid disease Thyroid physiology in pregnancy Pregnancy has a significant impact on thyroid physiology. The fetal thyroid does not secrete active thyroid hormone until 18–​20 weeks of gestation, hence maternal thyroid hormone production must increase by up to 50% in order to provide enough thyroid hormone for the developing fetus. As a result, many pregnant women, particularly in iodine deficient areas, will develop goitre. Interpretation of thyroid tests is also affected by pregnancy. Thyroid-​stimulating hormone (TSH) closely resembles β-​HCG at a molecular level, and due to cross-​reactivity in pregnancy normal TSH ranges are lower. Trimester-​specific reference ranges for use in pregnancy have been developed in many laboratories: these should

be used wherever possible, since TSH ranges will depend upon the population and ethnicity of the women studied.

Gestational thyrotoxicosis In early pregnancy, particularly in those with excessive vomiting or with twin pregnancies, excessively high β-​HCG levels can lead to apparent thyrotoxicosis. Most women with gestational thyrotoxicosis can be managed conservatively with fluids and antiemetics, although it is important to differentiate from Graves’ disease presenting in pregnancy: several clinical features can help to discriminate (Table 14.11.1).

Treatment of Graves’ disease in pregnancy Graves’ disease affects around 0.2% of pregnancies. Carbimazole (methimazole) is the most commonly used drug for thyrotoxicosis. Case reports (although not larger studies) have associated this drug with rare congenital malformations including aplasia cutis and oesophageal atresia, and so propylthiouracil has traditionally been recommended for use pre-​pregnancy. Propylthiouracil, however, has been associated with hepatotoxicity in late pregnancy, so a balance between the small risks associated with these two medications is required. Treatment, which can usually be down-​titrated, should be continued throughout pregnancy and into the early post-​ partum period to reduce the risk of early recurrence post-​partum (see Box 14.11.1). Block and replace regimes should be avoided in pregnancy. If antithyroid medications are ineffective or not tolerated, then surgical treatment should be considered; the use of radioactive iodine is contra-​indicated in pregnancy and while breastfeeding.

Table 14.11.1  Differentiation of Graves’ disease from gestational thyrotoxicosis Graves’ disease

Gestational thyrotoxicosis

Goitre

√

X

Thyroid receptor antibodies

√

X

Symptoms prior to pregnancy

√

X

Eye signs

√

X

14.11  Endocrine disease in pregnancy

Box 14.11.1  Management of Graves’ disease in pregnancy • Confirm diagnosis • Treat with propylthiouracil if diagnosed prior to planned pregnancy or in first trimester • Consider switch to carbimazole in second trimester — Aim to continue treatment until delivery • Monitor thyroid function tests 4–​6 weekly — Titrate dose where necessary • Check thyroid receptor antibodies (TRAB) in third trimester — Inform neonatologist if positive (risk of fetal thyrotoxicosis) • Review post-​partum — Check for recurrence

up to 15%. Although associated with adverse fetal and maternal outcomes in some studies, evidence that thyroxine treatment leads to an improvement in these outcomes is limited and conflicting. Recent guidelines from US and European Societies advocate treatment with thyroxine of women found to have subclinical hypothyroidism, although definitions differ between guidelines.

Fetal and neonatal thyroid dysfunction

Women are at risk of recurrence of Graves’ disease in the post-​ partum period, and thyroid function tests should be monitored regularly after delivery. Loss of ability to breast-​feed can be an early sign of recurrence. Both carbimazole and propylthiouracil are detectable in breast milk, although there is no evidence of harm to the baby: in general, if further pregnancy is desired then propylthiouracil is preferable.

In women with uncontrolled thyrotoxicosis or high thyroid receptor antibody (TRAB) titres, additional fetal ultrasound monitoring of fetal heart rate, growth, amniotic fluid volume, and assessment for fetal goitre should be undertaken. The diagnosis of fetal thyrotoxicosis can be confirmed if necessary by fetal blood sampling. Treatment is by maternal administration of high-​dose propylthiouracil (300–​450 mg/​day) together with thyroxine during gestation to prevent maternal hypothyroidism. Involvement of fetal medicine specialists is required. Neonatal hypothyroidism may very rarely occur at birth due to maternal TSH receptor blocking antibodies, maternal antithyroid drug administration, iodine deficiency, and maternal goitrogen ingestion. All these conditions are transient, and the mother can be reassured.

Hypothyroidism in pregnancy

Post-​partum thyroid dysfunction

Overt hypothyroidism is associated with several adverse maternal and fetal outcomes, including pre-​eclampsia, intrauterine growth restriction, preterm delivery, and reduced intelligence quotient (IQ) in the offspring. Treatment of overt hypothyroidism leads to an improvement in these outcomes and for this reason many clinicians advocate the universal screening of thyroid function in pregnant women. The aim in pregnancy is to maintain TSH within the trimester-​specific reference range. Some women with hypothyroidism will require an increase in daily dose of thyroxine of 25–​50 mcg to attain this: those with no thyroid gland because of previous radio iodine or surgical treatment are more likely to need a dose increase than those with autoimmune hypothyroidism. T3 does not cross the placenta, and its use should be avoided in pregnancy. Subclinical hypothyroidism describes TSH above the trimester-​ specific reference range, but with a normal fT4. Depending on the population studied, rates of this condition are reported to be

Up to 15% of women in the general population have positive thyroid peroxidase antibodies; of these 50% will develop a degree of post-​ partum thyroid dysfunction. The condition is thought to be caused by autoimmune-​associated release of preformed hormone from the thyroid. In general, the disease is characterized by transient thyrotoxicosis, followed by hypothyroidism, and then a return to normal (Fig. 14.11.1) The thyrotoxic phase is usually asymptomatic; in contrast the hypothyroid phase will often be associated with symptoms and require thyroxine treatment. There is a high risk of recurrence in future pregnancies, and up to 65% of women will develop permanent hypothyroidism during long-​term follow-​up. TSH should be measured annually in affected women.

Thyroid nodules in pregnancy Thyroid nodules occur in up to 10% of pregnant women, and in general these should be dealt with in a similar manner to outwith

fT4 and T3 levels

Reference range

TSH levels

Thyrotoxic phase 2–6 months

Hypothyroid phase 3–12 months

Recovery

Fig. 14.11.1  Pattern of thyroid dysfunction in post-​partum thyroid dysfunction.

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Section 14  Medical disorders in pregnancy

Thyroid nodule detected in pregnancy

History and examination TFTs Ultrasound reveals nodule >1cm

Benign ultrasound appearances

Ultrasound suspicious for malignancy

Compressive symptoms

Defer further investigation until after pregnancy

Consider FNA

Refer for surgery

Fig. 14.11.2  Investigation algorithm for thyroid nodules.

pregnancy. A  suggested algorithm for investigation is shown in Fig. 14.11.2. Surgery, if required, should be undertaken in the second trimester. Investigation of nodules identified in late pregnancy can be deferred until the post-​partum period.

Parathyroid disease Diseases of the parathyroid glands are uncommon in women of childbearing age, but hyperparathyroidism during pregnancy can lead to acute pancreatitis or severe hypercalcaemia. There is an increased incidence of prematurity and neonatal hypocalcaemia and tetany if maternal calcium levels are high. The high maternal calcium levels suppress fetal parathyroid hormone causing the neonatal calcium to fall following cord clamping at delivery. Surgical management can be undertaken safely in pregnancy and ideally in the second trimester. Hypoparathyroidism is treated with vitamin D analogues, with dosage often needing to be increased during pregnancy to maintain normocalcaemia, hence calcium levels should be monitored regularly throughout pregnancy, at least once in each trimester.

Adrenal disease Addison’s disease Addison’s disease can rarely present in pregnancy. Diagnosis can be difficult, but should be considered in women with unexplained hypotension, hyponatraemia/​hyperkalaemia, or pigmentation. In women already known to have the condition, many will require an increase in steroid dose particularly in the third trimester, if hyperemesis develops, or during any intercurrent infection. Higher doses of intravenous hydrocortisone are required for labour or operative delivery, and anaesthetists should be informed of the patient’s condition.

Cushing’s syndrome Cushing’s syndrome is associated with several adverse pregnancy outcomes, including diabetes, pre-​eclampsia, and wound healing problems. The presentation of Cushing’s syndrome in pregnancy

is similar to outwith pregnancy, but diagnosis can be challenging: elevated cortisol levels are seen in the second and third trimesters in normal pregnancy, dexamethasone suppression testing is less reliable in pregnancy, and reference ranges for urinary free cortisol in pregnancy have not been established. Unlike the general population, where adrenocorticotropic hormone-​dependent Cushing’s is more common, the proportion of Cushing’s syndrome due to adrenal lesions is higher in pregnancy than in the non​pregnant population. Since ongoing cortisol excess is associated with significant maternal and fetal morbidity, a surgical cure should be pursued.

Adrenal tumours Adrenal tumours in pregnancy are rare, but as with other tumours there is a risk of enlargement in pregnancy. Phaeochromocytoma can be mistaken for pre-​eclampsia, and should be considered in women with episodic hypertension, associated symptoms of headache or palpitations, or a family history. Diagnosis involves measurement of 24-​hour urinary or plasma metanephrines. In general, the lesion should be removed laparoscopically if identified in the first or second trimester; if the lesion is identified in the third trimester then adrenalectomy is usually deferred until a few weeks later. Women should be adequately α-​blocked (and then, if ­necessary, β-​blocked) prior to surgery and/​or delivery.

Congenital adrenal hyperplasia Congenital adrenal hyperplasia is a group of autosomal recessive conditions characterized by impaired cortisol synthesis. 21-​Hydroxylase deficiency is the most common cause, present in over 95% of cases. Fertility in women with the more severe variant (classical) congenital adrenal hyperplasia is reduced, owing to androgen excess, oligoanovulation, and chronically elevated levels of adrenal-​derived progesterone. Although androgen levels are often elevated in pregnancy, placental aromatase production prevents virilization of unaffected female fetuses. Fertility is less likely to be affected in women with the less severe (non​classical) form of the disease. Management of congenital adrenal hyperplasia in pregnancy involves adequate steroid replacement and adrenal androgen suppression. In women with classical congenital adrenal hyperplasia, hydrocortisone should be used in pregnancy; dexamethasone, which can cross the placenta, should be avoided. Genetic counselling may be considered for an index case desiring pregnancy, or in families with a previously affected infant.

Pituitary Prolactinomas Prolactinomas are the most common type of functioning pituitary lesion and since they have a peak incidence in women during childbearing years they are commonly encountered in pregnancy. Monitoring of prolactin levels in pregnancy is unhelpful: the normal pituitary expands by 30% in pregnancy, largely due to lactotroph expansion, and so normal pregnancy is associated with a 10-​fold increase in prolactin levels. Medical therapy with dopamine agonists is the treatment of choice for prolactinoma:  these reduce tumour bulk and

14.11  Endocrine disease in pregnancy

normalize prolactin levels in most patients. Women with lesions that are resistant to dopamine agonists or who are intolerant should be counselled regarding the benefits of surgery prior to pregnancy. Women with microprolactinomas should, in general, stop dopamine agonists when they find out they are pregnant, since the risk of enlargement causing visual field impairment is less than 1%. In women with macroprolactinomas, however, the risk is much higher, and such women may require to stay on their dopamine agonist therapy. After careful counselling they may wish to discontinue treatment in the last month of pregnancy to facilitate breast-feeding. Women with macroprolactinomas should have visual field monitoring throughout pregnancy, particularly if dopamine agonists are discontinued or if they develop symptoms. Symptoms indicative of expansion include headache, visual field deterioration, and cranial nerve palsies. If a lesion enlarges in pregnancy, then restarting or increasing dose of dopamine agonist therapy should be considered; there are now extensive safety data available for both cabergoline and bromocriptine in pregnancy.

Diabetes insipidus Central diabetes insipidus may present during pregnancy. It is seen in women with lymphocytic hypophysitis (see next) and in women with infiltrative disorders such as Langerhans’ cell histiocytosis. Synthetic desmopressin is normally used in the management of diabetes insipidus and can be given orally or intranasally. Use during pregnancy seems to be safe for both mother and baby:  synthetic desmopressin does not affect delivery and has no adverse effects on the neonate. Diabetes insipidus may be seen transiently at the end of otherwise normal pregnancy and in women with acute fatty liver of pregnancy. This is related to production of vasopressinase by the placenta, the breakdown of which is delayed in acute fatty liver.

Lymphocytic hypophysitis

Lymphocytic hypophysitis is increasingly recognized as a cause of hypopituitarism arising in late pregnancy and in the post-​partum period. The underlying aetiology is thought to be autoimmune, and pathology is characterized by dense infiltration of lymphocytes. Women may present with a pituitary mass lesion, headache, or visual field disturbance, and imaging resembles a pituitary adenoma in 80% of patients. Affected women will commonly have parAcromegaly tial hypopituitarism, with adrenocorticotropic hormone and TSH Fertility is reduced in women with acromegaly because of co-​ the most common deficiencies, and relative sparing of luteinizing secretion of prolactin along with growth hormone, and because of hormone (LH) and follicle-​stimulating hormone. Treatment is usudecreased gonadotrophin reserves due to the tumour expansion. In ally with corticosteroids. It has been speculated that many cases of affected women wishing to conceive, growth hormone and prolactin Sheehans’s syndrome, a now rare condition characterized by hypopituitarism associated with post-​partum haemorrhage, may in fact levels should be normalized prior to conception. In general, women with microadenomas should discontinue have been caused by lymphocytic hyophysitis. medical therapy in pregnancy and be assessed at each trimester. Women with macroadenomas should be monitored closely, with FURTHER READING visual field monitoring in each trimester and MRI scan when Casey BM, et al. (2017). Treatment of subclinical hypothyroidism or necessary. hypothyroxinemia in pregnancy. N Engl J Med, 376(9), 815–25. There are limited safety data for the use of somatostatin analogues de Groot L, et al. (2012). Management of thyroid dysfunction during in pregnancy, and if necessary use of dopamine agonists can be conpregnancy and postpartum: an Endocrine Society clinical practice sidered instead. guideline. J Clin Endocrinol Metab, 97, 2543–​65.

Non​functioning pituitary adenomas Although non​functioning pituitary adenomas represent 30% of pituitary adenomas overall, they tend to present in older age and are associated with reduced fertility, hence they are rarely encountered in pregnancy. Non​functioning lesions do not usually increase in size in pregnancy,s but monitoring of visual fields is recommended for women with macroadenomas. If symptomatic enlargement occurs, medical treatment with dopamine agonists or trans-​sphenoidal surgery can be considered.

Frise CJ, Williamson C (2013). Endocrine disease in pregnancy. Clin Med, 13, 176–​81. Lazarus J, et al. (2014). 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J, 3, 76–​94. Lindsay JR, Nieman LK (2006). Adrenal disorders in pregnancy. Endocrinol Metab Clin North Am, 35, 1–​20, v. Stagnaro-​Green A, et al. (2011). Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid, 21, 1081–​125.

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14.12

Neurological conditions in pregnancy Pooja Dassan

ESSENTIALS Pregnancy can influence the clinical course of an underlying neurological problem or precipitate the first presentation of a neurological disease. Epilepsy—​sodium valproate is associated with higher risk of major congenital malformations and impaired neuropsychological development than other antiepileptic drugs: lamotrigine or levetiracetam are preferred. Women taking antiepileptic drugs can breastfeed. Multiple sclerosis—​ relapse rate is reduced in pregnancy but substantially increased for three months post-​partum. Cerebrovascular disease—​stroke syndromes specific to pregnancy include pre-​eclampsia, which can lead to posterior reversible vasoconstriction syndrome. Reversible cerebral vasoconstriction syndrome presents after delivery and has many similarities to posterior reversible vasoconstriction syndrome. Cerebral venous thrombosis accounts for approximately 20% of all strokes occurring in pregnancy and puerperium. There are conflicting opinions as to whether pregnancy or delivery increases the risk of cerebral aneurysm or arteriovenous malformation rupture.

Computed tomography Computed tomography (CT) can be performed in pregnancy. The fetal exposure dose from a head CT scan is less than 0.1 mGy, which is low. The patient should be informed that no association has been proven between radiation exposure of less than 50 mGy and risk of spontaneous miscarriage or developmental malformations. Iodinated contrast should only be given if required in pregnancy:  it does cross the placenta, but no teratogenic effects have been described.

Magnetic resonance imaging This is the modality of choice in pregnancy. Despite theoretical concerns, there is no evidence to suggest that magnetic resonance imaging (MRI) exposure, irrespective of trimester, is associated with fetal harm. Contrast agents such as gadolinium are avoided in pregnancy because of an increased risk of harm; including stillbirth and neonatal death.

Headaches Introduction Neurological conditions in pregnancy are an important cause of mortality and morbidity in the United Kingdom. From 2010 to 2015, there were 50 maternal deaths in the United Kingdom related to diseases of the central nervous system. The commonest causes identified were subarachnoid haemorrhage, intracerebral haemorrhage, and epilepsy. During pregnancy, a range of haemodynamic and biochemical changes occur in the mother, and these can significantly impact and influence the natural history of an underlying neurological problem or precipitate the first presentation of neurological disease in pregnancy. This chapter will cover the management of common neurological diseases during pregnancy.

Headaches are common in women of childbearing age and pregnancy is no exception to this. The commonest headache presentations encountered in pregnancy include, tension headaches, and migraines. However, it is important to always be mindful of any red flag features, suggestive of a more sinister pathology, necessitating urgent evaluation (Box 14.12.1).

Migraine Migraines usually improve during pregnancy and 60–​70% of women report fewer migrainous attacks during pregnancy. In women who are troubled by headaches in pregnancy, non​pharmacological steps

Box 14.12.1  Red flags in headache presentation

Imaging in pregnancy This causes safety concern during pregnancy, but the clinician should put maternal well-​being at the centre of all decision-​making.

• Headaches of sudden onset • Headaches associated with neck stiffness • Patient reports worst headache ever • Headache with abnormal neurological signs

14.12  Neurological conditions in pregnancy

are usually advocated as part of the first line management. This includes advising patients to improve hydration, reduce consumption of caffeinated drinks, avoid sleep deprivation, and adopt regular eating patterns. Approaches to drug treatment should involve using non​opioid ­analgesics, such as paracetamol and non​steroidal anti-​inflammatory drugs, although the latter should be avoided after 30 weeks’ gestation. A prokinetic agent such as domperidone is a helpful adjunct to these abortive medications. Opiates, although safe to use during pregnancy, are usually avoided in migrainous patients as they can exacerbate nausea and, if anything, worsen gastric motility problems. If despite these initial measures the headaches are still troublesome, then a preventative medication is usually prescribed. Both propranolol and amitriptyline are reasonable first line options and should be used at the lowest effective dose.

Epilepsy An important aspect of the consultation with any female patient of childbearing age with epilepsy is preconception counselling (see Box 14.12.2). As approximately 50% of pregnancies are unplanned, clinicians must approach this subject at the earliest opportunity to ensure that the patient’s therapy has been optimized and folic acid 5  mg per day has been initiated for at least three months preconception.

Antiepileptic drugs Lamotrigine Lamotrigine’s teratogenic profile is more favourable than other antiepileptic drugs, in particular when compared with valproate. However, one drawback with lamotrigine use in pregnancy is that the apparent clearance increases steadily through pregnancy Box 14.12.2  Pre-​pregnancy counselling issues • Reassure the patient that most women with epilepsy give birth to a healthy child. • Aim to maintain the mother pre-​pregnancy on a single agent, at the lowest effective dose. Higher risk of malformations with polytherapy and dose-​ related effects are likely to be observed with most antiepileptic drugs (e.g. valproate). • Teratogenicity is defined in the following categories: — Structural malformations and these can be either major or minor; — Impaired neuropsychological development; — Reduced intrauterine growth. • Sodium valproate—The MHRA (Medicines and Healthcare products Regulatory Agency) recently updated their guidance in March 2018 recommending that valproate must no longer be used in any woman of childbearing age, unless she has a pregnancy prevention programme in place. This is designed to make sure patients are fully aware of the risks and the need to avoid becoming pregnant. If valproate is taken during pregnancy, up to 4 in 10 babies are at risk of developmental disorders, and approximately 1 in 10 are at risk of birth defects. • The magnitude of the risk of maternal seizures on the fetus is difficult to quantify. Overall, women with epilepsy who are having generalized seizures during pregnancy should be informed that the fetus may be at risk of harm with multiple or prolonged seizures, but the actual absolute risk—​particularly of a single seizure—​is probably low.

and notably peaks at 32 weeks, when it can be as high as 330% as compared with non​pregnant baseline. This can result in quite a significant fall in lamotrigine levels in the third trimester, with deterioration in seizure control as a consequence. This change in lamotrigine’s pharmacokinetics during pregnancy does revert back to pre-​pregnancy conditions within a few days of delivery. In our practice, we advocate checking serum lamotrigine level either pre-​pregnancy or in very early pregnancy and treating this as the mother’s baseline. Thereafter, the clinician should consider increasing the lamotrigine dose to prevent significant reduction of levels from baseline. Whether such increases should be based on clinical assessment or therapeutic drug monitoring is currently the subject of a multicentre randomized trial. Levetiracetam Levetiracetam is a newer generation antiepileptic mediation with a favourable side effect profile and is widely used to treat seizures. The emerging data suggest that the risk of major congenital malformation for mother’s taking levetiracetam is between 2 to 3%, which is comparable to the background risk. In addition, current evidence suggests that taking levetiracetam during pregnancy does not have a negative impact on the child’s cognitive and language development. Levetiracetam metabolism also increases in pregnancy and in our practice, we advocate checking drug levels once every trimester.

Management of pregnancy and labour Several antiepileptic drugs, including phenytoin and carbamazepine, are hepatic enzyme inducers and thus lead to a reduction in vitamin K-​dependent clotting factors in the fetus. Previously oral vitamin K was prescribed for women taking hepatic enzymeinducing antiepileptic drugs from 36 weeks’ gestation until delivery, to prevent hemorrhagic disease of the newborn. This is no longer necessary as all babies receive intramuscular (IM) vitamin K after birth. Women with epilepsy should be encouraged to deliver in hospital as it is recognized that 3% will have a seizure within 24 hours of delivery. The reasons behind this include fatigue and sleep deprivation, failure to adhere to usual antiepileptic drug regime during labour, and impaired absorption. If a mother is felt to be at particular risk of seizures during this period, then short-​term clobazam (a benzodiazepine derivative) can be used as an effective adjunct to her usual medication.

Breastfeeding All antiepileptic drugs are excreted in varying degrees into breast milk. Despite this, it is the opinion of experts to support breastfeeding in women using antiepileptic drugs, as the benefits of breastfeeding are likely to outweigh any theoretical risks.

Multiple sclerosis Most women with multiple sclerosis (MS) can safely conceive, give birth, and breastfeed without any significant ill-​ effects to the mother or baby. Important aspects to discuss during pre-​pregnancy counselling in women with MS are detailed in Box 14.12.3. Use of disease-​modifying drugs in pregnancy is described in Table 14.12.1.

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Box 14.12.3  Key issues to discuss during pre-​pregnancy counselling in women with multiple sclerosis • Fertility is not affected in multiple sclerosis (MS). • There is no single genetic cause of MS. The risk of MS in the general population is 0.13%. However, when a parent has MS, risk to the child is 2–​2.5%. • Safety of disease-​modifying drugs (DMDs)—​see Table 14.12.1 • Relapse rate is reduced by up to 70% in pregnancy, especially during the third trimester. • This is followed by a substantial increase in risk of relapses in the immediate post-​partum period and for up to three months thereafter. • Vitamin D supplementation (up to 4000 IU/day) can be used safely during pregnancy to reduce the relapse rate. • Mild relapses during pregnancy can be managed conservatively, but significant relapses leading to new disability can be treated with either intravenous methylprednisolone or oral prednisolone. Less than 10% of the maternal dose of methylprednisolone or prednisolone reaches the fetus as a result of metabolism to the inactive form by the placenta. • Mode of delivery should be guided by obstetric reasons and there is no documented adverse effect of regional anaesthesia.

Myasthenia gravis Myasthenia gravis affects skeletal muscles and does not affect the smooth muscles of the myometrium, thus uterine contractions are not impaired. The key to managing myasthenia gravis in pregnancy is the same as with any other autoimmune condition; to optimize control pre-​pregnancy. It is important to remember that several of the drugs used to treat myasthenia gravis (see Table 14.12.2) are safe in pregnancy and it is imperative that women are reassured of this. The issues pertaining to the management of myasthenia in the preconception stage, during pregnancy, and thereafter are covered in Table 14.12.3.

Cerebrovascular disease

of pregnancy-​related ischaemic strokes are cardioembolism, pre-​ eclampsia/​eclampsia and cerebral venous thrombosis. If a stroke is suspected, urgent imaging should be carried out, as in non​pregnant patients (see Fig. 14.12.1). In non​pregnant individuals, intravenous recombinant tissue plasminogen activator (t-​PA) is the recommended treatment for an acute ischaemic stroke presenting within 4.5 hours of onset. There is very little evidence relating to the use of this treatment in pregnant women but, overall, the evidence suggests that treatment with t-​PA should be considered in all pregnant patients with disabling strokes.

Stroke syndromes specific to pregnancy Pre-​eclampsia This is a multisystem disorder, primarily thought to be a disorder of placental implantation and presents with a constellation of symptoms including pregnancy-​induced hypertension and proteinuria. In approximately one-​third of cases of stroke diagnosed in pregnancy or the puerperium, pre-​eclampsia/​eclampsia is also concomitantly diagnosed. Haemorrhagic strokes occur most commonly. The pathophysiology underpinning this is complex but appears to be related to impaired endothelial function. In addition, pre-​eclampsia can lead to posterior reversible vasoconstriction syndrome, which is radiologically characterized with bilateral, symmetrical subcortical changes, often seen predominantly in the occipital and parietal areas (see Fig. 14.12.2). The imaging characteristics of this condition are of vasogenic oedema, although in a few patients areas of cytotoxic oedema have been identified, suggestive of irreversible ischaemic damage. It classically presents with a severe, often thunderclap, headache. Other clinical features include seizures, cortical blindness, fixed neurological deficits, and alteration in level of consciousness with eventual stupor. Urgent identification of these patients is paramount. Management entails adequate control of seizures (primarily with IV magnesium sulphate in patients with eclampsia), control of blood pressure and, on occasions, urgent delivery of the fetus is required. Reversible cerebral vasoconstriction syndrome

Ischaemic strokes The estimated incidence of stroke in pregnancy is 4–​7 cases per 100 000. The three common aetiologies accounting for most cases

This condition, like posterior reversible vasoconstriction syndrome, is recognized as a self-​limiting condition, occurring within the first week after delivery, often following an uncomplicated pregnancy and delivery. This condition characteristically presents with

Table 14.12.1  Use in pregnancy of disease-​modifying drugs for multiple sclerosis (MS) Disease-​modifying drugs (DMDs)

FDA pregnancy category

Advice in pregnancy

β-​interferon

C—​animal studies have shown adverse fetal effects; there are no adequate studies in humans; benefits of treatment may outweigh risks

• Large molecule, does not cross placenta • Emerging data suggest, it is safe to continue until at least

B—​animal studies have not shown adverse fetal effects; there are no adequate studies in pregnant women

• Large molecule, does not cross placenta • Emerging data suggest, it is safe to continue until at least

C—​animal studies have shown adverse fetal effects; there are no adequate studies in humans; benefits of treatment may outweigh risks

• Large molecule which crosses placenta via active transport

Glatiramer acetate

Natalizumab

conception and that the benefits of breastfeeding outweigh any associated risks.

conception and that the benefits of breastfeeding outweigh any associated risks. after first trimester

• During pre-conception counseling, the MS team should

discuss the pros and cons of stopping vs continuing on this treatment during pregnancy. Evidence shows that women who stop Nataizumab can experience a rebound of their MS (severe relapse) during pregnancy.

14.12  Neurological conditions in pregnancy

Table 14.12.2  Use in pregnancy and when breast feeding of drugs for myasthenia Drug

Pregnancy

Breastfeeding

Pyridostigmine

• Very little crosses the placenta, no reports of fetal harm

•​ 7.5 mg/​day, the consensus is to give a stress dose of hydrocortisone 100 mg TDS intravenously in labour • Care with anaesthetic agents which can precipitate myasthenia gravis Baby

• Transient neonatal myasthenia gravis is a well-​

• • •

•

recognized consequence of maternal myasthenia gravis and is independent of the severity of maternal myasthenia gravis Presents within the first week of life Occurs due to transplacental transfer of anticholinesterase receptor (AChR) antibodies Presents with hypotonia, poor sucking, or even respiratory muscle weakness. Treatment is usually supportive, but some may need pyridostigmine or even intravenous immunoglobulin Its presentation does not correlate with the onset of myasthenia gravis later in life

Fig. 14.12.2  Magnetic resonance imaging (MRI) of the brain showing symmetrical bilateral hyperintense lesions in the posterior cerebral hemispheres, typically seen in posterior reversible vasoconstriction syndrome.

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(a)

(b)

Fig. 14.12.3  MRI brain and magnetic resonance angiogram (MRA) showing changes compatible with reversible cerebral vasoconstriction syndrome. Top row (left to right) shows MRI brain scan (coronal section) with hyperintensity in the sulci of the frontal lobes compatible with subarachnoid haemorrhage (solid arrow) and MRA reveals multifocal beading of the cerebral arteries (dashed arrows). The bottom row shows resolution of both these changes.

Cerebral venous thrombosis Cerebral venous thrombosis accounts for approximately 20% of all strokes occurring in pregnancy and puerperium. It commonly presents with headaches (can be thunderclap), focal neurological deficit, low Glasgow Coma Scale, and seizures. Cerebral venous thrombosis can be diagnosed with an unenhanced CT (see Fig. 14.12.4), but MRI with magnetic resonance venography is the modality of choice during pregnancy as it can provide a detailed view of the cerebral venous system without any X-​ray exposure and does not require administration of contrast. The treatment of cerebral venous thrombosis involves anticoagulation, even if there is evidence of haemorrhage on the scan. Anticoagulation should be continued for a minimum of six months. Vascular malformations There are conflicting opinions as to whether pregnancy or delivery increases the risk of cerebral aneurysm or arteriovenous malformation rupture. This is primarily due to paucity of evidence. Cerebral aneurysm In patients diagnosed with a ruptured aneurysm during pregnancy, acute treatment should be offered during pregnancy as this

Fig. 14.12.4  (a) Unenhanced CT head scan showing a hyperdensity in the superior sagittal sinus, suggestive of a thrombosis (solid arrow) with fragmented parenchymal haemorrhage seen in the left posterior temporal lobe (dashed line). (b) CT venogram showing a filling defect in the superior sagittal sinus, known as the ‘empty delta sign’ (arrow).

leads to better outcomes. In pregnant patients with an unruptured aneurysm, the evidence suggests that there is not an increased risk of rupture during pregnancy or delivery. Recommendations regarding delivery are difficult and decisions should be made on an individual patient basis. A caesarean section is not mandatory in patients with unruptured aneurysm. In our clinical practice, we would routinely avoid a prolonged second stage of labour in this group of patients and recommend assisted delivery, should the need arise. Similarly, pregnant women with treated cerebral aneurysms should be encouraged to deliver vaginally without any specific considerations.

14.12  Neurological conditions in pregnancy

Table 14.12.4  Common peripheral nerve disorders associated with pregnancy Neuropathy

Clinical presentation

Treatment

Bell’s palsy (facial nerve)

Asymmetrical facial droop (lower motor neurone)

Short course prednisolone treatment, eye protection, and artificial tears

Carpal tunnel syndrome (median nerve)

Paraesthesia and pain in lateral side of hand and wrist, especially at night

Overnight wrist splints. Some require local steroid injections or even decompression

Meralgia parasthetica (lateral cutaneous nerve of the thigh)

Numbness and pain over anterior, lateral aspect of the thigh. Improves with sitting and lying down

Usually improves spontaneously but treatment options can include lidocaine patch or capsaicin cream

Femoral neuropathy

Weakness of the quadriceps (i.e. knee extension) and sensory loss anterior thigh and medial calf. Common mechanism of injury is excessive flexion of hip in lithotomy position

Conservative management with physiotherapy and analgesia Recovery usually within three to four months

Common peroneal nerve

Foot drop, foot eversion weakness compared with inversion and sensory loss over the dorsum of foot and lateral aspect of shin. Can be precipitated by prolonged squatting or stirrups

See treatment of femoral neuropathy

Obturator nerve

Weakness of hip adduction and sensory loss medial aspect of thigh. Usually precipitated during assisted delivery

See treatment of femoral neuropathy

Arteriovenous malformations Intracranial arteriovenous malformations are relatively uncommon but a recognized cause of catastrophic intracerebral haemorrhages. The evidence suggests that the risk of rupture in pregnancy is not increased. Furthermore, there are identified predictors of haemorrhage, such as age, location, and deep venous drainage, and these can be useful for evaluating risk. Treatment of unruptured arteriovenous malformations should largely be restricted to outside of pregnancy. Treatment options include endovascular embolization, surgery, or stereotactic radiotherapy. In terms of the issues surrounding labour, these are similar to those mentioned in the management of cerebral aneurysms, and decisions should be made on an individual patient basis.

Peripheral nerve disorders The most frequent examples of peripheral nerve disorders encountered during pregnancy, labour, and the post-​partum period are listed in Table 14.12.4.

FURTHER READING Bove R, et al. (2014). Management of multiple sclerosis during pregnancy and the reproductive years. Obstet Gynecol, 124, 1157–​68. Bove RM, Kleim JP (2014). Neuroradiology in women of childbearing age. Continuum, 20, 23–​41. Knight M, et al. on behalf of MBRRACE-UK (2017). Saving lives, improving mothers’ care - lessons learned to inform maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity 2013–15. National Perinatal Epidemiology Unit, University of Oxford, Oxford. Harden CL (2014). Pregnancy and epilepsy. Continuum, 20, 60–​79. Macgregor EA (2014). Headaches in pregnancy. Continuum, 20, 128–​47. Marsh MS, Nashef LAM, Brex PA (2012). Neurology and pregnancy. Informa Healthcare, London. Norwood F, et al. (2014). Myasthenia in pregnancy: best practice guidelines from a UK multispecialty working group. J Neurol Neurosurg Psychiatry, 85, 538–​43. Powrie RO, Greene MF, Camman W (2010). De Swiet’s medical disorders in obstetric practice. Blackwell Publishing, Chichester. Wiles KS, et al. (2015). Reversible cerebral vasoconstriction syndrome: a rare cause of postpartum headaches. Pract Neurol, 15, 141–​4.

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The skin in pregnancy Gudula Kirtschig and Fenella Wojnarowska

ESSENTIALS Dermatoses in pregnancy are common, they may be very itchy and may impact the life of a pregnant woman dramatically. There are four classical dermatoses of pregnancy. It is particularly important to recognize these as they may have serious health implications for mother and child. Intrahepatic cholestasis of pregnancy—​occurs in 1/​40 to 1/​500 pregnancies and is the most serious cause of itch in pregnancy, with potentially substantial effects on mother and fetus. Treatment is with ursodeoxycholic acid. Atopic eruption of pregnancy—​affects 1/​300 pregnancies, typically with an eczematous eruption over abdomen and limbs. Treatment is with topical steroids. Polymorphic eruption of pregnancy—​a ffects about 1/​240 pregnancies, usually beginning with red papules and plaques on the abdomen and thighs before spreading more widely. Treatment is with reassurance and emollients, with topical steroids if neccessary. Pemphigoid gestationis—​ occurs in 1/​ 50 000 pregnancies and is due to circulating antibodies against the skin basement membrane zone. The eruption often begins around the umbilicus and spreads to the whole trunk, limbs, hands, and feet. If potent topical steroids fail systemic steroids are required. Transplacental transmission to the fetus may occur. Recurrence in future pregnancies is to be expected.

Common skin changes in pregnancy Vascular changes and lesions There is increased skin blood flow during pregnancy, possibly resulting in oedema (e.g. manifest as tightening of rings and shoes), erythema, and itch. Spider naevi and palmar erythema are common, and there maybe erythema of the gums (with gingivitis) and the vulvovaginal area. Unilateral telangiectasia may appear for the first time, as may haemangiomas. Varicose veins may develop during pregnancy. Swollen skin around the ankles may be a first sign, worsening during the day and improving over night when lying down. Supportive stockings or flight socks should be worn: special pregnancy types are available. If there is a family or personal history of the development of varicose veins or thrombophlebitis/​phlebothombosis, further risk assessment for venous thromboembolism is required. Pyogenic granuloma, a benign tumour with a tendency to ulcerate and bleed, may develop on the skin or oral cavity, where they are known as pregnancy tumours (Fig. 14.13.1). They are

Introduction The skin undergoes profound alterations during pregnancy as a result of endocrine, metabolic, and physiological changes. Some of these are trivial and chiefly cosmetic, producing no or minor symptoms; some will improve during or after pregnancy and others can be distressing and/​or of major medical importance. Pregnancy will profoundly modify expression of pre-​ existing skin disease, and there are dermatoses that are specific Fig. 14.13.1  Pyogenic granuloma on the finger. to pregnancy. Courtesy of Dr Jonathan Bowling, Oxford Radcliffe Hospital NHS Trust, UK.

14.13  The skin in pregnancy

shedding after parturition gives rise to the distressing post-​partum telogen effluvium three months after delivery. This is completed 6–​12 months later and treatment is not needed. Hirsutism may begin or worsen in pregnancy, driven by an increase in androgens and usually resolving a few months after delivery.

Pilosebaceous changes/​acne The development of acne during pregnancy is unpredictable. Skin in pregnancy is often more greasy, termed ‘pregnancy glow’. The increase in oestrogens usually improves acne, but there may be worsening of acne in some unfortunate patients. Acne treatment in pregnancy may be tricky as topical and oral vitamin A derivatives must be avoided because they are teratogenic. Topical treatment with benzoyl peroxide and clindamycin for limited areas (most commonly the face) are the treatments of choice in pregnancy.

Striae gravidarum

Fig. 14.13.2 Melasma. Courtesy of Dr Christina Ambros-​Rudolph, University of Graz, Austria.

sometimes confused with melanoma and often recur after local destruction.

Striae gravidarum (stretch marks) are common in pregnancy, affecting about 50% of women. They are more frequently seen in young women, in women with a raised body mass index, and those who have large babies. They are familial in about 50% of cases and are more likely if a woman has had them previously. The breasts and sides and lower areas of the abdomen are the typical sites, but thighs and arms can be affected. They start as linear depressed purple lines and fade to pale, atrophic, scar-​like lesions. They may be itchy. There is an association with subsequent tendency to prolapse. There is no good treatment. Olive oil massage, castor oil, cocoa butter, glycolic or fruit acids, homeopathic creams and/​or oils are used, but the benefit of these is not proven.

Pruritus

Pigmentary changes and pigmented lesions

Itching occurs in about 20% of pregnancies, frequently in associIncreased skin pigmentation is common, particularly in dark-​ ation with an inflammatory dermatosis such as atopic eczema, polyskinned women, up to 90% of whom may be affected. There is morphic eruption of pregnancy, allergic reactions, or infectious darkening of the nipples, genitalia, and linea alba. In some women diseases. The underlying dermatosis must be treated. Oral antihistarecent scars will darken. The unsightly and sometimes psychologic- mines such as loratadine are safe to be used in pregnancy and can be ally distressing facial pigmentation of melasma (chloasma, formerly used for symptomatic relief (see Table 14.13.1). Pruritus may occur known as the ‘mask of pregnancy’) affects many women. It gets without physical signs, other than scratch marks. The most serious worse with sunlight and can be reduced by using high protection cause is intrahepatic cholostasis of pregnancy, which is diagnosed in factor (SPF 50) UVB and UVA sunscreens (Fig. 14.13.2). Melasma about 3% of itchy pregnant women (see below and Chapter 14.9). If often disappears spontaneously after delivery, but treatment with no underlying dermatosis exists emollients and antihistamines may topical vitamin A  derivatives and hydrochinon may be indicated be useful. after pregnancy in some women. Urticaria Pigmented naevi can increase in size, in particular around the abdomen due to the increased body circumference, and pigmenta- Urticaria (hives) and dermographism (wealing in response to prestion during pregnancy. Any asymmetrical change is suspicious of sure, e.g. scratching) may be precipitated by pregnancy and are very malignant change. Melanoma may occur and is not associated with itchy conditions. Urticaria has been attributed by some authors to a poorer prognosis in pregnant women. Any rapidly changing, ir- physiological changes in vascular reactivity. Physical factors such as regularly shaped, or irregularly pigmented lesion larger than 6 mm in diameter should be excised under local anaesthesia to exclude a dysplastic naevus or melanoma. Risk factors for developing a mel- Table 14.13.1  Antihistamines safe to be used in pregnancy anoma are fair skin, high density of freckles, red hair, more than 50 Group Generic name moles, the presence of more than five atypical moles (irregular shape Sedating Chlopheniramine, chlorphenamine and colour), a history of severe sunburns during childhood, espeuseful at night if pruritus prevents cially with blistering, and a family history of melanoma. Clemastine sleep

Dimetinden

Hair changes There is diminished shedding of hair due to prolongation of the anagen phase. This is perceived as thickening of the hair. The synchronized

Non​sedating treatment of choice

Cetirizine Loratadine

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Section 14  Medical disorders in pregnancy

pressure and heat may evoke it. Particular drugs or foods may be the cause in some patients and must be avoided in such cases. Treatment with a non​sedating antihistamine such as loratidine, cetirizine or sedating chlopheniramine is safe.

Cutaneous infections Candida of the vulva as well as the vagina is common and occurs in about 15% of pregnant women, causing itching, burning, and discharge. During pregnancy, treatment with miconazole or clotrimoxazole cream or vaginal pessaries is preferred and may need to be repeated several times or preventative treatment may be necessary. Oral antiyeast treatments must not be used for vulvo-​vaginal yeast infection during pregnancy. Dermatophyte infections (tinea/​ ringworm) are common and may affect pregnant women. They typically manifest interdigitally (athlete’s foot) or in the groin, but can affect any body site including the nails. In uncomplicated cases tinea is usually treated with topical antifungals; in pregnancy, clotrimazole and miconazole are preferred. Oral antifungals must be avoided in pregnancy and treatment for onychomycosis postponed until after delivery. Cutaneous and genital warts thrive in pregnancy, often commencing, proliferating, or enlarging. Treatment for genital warts should be started as soon as possible. However, in the last eight weeks of pregnancy methods that destroy the warts and harm the skin over large areas should be avoided so there is no damage to the skin before delivery. The choice of the therapy is dependent on the type, the extent, and the location of the warts. Localized lesions can be treated with freezing (cryotherapy), electro surgery or with trichloracetic acid (TCA, 33–​50%), which is a liquid that ‘burns’ or ‘peels’ the warts away and can be applied to the lesions with a cotton tip by a physician once every one to three weeks. Imiquimod has been used in pregnancy without observed adverse effects, but it is not licensed for use in pregnancy. Podophyllin or 5-​Fluorouracil must not be used in pregnancy. Genital herpes simplex infections during pregnancy can affect the unborn child. The baby can catch the virus by transmission from the mother via the placenta or during delivery. If the baby is infected before delivery it is at risk of abnormalities, mainly of the brain and the eyes, but herpes virus transmission predominantly occurs during delivery and not during pregnancy. The risk for infection depends mainly on the severity and timing of the mother’s infection (highest if the mother is very ill with herpes, or the baby is premature). If the baby is infected by the virus during delivery or as a newborn the infection may be restricted to the skin, mucosa, and/​or the eyes (45%), the infection may involve the brain (30%), or the infection may be wide spread involving many organs including lungs, liver, and the brain (25%). The risk of transmission from the mother to the baby at delivery is highest (30–​50%) among women who acquire genital herpes (primary herpes infection) near the time of delivery (within six weeks). In a primary infection during the first or the second trimester of pregnancy aciclovir or valaciclovir may be used, depending on the severity of the disease. Antiviral treatment may be used for four weeks before delivery to prevent recurrences and viral shedding around delivery; a caesarean section is usually not indicated. Primary herpes infection during the third trimester must be treated with aciclovir or valaciclovir. A caesarean section

in pregnant women developing a primary infection in the six weeks preceding delivery and in women with recurrent disease if they have lesions at the time of delivery is controversially discussed, but there is no certain reduction of the infectious risk for the baby. Lice may be seen as head lice or pubic/​crab lice. A very safe and effective treatment for head lice is combing with dimeticon or, alternatively, coconut oil or vinegar water. For easier combing, conditioner (possibly containing tea tree oil) may be used. Malathion (lice resistance is reported) or pyrethrum extract and synthetic pyrethroids (permethrin topical 5% cream/​scalp treatment) are the treatment of second choice. Pump sprays should be avoided because of the danger of systemic intake through the air. Pubic lice may be treated with malathion or permethrin 5% cream applied to the affected site. Scabies is a common and very itchy skin condition caused by human scabies mites. It can affect people of any age but is most common in the young. Itching is the main symptom, usually starting about a month after the mites were picked up. The itching affects the body and limbs but usually spares the head and neck, except in infants. The rash of scabies is a mixture of scratch marks and red scaly areas; later it can become superinfected. This itchy rash covers much of the skin, but the mites themselves show up mainly where they burrow, typically on the sides of the fingers and hands, and around the wrists, ankles, feet, breasts, and genitals. Usually several members of a family are affected and need to be treated. Permethrin seems more effective than other treatments, but there are no studies that prove absolute safety in pregnancy. Permethrin 5% cream is applied all over the body, except the head, and washed off after about 12 hours; re-​treatment of hands if washed with soap in between is recommended. Taking a bath or shower before treatment is not recommended. The treatment should be repeated after seven days. Benzyl benzoate, malathion, and crotamiton seem less effective but are considered safe. Oral Ivermectin (200 microgr/kg body weight in one dose) is not recommended during pregnancy, however, harm to the baby after accidental use is not reported.

The pregnancy dermatoses Historical perspective The striking blistering eruption known as ‘pemphigoid gestationis’ was described in 1867 by Wilson and named by Milton in 1872 as ‘herpes gestationis’. During the 1980s it was characterized as an autoimmune blistering disease by Black, Charles-​Holmes, and Shornick, and renamed as ‘pemphigoid gestationis’ to emphasize the close relationship to the commoner autoimmune blistering disease bullous pemphigoid and to prevent confusion with viral herpes disease. Further skin diseases that arise in pregnancy have been confusing in their nomenclature and clinical descriptions, but recently Ambros-​ Rudolph and colleagues proposed a new and much simpler classification (Table 14.13.2).

Intrahepatic cholestatis of pregnancy It is particularly important to recognize itch/​ pruritus due to intrahepatic cholestasis of pregnancy (obstetric cholestasis, cholestasis of pregnancy, and pruritus/​prurigo gravidarum), which has important implications for the health of both mother and fetus (see Chapter 14.9). It is the most serious cause of itch in pregnancy.

14.13  The skin in pregnancy

Table 14.13.2  Four major pregnancy dermatoses (numbers are based on 505 pregnant patients with skin problems; Ambros-​Rudolph et al. 2006)

a

Pregnancy dermatosis

Frequency (%)

Effect on fetus

Effect on mother

Intrahepatic cholestatis of pregnancy

 3

Can be substantial (see Chapter 14.9)

Can be substantial (see Chapter 14.9)

Atopic eruption of pregnancy

50

None described

Usually improves after delivery

Polymorphic eruption of pregnancy

22

None described

Pemphigoid gestationis

 4a

Small for dates

May be major, usually resolves months after delivery

Raised frequency as tertiary referral centre.

In Europe about 0.2–​2.4% of pregnant women will get the condition; in Scandinavia and South America intrahepatic cholestatis of pregnancy is more common and it may also occur in women on the oral contraceptive pill. The itching begins typically in the third trimester and affects the abdomen, palms, and soles. The longer the itch persists, the more skin changes due to scratching may be present. Excoriations and prurigo nodules typically involve the shins, arms, and buttocks. Apart from these changes, there is usually no rash associated with intrahepatic cholestatis of pregnancy. Loss of sleep, loss of appetite, and an inability to perform normal daily tasks can be a result of the intense itching. Less common symptoms include dark urine and/​or pale stools, jaundice, abdominal pain, and nausea. Liver function tests may be normal, but bile salts are typically raised. Other causes for itchy skin such as hepatitis, iron deficiency, specific dermatoses of pregnancy, or infectious causes should be excluded. The condition resolves post-​partum but will recur in subsequent pregnancies. Reducing the bile acids is essential. Ursodeoxycholic acid (UDCA—​a naturally occurring bile acid) is currently the best treatment for intrahepatic cholestatis of pregnancy. It is not licensed for use in pregnancy but may be prescribed on an individual basis. It improves liver function and helps to reduce the toxic bile acid concentration, and it is the only treatment that has been shown to reduce fetal risks in intrahepatic cholestatis of pregnancy. UDCA tablets, 15 mg/​kg/​day or simply 1 g daily, are given either as a single dose or divided into two to three doses and continued until delivery, when treatment can usually be stopped. Symptomatic management is with emollients and sometimes antihistamines.

Atopic eruption of pregnancy

Fig. 14.13.3  Atopic eruption of pregnancy in a 24-​year-​old gravida 2 at 19 weeks’ gestation: small red pruritic papules and eczematous features on the trunk (and limbs).

This condition includes entities formerly known as prurigo of pregnancy and pruritic folliculitis. It may affect 1 in 300 pregnancies. It occurs in women with an atopic background (personal or family history), of whom about 20% have had previous eczema. The immunological changes of pregnancy and the tendency to pruritus may both contribute to the worsening of atopic eczema or its first occurrence with pregnancy. Atopic eruption of pregnancy thus affects women who already have atopic eczema but experience a flare-​up of the disease, and women with their first occurrence of eczema during pregnancy (80%). It can be severe and life-​ruining, and life-​threatening if secondary infection with herpes simplex (eczema herpeticum) or streptococci occurs. Atopic eruption of pregnancy commences early, in three-​quarters of women before the beginning of the third trimester. There is intense pruritus, it typically presents with an eczematous eruption over abdomen and limbs (Fig. 14.13.3). The lesions can be chiefly eczematous with red, dry, and scaly skin, with areas of excoriation and thickening or lichenification. Pre-​existing atopic eczema

often deteriorates becoming more widespread and may result in erythroderma in the most severe cases. Another presentation is with excoriated papules and nodules (prurigo of pregnancy). The least common form is follicular pruritic papules and pustules (pruritic folliculitis), which may present in the third trimester and in a small series was associated with male infants and low birth weight. Secondary infection with Staphylococcus aureus and streptococci is a frequent complication. Histopathology is usually non​specific, but may show a perivascular infiltrate with thickened epidermis. Direct and indirect immunofluorescence are negative. Treatment is with moderate to potent topical steroids that although absorbed do not adversely affect the fetus. The use of emollients may lessen the requirements for topical steroids, and steroids should be used in the minimum quantities and strengths necessary to control the disease (see Table 14.13.3). Many topical

Courtesy of Dr Christina Ambros-​Rudolph, University of Graz, Austria.

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Table 14.13.3  Examples of topical steroids. Prolonged treatment with very potent topical steroids may lead to fetal growth restriction; see guidelines for the use of topical steroids in pregnancy Group

Generic name

Mild

Hydrocortisone 1%

Moderately potent

Hydrocortisone 1% with urea Clobetasone butyrate 0.05% Flurandrolone

Potent

Betamethasone valerate 0.025%/​0.1% Betamethasone dipropionate Hydrocortisone 17-​butyrate Fluticasone propionate Mometasone furoate

Very potent

Clobetasol propionate 0.05%

steroids contain antiseptics and antibiotics that will be absorbed, and some may be contraindicated in pregnancy. The sedating antihistamine chlorpheniramine may help with sleep. Secondary infection often requires systemic antibiotics such as oral penicillins or erythromycin. The condition resolves in days to weeks after delivery. It may recur in one-​third of pregnancies.

Polymorphic eruption of pregnancy Polymorphic eruption of pregnancy was formerly known as ‘pruritic urticated papules and plaques of pregnancy’ or ‘toxic erythema of pregnancy’. Its aetiology is unknown, but there is an association with a low serum cortisol. It affects 1 in 240 singleton pregnancies, being most common in first pregnancies, with multiple births (hence following in vitro fertilization)—​perhaps related to the mechanical effect of the abdominal stretching or to an increased immune complex load—​and with a male fetus. This condition usually begins in the third trimester and occasionally post-​partum. Red papules and plaques typically begin in striae on the abdomen and thighs and then spread to the whole trunk and limbs, including the hands and feet. They are very itchy, and the itching can be so severe as to prevent sleep. Initially the lesions are raised red papules (Fig. 14.13.4) and plaques; with time they become more diverse in morphology, occasionally polycyclic or blistering. The histopathology shows oedema, perivascular lymphocytes, and eosinophils. Immunofluorescence does not demonstrate any circulating or bound immunoreactants. Treatment is with reassurance and emollients (e.g. cold cream containing 1–​2% menthol). This is helpful, but not always sufficient. Antihistamines and moderate to very potent topical steroids, which may be absorbed through the skin (see Table 14.13.3), may be required, and occasionally systemic steroids for induction of remission. The condition resolves over days to weeks after delivery. It does not usually recur. The outcome of the pregnancy is not adversely affected.

Pemphigoid gestationis Pemphigoid gestationis, formerly herpes gestationis (a name best abandoned as ‘herpes’ refers to the herpetiform grouping of the blisters rather than herpes infection), is an autoimmune blistering disease

Fig. 14.13.4  Polymorphic eruption of pregnancy: urticated papules and plaques on the thigh.

characteristically occurring in pregnancy. Pemphigoid gestationis is the most severe of the pregnancy dermatoses. It is due to circulating antibodies against adhesion molecules of the skin basement membrane zone. Very potent topical or systemic steroids are usually required. Transplacental transmission to the fetus may occur. Recurrence in future pregnancies is to be expected. The aetiology is only partially understood. The pathogenicity of the circulating basement membrane zone antibodies is demonstrated by transplacental transmission of the disease. The major target antigen is BP180/​collagen XVII (chief epitope being the transmembrane NC16A domain); BP230 is a less common antigen. Both antigens are present in skin, mucosa, and amnion, associated with the hemidesmosome and adhesion complex linking epithelium to dermis/​mesenchyme, which are targets in other autoimmune blistering diseases. The placenta shows increased expression of antigen-​ presenting cells, but it is unclear why breakdown of tolerance occurs, and why normal components of amnion and stratified squamous epithelium become antigenic. The mothers have the HLA DR 3, 4, haplotype and are C4 null, and there is an association with thyroid and less commonly other autoimmune disease. Pemphigoid gestationis occurs in approximately 1 of 50 000 pregnancies. It commences from the second trimester onwards and quite often in the first week post-​partum (range from five weeks of gestation to four weeks post-​partum). It usually occurs in the first and subsequent pregnancies, although 8% of pregnancies are skipped. The eruption typically begins around the umbilicus and spreads to the whole trunk, limbs, hands, and feet, including the palms and soles, and rarely the face. The mouth and vulva may be involved showing blisters or erosions. Vesicles and blisters are characteristic, but lesions comprise annular lesions, papules, and plaques (Fig. 14.13.5). Pruritus is severe and sleep often impaired.

14.13  The skin in pregnancy

Fig. 14.13.5  Pemphigoid gestationis: urticated papules and blisters. From Charles-​Holmes R, Black MM (1990). Herpes gestationis. In: Wojnarowska F, Briggaman RA (eds) Management of blistering disease, pp. 93–​104. Chapman & Hall, London, with permission.

Transplacental transmission of antibodies to the fetus occurs in about 3% of affected pregnancies, the neonate developing transient self-​limiting blistering (Fig. 14.13.6). Histopathology demonstrates an eosinophilic infiltrate, papillary oedema, and subepidermal blisters. Direct immunofluorescence demonstrates that C3 component of complement and IgG1 are bound at the basement membrane zone of the dermoepidermal junction. The patient’s serum has circulating IgG1 basement membrane zone antibodies that bind C3. These immunoreactants are also found at the basement membrane zone of the amnion (Fig. 14.13.7). Treatment with potent or very potent topical steroids and chlorpheniramine is recommended, however, systemic steroids (e.g. prednisolone 0.3–0.5 mg/kg body weight daily) may be required, the dose adjusted according to disease activity. There is usually a post-​ partum flare, necessitating increased steroids. Azathioprine and Ciclosporin may reduce steroid requirement in selected cases. The disease slowly resolves post-​partum, but may persist for several months. Recurrence in subsequent pregnancies is usual, only about 8% being spared. The classical teaching is that it recurs earlier and is more severe in subsequent pregnancies, but this has not always been our experience. Onset of pemphigoid gestationis in the first or second trimester and presence of blisters may lead to adverse pregnancy outcomes, including decreased gestational age at delivery,

Fig. 14.13.7  Pemphigoid gestationis: linear deposition of C3 at the amnion basement membrane zone as demonstrated by immunofluorescence. The nuclei are counterstained with propidium iodide. Courtesy of B.S. Bhogal and M.M. Black, St John’s Institute of Dermatology, St Thomas’s Hospital, London.

preterm birth, and children with low birth weight. Such pregnancies should be considered high risk and appropriate obstetric care should be provided. Systemic corticosteroid treatment, in contrast, does not substantially affect pregnancy outcomes, and its use for pemphigoid gestationis in pregnant women is justified.

Classical dermatoses affecting pregnant women Psoriasis Psoriasis improves in most women during pregnancy, but can deteriorate. Therapy poses special problems as most systemic treatments are contraindicated. Methotrexate is a folic acid antagonist and can cause miscarriage; acitretin is teratogenic; fumaric acid causes leukopenia (whether this affects the fetus is unknown, but case reports have shown no harm). Oral psoralens with UVA (PUVA) are still not proven to be safe, but topical PUVA and UVB light treatment is safe. Ciclosporin and tumour necrosis factor (TNF) α inhibitors are reserved for severe cases. Topical therapy with steroids can be used if needed. Coal tars and dithranol have been widely used in pregnancy but are not proven to be safe. The new vitamin D analogues are not licensed for use in pregnancy, but there is no hint from case reports that indicate harm if used in usual doses. The ideal is minimum treatment, encouraging emollient use and if necessary UVB. A severe form of pustular psoriasis, impetigo herpetiformis, may occur in pregnancy and is best managed with bed rest, emollients, and moderate potent topical steroids or low doses of oral prednisolone. In severe cases topical PUVA or oral Ciclosporin are used, and induction of labour may be indicated if the mother is at risk.

Cutaneous lupus erythematosus Fig. 14.13.6  Pemphigoid gestationis: urticated papules in the neonate. From Charles-​Holmes R, Black MM (1990). Herpes gestationis. In: Wojnarowska F, Briggaman RA (eds) Management of blistering disease, pp. 93–​104. Chapman & Hall, London, with permission.

Cutaneous lupus erythematosus may be adversely affected or improved or unchanged by pregnancy. However, such patients should be screened for anti-​Ro and anticardiolipin antibodies, preferably prior to conception, to identify at-​risk pregnancies (see Chapter  14.14).

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Autoimmune bullous diseases Linear IgA disease, an autoimmune blistering disease with linear IgA basement membrane zone antibodies, usually improves with pregnancy, such that some patients can discontinue their therapy, usually dapsone. Despite the deposition of immunoreactants in the amnion basement membrane zone, the fetus is not adversely affected. There is usually an exacerbation three months post-​partum. Pemphigus vulgaris is an autoimmune blistering disease with widespread mucosal and/​or cutaneous erosions caused by IgG antibodies to desmosomal components of the epithelium. The desmosomal antibodies are directed at desmoglein 3, a major adhesion molecule in mucosa and neonatal skin, and can be transmitted across the placenta, causing severe neonatal pemphigus with devastating results to the fetus. This does not occur in the related pemphigus foliaceus, which is endemic in Brazil, characterized by superficial cutaneous erosions and mediated by desmoglein 1 antibodies that do not cause oral lesions or affect neonatal skin. Both forms of pemphigus may worsen in pregnancy and treatment may require systemic steroids and immunosuppressants like azathioprine. Spontaneous remission after pregnancy is described.

Vulval dermatoses Many dermatoses may affect the vulval skin, and this may be particularly distressing in pregnancy as concerns regarding delivery may arise. A disease commonly seen at the vulva is lichen sclerosus, a chronic inflammatory condition of unknown cause. This is usually treated with very potent topical steroids. Their use should be limited during pregnancy to a minimum, but the disease may improve during pregnancy and does not inhibit vaginal delivery, although episiotomy may be required and should be anticipated.

FURTHER READING Ambros-​Rudolph CM, et al. (2006). The specific dermatoses of pregnancy revisited and reclassified:  results of a retrospective two-​ center study on 505 pregnant patients. J Am Acad Dermatol, 54, 395–​404. Chi CC, et al. (2009). Pemphigoid gestationis: early onset and blister formation are associated with adverse pregnancy outcomes. Br J Dermatol, 160, 1222–​8. Chi CC, et al. (2015). Safety of topical corticosteroids in pregnancy. Cochrane Database Syst Rev. Oct 26;(10):CD007346. doi:10.1002/14651858.CD007346.pub3. Review. European Academy of Dermatology and Venereology. Patient Information Leaflets. http://​www.eadv.org/​patient-​corner/​leaflets/​ Jenkins RE, Hern S, Black MM (1999). Clinical features and management of 87 patients with pemphigoid gestationis. Clin Exp Dermatol, 24, 255–​9. Kirtschig G, Cooper S (2016). Gynaecologic dermatology: symptoms, signs and clinical management. Jaypee Brothers, New Delhi. Kirtschig G, Schäfer C (2015). Dermatological medications and local therapeutics. In: Schaefer C, Peters P, Miller RK (eds) Drugs during pregnancy and lactation, 3rd edition. Elsevier, London, pp. 467–​510. Muller S, Stanley JR (1990). Pemphigus: pemphigus vulgaris and pemphigus foliaceus. In: Wojnarowska F, Briggaman RA (eds) Management of blistering disease, Chapman & Hall, London, pp. 43–​62. Vaughan Jones S, Ambros-​Rudolph C, Nelson-​Piercy C (2014). Skin disease in pregnancy. BMJ, 348, g3489. Vaughan Jones SA, et al. (1999). A prospective study of 200 women with dermatoses of pregnancy correlating clinical findings with hormonal and immunopathological profiles. Br J Dermatol, 141, 71–​81. Zhang Y, et al. (2016). Ursodeoxycholic acid and S-adenosylmethionine for the treatment of intrahepatic cholestasis of pregnancy: a meta-analysis. Hepatitis Monthly, 16(8), e38558. doi:10.5812/hepatmon.38558.

14.14

Autoimmune rheumatic disorders and vasculitis in pregnancy May Ching Soh and Catherine Nelson-​Piercy

ESSENTIALS Autoimmune diseases affect 5–​7% of people, are more common in women of childbearing age, and are frequently encountered in pregnancy. They may remit or improve during pregnancy, but can flare or present in pregnancy or post partum.

Systemic lupus erythematosus The mother—​ pregnancy probably exacerbates systemic lupus erythematosus and increases the likelihood of a flare, which can be difficult to diagnose since many clinical features also occur in normal pregnancy. Differentiation of active renal lupus from pre-​eclampsia is notoriously difficult:  renal flares are more common if disease is active within six months of conception, in particular in women with hypertension, heavy proteinuria, or high baseline serum creatinine. There is an increased risk of maternal thrombosis and premature atherosclerosis. The fetus—​systemic lupus erythematosus is associated with increased risks of adverse pregnancy outcome including fetal death and intrauterine growth restriction. Most fetal losses occur in association with secondary antiphospholipid syndrome or active disease, particularly renal. For women with systemic lupus erythematosus in remission and without hypertension, renal involvement, or the antiphospholipid syndrome, the risk of problems in pregnancy is similar to that of the general population. Management—​flares of systemic lupus erythematosus must be actively managed, pre-​pregnancy counselling should be encouraged with treatment depending on both organ involvement and severity. Mild cases can be managed with analgesics alone (paracetamol); rash and arthritis will usually respond to non​steroidal anti-​inflammatory drugs, low-​dose prednisolone and/​or hydroxycholorquine; more severe disease may require introduction of a disease-​modifying agent (e.g. azathioprine or higher steroid dose). Steroids remain first-​line treatment for severe lupus flares in pregnancy (and treatment of other autoimmune conditions). The baby—​neonatal lupus syndromes are caused by transplacental passage of autoantibodies directed against cytoplasmic ribonucleoproteins Ro and La. Cutaneous neonatal lupus is the most common manifestation (5%) and congenital heart block the most serious (20% mortality).

Antiphospholipid syndrome Clinical features—​antiphospholipid antibodies include anticardiolipin antibodies (IgG and/​ or IgM), lupus anticoagulant, and anti-​ β2-​ glycoprotein-​ I antibody. Antiphospholipid syndrome is the combination of any of these with one or both of the following clinical features:  (1) thrombosis—​arterial, venous, or small vessel; (2) specific pregnancy morbidity. Women with isolated but persistent antiphospholipid antibodies without clinical features of antiphospholipid syndrome have obstetric outcomes similar to the general population. Management—​aim is to improve pregnancy outcome and prevent maternal thrombosis. This requires low-​dose aspirin from early pregnancy for prevention of pre-​eclampsia ± low-​molecular-​ weight heparin. Close fetal and maternal surveillance are required.

Rheumatoid arthritis Rheumatoid arthritis improves with pregnancy in some women. Methotrexate is teratogenic, but with the advent of treatment with biologics, more women with rheumatoid arthritis are now attempting pregnancy. Birth outcomes of women on anti-​TNFα agents are reassuring and there is no link with teratogenicity, but concern about immunosuppression of the fetus through transplacental transfer means treatment with some agents should be discontinued in later pregnancy. Overall the risk of adverse obstetric outcomes remains minimal and similar to the normal population. Post-​partum flares of rheumatoid arthritis are common.

Introduction Autoimmune diseases affect 5–​7% of the population and are more common in women of childbearing age. Many women with autoimmune rheumatic diseases have been advised against pregnancy in the past, but this is no longer appropriate with a new generation of pregnancy-​friendly disease-​modifying antirheumatic drugs and biological agents that afford excellent disease control without compromising fertility. Nevertheless, many women with autoimmune rheumatic diseases are older and have more comorbidities (i.e. hypertension, obesity, diabetes, cardiovascular disease, and so on) when they do attempt pregnancy.

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Section 14  Medical disorders in pregnancy

The importance of planned pregnancies with good preconception advice from clinicians knowledgeable in both the disease process and its effects on pregnancy (and lactation), and vice versa, cannot be overemphasized. Pregnancy is associated with suppressed cell-​mediated immunity (Th1) and enhanced humoral immunity (Th2), but these changes revert post-​partum accompanied by rapid reductions of oestrogen, progesterone, and cortisol levels. The post-​partum period is therefore a time of susceptibility to autoimmune disorders; and women who already have an autoimmune disorder may suffer disease exacerbation following pregnancy. Conversely, some autoimmune diseases may remit or improve during pregnancy, but this is not a universal rule. Flares in pregnancy are often accompanied by adverse obstetric outcomes for both mother and fetus. This chapter considers the relationship between pregnancy and systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, vasculitides, and scleroderma, and how pregnancy affects treatment of these conditions.

Systemic lupus erythematosus Systemic lupus erythematosus is much more common in women than men (ratio 9:1), with peak onset during the childbearing years. A  recent extensive review of published epidemiological studies demonstrated that the prevalence ranges from 0.07/​1000 in Caucasian Americans to 1.59/​1000 in a British Afro-​Caribbean population.

Effect of pregnancy on systemic lupus erythematosus Flares of systemic lupus erythematosus may be difficult to diagnose during pregnancy since many features such as hair loss, oedema, facial erythema, fatigue, musculoskeletal pain, anaemia, and raised erythrocyte sedimentation rate (ESR) also occur in normal pregnancy. Several disease activity scores are being validated for use in pregnancy. Active systemic lupus erythematosus in the four to six months preceding conception increases the likelihood of a flare during pregnancy. Several case–​control studies have addressed this issue, but differ in patient ethnicity, criteria for flare and systemic lupus erythematosus activity scales employed. The type of flare usually follows previous disease pattern. Hydroxychloroquine has been linked with better disease control and improved obstetric outcomes, and therefore should be continued in pregnancy. Conversely, steroids do not prevent flares, hence it is not appropriate to prescribe or increase the dose of steroids prophylactically during pregnancy or during the post-​partum period. Ideally, pregnancy should be planned when systemic lupus erythematosus is in remission, while on drugs that are suitable to be continued in pregnancy. Renal flares are more common if disease is active within six months of conception. There is a risk of deterioration of renal function in pregnancy, particularly if the patients are hypertensive, have pre-​existing heavy proteinuria, or a high baseline serum creatinine. A recent meta-​analysis reported that the incidence of renal lupus flares during pregnancy was 11–​69% and renal impairment occurred in 3–​27%, which was irreversible in up to 10%. Tacrolimus is being increasingly used as a treatment for lupus nephritis. De novo presentations of lupus nephritis

during pregnancy are not uncommon, particularly in those who are not treated. Women with systemic lupus erythematosus and secondary antiphospholipid syndrome have an increased risk of maternal thrombosis, especially in the puerperium. There should be a low threshold for empiric treatment with low-​molecular weight heparin pending appropriate diagnostic imaging. Young women with systemic lupus erythematosus are also at risk of premature atherosclerosis, even in the relative paucity of cardiovascular risk factors. It is possible the pregnancy and its associated complications accelerate this process. Hence, myocardial infarction should be considered as a differential if she presents with chest pain or shortness of breath. Pulmonary hypertension present in up to 14% of patients. It carries a significant risk of maternal death. Idiopathic pulmonary hypertension is associated with an up to 25% risk of maternal mortality, and this risk is even higher in women with underlying connective tissue disorders. Women who have pulmonary hypertension should be advised against pregnancy and when pregnant, offered the option of termination on the basis of life-​threatening maternal disease. Nevertheless, the most common cause of maternal death in women with systemic lupus erythematosus is infection.

Effect of systemic lupus erythematosus on pregnancy Women with systemic lupus erythematosus remain fertile, except during severe flares or after exposure to prolonged high doses of cyclophosphamide, which results in premature ovarian failure. However, systemic lupus erythematosus is associated with increased risk of early pregnancy losses and the later adverse pregnancy outcome as a result of placental insufficiency, and manifest as pre-​eclampsia, fetal growth restriction, or small for gestational age infants, placental abruption, and stillbirth—​collectively known as maternal-​placental syndrome. These complications often lead to preterm deliveries. The main factors influencing pregnancy outcomes in women with systemic lupus erythematosus are disease activity (especially at time of conception), hypertension, renal involvement, secondary antiphospholipid syndrome, and anti-​Ro/​La antibodies (see next). Pregnancy outcomes in women with systemic lupus erythematosus have greatly improved in recent years due to continuation of hydroxychloroquine in pregnancy, fetal surveillance in women who are Ro and La positive, improved disease control even in the non-​ pregnant cohort, likely milder disease course as diagnostic latency is shortened and clinicians are now more comfortable with the management of systemic lupus erythematosus in pregnancy thereby reducing the rate of iatrogenic preterm delivery. Presence of renal disease is closely associated with pregnancy outcomes in women with systemic lupus erythematosus. In a meta-​ analysis active nephritis at conception was associated with 25–​50% rate of fetal loss as compared to 8–​12% if the disease was inactive. One case–​control study showed that 28% of patients with class III or IV lupus nephritis developed pre-​eclampsia, 35% had a preterm delivery, and a significantly lower birth weight compared to the women with systemic lupus erythematosus without nephritis. A higher baseline creatinine is also associated with poor pregnancy outcomes. Women with systemic lupus erythematosus in clinical remission but with persistently low complement levels or positive anti-​double

14.14  Autoimmune rheumatic disorders and vasculitis in pregnancy

Box 14.14.1  Baseline investigations to assess risk of pregnancy in patients with systemic lupus erythematosus • Blood pressure • Urinalysis and quantification of proteinuria (albumin/​ protein creatinine ratio and/​or 24 h urinary protein) • Full blood count, ESR • Urea, creatinine, and electrolytes • Liver function tests • Uric acid • Serology—​ antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies, anti-​β2glycoprotein I antibodies), ENA (esp. Ro and La antibodies), ANA, ds-​DNA • Complements: C3 and C4

stranded DNA (anti ds-​DNA) in the second trimester have worse pregnancy outcomes than seen in women with normal complement or negative anti ds-​DNA. However, it is women with both serological and clinically active disease who have the highest rates of pregnancy loss and preterm delivery. Positive anti ds-​DNA was more closely associated with high clinical systemic lupus erythematosus activity in pregnancy, but low complement alone was not.

Management of systemic lupus erythematosus in pregnancy Preconception counselling When possible, management should begin with preconception counselling. Baseline renal function, blood pressure, and the anti­ phospholipid and anti-​Ro/​La antibody status allow prediction of the risks to the woman and her baby (see later). Appropriate baseline investigations are listed in Box 14.14.1. A decision should be made as to whether to start aspirin and/​or low-​molecular weight heparin if the woman is at risk of thromboses. The outlook is better if conception occurs during remission, and women should be advised to avoid pregnancy for at least 6 months post-​flare, especially if there is renal involvement. Her medications should be reviewed and changed to pregnancy-​friendly drugs (if possible). It is important to ensure clinical stability on this regime for at least six months preconception. Maternal surveillance Pregnancy care is best undertaken in multidisciplinary, combined clinics where physicians and obstetricians can monitor disease activity, fetal growth, and uterine and umbilical artery Doppler blood flow. Women will need to be regularly reviewed for any signs of pre-​ eclampsia or a flare. Frequency of visits depends on gestation and maternal disease activity. As a rule of thumb, the visits increase in frequency towards and during the third trimester—​when superimposed pre-​eclampsia is commonest. Diagnosis of flare Differentiation of active renal lupus from pre-​eclampsia is notoriously difficult, and the two conditions may co-​exist. Table 14.14.1 lists features to help to distinguish them. The gold standard is a renal biopsy to differentiate a renal lupus flare from pre-​eclampsia. Renal biopsies can be performed in pregnancy, but there is an increased risk of bleeding and haematoma formation due to increased vascular perfusion to kidneys during pregnancy. Renal biopsies are performed rarely in pregnancy and only before 24 weeks’ gestation. Other useful markers for

Table 14.14.1  Features to help distinguish lupus nephritis flare and pre-​eclampsia Pre-​eclampsia

Flare of SLE

Hypertension

Yes

Often present

Other organs

No

Malar rash, photosensitive rash, or arthritis

Seizures

If eclampsia

Only if there is neurological involvement

Proteinuria

++ ≥0.3 g/​day or PCR ≥30

++ (in lupus nephritis)

Urinary casts

Absent

Present (if lupus nephritis)

RBC in urine

Absent

Present (if nephritic)

Urate

Elevated

Not elevated unless CKD

Albumin

Low

Very low if nephrotic syndrome

LFT

May be deranged

Rarely deranged in a flare of SLE

C3 and C4

Unchanged from baseline in early pregnancy

Low compared to baseline in early pregnancy

Anti-​ds-​DNA

Unchanged

Elevated

CKD, chronic kidney disease; LFT, liver function test; RBC, red blood count; SLE, systemic lupus erythematosus.

a flare of lupus nephritis include a raised ds-​DNA and active urinary sediment or the presence of casts in the urine. Management of flare Disease flares must be actively managed. Delivery is seldom the sole management of choice as post-​partum flares are common and severe. Treatment will depend on the organ involvement and severity (see the later section in this chapter, ‘The use of antirheumatic drugs, immunosuppressive agents, and biologics in pregnancy’ for a summary of the therapeutic options available). Most drugs can be used in pregnancy. Teratogenic agents such as cyclophosphamide should be avoided in the first 12 weeks during which organogenesis occurs. There are long-​term safety data on the use of cyclophosphamide later in pregnancy with a cohort of children exposed in utero showing no signs of neurodevelopmental delay or other adverse effects when followed up to adolescence. Due to the prolonged action of rituximab, it is best avoided for six months prior to delivery. However, its use in pregnancy (for other indications, e.g. idiopathic thrombocytopenic purpura or as part of a chemotherapy regimen) has not been associated with adverse neonatal effects, and the exposed infants are able to mount an adequate response to vaccination despite the reduction of lymphoid B cells in the reticuloendothelial system seen in the offspring of exposed primates. Corticosteroids are the most widely prescribed drug for a flare in pregnancy as they have a well-​established safety profile. Non-​ fluorinated steroids (e.g. prednisolone), are metabolized by the placenta, and the fetus also inactivates steroids by way of sulphate conjugation, hence very little (7.5 mg/​day for >2 weeks) require parenteral steroids to cover the stress of labour and delivery. Prednisolone is safe in breastfeeding mothers since less than 10% of active drug is secreted into breast milk. Notwithstanding the above risks, steroids remain first-​line treatment for severe lupus flares in pregnancy (and treatment of other autoimmune conditions), as the benefits of rapid disease control outweigh the risks. Disease-​modifying antirheumatic drugs are discussed later in this chapter, in the section ‘The use of antirheumatic drugs, immunosuppressive agents, and biologics in pregnancy’.

Neonatal lupus syndromes About 30% of patients with systemic lupus erythematosus are anti-​ Ro positive. In such women the risk of transient cutaneous lupus is about 5% and the risk of congenital heart block about 2%, with the two conditions rarely coexisting. Anti-​Ro antibodies are present in 90 to 100% of mothers of affected offspring, and 68 to 91% have anti-​La antibodies. Maternal titres of anti-​Ro antibodies as high as 50 U/​ml or more are more likely to be associated with congenital heart block. There is no relationship between anti-​La titre and neonatal lupus. The risk of neonatal lupus is increased if a previous child has been affected, at 15–​25% if one and 50% if two previous children are affected. Not all anti-​Ro/​La positive mothers of neonates with congenital heart block have systemic lupus erythematosus or Sjögren’s syndrome, some are asymptomatic, but 48% of these developed symptoms of connective tissue disease in a median 3.7 years follow-​up in one study. In mothers who do have systemic lupus erythematosus there is no correlation between the severity of maternal disease and the incidence of neonatal lupus. Cutaneous neonatal lupus usually manifests in the first two weeks of life. The infant develops typical annular skin lesions similar to those of adult subacute cutaneous lupus, usually of the face and scalp, which appear after sun or UV light exposure. The rash disappears spontaneously within six months. Residual hypopigmentation or telangiectasia may persist for up to two years, but scarring is unusual. No specific treatment is required, except topical steroids in severe cases.

Congenital heart block usually appears in utero, around 18–​ 20 weeks and is associated with a structurally normal heart. The mechanism of damage appears to involve binding of the anti-​Ro/​La antibodies to antigens on the fetal cardiocytes, inducing an inflammatory process which leads to tissue damage and fibrosis of the conducting system. In women known to be anti-​Ro/​La positive, the fetal heart rate should be monitored at each visit (from 16 weeks onwards), and fetal cardiology scans offered at approximately 18–​20 weeks’ gestation and again at 28 weeks. Complete heart block causes bradycardia which can be detected on auscultation, but lesser degrees of heart block require Doppler echocardiography. Overall mortality is around 20%, with deaths usually occurring in utero (after developing hydrops, pleural and pericardial effusions) or the neonatal period, but can occur up to three years of age. Most infants who survive the neonatal period do well, although two-​thirds require pacemakers. There is no treatment that reverses complete heart block. In the past, intravenous immunoglobulins, fluorinated glucocorticosteroids, plasmapheresis, salbutamol, and digoxin have all been tried and found to be ineffective. Studies on congenital heart block have been difficult to conduct due to the rarity of the condition. However, a large retrospective study did find an association between maternal hydroxychloroquine use, and a reduction in heart block in the offspring. Its follow-​on study focusing on subsequent pregnancies of women whose offspring were affected found that there was a definite reduction in the incidence of heart block in the offspring of the women who were receiving hydroxychloroquine. Hence, hydroxychloroquine should be used in women who are planning pregnancy (or in early pregnancy) and are Ro or La antibody positive, even if they are asymptomatic.

Antiphospholipid syndrome and antiphospholipid antibodies Antiphospholipid antibodies include anticardiolipin antibodies (IgG and/​or IgM), lupus anticoagulant, and anti-​β2-​glycoprotein-​I antibody. The combination of any of these with one or more of the characteristic clinical features of thrombosis, recurrent pregnancy loss, or adverse pregnancy outcome (as detailed in Table 14.14.2) is known as the antiphospholipid syndrome. antiphospholipid

Table 14.14.2  Revised (2006) classification criteria for the antiphospholipid syndrome Revised classification criteria (Sydney criteria) for antiphospholipid syndrome.

Vascular thrombosis: ≥1 clinical episode of arterial, venous, or small vessel thrombosis. Thrombosis must be objectively confirmed. For histopathologic confirmation, thrombosis must be present without inflammation of the vessel wall. Pregnancy morbidity: a. ≥1 unexplained death of a morphologically normal fetus ≥10 weeks of gestation. b. ≥1 premature delivery of a morphologically normal fetus 99th percentile) of IgG or IgM isoforms c. anti-​ß2 glycoprotein-​I antibody (anti-​ß2GP I) of IgG or IgM present in plasma. Adapted from Miyakis S, et al. (2006). International consensus statement on an update of the classification criteria for definite antiphopholipid syndrome (APS). J Thromb Haemost, 4, 295–​306.

14.14  Autoimmune rheumatic disorders and vasculitis in pregnancy

antibodies are common and are not always associated with a clinical picture of pregnancy losses, obstetric complications, or thrombosis.

The implications of antiphospholipid antibodies and antiphospholipid syndrome in pregnancy Antiphospholipid syndrome is the most commonly acquired thrombophilia. Antiphospholipid antibodies are prevalent in the general population. In a cross-​sectional study of healthy blood donors, lupus anticoagulant was present in 8% and anticardiolipin antibodies in 10%. However, these antibodies were transient and persistence occurred in less than 2%. Antiphospholipid antibodies can be generated after exposure to certain medications, after infection (e.g. with HIV, HTLV-​1, hepatitis A, B, or C, CMV, EBV, VZV, TB, or poststreptococcal rheumatic fever, syphilis, Klebsiella, malaria), following a miscarriage, or in association with certain malignancies. However, these antiphospholipid antibodies—​particularly those generated after infection or following a pregnancy loss—​are transient and are unlikely to be of clinical significance, hence the importance of retesting antiphospholipid antibodies after more than 12 weeks. The presence of antiphospholipid antibodies does not equate to clinical disease. Only 8% of those with primary antiphospholipid syndrome developed systemic lupus erythematosus or 5% a ‘lupus-​like’ disease over a nine-​year follow-​up interval. The association with thrombosis is more robust in lupus anticoagulant than with anticardiolipin antibodies (OR 11.0 vs. 1.6). For those with antiphospholipid antibodies only, several case–​control studies, and a prospective multicentre study have shown the incidence rate of thrombosis is 1.86% per 100 patients per year. In the obstetric setting, women with antiphospholipid syndrome are at increased risk of recurrent early fetal loss, severe early onset pre-​eclampsia, placental abruption, intrauterine fetal death, or fetal growth restriction without hypertension. Recurrent pregnancy loss in women with antiphospholipid syndrome is typically in the second trimester. Fetal death is typically preceded by fetal growth restriction and superimposed pre-​eclampsia. Quantifying the risk is difficult. In a meta-​analysis, lupus anticoagulant in particular was more strongly and consistently associated with fetal loss (OR 7.79; 95% CI:2.3–​26.45). The pathogenesis of fetal loss in these patients is not fully understood, although a variety of mechanisms have been suggested and there appear to be both thrombotic and inflammatory components. Women with obstetric antiphospholipid syndrome have a much higher risk of severe early onset (10 weeks’ gestation, early onset pre-​eclampsia necessitating 250 cells/​mm3 in spontaneous bacterial peritonitis

Cytology

High yield in ovarian cancer

Amylase

Pancreatic duct leak in chronic pancreatitis from pancreatic injury Rarely associated with jaundice from biliary obstruction

It is also useful in mapping the extent of biliary obstruction in bile duct cancers, particularly hilar cholangiocarcinomas, to help in deciding if stenting will improve jaundice and decide between endoscopic and percutaneous approach. MRCP will also identify chronic pancreatitis and swollen pancreas typical of IgG4 disease. Endoscopic retrograde cholangiopancreatography (ERCP) is also used to confirm diagnosis and for therapy. Pancreatic CT is needed before endoscopic stenting to stage/​assess operability of ampullary, pancreatic, or bile duct cancers because further assessment of operability is impossible if post-​ERCP pancreatitis occurs (1 in 20 risk).

Liver biopsy Liver histology is often needed once posthepatic biliary obstruction and acute viral hepatitis have been excluded, to stage the degree of liver injury, to differentiate acute from chronic liver damage, and to aid diagnosis. It is a major component of the diagnostic criteria for autoimmune liver disease and is often needed to make a diagnosis in the presence of a hepatitic liver function test once acute viral hepatitis has been excluded serologically. Percutaneous liver biopsy has a 0.5% risk of bleeding and a small risk of pneumothorax. Other rare complications include intrahepatic arteriovenous fistulae and haemobilia. Transjugular liver biopsy is indicated in the presence of ascites, a platelet count less than 50 × 109/​litre, and a prolonged prothrombin time. Noninvasive markers of liver fibrosis such as FibroScan are less useful in the presence of jaundice as inflammation can increase FibroScan scores, incorrectly suggesting cirrhosis. Ascites also reduces the sensitivity and specificity of FibroScan.

Other tests In a patient with cirrhosis less than 40 years of age and with haemolysis, particularly in the presence of a normal or low ALP, Wilson’s disease should be considered and examination for Kayser–​Fleischer rings with a slit lamp should be performed.

15.22.1  Investigation and management of jaundice

JAUNDICE

Abnormal ALP/ALT

Normal ALT/ALP Normal albumin/platelets*

Ultrasound scan

No evidence of haemolysis Unconjugated bilirubin

Undilated CBD**/*

Dilated CBD Gilbert’s syndrome

High ALT MRCP/ERCP

See Table 15.22.1.5

High ALP

Exclude drugs AMA MRCP to exclude PSC

No cause identified

Liver biopsy (diagnosis/staging) **If pain and gallbladder stones and elevated ALP or ALT 5%, through inflammatory nonalcoholic steatohepatitis (NASH), to fibrosis or cirrhosis, and in some cases hepatocellular carcinoma. Critically, most patients with NAFLD do not progress beyond steatosis, but a substantial minority do progress to cirrhosis and end-​stage liver disease and so experience associated morbidity and mortality. The presence of NAFLD is also an independent risk factor for development of cardiovascular disease and stroke. The key challenge in the management of NAFLD is to identify the patients at greatest risk of disease progression so that treatment may be targeted at those that will benefit most.

Aetiology Hepatic steatosis and steatohepatitis may be attributable to a diverse range of acquired exposures as well as numerous rare monogenic inherited disorders (summarized in Table 15.24.2.1). The

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NAFLD

Steatohepatitis (NASH)

Steatosis (NAFL)

Fat infiltration >5% with or without mild inflammation

Steatosis + necroinflammation (ballooning, Mallory bodies, megamitochondria)

Cirrhosis

Increasing fibrosis, eventually leading to cirrhosis

Fig. 15.24.2.1  NAFLD—​a spectrum of liver disease. Table 15.24.2.1  Aetiology of steatosis and steatohepatitis Aetiological factor

Predominant pattern of histological steatosis

Metabolic syndrome (obesity, insulin resistance/​ type 2 diabetes mellitus)

Macrovesicular

Starvation and cachexia

Macrovesicular

Protein malnutrition (Kwashiorkor, anorexia nervosa)

Macrovesicular

Dietary choline deficiency

Macrovesicular

Total parenteral nutrition

Macrovesicular

Drugs

Macrovesicular

Aspirin

Microvesicular

Chloroquine

Macrovesicular

Corticosteroids

Macrovesicular

Methotrexate

Macrovesicular

NSAIDs (naproxen, ibuprofen, ketoprofen)

Microvesicular

Nucleoside analogues used in HAART (zidovudine, didanosine, zalcitabine, fialuridine, etc.)

Microvesicular

Oestrogens

Macrovesicular

Tamoxifen

Macrovesicular

Tetracycline

Microvesicular

Valproic acid

Microvesicular

Toxins

Amanita phalloides mushroom poisoning Bacillus cereus emetic toxin

Microvesicular

Carbon tetrachloride Ethanol

Macrovesicular

Petrochemicals Toxic shock syndrome

Predominant pattern of histological steatosis

Genetic factors

Acquired metabolic and/​or nutritional disorders

Amiodarone

Aetiological factor

Microvesicular

Abetalipoproteinaemia

Macrovesicular

Alpers’ disease

Microvesicular

Cholesterol ester storage disease

Microvesicular

Familial combined hyperlipidaemia Familial hypobetalipoproteinaemia Glycogen storage disease Inherited defects in fatty acid β-​oxidation

Microvesicular

Lecithin–​cholesterol acyltransferase deficiency

Microvesicular

Lipodystrophy

Macrovesicular

Lysosomal acid lipase deficiency (Wolman’s disease)

Microvesicular

Ornithine transcarbamylase deficiency

Microvesicular

Wilson’s disease

Macrovesicular

Infections

Chronic hepatitis C (genotype 3)

Macrovesicular

Bacterial overgrowth following jejunoileal bypass

Macrovesicular

Others

Acute fatty liver of pregnancy

Microvesicular

Coeliac disease HELLP syndrome

Microvesicular

Reye’s syndrome

Microvesicular

Metals HAART, highly active antiretroviral therapy; NSAIDs, nonsteroidal anti-​inflammatory  drugs.

15.24.2  Nonalcoholic fatty liver disease

Environmental Factors Diet, Microbiome, Xenobiotics

Genetic & Epigenetic Factors Genetic variants in PNPLA3, TM6SF2, MBOAT7, HSD17B13 DNA methylation

lantation

th or Transp

Risk of Dea

Steatosis

Steatosis + Lobular Inflammation

NASH +/–Portal Inflammation

Early fibrosis

F1

F2

F3

F4

Advanced fibrosis & Cirrhosis

Rates of Fibrosis Progression vary between individuals

Steatotic/Steatohepatitic phase

Fibrotic phase

Fig. 15.24.2.2  Natural history of NAFLD.

most common aetiological factors underlying the development of NAFLD are central obesity, insulin resistance/​type 2 diabetes mellitus, hypertension, and dyslipidaemia, a group of chronic conditions indicative of increased cardiovascular risk that together comprise the ‘metabolic syndrome’. NAFLD is also associated with conditions including polycystic ovary syndrome, obstructive sleep apnoea, and small-​bowel bacterial overgrowth. Due to sedentary lifestyles and the increasing consumption of diets enriched in fats and carbohydrates, the metabolic syndrome is now endemic in many developed countries and so the incidence of NAFLD has risen rapidly to become the leading cause of chronic liver disease worldwide.

Epidemiology The true worldwide prevalence of NAFLD is not known as estimates vary between the populations studied due to different ethnicities, dietary patterns, and the sensitivity of the modality used to detect disease. Overall, however, NAFLD is estimated to affect approximately 20 to 30% of the population in Western countries and 5 to 18% in Asia, with about 1 in 10 NAFLD cases exhibiting features of NASH. Studies from the United States of America indicate that the frequency of steatosis varies significantly with ethnicity (45% in Hispanics, 33% in white people, and 24% in black people) and sex (42% white males vs 24% white females). Prevalence increases dramatically when populations with known metabolic syndrome risk factors are selected. Illustrating this, 91% of obese patients (body mass index (BMI) ≥30  kg/​m2), 67% of overweight (BMI 25–​30 kg/​m2), and 25% in normal weight individuals in an unselected European population sample had NAFLD, and 40 to 70% of patients with type 2 diabetes mellitus also have NAFLD. Of concern, while the prevalence of most liver diseases is stable, the prevalence of NAFLD is increasing, placing a greater burden on healthcare resources.

There is an important paradox: most individuals with features of the metabolic syndrome develop steatosis and so NAFLD is highly prevalent in the general population, but only a subgroup progress to advanced liver disease and experience liver-​related morbidity (Fig. 15.24.2.2). During a median 12.6-​year follow-​up period in a cohort of 619 NAFLD patients, an overall 33.2% risk of death or liver transplantation was observed, with liver-​related mortality being the third most common cause of death, after cardiovascular disease and extrahepatic malignancy. Challenging the dogma that ‘simple’ steatosis is a benign condition with no clinical sequelae, serial biopsy studies indicate that patients with either steatosis or NASH may exhibit progressive fibrosis, with approximately 40% showing increased fibrosis, 40% stable disease, and 20% disease regression over a 6-​to 7-​year period. The presence and severity of hepatic fibrosis on liver biopsy (or as assessed by noninvasive testing) appears to be the single most important determinant of long-​term prognosis, with advanced fibrosis/​cirrhosis (fibrosis stages F3–​4) being predictive of liver-​related events, transplantation, and death in patients with NAFLD. Compared with cases without histological evidence of fibrosis, the presence of early [F1–​2] fibrosis conferred an 11.2-​fold risk. This increased to an 85.8-​fold risk in patients with advanced [F3–​4] fibrosis/​cirrhosis. The average age of NASH patients is 40 to 50 years and for NASH cirrhosis is 50 to 60 years, but the emerging epidemic of childhood obesity means that NAFLD is present in increasing numbers of younger patients and so the age that patients develop significant liver disease is likely to fall.

Pathogenesis/​pathology It is generally accepted that the initiating events in NAFLD are dependent on the development of obesity and insulin resistance. Together these lead to increased fatty acid content in the liver due to the combination of de novo lipogenesis and fatty acid import from

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dietary sources and adipose tissue stores. This places hepatocytes under considerable metabolic pressure, promotes lipotoxicity, increases oxidative stress secondary to free radical production during β-​and ω-​fatty acid oxidation, and induces endoplasmic reticulum stress. Hepatocellular triglyceride accumulation (i.e. steatosis) is the histologically visible evidence of these metabolic stressors but is itself unlikely to be directly harmful to the liver, being an adaptive response through which potentially lipotoxic fatty acids are partitioned into relatively inert intracellular stores. Ultimately, these insults combine with the additive effects of endotoxin-​initiated Kupffer cell cytokine release and immune-​mediated hepatocellular injury to induce cellular damage and activate cell death pathways, marking the transition to steatohepatitis. If these processes persist, stellate cell activation, collagen deposition, and hepatic fibrosis occur. Interpatient variation in disease progression and prognosis is thought to be determined by the combined effects of environmental (dietary and intestinal flora) exposures acting on a susceptible polygenic background. Studies implicate single nucleotide polymorphisms in a number of genes including PNPLA3, TM6SF2, MBOAT7 and HSD17B13 as factors that modify development of NAFLD and subsequent progression of fibrosis.

Clinical features NAFLD is frequently asymptomatic although may be associated with nonspecific symptoms such as fatigue and mild right upper quadrant abdominal discomfort due to steatotic hepatomegaly distending the liver capsule. It is most commonly identified as an incidental radiological finding or a mild biochemical abnormality noted during routine blood tests taken for another indication. Alternatively, patients with progressive NAFLD may present late in the course of disease with complications of cirrhosis and portal hypertension such as variceal haemorrhage, or hepatocellular carcinoma (HCC). HCC is a frequent complication of NAFLD (cumulative incidence 2.4–​12.8%) that may occur in both precirrhotic and postcirrhotic patients. Recognized independent risk factors for NAFLD progression and advanced fibrosis include age greater than 45  years, presence of diabetes (or severity of insulin resistance), obesity (BMI >30  kg/​m2), and hypertension (Table 15.24.2.2). These

factors are clinically useful as they assist with identification of ‘high-​risk’ patient groups. There are no specific physical signs to establish a diagnosis of NAFLD. Hepatomegally may be noted, but abdominal adiposity may hamper effective examination. In the absence of advanced disease, where the classical stigmata associated with the presence of chronic liver disease such as jaundice, spider naevi, and ascites may be apparent, clinical examination is frequently unremarkable. In light of the strong association between NAFLD and the metabolic syndrome, height and weight should be recorded, hip/​waist circumference measured, and evidence of end-​organ damage due to insulin resistance and hypertension sought.

Differential diagnosis Key to the diagnosis of NAFLD is recognition that an individual possesses features of metabolic syndrome (central obesity, insulin resistance/​type 2 diabetes mellitus, dyslipidaemia, and hypertension) and therefore is at risk of NAFLD. The more features of the metabolic syndrome that are present, the higher the probability that a patient has underlying NAFLD and the more likely they are to exhibit steatohepatitis and progressive liver disease. There are many causes for steatosis and steatohepatitis and hence a potentially wide differential diagnosis (Table 15.24.2.1). In practice, the principal differential is between metabolic syndrome-​ related NAFLD and alcoholic liver disease. Discriminating these is reliant upon a detailed history and seeking corroboration from family members (where available) to ensure that any history of concealed excessive alcohol consumption is excluded. An arbitrary threshold for ethanol consumption of less than 20 g/​day for women and less than 30 g/​day for men is adopted to sustain a diagnosis of NAFLD. Metabolic syndrome-​related NAFLD sensitizes the liver to the effects of other injurious processes such as alcohol consumption. As obesity and the wider metabolic syndrome become endemic within the population, the distinction between NAFLD and alcohol-​related liver disease can easily become blurred with these apparently mutually exclusive conditions coexisting in some individuals. To avoid this diagnostic oxymoron, the condition may be described as ‘dual-​aetiology fatty liver disease’.

Table 15.24.2.2  Common risk factors for NAFLD Risk factor

Effect

Age

Higher risk of NAFLD and advanced fibrosis aged >45

Metabolic syndrome (obesity, insulin resistance/​type 2 diabetes mellitus, dyslipidaemia, and hypertension)

70–​90% of metabolic syndrome patients have NAFLD. The more features an individual possesses, the greater the likelihood of NASH and severity of fibrosis

Sex

Males >females

Ethnicity

High risk in Hispanics, white individuals intermediate, lower risk in black individuals

Dietary factors

Diets high in cholesterol, saturated fats, and fructose but low in carbohydrate increase risk Caffeine may be protective

Obstructive sleep apnoea

Increased risk of hepatic fibrosis

Genetic factors

Variants in Patatin-​like phospholipase domain-​containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genes are associated with greater steatosis, NASH, and more advanced liver fibrosis. PNPLA3 mutations also increase the risk of NAFLD-​associated hepatocellular carcinoma

15.24.2  Nonalcoholic fatty liver disease

A detailed drug history including prescribed medication, over-​ the-​counter medication, and traditional/​herbal remedies should be taken.

hepatitis, and haemochromatosis respectively. Raised ferritin levels and the presence of increased IgA levels are indicative but not diagnostic of more advanced fibrosis.

Radiological studies

Clinical investigation Once excessive alcohol consumption has been excluded and other confounding environmental factors discounted, investigation of suspected NAFLD should be directed first towards exclusion of other liver diseases and then confirming the presence of NAFLD: • Exclusion of other liver diseases:  laboratory testing should confirm absence of chronic viral hepatitis (hepatitis B virus surface antigen and hepatitis C virus serology), autoimmune liver disease (antinuclear antibodies, antimitochondrial antibodies, smooth muscle antibodies, liver–​kidney microsomal type 1 antibodies, immunoglobulins) and other treatable metabolic diseases (haemochromatosis, Wilson’s disease, coeliac disease, α1 antitrypsin deficiency). • Confirmation of the presence of NAFLD:  may be obtained radiologically or histologically. • Assessment of underlying liver damage: discriminating steatosis from NASH and determining the extent of hepatic fibrosis present (i.e. grade and stage of disease) is important to assist with individual risk stratification and prognostication. This has traditionally necessitated liver biopsy for histological assessment, but techniques for noninvasive testing to detect significant liver fibrosis are becoming more robust.

Biochemical tests The diagnosis, staging, and long-​term follow-​up of NAFLD is made more complicated as there is no single blood test that is diagnostic for NAFLD or which can be used to accurately determine disease severity and treatment response. Aminotransferases Elevations of serum alanine transaminase (ALT) and aspartate transaminase (AST) are modest and usually less than twice the upper limit of normal. Although many NAFLD cases are first detected due to the incidental finding of a mild transaminitis, these routine biochemical tests are insensitive with approximately 80% of patients having normal-​range ALT levels. Indeed, ALT levels fall as hepatic fibrosis progresses and so the characteristic AST/ALT ratio of less than 1 commonly seen in NAFLD reverses (AST/ALT >1) as fibrosis progresses toward cirrhosis, meaning that fibrosing steatohepatitis and/​or advanced liver disease may be present even in those with normal-​range ALT levels. Other biochemical markers Other laboratory abnormalities that may be present include non­ specific elevations of γ-​glutamyl transferase, low-​titre antinuclear antibodies, and/​or antismooth muscle antibody in 20 to 30% of patients, and elevated ferritin levels despite normal transferrin saturation. These can lead to diagnostic uncertainty as they may be incorrectly ascribed to high alcohol consumption, autoimmune

Steatosis can readily be detected by various imaging modalities. Ultrasonography is widely available and cost-​effective and is therefore most often used. A  steatotic liver appears ‘bright’ due to increased echogenicity, but this finding is subjective and provides only a qualitative assessment of hepatic fat content. Sensitivity of ultrasonography is poor when less than 33% of hepatocytes are steatotic and so significant steatosis can be missed. Alternatives include CT, MRI-derived Proton Density Fat Fraction (MRI-PDFF), or magnetic resonance spectroscopy, which offer greater sensitivity for detecting lesser degrees of steatosis but are resource intensive and not widely used in routine practice. Currently no widely available clinical imaging modality can distinguish steatosis from steatohepatitis or accurately quantify intermediate stages of fibrosis short of cirrhosis.

Assessing the severity of the underlying liver disease In the absence of routinely available ‘standard’ tests to confirm the diagnosis, assess the degree of inflammation, and accurately determine the extent of liver fibrosis to assist prognostication, liver biopsy is commonly used and remains the ‘gold standard’ investigation. However, it is invasive, carries a modest but appreciable risk of complications, and is unsuitable for widespread use outside the secondary care setting. Several noninvasive techniques, both commercial and noncommercial, have been proposed that may be used to predict the presence of NAFLD or the stage of fibrosis. The performance of selected tests that are commonly used are summarized in Table 15.24.2.3. Of these, simple scores like the NAFLD Fibrosis Score and FIB-​4 Score, or specialist panels such as the Enhanced Liver Fibrosis (ELF) Test, offer the ability to rule out significant underlying liver disease (fibrosis stages F3–​4) with a high degree of confidence and so are widely used to assist risk stratification, enabling invasive testing to be reserved for those where it may offer clinically relevant additional information. All three tests have also been shown to be predictive of long-​term disease outcome and mortality. Techniques that measure liver stiffness as a surrogate for fibrosis severity, such as ultrasonography-​based transient elasto­ graphy (Fibroscan), are also widely adopted, although adiposity can interfere with accuracy in some patients. Promising alternatives that are emerging include acoustic radiation force impulse imaging and magnetic resonance elastography. In general, noninvasive techniques have good negative predictive values for advanced fibrosis but more modest specificity and so lower positive predictive values. A suggested algorithm for the assessment and risk stratification of patients with NAFLD is provided in Fig. 15.24.2.3. Histology NAFLD ranges from hepatic steatosis, through inflammatory steatohepatitis, to fibrosis or cirrhosis (Fig. 15.24.2.1). The histological classification of NAFLD, which allows grading of disease

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Table 15.24.2.3  Noninvasive tests for NAFLD and NAFLD fibrosis Test

Formula

Sensitivity and specificity

Fatty Liver Index (FLI) predicts NAFLD

FLI = (e 0.953 × loge (triglycerides) + 0.139 × BMI + 0.718 × loge (γGT) + 0.053 × waist circumference − 15.745)/​(1 + e 0.953 × loge (triglycerides) + 0.139 × BMI + 0.718 × loge (γGT) + 0.053 × waist circumference − 15.745) × 100

High risk (FLI >60) Intermediate (FLI 30–​60) Low risk (FLI 0.676): Se 0.51, Sp 0.98, PPV 0.90, NPV 0.85 Indeterminate (NFS −1.455 to 0.676). Low risk (NFS 2.67): Se 0.33, Sp 0.98, PPV 0.80, NPV 0.83 Indeterminate (1.30–​2.67) Low risk (FIB-​4  0.3576): Se 0.80, Sp 0.90, PPV 0.71, NPV 0.94 Low risk (ELF < 0.3576)

Fibroscan predicts advanced fibrosis [F3–​4]

Ultrasonography-​based transient elastography measures the velocity of an elastic shear wave propagating through the liver to assess liver stiffness. Three probes S, M, and XL are used according to body habitus. Greater adiposity may limit test accuracy

High risk (M >9.6 kPa; XL >9.3 kPa): M/​XL Se 0.75/​0.57, Sp 0.92/​0.90, PPV 0.72/​0.71, NPV 0.93/​0.84 Indeterminate (M 7.9–​9.6; XL 7.2–​9.3) Low risk (M 4 foci per ×20 field

(S) Steatosis score 0–​3 Hepatocyte ballooning

PLUS

2 PLUS Inflammation

PLUS 0 1 2

None < 2 foci per 20× field > 2 foci per 20× field

(A) Total = activity score 0–​4 Fibrosis

Hepatocyte ballooning

0 1a 1b 1c 2 3 4

Inflammation

(NAS) Total = NAFLD activity score 0–​8 No fibrosis Zone 3 mild perisinusoidal Fibrosis Zone 3 moderate Perisinusoidal fibrosis Periportal/​portal fibrosis only Zone 3 plus portal/​periportal fibrosis Bridging fibrosis Cirrhosis

(F) Fibrosis score 0–​4

of thiazolidinediones in patients with diabetes has been associated with congestive heart failure, bladder cancer, and bone fractures. Preliminary data suggests that the glucagon-​like peptide-​1 agonist Liraglutide may be beneficial in slowing NAFLD progression, which effect may be largely through weight loss. Vitamin E (800 IU/​day) has been shown to lower ALT levels and to ameliorate histological steatohepatitis in pre-cirrhotic, nondiabetic patients in the PIVENS and TONIC trials, but a clear benefit on liver fibrosis was not demonstrated. Concern regarding an association with increased all-​cause mortality and prostate cancer mean that its use remains controversial, but it is considered by many to be a first-​ line therapy for selected patients with histologically confirmed NASH without cirrhosis or type 2 diabetes. A Cochrane analysis in 2017 of pharmacological interventions for NAFLD found most of the evidence to be of very low quality and concluded that there was no proven benefit for the majority of agents tested up to that point. However, there is substantial drug development activity in this field with a number of pharmacological agents currently in clinical trials such as FXR agonists, PPARa/d/g agonists and CCR2/5 antagonists. It is therefore likely that additional, liver-​ directed therapies will become available within the next few years.

Prognosis The presence of NAFLD appears to be associated with greater all-​cause mortality, estimated to be 34 to 69% higher than the age and sex-​ matched general population. In most cases it has an indolent course, with patients ultimately succumbing to nonhepatic causes of death (principally cardiovascular disease), but some patients exhibit a more aggressive and rapidly progressive form of disease that leads to cirrhosis.

Fibrosis

0 1a 1b 1c 2 3 4

No fibrosis Zone 3 mild perisinusoidal Fibrosis Zone 3 moderate Perisinusoidal fibrosis Periportal/​portal fibrosis only Zone 3 plus portal/​periportal fibrosis Bridging fibrosis Cirrhosis

Fibrosis score 0–​4

FURTHER READING Natural history Angulo P, et al. (2015). Liver fibrosis, but no other histologic features, is associated with long-​term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology, 149, 389–​97.e10. Anstee QM, Targher G, Day CP (2013). Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol, 10, 330–​44. Ekstedt M, et al. (2015). Fibrosis stage is the strongest predictor for disease-​specific mortality in NAFLD after up to 33 years of follow-​ up. Hepatology, 61, 1547–​54. McPherson S, et al. (2015). Evidence of NAFLD progression from steatosis to fibrosing-​steatohepatitis using paired biopsies: Implications for prognosis and clinical management. J Hepatol, 62, 1148–​55. Musso G, et al. (2011). Meta-​analysis: natural history of non-​alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-​invasive tests for liver disease severity. Ann Med, 43, 617–​49.

Diagnosis and risk-​stratification Angulo P, et al. (2007). The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology, 45, 846–​54. Anstee Q, Day C (2015). The genetics of non-​alcoholic fatty liver disease:  spotlight on PNPLA3  & TM6SF2. Semin Liver Dis, 35, 270–​90. Burt AD, Lackner C, Tiniakos DG (2015). Diagnosis and assessment of NAFLD:  definitions and histopathological classification. Semin Liver Dis, 35, 207–​20. Dyson JK, McPherson S, Anstee QM (2013). Non-​alcoholic fatty liver disease:  non-​invasive investigation and risk stratification. J Clin Pathol, 66, 1033–​45.

15.24.3  Drug-induced liver disease

Therapy Gawrieh S, Chalasani N (2015). Pharmacotherapy for non-​alcoholic fatty liver disease. Semin Liver Dis, 35, 338–​48. Lombardi R, et  al. (2017). Pharmacological interventions for non-​ alcohol related fatty liver disease (NAFLD): an attempted network meta-​analysis. Cochrane Database Syst Rev, 3, CD011640. Nguyen V, George J (2015). Non-​alcoholic fatty liver disease management: dietary & lifestyle modifications. Semin Liver Dis, 35, 318–​37.

15.24.3  Drug-​induced liver disease Guruprasad P. Aithal ESSENTIALS Drug-​induced liver disease encompasses a wide range of pathology including idiosyncratic drug-​induced liver injury (DILI), acute fatty liver, autoimmune hepatitis, sclerosing cholangitis, granulomatous hepatitis, and nodular regenerative hyperplasia, as well as drug-​ associated fatty liver disease, cirrhosis, and liver tumours. The vast majority of commonly used drugs are reported to be associated with DILI, including over-​the-​counter preparations, herbal remedies, and dietary supplements. It is important to consider drug therapy as an aetiology when assessing patients presenting with hepatocellular or cholestatic patterns of liver injury. Systematic evaluation and prompt diagnosis followed by discontinuation of the particular medication is crucial to prevent the development of acute liver failure and to avoid inappropriate investigations. Both candidate gene and genome-​wide association studies have identified the critical role of the adaptive immune system in the pathogenesis of idiosyncratic DILI. Human leucocyte antigen alleles that are strongly associated with DILI have the potential to assist in the clinical investigation of patients suspected to have DILI in particular circumstances.

Introduction The term hepatotoxicity has been used nonspecifically in the literature to describe the pathological process leading to hepatocyte death and liver injury from medications, alcohol, illicit drugs, and environmental toxins as well as overdoses. Drug-​induced liver disease encompasses a wide range of pathologies where drug therapy has been implicated as an underlying aetiology. Over 350 medications have been associated with adverse effects on the liver, which is probably due to the central role of the liver in the metabolism and clearance of most drugs. Idiosyncratic drug-​induced liver injury (DILI) is defined as an adverse hepatic reaction that is unexpected on the basis of the pharmacological action of the drug administered; this includes acute liver injury, the most common form, and should be distinguished from the consequences of drug overdose.

Case definitions and phenotypes Liver biochemical tests are most commonly used in clinical practice to detect liver injury. These generally include serum alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, and albumin. Case definitions for DILI include one of the following thresholds: (1) fivefold or higher elevation above the upper limit of normal (ULN) for ALT, (2) twofold or higher elevation above the ULN for ALP (particularly with accompanying elevations in concentrations of γ-​glutamyl transferase in the absence of known bone pathology driving the rise in ALP level), or (3) threefold or higher elevation in ALT concentration and simultaneous elevation of bilirubin concentration exceeding twice the ULN. Liver injury is designated ‘hepatocellular’ when there is a fivefold or higher rise in ALT alone, or when the ratio of serum activity (activity is expressed as a multiple of ULN) of ALT to ALP is 5 or more. Liver injury is designated ‘cholestatic’ when there is a twofold or higher rise in ALP alone, or when the ratio of serum activity of ALT to ALP is 2 or less. When the ratio of the serum activity of ALT to ALP is between 2 and 5, liver injury is termed ‘mixed’. Several other distinct phenotypes of drug-​induced liver diseases are discussed in this chapter. Each of these forms is identified using the same characteristic features as used to define the primary condition such as autoimmune hepatitis, primary sclerosing cholangitis, and others.

Epidemiology Standard toxicological studies during the preclinical phase of drug development do not reliably detect potential hepatotoxicity of a novel agent; the concordance between liver toxicity in animals and humans is poor. Hepatic adverse reactions are therefore one of the top three organ toxicities identified in phase I to III trials, and are responsible for 22% of 79 drug candidates being dropped from clinical development. As hepatic adverse reactions are too low in incidence to be detected in clinical trials, the hepatotoxic potential of new medications may only be recognized when a large number of people have been exposed to the drug; therefore, hepatotoxicity has been the second most common reason for withdrawal of approved drugs from the market worldwide, accounting for 32% of 47 such drug withdrawals between 1975 and 2007.

Incidence and prevalence of DILI Idiosyncratic DILI due to commonly used medications continues to be encountered in clinical practice. A prospective population-​based study from Iceland estimated the crude incidence of DILI to be 19 per 100 000 inhabitants per year. The incidence of DILI was similar in women and men, but increased from 9 per 100 000 among 15-​to 29-​year-​olds to 41 per 100 000 among those over 70 years of age. The increase in DILI incidence with age has been attributed to increasing use of medications with age. The incidence of acute serious liver injury requiring hospitalization has been estimated to be 0.7 to 1 per 100 000 population per year. In a recent audit from the United Kingdom, involving 881 consecutive patients presenting with jaundice in whom biliary obstruction had been ruled out by imaging, DILI was the underlying

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aetiology in 15% of cases and the second most common cause of hepatocellular jaundice after alcoholic liver disease, which accounted for 25% of cases. Idiosyncratic DILI contributes to 7 to 22% of cases of acute liver failure worldwide, highlighting the potentially serious consequences of this adverse reaction.

on re-​exposure) were described with over 90% of these agents, and all of these drugs were linked to death. Table 15.24.3.1 includes a list of common agents associated with particular forms of drug-​induced liver disease.

Drugs implicated

In the population-​based cohort, 1% of patients presenting with DILI die, while large registries of idiosyncratic DILI (consisting mainly of cases from secondary care) report that 5 to 10% of patients die or receive liver transplantation in a period of 6 months after DILI onset. Those who present with jaundice are more likely to reach these outcomes compared to those who present with less severe manifestations (13 vs 4%), and a hepatocellular pattern of DILI has a worse prognosis than a cholestatic or mixed pattern. The prognosis of those who develop acute liver failure as a consequence of idiosyncratic DILI is worse than that due to other aetiologies. Once acute liver failure develops in patients with DILI, 50 to 80% either die or require transplantation in contrast to 15 to 40% of those secondary to paracetamol overdose. Acute liver injury due to drugs resolves in those who survive the initial episode, but evidence of persistent liver injury (‘chronicity’) 12 months after the onset of DILI has been observed in a small, yet significant proportion of patients on long-​term follow-​up. Several longitudinal cohorts have reported that 6 to 14% of patients have persistent elevation of liver enzymes. In those who were investigated with liver biopsy, chronic hepatitis, fibrosis, ductopenia (vanishing bile duct syndrome), and cirrhosis have been detected histologically. Among 685 survivors of DILI with jaundice at presentation from one cohort, 3.4% were hospitalized over 10 years of follow-​up for reasons related to their liver disease. Diagnoses of autoimmune

Spontaneous reporting, case reports or series, and more recently hepatotoxicity registries have been the main source of information regarding hepatic adverse reaction due to specific drugs or a class of drugs. In addition to variability of reporting, lack of an accurate denominator (number of people taking the particular medication) means that neither the incidence of DILI due to a particular medication nor its relative contribution to the burden of DILI can be reliably estimated. This issue has been exemplified by the findings of a recent prospective study which estimated that 1 in 2350 taking co-​amoxiclav and 1 in 133 on azathioprine developed DILI when compared to previous estimates of 1 in 10000 and 3.4 in 100, respectively. A systematic evaluation of reports of hepatotoxicity due to drugs compiled at the website LiverTox (established by the National Institutes of Health, Bethesda, Maryland, United States of America) has resulted in the categorization of drugs based on the number of convincing reports in the published literature. This process concluded that 353 drugs (excluding herbal remedies, dietary supplements, and illicit substances) were linked to DILI, of which 48 were implicated in more than 50 cases each and included in the highest category of causes of DILI (the vast majority are listed in Table 15.24.3.1). Over 80% of the drugs included in this category were associated with more than 100 reports of DILI, positive rechallenge (recurrence of DILI

Prognosis

Table 15.24.3.1  Common drugs associated with specific forms of drug-​induced liver diseases Phenotype of liver disease

Drug group

Medications

Idiosyncratic DILI

Antimicrobials

Co-​amoxiclav, erythromycin, flucloxacillin, interferon alpha/​peginterferon, isoniazid, ketoconazole, minocycline, nevirapine, nitrofurantoin, pyrazinamide, rifampicin, co-​trimoxazole, and sulphonamides

Central nervous system

Carbamazepine, chlorpromazine, dantrolene, halothane, phenytoin, and valproate

Cardiovascular

Amiodarone, hydralazine, methyldopa, quinidine, statins (atorvastatin and simvastatin)

Immunomodulatory

Azathioprine/​6-​mercaptopurine, infliximab, interferon beta, methotrexate, and thioguanine

Antineoplastic

Busulfan, floxuridine, and flutamide

Rheumatological

Allopurinol, auranofin/​gold products, diclofenac, ibuprofen, nimesulide, and sulindac

Endocrine

Anabolic androgenic steroids, oestrogens/​progestins, and propylthiouracil

Others

Disulfiram and ticlopidine

Autoimmune hepatitis

Diclofenac, halothane, indomethacin, infliximab, methyldopa, minocycline, nitrofurantoin, and statins

Secondary sclerosing cholangitis

Amiodarone, atorvastatin, co-​amoxiclav, gabapentin, infliximab, 6-​mercaptopurine, sevoflurane, and venlafaxine

Granulomatous hepatitis

Allopurinol, carbamazepine, methyldopa, phenytoin, quinidine, and sulphonamides

Acute fatty liver

Amiodarone, didanosine, stavudine, valproate, and zalcitabine

Drug-​associated fatty liver disease

Methotrexate, 5-​fluorouracil, irinotecan, and tamoxifen

Nodular regenerative hyperplasia

Azathioprine, busulphan, bleomycin, cyclophosphamide, chlorambucil, cysteine arabinoside, carmustine, doxorubicin, 6-​ thioguanine, and oxaliplatin

Ductopenic (vanishing bile duct) syndrome

Azathioprine, androgens, co-​amoxiclav, carbamazepine, chlorpromazine, erythromycin, oestradiol, flucloxacillin, phenytoin, terbinafine, co-​trimoxazole

Liver tumours

Anabolic androgenic steroids and oral contraceptives

15.24.3  Drug-induced liver disease

hepatitis as well as cirrhosis leading to decompensation and death were observed as long-​term outcomes.

Risk factors Pathogenesis of DILI involves interaction of a number of drug and host-​related factors which determine the occurrence of these rare events during entirely appropriate therapeutic use of medications (Fig. 15.24.3.1). There are indications that certain risk factors may also influence the phenotype of the adverse reaction, its severity, or duration.

Nongenetic factors Idiosyncratic DILI is clearly distinct from overdose, but the therapeutic dose of a drug could influence the amount of reactive metabolite formed and hence make further downstream events leading to clinical DILI more likely. Drugs with a daily dose of up to 10 mg are less likely to be associated with DILI than those with a dose of at least 50 mg/​day dose. The latter group of drugs is also associated with severe consequences of DILI, such as acute liver failure, transplantation, and death. Similarly, medications with greater than 50% hepatic metabolism and biliary excretion are more frequently associated with severe DILI. Although there is no clear association between age and sex and susceptibility to DILI, these host factors may influence the phenotype of DILI; while hepatocellular pattern of DILI is more common in women less than 50 years of age, men over 60 years of age develop a predominantly cholestatic pattern of DILI.

Genetic susceptibility Absorption, distribution, metabolism, and excretion genes Since drug absorption, distribution, metabolism, and excretion are the key determinants of variability in drug responses in humans, genes that encode proteins involved in regulating these aspects of drug disposition have been investigated as risk factors for DILI.

Daily dose, hepatic metabolism, biliary excretion

HLA genotypes

Cytochrome P450, UDP-glucuronosyl transferase, Nacetyltransferases, pregnane X receptor, ABC transporters

Fig. 15.24.3.1  Genetic and nongenetic risk factors that contribute to the development of DILI.

Cytochrome P450 Genes from the cytochrome P450 family have potentially a key role in determining susceptibility to DILI due to the involvement of these enzymes in oxidative metabolism of drugs, including the formation of reactive intermediates. One such example is that of bosentan (the endothelin receptor antagonist)-​related DILI with the CYP2C9*2 variant which is associated with decreased enzyme activity. Isoform CYP2B6 has been linked to DILI secondary to ticlopidine and efavirenz; oxidative metabolism of both of these drugs is mediated by CYP2B6 enzyme activity. The alleles CYP2B6*1H and *1J associated with increased CYP2B6 activity have been found to increase the risk of ticlopidine DILI, while the CYP2B6*6 allele, associated with decreased CYP2B6 activity and higher levels of plasma efavirenz, is a risk factor for DILI from this drug. UDP glucuronosyltransferases Conjugation with glucuronic acid is a major pathway of drug metabolism. Drugs which include carboxylic acid groups form acyl glucuronides, and these conjugates may form covalent adducts with cellular proteins leading ultimately to DILI. Other glucuronides such as phenol glucuronides have also been implicated in DILI. Slow metabolism of tolcapone may be associated with hepatotoxicity as polymorphisms in the gene encoding the main tolcapone metabolizing enzyme UGT1A6 are significantly associated with elevated transaminase levels. Another UDP-​glucuronosyltransferase gene UGT2B7 has been linked to liver injury from diclofenac. Possession of UGT2B7*2 is associated with higher glucuronidation and increased hepatic levels of diclofenac acyl glucuronide, hence an increased risk of hepatic adverse reaction. In addition, a recent genome wide association study (GWAS) demonstrated that two intronic single nucleotide polymorphisms (SNPs) in UGT2B7 and another in the adjacent UGT2B4 gene were associated with DILI due to diclofenac. N-​acetyltransferases The N-​acetyltransferases conjugate xenobiotics with acetyl groups; NAT1 and NAT2 are two isoforms. Isoniazid, an essential component of most antituberculosis regimens, is metabolized by genetically polymorphic N-​acetyltransferase 2 (NAT2). NAT2 metabolic activity depends on the number of active alleles (NAT2*4 and *12). A  meta-​analysis of 38 studies involving 2225 patients and 4906 controls concluded that slow acetylators (without any active alleles) develop hepatotoxicity more often than rapid acetylators (with two active alleles); the risk ratio of the association between NAT2 genotype and adverse hepatic reaction varied among different ethnic groups. ATP-​binding cassette transporters ATP-​ binding cassette (ABC) transporter family gene products transport both bile acids and drugs. ABCC2 has a major role in the biliary excretion of many glucuronide conjugates. Carriage of an upstream SNP in ABCC2 (C-​24T) has been associated with the risk of DILI among diclofenac users; this SNP lowers the expression of the ABCC2 protein and leads to cellular accumulation of the reactive diclofenac acyl glucuronide. In a study based in Korea, one SNP in linkage disequilibrium with C-​24T and another in the promoter region of ABCC2 were risk

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factors for DILI caused by a range of drugs. Genotypes of ABCB1 which codes for another transporter have been associated with DILI due to nevirapine. Pregnane xenosensing receptor The nuclear receptor pregnane xenosensing receptor (PXR) is a transcriptional regulator for several genes responsible for metabolism and disposition of both drugs and endogenous factors such as bile acids. Numerous drugs act as PXR agonists. SNPs in the PXR gene (NR1I2) have been associated with an increased risk of DILI due to flucloxacillin and diclofenac. Antioxidant genes It is plausible that an individual’s ability to deal with oxidative stress generated by reactive metabolites is one of the determinants of susceptibility to DILI. Accordingly, genotypes of isoforms of glutathione S-​transferases (GSTM1 and -​T1), glutathione peroxidase I  (GPX1), and mitochondrial manganese-​dependent superoxide dismutase (SOD2) have been investigated as risk factors for DILI. Perspective Overall, it is difficult to draw firm conclusions from the studies discussed previously due to heterogeneity between the cohorts and lack of replication. It is also important to note that most of the evidence related to the role of absorption, distribution, metabolism, and excretion genes in DILI has come from candidate gene case–​control studies with small sample sizes, variable case definitions, and the modest relative risks associated with particular alleles or genotypes. Human leucocyte antigen genetic risk factors Several candidate gene studies and GWAS have found consistent associations between both human leucocyte antigen (HLA) class I as well as class  II alleles and DILI. Strongest of such associations is that between HLA‐B*5701 and flucloxacillin-​induced liver injury, where 84% of patients carried the risk allele (compared to 5% of the population-​based controls) with an 81-​fold increased risk of DILI. HLA class II haplotype DRB1*1501-​DQB1*0602 has been found to be a risk factor for co-​amoxiclav DILI consistently across different ethnic groups; the haplotype is found in 53 to 70% of patients compared to 12 to 33% of controls. Association between DILI due to lapatinib (a kinase inhibitor) and DRB1*07:01-​DQA1*02:01 has also been confirmed in two different cohorts. However, as there is extensive linkage disequilibrium in the major histocompatibility complex (MHC) region, it is difficult to conclude that HLA alleles which have the strongest associations are causally related to particular forms of DILI. In addition to influencing the susceptibility to DILI, specific HLA genotypes have also shown protective associations; an 80% reduction in co-​amoxiclav DILI was seen in those carrying the DRB1*07 allele. In contrast, DRB1*07 is associated with an increased risk of flucloxacillin DILI, while DRB1*15 is associated with a reduced risk. Recently, a GWAS demonstrated an association between the HLA class I allele A*33:01 and DILI in general, and the cholestatic or mixed form of DILI in particular. DILI secondary to a number of structurally dissimilar compounds including terbinafine, fenofibrate, ticlopidine, sertraline, enalapril, and erythromycin contributed to this association, highlighting a crucial role for adaptive immune response in the pathogenesis of DILI.

Pathogenesis It is increasingly clear that the grouping of DILI as metabolic or immunological idiosyncrasy is too simplistic. The rarity of idiosyncratic DILI among those exposed to a drug indicates that combinations of a number of drug-​specific and host-​related factors are involved in its pathogenesis.

Formation of protein reactive molecules (haptens) Drugs (prohaptens) in general are low molecular weight organic chemicals and therefore too small to be antigenic. The liver is central to the biotransformation of most drugs, a process which generally leads to the formation of stable metabolites and their safe excretion. Genetic and environmental factors that influence the expression and activities of the drug metabolizing enzymes (phases I and II), transporters involved in the excretion (phase III) of drug metabolites, and PXRs that regulate a number of these processes, together determine the rate of formation and accumulation of reactive metabolites. Overwhelming oxidative stress induced by reactive metabolites can lead to hepatocellular injury, particularly when cellular defence is impaired or these reactive metabolites covalently bind to cellular proteins interfering with vital cellular function. However, unlike in the case of hepatotoxicity as a result of paracetamol overdose, formation of reactive metabolites alone is insufficient to cause clinically significant idiosyncratic DILI. Instead, development of subclinical hepatocyte injury may underlie asymptomatic elevations of liver enzymes seen more frequently in association with exposure to medications. These initial steps are probably necessary precursors of downstream events in pathogenesis (Fig. 15.24.3.2), hence drug-​ specific factors such as daily dose, lipophilicity, hepatic metabolism, and biliary excretion influence the hepatotoxic potential of a particular compound.

Role of drug-​specific antigens and antibodies The importance of further downstream events in the development of DILI is highlighted by the fact that an increasing number and range of medications such as diclofenac, antibiotics, and antitubercular agents taken in their standard therapeutic doses have been associated with drug metabolite–​protein adducts. Antibodies to drug-​ related adducts have also been found in those taking diclofenac in the absence of DILI, although these adducts have been detected more frequently in patients with DILI. A  wide range of anti-​isoniazid, anticytochrome P450, and autoantibodies have been demonstrated in most of a group of patients with antituberculosis therapy-​induced acute liver failure, although the role of these antibodies in the development of organ damage remains unclear.

Adaptive immune response The observations that there is a period of latency between the exposure to the drug and manifestation of DILI, as well as its recurrence with the re-​exposure to the drug (consistent with the formation of memory T cells) following its initial resolution on drug withdrawal, suggest that the adaptive immune response contributes to underlying mechanisms. Emerging evidence from recent GWASs further establishes a central role of components of the adaptive immune system, especially drug-​specific T cells, in mediating the immune responses in the pathogenesis of DILI.

15.24.3  Drug-induced liver disease

activated T cell destroys hepatocyte

HEPATOCYTE endogenous protein

BILE CANALICULUS

no presentation so no response

processing + HLA

Covalent adduct

DRUG

CD8+ T CELL

self protein gives no response

metabolite

metabolite Covalent adduct

MHC I presentation

DRUG

activates cytotoxic immune response

Hapten pathway TCR

damage ‘danger’ signals

metabolite

DRUG

Covalent adduct

non-covalent

Covalent adduct direct bindin

g

no APC required

pi pathway MHC II presentation

APC

CD4+ T CELL

DRUG

endocytosis

MEMORY B CELL Antibodies

pi pathways proliferation

Covalent adduct

altered peptide repertoire pathways

processing + HLA

activates immune responses

Y Y Y

Y Y

endogenous protein

B CELL

Hapten pathway other endogenous proteins

if costimulation by cytokines/danger signals

Fig. 15.24.3.2  Putative mechanisms underlying the pathogenesis of idiosyncratic DILI. pi, pharmacological interaction.

HLA molecules are central to the activation of T cells responsible for initiating the inappropriate immune response that underlies DILI. Both branches of the highly specific adaptive immune response rely on the selective presentation of antigens to T cells by HLAs, highly polymorphic proteins also known as MHC proteins. MHC class I molecules are expressed by almost all nucleated cells, including hepatocytes as well as biliary epithelial cells, and these are encoded by the HLA-​A, HLA-​B, and HLA-​C loci. MHC class I proteins usually associate with peptide antigens consisting of 9 to 11 amino acids generated by the partial degradation of self-​proteins which could include drug metabolite–​ cellular protein adducts. The MHC I–​antigen complex is then expressed on the cell surface and elicits an immune response if a non-​self antigen is recognized,

causing the activation of CD8+ T cells, which leads to the cell-​ mediated killing of the original cell. The first GWAS involving DILI demonstrated that possession of the HLA-​B*5701 allele was associated with an 81-​fold increased risk of DILI on exposure to flucloxacillin when compared with ancestry-​matched controls. Another GWAS involving co-​amoxiclav DILI described a novel association involving HLA-​A*02:01. Both flucloxacillin and co-​amoxiclav DILI cohorts include a predominantly cholestatic/​ mixed pattern of DILI cases. Most recently, a GWAS demonstrated an association between DILI, treated as a single phenotype, and HLA-​A*33:01; this association was stronger with cholestatic/​mixed pattern of cases and strongest with terbinafine DILI.

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MHC class II proteins are only expressed by specialized antigen-​ presenting cells and are encoded by the HLA-​DP, HLA-​DQ, and HLA-​DR loci within the MHC genetic region. MHC class II proteins have a larger binding cleft that can accommodate 12 to 25 residues of an antigenic peptide often derived from an extracellular, non-​ self protein (processed in the endosome following endocytosis). These MHC class  II–​antigen complexes are recognized by CD4+ T cells, which subsequently elicit an immune response. The association of a single HLA allele with DILI due to several chemically unrelated compounds has been observed in relation to the association of DRB1*15:01 with co-​amoxiclav and lumiracoxib, as well as DRB1*07:01 with DILI from lapatinib and ximelagatran. The associations of A*33:01 with DILI in general and DILI secondary to a number of structurally dissimilar compounds including terbinafine, fenofibrate, ticlopidine, sertraline, enalapril, and erythromycin, together with recent findings from in vitro studies on T-​cell responses to flucloxacillin and amoxicillin–​clavulanate, support the hypothesis that either the parent drug or metabolites bind covalently to cellular or circulating protein to form adducts. The drug metabolite–​protein complex then binds to the peptide binding groove of HLA molecules leading to activation and differentiation of T cells with a consequent adaptive immune response-​mediated liver injury (Fig. 15.24.3.2). Evidence that most drugs showing the A*33:01 association undergo hepatic metabolism and biliary excretion may explain the association of A*33:01 with a cholestatic pattern of DILI and could indicate that metabolites contribute to the mechanism leading to hepatotoxicity. In the case of co-​amoxiclav, neither the amoxicillin nor the clavulanic acid components are subject to P450-​mediated metabolism, and in the case of flucloxacillin, the extent of metabolism is very limited. However, activation of T cells by flucloxacillin requires covalent binding to protein and presentation of the drug by antigen-​ presenting cells expressing HLA-​B*57:01; broadly similar findings have been reported for co-​amoxiclav-​induced T-​cell proliferation. Pharmacological interaction concept The pharmacological interaction concept hypothesizes that drugs act directly via noncovalent interactions with MHC proteins or T-​ cell receptors without the presence of an antigenic peptide. Drugs could also interact with peptides that are already associated with an MHC molecule to activate T cells. In the case of ximelagatran, neither the drug nor its metabolites bind covalently to proteins specifically, hence neoantigen formation required for the hapten pathway does not occur. However, in vitro studies have demonstrated that ximelagatran as well as its intermediate metabolite melagatran-​ethyl can directly bind to an HLA-​DRB1*0701 molecule, indicating that pharmacological interaction may be the underlying mechanism leading to the activation of immune response (Fig. 15.24.3.2). Altered peptide repertoire model According to this model, drugs can noncovalently occupy sites within the peptide binding groove of MHC proteins, hence altering the specificities of the MHC peptide binding. This leads to the presentation of self-​peptide antigens that are different to those normally bound. This has been proposed as the central mechanism mediating the cutaneous hypersensitivity reaction secondary to abacavir. In the experiments that described this mechanism, flucloxacillin did

not modify the affinity of HLA-​B*5701-​binding peptides for HLA, indicating that the particular mechanism may not be involved in DILI.

Danger signal This ‘costimulation or danger hypothesis’ proposes that immune activation requires two signals, first an engagement of the T-​cell receptor with an MHC–​peptide complex presenting the antigen, then a second costimulatory ‘alarm or damage signal’ from injured or distressed cells. Danger signals are released by cells following damage caused by infection, toxins, and sterile inflammation. Immune recognition of danger signals occurs through pattern recognition receptors including Toll-​like receptors expressed by most cells found in the liver. In this context, it is interesting to note that antibiotics—​ even with their short duration of exposure (as prescribed in courses of days to weeks)—​are a group of drugs commonly associated with DILI; it plausible that ongoing sepsis could act as a costimulatory signal. In addition to pathogen-​associated molecular patterns (representing exogenous danger), damage-​associated molecular patterns (representing endogenous damage) can also be recognized by Toll-​ like receptors. Drugs or their reactive metabolites may cause subtle hepatocyte injury or bind to cellular components disrupting their function. Damage-​associated molecular patterns released as a result of subclinical injury may act as the necessary costimulatory signal leading to the activation of antigen-​ presenting cells to trigger an immune-​mediated hepatocyte and/​ or cholangiocyte damage.

Diagnosis Hepatotoxicity shares its manifestations with liver diseases from other aetiologies and therefore has to be considered in the differential diagnosis of all acute presentations of liver disease, including those presenting with what appears to be hepatic manifestations of systemic diseases. Specific drugs could also be risk factors for certain forms of chronic liver diseases. Both misinterpretation of liver biochemistry results and failure to recognize the possibility of specific drug therapy as an underlying reason behind a particular pattern of liver biochemical abnormalities continue to occur. One hospital-​based study found that a proactive system identified a 12-​fold higher incidence of acute drug-​induced liver enzyme elevations compared to that identified in routine clinical practice, hence raising suspicion is the first step in the process of diagnosis of DILI (Fig. 15.24.3.3). Diagnosis of DILI is incorrectly made in half of cases; failure to identify a drug as the cause of clinical manifestation, as well as missing a correct alternative diagnosis, both occur in routine practice. Accuracy of clinical diagnosis of DILI (about 45%) is a problem both in primary care and in hospital settings. Delay in diagnosis can mean continued exposure to the offending medication, with consequent worsening of DILI leading to acute liver failure in some cases. Prolonged exposure to drugs has also been associated with delayed resolution of DILI, even after withdrawal of the drug, and with chronicity in a few cases. Missed diagnoses such as biliary obstruction from gallstones and autoimmune hepatitis due to incorrect attribution of the clinical problem to DILI can

15.24.3  Drug-induced liver disease

Consider DILl Acute rise in liver biochemistry * ALT ≥ 5 × ULN * ALT ≥ 3 × ULN and Bilirubin ≥ 2 × ULN * ALP ≥ 2 × ULN

New-onset manifestations • Jaundice • Acute liver failure

New systemic manifestations • Generalized itching • Skin rash • Eosinophilia

Drug history • • • •

New medication introduced (with in the past 3 months in particular) Course of antibiotics in the past 6 weeks Over-the-counter medications Herbal remedies or complementary medications

Causality assessment • • • •

Temporal relationship with the drug and the manifestation Exclusion of biliary obstruction Evidence to support or refute alternative explanation for the manifestation Tests that support or refute alternative diagnosis

Consider specific tests for DILl • HLA genotyping • Lymphocyte transformation test

Fig. 15.24.3.3  Clinical approach to the diagnosis of DILI.

have serious consequences, hence systematic assessment is the key to an accurate diagnosis.

Causality assessment methods These involve structured evaluation of several factors in relation to the clinical presentation that support or refute the link between the drug and the manifestations. The temporal relationship between intake and discontinuation of the suspected drug and onset and disappearance of the manifestation is one of the important factors to consider in the diagnosis. This requires precise information regarding all the drugs, their doses, and durations, including nonprescription (over-​ the-​ counter), herbal, and complementary medications which patients may not consider as relevant. Most DILI occurs between day 4 and 3 months of initial therapy, although some occur later during the first year of treatment. By contrast, DILI due to some drugs (e.g. nitrofurantoin) typically appears more than a year after initial exposure. Ischaemic hepatitis with its characteristic rapid ALT elevation peaking within the first 72 h following circulatory shock, cardiorespiratory arrest, or exacerbation of heart failure is an important differential diagnosis to consider, especially in secondary care. Similarly, perioperative hypotension manifests with liver injury earlier during the postoperative period than DILI from anaesthetic agents. Different components that form causality assessment have been incorporated into tools that assist in a structured evaluation of cases suspected to have DILI. Two such tools are the Roussel Uclaf Causality Assessment Method, developed by Council for International Organizations of Medical Sciences, and the Clinical Diagnostic Scale. These tools attribute scores (numerical weighting) with regards to specific domains that include the temporal

relationship between drug exposure and clinical features, the course of these manifestation once the drug is discontinued, the recurrence of liver injury on re-​exposure to the drug, rigour of exclusion of alternative diagnoses, the presence or absence of risk factors and extrahepatic features of an adverse liver reaction, as well as the strength of previous reports of a particular type of DILI. These validated tools were developed to facilitate pharmacovigilance of hepatic adverse reactions and have been effectively used to harmonize phenotyping of DILI between international groups of researchers. Although it is unrealistic to apply causality assessment tools routinely in clinical practice, these provide a template on which a reliable process of diagnosis and decision-​making can be based. Acute biliary obstruction (e.g. from gallstones within the common bile duct) accounts for more than half the cases of jaundice, and one-​ quarter of cases presenting with an acute hepatocellular pattern of liver enzyme increase (AST >400 IU/​litre) and 5% of those with ALT greater than 1000 IU/​litre. It is therefore imperative to perform hepatobiliary imaging first to exclude this aetiology. Autoimmune hepatitis has an acute presentation in about 40% of people, and it can have a remitting and relapsing course. Early diagnosis and intervention is crucial to improve outcomes in both DILI and autoimmune hepatitis, hence in-​depth investigations are of paramount importance. Ischaemic hepatitis is associated with greater than 50% in-​hospital mortality and should be distinguished from DILI as comorbidity associated with ischaemic hepatitis precludes the consideration of liver transplantation, even when fulminant liver failure ensues. In about 80% of patients with ischaemic injury, lactate dehydrogenase reaches very high concentrations with an ALT/​lactate dehydrogenase ratio less than 1, a pointer that can be used in the diagnostic

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process. Recently, hepatitis E infection has become a more common cause of acute viral hepatitis than hepatitis A, B, and C infections; cytomegalovirus, Epstein–​Barr virus, and herpes zoster virus also contribute a few cases, all of which resemble DILI in their clinical features. The list of other exclusions to secure a confident diagnosis of DILI is exhaustive: investigations should be tailored to suit the particular clinical context.

HLA genotyping is being carried out regularly in centres with transplantation programmes and these services are readily accessible to other secondary care hospitals. In particular, HLA B*5701 genotyping is routinely performed prior to prescription of abacavir (effectively reducing cutaneous hypersensitivity due to the drug), hence protocols and processes are well established with an ability to perform genotyping within 1 day of receipt of a sample.

Role of liver biopsy

Lymphocyte transformation test

DILI can cause any known pattern of liver pathology, but certain histological features are particularly suggestive of drug-​induced aetiology although there are no specific diagnostic histological features. The benefits of performing a liver biopsy should be weighed against the disadvantages and its limitations. Liver biopsy is worthwhile when (1) autoimmune hepatitis is one of the differential diagnoses under consideration (Fig. 15.24.3.4), (2) the event does not resolve as expected on drug discontinuation, and (3)  in circumstances where the clinical/​laboratory features are atypical, or (4) the patient appears to suffer an as yet unrecognized form of DILI.

This investigation, also called the lymphocyte proliferation or stimulation test, measures the proliferation of T cells from the blood samples of a patient suspected to have suffered DILI in response to that particular drug. Principles underlying this test have been supported by the generation of drug-​specific T-​cell clones from individuals who have had a positive response, and also by the pharmacological interaction concept which states that drugs can directly interact with the T-​cell receptor, without previous metabolism or need to bind to proteins. When applied to a cohort of well-​characterized patients with DILI, results of lymphocyte transformation tests have been variable, ranging from occasional positive cases based on reports from Europe to about a 45% positive rate in cohorts from Japan. In addition, when evaluated in the context of cutaneous hypersensitivity, the test has an estimated 15% false-​positive rate. The lymphocyte transformation test is cumbersome, technically demanding, and hence not widely available.

Genetic tests A strong and consistent association between HLA genotypes and DILI has raised the prospect of the potential use of genetic testing in the risk stratification of patients prior to therapy, but the incidence of DILI is too low to use such testing routinely. However, most HLA alleles associated with DILI have a very high negative predictive value of greater than 0.95; hence, they can be used to rule out adverse hepatic reactions due to particular drugs when the certainty of diagnosis is of paramount importance. Key examples of associations of specific HLA alleles with DILI from particular medications include HLA-​B*5701 with flucloxacillin, HLA-​DRB1*1501 with co-​amoxiclav, and HLA-​A*33:01 with terbinafine and other drugs (fenofibrate, ticlopidine sertraline, enalapril, and erythromycin). A high negative predictive value of a genetic test can also be used to identify the correct agent underlying DILI when the patient has been exposed to two concomitant medications, both with the propensity to cause DILI.

Other forms of drug-​induced liver disease Drug-​induced autoimmune hepatitis Many drugs have been reported to have induced the syndrome that shares many features of idiopathic autoimmune hepatitis. In a cohort of cases with the diagnosis of autoimmune hepatitis, 9% were considered to be induced by drugs, and conversely drug-​induced autoimmune hepatitis accounts for 9% of all DILI. Most of these drugs have appeared in case reports or small case series and include nitrofurantoin, minocycline, diclofenac, statins, and antitumour necrosis factor-​α agents (Table 15.24.3.1). Drug-​induced autoimmune hepatitis is difficult to distinguish from the idiopathic form as both have very similar biochemical, clinical, and liver histological features, hence the causal relationship between the drug and autoimmune hepatitis can be best established only when the manifestations resolve completely on drug withdrawal and do not recur on prolonged follow-​up (over 2 years).

Secondary sclerosing cholangitis

Fig. 15.24.3.4  Liver biopsy showing portal inflammation and interphase hepatitis secondary to diclofenac-​induced autoimmune hepatitis.

Previously, sclerosing cholangitis had been described following transarterial infusion of chemotherapeutic agents, but these are results of ischaemic injury to the biliary tract rather than toxicity from chemotherapeutic agents themselves. However, secondary sclerosing cholangitis with diffuse inflammatory stricturing of the biliary tree on magnetic resonance cholangiopancreatography has more recently been described in a small proportion of patients presenting with acute cholestatic DILI (Fig. 15.24.3.5), over 90% of whom were women, with two-​thirds presenting with jaundice. Drugs implicated were co-​amoxiclav, sevoflurane, amiodarone, infliximab, 6-​ mercaptopurine, gabapentin, venlafaxine, and atorvastatin.

15.24.3  Drug-induced liver disease

in children on combination of multiple drugs. A case–​control study demonstrated an association between variation in the polymerase γ gene, POLG, which codes for the mitochondrial DNA polymerase γ, and valproate-​induced hepatotoxicity. Nucleoside analogue reverse transcriptase inhibitors are one class of drugs which are liable to cause hepatotoxicity by interfering with mitochondrial function. Symptomatic adverse hepatic reactions occur with an incidence of 1.2 times per 1000 person/​year. Stavudine, zalcitabine, and didanosine have higher affinities for mitochondrial DNA polymerase γ, leading to the depletion of mitochondrial DNA, and hence have a higher rate of hepatotoxicity than abacavir, zidovudine, lamivudine, and tenofovir. Early recognition and withdrawal of the drug is the critical step in the management of these potentially life-​threatening adverse events.

Fatty liver disease

Fig. 15.24.3.5  Magnetic resonance cholangiopancreatography showing diffuse structuring of intra-​and extrahepatic bile ducts due to drug-​induced sclerosing cholangitis.

Granulomatous hepatitis Granulomata are circumscribed accumulations of macrophages, some of which may fuse to form multinucleated giant cells, with a surrounding rim consisting of lymphocytes that have developed with stimulation of mononuclear cells from a variety of cytokines. Considering the long list of infectious and immunological conditions associated with hepatic granulomata, the diagnosis of drug-​related granulomatous hepatitis depends upon a temporal relationship between exposure to the drug and the clinical manifestation, ruling out an alternative explanation for histological changes, and previous reports in the literature. Allopurinol, carbamazepine, phenytoin, quinidine, methyldopa, and sulphonamides are some of the medications which have been associated with this form of hepatotoxicity.

Acute fatty liver This is a distinct form of acute hepatotoxicity associated with drugs that affect mitochondrial function. Microvesicular steatosis and the absence of glycogen in the hepatocytes are characteristic histological features as the liver uses glycolysis to compensate for the lack of ATP produced by mitochondria. Impaired mitochondrial function leads to apoptosis and liver failure manifesting with hypoglycaemia, lactic acidosis, hyperammonaemia, and cerebral oedema. Dramatically rapid development of organ failure precedes the clinical syndrome, with an acute rise in liver enzymes and jaundice that follow, hence having a high index of suspicion is crucial in identifying the drug aetiology when approaching a patient with ‘anicteric hepatic encephalopathy’. Described initially as ‘Reye’s syndrome’ in children treated with salicylate, the incidence of this condition has been reduced markedly by restricting the use of aspirin in those under the age of 16 years and the use of parenteral preparations of tetracycline. Sodium valproate is one of the drugs currently used that has been linked to the development of acute fatty liver; idiosyncratic hepatotoxicity occurs 1 in 37 000 people taking the drug, and the risk increases to 1 in 500

Nonalcoholic fatty liver disease (NAFLD) is an entity associated with accumulation of fat in more than 5% of hepatocytes, with or without inflammation and fibrosis, in those who do not consume alcohol over the amount considered moderate (14 units in men and women per week). When the condition is associated with metabolic syndrome or idiopathic it is considered primary NAFLD; drugs are the aetiology behind some secondary NAFLD cases. This entity is different from acute fatty liver described previously. Methotrexate After more than five decades of clinical use, methotrexate is the most frequently used nonsteroidal immunosuppressant  therapy  worldwide, with rheumatoid arthritis and psoriasis being common indications for its use. Reports that long-​term methotrexate therapy is associated with fatty infiltration and fibrosis with a potential to progress to cirrhosis have resulted in a plethora of guidelines recommending intense monitoring regimens, including liver biopsies at regular intervals. The proportion of patients estimated to have any degree of liver fibrosis varies from 6 to 72%; with advanced fibrosis ranges from 0 to 33%, and cirrhosis from 0 to 26%. Such wide ranges of reported pathology are due largely to heterogeneity of cohorts, study designs, methods of evaluating histological changes, and case mix. A recent study highlighted the rarity of decompensated cirrhosis associated with methotrexate therapy; of over 150  000 adults who had been listed for or received liver transplantation during a 24-​year period, only 117 (0.07%) had methotrexate-​associated cirrhosis. Methotrexate polyglutamate within the cell interferes with pyrimidine and purine synthesis, through which it exerts its therapeutic effect. In addition, methotrexate indirectly affects methylenetetrahydrofolate reductase and hence the generation of methionine from homocysteine. Excess homocysteine induces endoplasmic reticulum stress, which, when unresolved, leads to fatty infiltration of the liver. Homocysteine, in addition, can also activate proinflammatory cytokines and activate hepatic stellate cells, leading to liver fibrosis. The development and progression of chronic drug-​associated liver disease is determined by interaction between a number of factors related to the drug (such as cumulative dose), the host (such as SNPs in the methylenetetrahydrofolate reductase gene), and/​or the environment (such as alcohol consumption, obesity, and type 2 diabetes). Caucasian ethnicity and female sex are associated with

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decompensated cirrhosis although it is unclear whether this merely reflects the predominance of women and Caucasians among patients with rheumatoid arthritis and psoriasis respectively. Assessment of the risk:benefit ratio of long-​term methotrexate therapy depends upon the efficacy of the drug in an individual weighed against the rate of progression of hepatic fibrosis. The primary objective of monitoring is to detect hepatic fibrosis that is of clinical significance, yet reversible on withdrawal of the drug. Several clinical algorithms that incorporate noninvasive markers of liver fibrosis such as ‘enhanced liver fibrosis’ panel and transient elastography are currently being evaluated as tools to monitor patients on methotrexate therapy. Tamoxifen Treatment with tamoxifen, an oestrogen-​ receptor antagonist, has been associated with accumulation of fat within the liver. In a multicentre trial involving more than 5000 women, tamoxifen therapy was associated with a twofold risk of developing fatty liver over a 5-​year period, with an incidence of 0.4% per year in the treated group compared with 0.2% in the placebo group. This association was restricted to overweight and obese women, and the increased risk manifested within the first 2 years of treatment. Other factors associated with the development of nonalcoholic fatty liver disease included hypercholesterolaemia and arterial hypertension. Among those who had a liver biopsy, most had mild to moderate nonalcoholic steatohepatitis histologically (Fig. 15.24.3.6), but none progressed to cirrhosis after a median follow-​up of 8.7 years. In a large registry of 810 patients with breast cancer treated with tamoxifen, 16 (2%) developed fatty liver on treatment. Tamoxifen was associated with an eightfold risk of developing fatty liver; age and body mass index were other risk factors. The median time from the start of tamoxifen to the diagnosis of drug-​associated fatty liver disease was 22 months; when tamoxifen was discontinued, liver enzymes improved. Only two patients had biopsy-​documented cirrhosis in this registry, although a few more have been described in case reports. Chemotherapy-​associated steatohepatitis

steatosis; obesity is associated with an increased risk. Drugs commonly associated with steatohepatitis include 5-​fluorouracil and irinotecan. Chemotherapy-​associated steatohepatitis increases the risk of infections, liver failure, and overall mortality following major liver resections (for hepatic metastasis).

Nodular regenerative hyperplasia Some drugs can injure endothelial cells of sinusoids and portal venules with consequent occlusion or dropout of smaller radicles. Widespread vascular changes lead to diffuse nodularity within the hepatic parenchyma. The hepatocytes within the nodule are arranged in plates that are more than one cell in thickness, while hepatocytes are compressed and atrophic into thin, parallel plates between nodules (Fig. 15.24.3.7). Characteristically, the nodules are not separated by fibrosis, although there can be perisinusoidal fibrosis and incomplete fibrous septa. In patients on azathioprine therapy, the cumulative rate of development of nodular regenerative hyperplasia has been estimated to be 0.5% over 5 years and 1.5% in 10 years. Other drugs associated with this form of liver disease are 6-​thioguanine, busulphan, bleomycin, cyclophosphamide, chlorambucil, cysteine arabinoside, carmustine, and doxorubicin. In recent literature, oxaliplatin is the most common drug associated with this pathology. In a large group of patients treated with oxaliplatin, nodular regenerative hyperplasia was found on histology in 25% and features consistent with sinusoidal obstruction syndrome in over 50% of patients.

Liver tumours Liver cell adenoma is a benign neoplasm of the liver with an estimated incidence of 3 per million per year. Among regular users of oral contraceptives, its annual incidence is at 3 to 4 per 100 000 although it may be lower with newer pills. The hormonal dose and duration of medication have been associated with the risk of adenoma development, which is highest in women over 30 years of age after using oral contraceptives for more than 24 months. The morphology of hepatic adenomas, with their extensive proliferation of blood-​filled sinusoids supplied by high-​pressure arterial

Reactive oxygen species generated by chemotherapy and intended to induce tumour cell apoptosis can also lead to the development of steatohepatitis, especially in those with pre-​ existent hepatic

Fig. 15.24.3.6  Liver biopsy showing evidence of fat-​laden hepatocytes and fibrosis due to tamoxifen-​associated fatty liver disease.

Fig. 15.24.3.7  Liver biopsy with reticulin stain demonstrating hypertrophic cell plates surrounded by atrophic cell plates typical of nodular regenerative hyperplasia attributed to azathioprine therapy.

15.24.3  Drug-induced liver disease

flow, makes 20 to 40% of them bleed spontaneously causing right upper quadrant pain; intraperitoneal bleeds and ruptures leading to deaths have been reported. Progression to hepatocellular carcinoma occurs in about 10% of adenomas. Ultrasonographic features of hepatic adenomas are nonspecific, but triple-​phase CT scanning or MRI are able to distinguish them from haemangiomas, fibronodular hyperplasia, and hepatocellular carcinomas in the vast majority of patients. A causal association between oral contraceptives and hepatic tumours has been accepted as there have been several reports of regression or resolution of adenomas after cessation of the drugs, although such regression may be less likely when the exposure to oral contraceptives is prolonged. Hormone receptors have also been found in many hepatic adenomas. However, there have also been reports of progression to hepatocellular carcinoma 3 to 5 years after stopping oral contraceptives; hence, surgical resection should be considered based on the site, size, and number of hepatic tumours, as well as certainty regarding their nature on imaging. An association of liver tumours with androgens was first described in patients with Fanconi’s anaemia on anabolic androgenic steroids. Hepatic adenomas, hepatocellular carcinomas, and others (cholangiocarcinoma and angiosarcoma) occur in those who take androgens for Fanconi’s anaemia and other forms of aplastic anaemia as well as for other reasons (such as body builders, hereditary angio-​oedema, and immune thrombocytopenia). In a large series including 133 cases, hepatocellular carcinomas were associated with oxymetholone and methyltestosterone, while adenomas were associated with danazol. Both oral and parenteral therapies were associated with the development of tumours, which appeared after a median period of 4 to 6 years of exposure to the medications. Male predominance among cases may be related to exposure of males to this medication. The causal association between anabolic androgenic steroids and hepatic tumours has been inferred from observations of regression of hepatic lesions upon discontinuation of the medications, but the occurrence of tumours many years after discontinuation of therapy has been reported.

Management The importance of drug-​induced liver disease and DILI in particular lies not in the overall number of cases alone, but in the severity of some reactions and their potential reversibility on prompt discontinuation of the offending medication. The role of corticosteroids in the treatment of DILI has not been systematically evaluated, but corticosteroid therapy does not improve clinical outcomes in drug-​induced acute liver failure. However, it is difficult to distinguish drug-​induced autoimmune hepatitis from the idiopathic form; hence, in practice, some patients are treated with corticosteroids at the time of acute presentation. Under such circumstances, one should consider withdrawal of all immunosuppressant drugs when clinically appropriate, and then monitor closely. Patients who do not relapse within a period of 24 months of complete withdrawal of immunosuppressive therapy can be considered to have suffered drug-​induced autoimmune hepatitis. There is no clear evidence that ursodeoxycholic acid therapy changes outcome in the cholestatic form of DILI, although the drug has been widely used for all forms of cholestasis.

In 11 to 30% of patients with DILI, re-​exposure to the particular agent will result in the recurrence of the adverse reaction. Recurrent DILI develops more rapidly (generally after days or weeks) than following initial exposure, manifests with jaundice in two-​thirds, requires hospitalization in half of cases, and in 13% leads to death. Inadvertent re-​exposure to the particular drug must therefore be avoided. The only exception to this could be the first line antituberculosis regimen that is highly effective, relatively inexpensive, and yet associated with the well-​recognized risk of DILI. If second-​line antituberculosis medications are entirely unaffordable, then the benefits of reintroduction of the same drugs following resolution of the initial event with careful monitoring should be weighed against the risks of recurrent DILI.

Prevention Recent advances in the understanding of the molecular basis of DILI have highlighted the role of adaptive immunity and the contribution of host susceptibility in the pathogenesis of these adverse reactions. Incorporating these factors into the in vitro models used during preclinical evaluation of new compounds would improve the detection of the hepatotoxic potential of these molecules early during drug development. However, it is unrealistic to expect each and every effective drug to be entirely free from adverse effects. Although preprescription pharmacogenetics testing is currently not cost-​effective, it is foreseeable that both genetic and nongenetic factors are incorporated into refined algorithms which will allow minimizing the risk of a particular medication in an individual under specific circumstance.

FURTHER READING Aithal GP (2011). Hepatotoxicity related to antirheumatic drugs. Nat Rev Rheumatol, 7, 139–​50. Aithal GP (2015). Pharmacogenetic testing in idiosyncratic drug-​ induced liver injury (DILI): current role in clinical practice. Liver Int, 35, 1801–​8. Aithal GP, et al. (2011). Case definition and phenotype standardization in drug-​induced liver injury (DILI). Clin Pharmacol Ther, 89, 806–​15. Bjornsson ES, Aithal GP (2014). Immune-​mediated drug-​induced liver injury. In Gershwin ME, Vierling JM, Manns MP (eds) Liver immunology: principles and practice, 2nd edition, pp. 401–​12. Springer, New York. Björnsson ES, et al. (2013). Incidence, presentation, and outcomes in patients with drug-​induced liver injury in the general population of Iceland. Gastroenterology, 144, 1419–​25. Björnsson ES, Hoofnagle JH (2015). Categorization of drugs implicated in causing liver injury: critical assessment based upon published case reports. Hepatology, 63, 590–​603. Dawwas MF, Aithal GP (2014). End-​stage methotrexate-​related liver disease is rare and associated with features of metabolic syndrome. Aliment Pharmacol Ther, 40, 938–​48. Grove JI, Aithal GP (2015). Human leukocyte antigen genetic risk factors of drug-​induced liver toxicology. Expert Opin Drug Metab Toxicol, 11, 395–​409. Hunt CM (2010). Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-​induced liver injury: a systematic review. Hepatology, 52, 2216–​22.

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Padda MS, et  al. (2011). Drug-​induced cholestasis. Hepatology, 53, 1377–​87. Ramappa V, Aithal GP (2013). Hepatotoxicity related to anti-​ tuberculosis drugs:  mechanisms and management. J Clin Exp Hepatol, 3,  37–​49. Urban, Daly AK, Aithal GP (2014). Genetic basis of drug-​induced liver injury: present and future. Semin Liver Dis, 34, 123–​33.

15.24.4  Vascular disorders of the liver Alexander Gimson

Other conditions discussed include congestive hepatopathy, ischaemic hepatopathy, hepatic artery aneurysm, and portal vein thrombosis.

Budd–​Chiari syndrome Budd–​Chiari syndrome is caused by obstruction to hepatic venous outflow. It is described as primary when the obstruction is caused by a process arising within the veins (e.g. thrombosis), and secondary when due to another process (e.g. compression or invasion by malignancy). It is a rare condition (incidence about 2 per million in both men and women) that can present at any age (median 50 years). Most cases develop insidiously over months, but about 20% present acutely. An underlying predisposing cause can be found in most patients, often in combination (Table 15.24.4.1).

Clinical features

ESSENTIALS The liver’s complex blood supply and high metabolic activity may be affected in a number of clinical situations when there is reduced splanchnic inflow and impaired hepatic venous outflow. Budd–​Chiari syndrome is caused by obstruction to hepatic venous outflow, usually by thrombosis within the hepatic veins. Causes include myeloproliferative disease, malignancy, and hypercoagulable states. Presentation may be acute, subacute, or chronic, and the diagnosis requires consideration in any patient presenting with acute liver failure, acute hepatitis, or chronic liver disease. Diagnosis is made by Doppler ultrasonography of the hepatic veins and confirmed with CT or MRI scanning. Management depends on the presentation, but involves anticoagulation in all cases, and thrombolysis, measures to decompress the liver, and liver transplantation in some. Survival is about 75% at 5 years.

Acute Budd–​Chiari syndrome, which develops over a few weeks, typically presents with fever, right upper quadrant pain, and tender hepatomegaly, which may be associated with hepatic encephalopathy if there is fulminant liver failure (5% of cases). Jaundice and ascites develop rapidly but may not be evident at presentation. Liver blood tests show elevation of bilirubin, aminotransferases (typically 100–​500 IU/​L), and alkaline phosphatase (typically 300–​400 IU/​L). Subacute Budd–​Chiari syndrome usually presents with vague epigastric or right upper quadrant pain. Ascites and pedal oedema may be present but are not invariable. The latter is thought to be due to hypertrophy of the caudate lobe of the liver causing compression of the inferior vena cava, into which it drains directly, rather than through the hepatic veins. Abnormal venous collaterals may be seen on the abdominal wall. Variceal bleeding can occur. Patients with chronic Budd–​Chiari syndrome develop symptoms as a consequence of cirrhosis. In both subacute and chronic cases,

Table 15.24.4.1  Causes of the Budd–​Chiari syndrome Cause

Example

Myeloproliferative disease (50% cases of Budd–​Chiari syndrome)

Polycythaemia rubra vera Essential thrombocythaemia

Malignancy (10% cases)

Hepatocellular carcinoma

Benign liver lesions (5–​10% cases)

Hepatic cysts and abscesses

Hypercoagulable states

Oral contraceptive use Clotting factor mutations, e.g. factor V Leiden, factor II (G20210A) deficiency, antithrombin III, protein C and S deficiency, antiphospholipid syndrome Paroxysmal nocturnal haemoglobinuria

Anatomical abnormality

Membranous webs of inferior vena cava and/​or hepatic veins

Miscellaneous conditions

Behçet’s disease Inflammatory bowel disease Coeliac disease Other autoimmune conditions

Idiopathic

Notes

Nearly 20% of cases occur in women who are taking the oral contraceptive, are pregnant, or have recently given birth

Some may have undiagnosed myeloproliferative disorder; always check for JAK2 mutations

Note: multiple risk factors may contribute in an individual case, for example, a combination of factor V Leiden mutation with a myeloproliferative disorder or use of the oral contraceptive.

15.24.4  Vascular disorders of the liver

serum bilirubin, aminotransferases, and alkaline phosphatase may be normal or mildly/​moderately elevated, but clinically obvious jaundice is rare.

Diagnosis The very variable presentations of Budd–​Chiari syndrome mean that it should be considered in the differential diagnosis of patients presenting with acute liver failure, acute hepatitis, or chronic liver disease. The diagnosis can usually be made by Doppler ultrasonography of the hepatic veins (Fig. 15.24.4.1) and confirmed with CT or MRI scanning (Fig. 15.24.4.2), which provide additional information required for treatment planning. Venography may be required if uncertainty remains after these tests, looking for the characteristic ‘spider’s web’ pattern in occluded hepatic veins. Liver biopsy is not generally required. Causes listed in Table 15.24.4.1 should be sought.

Management and prognosis Treatment, when possible, should be given for any underlying cause. With regards to the thrombosis within the hepatic veins, the initial priorities are to initiate anticoagulation (usually commencing with low molecular weight heparin), unless there are very strong contraindications, and to deal with any complications of portal hypertension that are present. Thrombolysis may be given, depending on balance of benefits and risks in each case, if imaging reveals an acute (usually regarded as 95% in good hands). The presence of dilated ducts gives evidence of obstruction, and ultrasonography is around 30 to 70% sensitive and 90% specific for common bile duct stones depending on symptoms and blood tests (pretest probability). A normal examination does not, therefore, rule them out, and where suspicion is high, other tests should be used. MRCP or EUS are the usual next steps depending on availability, with sensitivities of around 95% when pretest probability is moderate to high. Each has its advantages and disadvantages. MRCP has no endoscopic or sedation risks, is useful where there is altered anatomy, and allows later independent review of images (Fig. 15.25.7). EUS can often be used where MRCP is not possible due to the presence of a pacemaker/​implanted cardiac defibrillator, mechanical heart valves, intracranial metal clips, morbid obesity, or severe claustrophobia. CT also has a role as it is often used when the cause of pain or sepsis is uncertain and is useful for differential diagnosis. Obstructing disease of the bile ducts is most commonly due to gallstones (Fig. 15.25.8), but a wide range of stricturing disorders both benign and malignant must also be considered.

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injury to a duct within the gallbladder bed, which usually closes with simple drainage or drainage combined with duct decompression by sphincterotomy and stent. Cholecystectomy relieves symptoms of biliary colic and acute cholecystitis, but other nonspecific symptoms often persist after operation. Common bile duct stones Optimal elective management of common bile duct stones is by ERCP. If the gallbladder is in situ this may be either before or soon after laparoscopic cholecystectomy. ERCP during cholecystectomy may be cost-​effective and convenient for patients but is rarely practical. Laparoscopic bile duct exploration with a flexible choledocoscope is another option and is preferred to open duct exploration because of a lower rate of trauma to the duct, increased chance of primary duct closure, and less use of T tubes with a lower risk of biliary strictures in the future. Preoperative imaging or intraoperative cholangiography is recommended for patients with a high pretest probability of stones (principally those with dilated ducts on ultrasound). Fig. 15.25.7  MRCP revealing stones in the distal common bile duct (arrow).

Management Laparoscopic cholecystectomy With the introduction of laparoscopic cholecystectomy, a shift occurred in the balance between benefit of operation and the associated risks and discomfort. Very few patients are now treated by alternative techniques. Laparoscopic surgery allows most patients to be treated as a day case, with return to normal activities within 2 weeks. Complication rates are low, the most serious being injury to the bowel or a bile duct, which occur in less than 1% of cases. About half of those with persistent bile leak after surgery arise from

Endoscopic removal of gallstones ERCP is an evolving technique for the removal of stones and employs increasingly complex therapeutic options. The basic principles of treating stone disease are as follows: (1) gain and then increase access to the common bile duct by cutting (sphincterotomy) (Fig. 15.25.9) with or without stretching (sphincteroplasty) the

CBD stones

Fig. 15.25.8  ERCP cholangiogram demonstrating stones (seen as filling defects) in the common bile duct (CBD).

Fig. 15.25.9  Balloon sphincteroplasty to facilitate removal of large common bile duct stones. Variable sizes of balloon are available, but in general it is wise not to exceed the diameter of the common bile duct above in order to reduce the risk of perforation.

15.25  Diseases of the gallbladder and biliary tree

Fig. 15.25.11  Crushing lithotripter for stone removal.

Open surgery Fig. 15.25.10  Clearance of common bile duct stones with a balloon trawl (black arrow). Note previous cholecystectomy clips (white arrows).

sphincter of Oddi; (2)  obtain a cholangiogram to identify the number and size of the stones; (3) where necessary, reduce the size of stones in order to facilitate their removal, either by crushing (Fig. 15.25.10) or applying direct energy to them; (4) remove the stones by dragging or grasping them from the duct (Fig. 15.25.11); (5) where removal is not possible, ensure biliary drainage is secured with appropriate stenting.

Despite all of these techniques, endoscopic therapy occasionally fails and a surgical solution may be sought. Where the gallbladder is still present, this may involve laparoscopic bile duct exploration at the time of cholecystectomy. Where the gallbladder has (a)

(b)

(c)

(d)

Other methods of treating gallstones Extracorporeal shock wave lithotripsy, oral bile acid therapy, and contact dissolution of gallstones are seldom used in the era of laparoscopic surgery and ERCP. These treatments lost their appeal when laparoscopic surgery became available because they are slow, requiring many months, and cumbersome, with repeated imaging needed to monitor progress. They also leave the gallbladder in situ and the patient is thus at risk of recurrence of gallstones. By contrast, laparoscopic cholecystectomy and ERCP are day-​case treatments that remove the gallbladder, permanently relieve symptoms in most patients, and have a very low complication rate in skilled hands. Direct cholangioscopy-​facilitated electrohydraulic lithotripsy (EHL) or laser lithotripsy Under direct vision at cholangioscopy, energy can be delivered directly to large troublesome stones to cause fragmentation. EHL uses a high-​voltage spark to create rapid thermal expansion of fluid and a subsequent hydraulic pressure wave. Laser lithotripsy (Fig. 15.25.12) uses pulsed energy to create the same effect. Following fragmentation, stones can be removed by traditional methods including balloons and baskets.

Fig. 15.25.12  Laser lithotripsy of difficult common bile duct stones. Gallstones are targeted and fragmented with high-​energy lasers under direct vision using cholangioscopy, thereby allowing extraction with baskets and balloons. Panels (a) and (b), before lithotripsy; panels (c) and (d), after lithotripsy.

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previously been removed, open duct exploration may be required. In rare cases where stones cannot be removed (usually after multiple attempts), hepaticojejunostomy may be required because of the long-​term risk of secondary biliary cirrhosis and recurrent cholangitis. Laparoscopic-​assisted ERCP in altered surgical anatomy Increasing use of bariatric surgery means that it may not be possible to access the bile duct from the duodenum via the mouth. Nevertheless, gallstone disease is very common after bariatric surgery and stones in both the gallbladder and common bile duct represent a difficult problem. This may be overcome by a combined approach of the surgical team using laparoscopic techniques to access the stomach remnant and hence duodenum via the transperitoneal route. The ERCP can then be carried out as normal. Alternatives to cholecystectomy In some very frail, elderly persons, those with significant comorbidi­ ties, and those with advanced cirrhosis, cholecystectomy presents too great a risk. In these situations, ERCP is often undertaken as definitive treatment of bile duct stones, or to prevent recurrence of pancreatitis, with biliary sphincterotomy and ductal clearance. Where stone extraction is not possible, biliary stenting is often used, usually with placement of double-​pigtail stents to ensure that drainage is maintained, although cholangitis is still a common complication. With this approach, regular stent changes every 3 months are associated with much lower rates of cholangitis and mortality than with an ‘on-​demand’ stent change practice.

Most patients with symptoms after cholecystectomy have nonulcer dyspepsia. If the symptoms are troublesome, investigations should aim to exclude other pathology. Liver function and liver ultrasonography will exclude parenchymal disease; upper gastrointestinal endoscopy may be helpful to look for peptic ulceration and gastro-​ oesophageal reflux, and colonoscopy or CT colonography may be considered if there are lower gastrointestinal symptoms. Serology for Helicobacter pylori and for endomysial antibody to exclude coeliac disease may be helpful. Any treatable condition should be managed appropriately. Gastro-​oesophageal  reflux Reflux symptoms occur or are increased after cholecystectomy in at least 10% of patients as a result of disruption of the feedback mechanism that controls release of cholecystokinin (CCK). After cholecystectomy, postprandial and fasting CCK levels in the blood are raised. In addition to causing gallbladder contraction and relaxation of the sphincter of Oddi, CCK also causes relaxation of the gastric cardia and a fall in lower oesophageal sphincter pressure, which facilitates reflux. In most patients these symptoms settle within 12 months, but some will require temporary or long-​term proton pump inhibitors. Bile salt diarrhoea

After cholecystectomy, between 1 and 5% of patients report increased bowel frequency. Stools may be softer than previously but are rarely loose. This occurs in the absence of identifiable bowel pathology and is caused by disruption of circulation of bile salts so that more enter the colon where they are irritant to the mucosa. Normal Complications of management of gallstones enterohepatic circulation of bile salts requires almost complete reComplications of ERCP absorption in the terminal ileum. The absence of the gallbladder reERCP is an invasive surgical procedure and must not be under- duces the capacitance of the biliary system so that bile production taken lightly. The most common complication is pancreatitis, during fasting cannot be accommodated. Some bile enters the duowhich overall occurs in 2 to 3% of cases, even in expert hands. denum as a result. In addition, the raised fasting levels of CCK after Risk factors for pancreatitis include multiple cannulation attempts, cholecystectomy may reduce sphincter pressure, and also favour remultiple cannulations, and injection of contrast into the pancre- lease of bile in the absence of food. The higher concentration of bile atic duct. Perforation may occur in any part of the upper gastro- salts reaching the colon in the absence of luminal residue which usuintestinal tract in relation to passage of the endoscope but is most ally adsorbs some of the bile salts leads to mucosal irritation in the commonly related to sphincterotomy and/​or precut papillotomy. caecum. This impairs water absorption leading to passage of softer, Guide-​wire perforation also occurs. When recognized and treated more frequent stools. The diagnosis can be confirmed with a SeHCAT test. Radiolabelled by keeping the patient nil by mouth and administering antibiotics, most cases of guide-wire perforation settle without the need for bile salt is ingested and 1 week later the amount of retained isotope indicates normal or impaired bile salt absorption. Mild symptoms surgery. Sepsis and bleeding also occur. Rectal indomethacin (100 mg) has been shown to halve the rate may require no treatment other than explanation of the cause. More of post-​ERCP pancreatitis. In difficult cases where access to the pan- severe symptoms often respond to reduction of dietary fibre and/​or creatic duct inadvertently occurs, the placement of a pancreatic duct antidiarrhoeal medication (codeine or loperamide). Cholestyramine which binds intraluminal bile salts is effective, but many patients stent can further reduce incidence of pancreatitis. find it unpalatable and prefer other measures or adjust to their new Postcholecystectomy syndromes bowel habit. There is often improvement in symptoms during the This is a poorly defined group of symptoms which includes some months after operation, but if symptoms are still present after 1 year specific conditions (e.g. bile salt-​ related diarrhoea and gastro-​ they are likely to be permanent. oesophageal reflux) that result from cholecystectomy. However, many patients given this label in fact have some other condition Sphincter of Oddi dysfunction which has not been affected by the removal of the gallbladder. It is self-​evident that, if cholecystectomy has been performed in patients with symptoms unrelated to the gallbladder (whether or not they Sphincter of Oddi dysfunction is an increasingly recognized clinical have typical biliary colic or acute cholecystitis), then these symp- syndrome comprising right upper quadrant pain with or without abnormal liver biochemistry and with or without dilated bile ducts. toms will still be present after operation.

15.25  Diseases of the gallbladder and biliary tree

Table 15.25.3  Milwaukee Classification for sphincter of Oddi dysfunction 1

Biliary pain, abnormal liver function tests (LFTs), dilated bile ducts

2

Biliary pain, abnormal LFTs or dilated ducts

3

Biliary pain

Indeterminate stricture History, examination, CT/MRI/bloods Associated mass? No

The gold standard for diagnosis is biliary manometry. An alternative strategy involves injection of botulinum toxin into the sphincter and clinical assessment of symptoms. When the diagnosis is confirmed, formal sphincterotomy can be performed, often resulting in long-​ lasting relief of pain. Risk of pancreatitis is very high in this group and the patient should be counselled to this effect. This syndrome can be subclassified into types 1, 2, and 3 by the Milwaukee system (Table 15.25.3) with the best results reported in type 1 patients who have abnormal liver function associated with dilated ducts during an attack of pain. See Chapter 15.26.1 for further discussion of sphincter of Oddi dysfunction in the context of acute pancreatitis, including the Rome III diagnostic criteria.

Indeterminate biliary strictures Biliary strictures are a diagnostic challenge because of their wide differential diagnosis, common lack of unequivocal features on imaging, and the need to obtain tissue, which can be difficult to get. The wide range of possible pathologies (Table 15.25.4) have very different outcomes and management.

Table 15.25.4  Aetiology of biliary strictures with key clinical features Pathology

Clinical features

Cholangiocarcinoma

Imaging, cytology/​FISH/​histology

PSC with dominant stricture

Imaging, negative cytology/​histology

Autoimmune (IgG4) cholangitis

Imaging, serology, IgG4 cytology/​histology Involvement of other organs

Mirrizi’s syndrome

History compatible with cholecystitis

Postoperative

History of gallbladder/​bile duct surgery, often with associated complications. History of liver transplant, type of anastomosis

Stone-​related stricture

History, stones on imaging

Trauma

History

Post radiation

History

Ischaemic/​post-​transarterial chemoembolization

History

Vasculitis

History, serology

Infection, e.g. HIV, tuberculosis, worms

History, serology

Extraluminal compression: • Pancreatic cancer • Chronic pancreatitis • Lymph node metastases • Lymphoma • Pancreatic cysts • Retroperitoneal disease

History, imaging

Yes

ERCP +/-Spyglass +cytology/fish/dia/biopsy

EUS/percutaneous biopsy Diagnosis?

No

Yes

Definitive treatment

Re-evaluate

? Trial of steroids

Fig. 15.25.13  Algorithm for investigation of indeterminate biliary strictures.

Pragmatic approaches which assume a cancer diagnosis run the risk of high-​morbidity surgery or inappropriate metal stenting in benign cases. Watchful waiting risks missing cancers when they are potentially curable. This is a common problem in hepatobiliary medicine and the diagnostic algorithms are continuously evolving: a suggested approach to diagnosis is shown in Fig. 15.25.13. With the increasing recognition of IgG4 disease in these difficult cases, a trial of steroids for 4 to 6 weeks may be justified on the grounds that major surgery can be avoided in some. The disadvantage to this approach is that time may be lost where a tumour becomes impossible to resect, and infective complications might be more common.

Obstructive jaundice due to biliary tract disease Regardless of the type of obstruction, effective biliary decompression (either endoscopically or percutaneously) is of benefit to patients. This improves symptoms of cholestasis, improves nutrition, and, in some cases, improves survival. In gallstone-​related disease, removal of the offending stone is usually sufficient to relieve obstruction. In stricturing disease, stenting is usually required. In malignant disease, drainage allows palliative chemotherapy or neoadjuvant chemotherapy to be given. For palliation, stenting has less morbidity than surgical bypass. At least a third of the liver needs to be drained for decompression to be effective. The best mode of decompression therefore depends on the location of the obstruction. Distal disease involving the common bile duct or common hepatic duct can be treated with a single stent, which is best placed endoscopically. Between 75 and 80% of hilar strictures can be successfully decompressed with a single stent, but strictures at the hilum may require multiple stents, which can sometimes be achieved at ERCP although more often PTC is required. For malignant disease, there is increasing use of self-​expanding metal stents which give longer palliation and long-​ term patency (Fig. 15.25.14, Fig. 15.25.15). In malignant disease where strictures are present, there are several novel endoscopic approaches to therapy aimed at maintain­ing longer patency of the stent. These include photodynamic therapy,

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(a)

(b)

Symptomatic strictures warrant endoscopic therapy with ERCP which should also include the acquisition of brush cytology with or without FISH/​DIA where available. Biliary sphincterotomy and balloon dilatation of stricture under antibiotic cover appears to improve survival and reduce the risk of cholangiocarcinoma developing subsequently. The role of placing biliary stents is unclear; there is no evidence of benefit for plastic stents, although fully covered self-​ expanding metal stents may help by slowly dilating the stricture.

IgG4-​related sclerosing cholangitis

Fig. 15.25.14  (a) Hilar stricture with almost complete occlusion of the hepatic duct going into the right hepatic duct and with no filling of left ducts. (b) Placement of an uncovered self-​expanding metal stent with decompression of right-​sided biliary ducts.

radiofrequency ablation, and brachytherapy. All of these techniques need to be combined with self-​expanding metal stents for optimal results.

Specific causes of biliary strictures Primary sclerosing cholangitis Primary sclerosing cholangitis (PSC) is discussed in Chapter 15.23.4. Dominant strictures of the extrahepatic bile ducts are defined as a stenosis of 1.5 mm or less in the common bile duct or 1 mm or less in the hepatic duct. The presence of a dominant stricture in patients with PSC is a common clinical problem and one which carries a worse overall prognosis (especially in the setting of inflammatory bowel disease). They may be present at presentation, when evaluation is as for an indeterminate stricture. If a dominant stricture develops in a patient with known PSC, it is crucial to exclude a cholangiocarcinoma. (a)

(b)

Fig. 15.25.15  Biliary stricture just below the hilum before (a) and after (b) placement of an uncovered self-​expanding metal stent. The stent is traversing the ampulla and extends up into the intrahepatic ducts. Bile in the side branches will drain through the mesh of the stent.

IgG4-​related disease is a multisystem disorder, first described in 2003 as autoimmune pancreatitis. It is now recognized to affect many organs with several clinical phenotypes. IgG4 disease of the bile duct is increasingly recognized as an important cause of indeterminate strictures. Its diagnosis is important as it has a specific treatment, and diagnosis avoids major surgery or problems related to ‘pragmatic’ metal stent placement. Tissue acquisition with direct cholangioscopy and immunostaining of biopsies for IgG4 facilitates diagnosis. The HISORt criteria (histology, imaging, serology, other organ involvement, and response to therapy) (Table 15.25.5) encompass a number of clinical features to assist with diagnosis. There is a male preponderance and it mainly occurs in the fifth and sixth decades of life. The natural history is not yet established and the differential diagnosis includes cholangiocarcinoma, pancreatic carcinoma, and primary and secondary sclerosing cholangitis depending on the location of the strictures. Pathogenesis is poorly understood but differs from many other autoimmune diseases in that there appears to be T helper (Th)-​2 and regulatory T-​cell drivers as opposed to the more normal Th1/​Th17 phenotype. Treatment is typically with steroids, although there are no high-​ quality trials at the time of writing: 30 to 40mg of prednisolone is typically given for 4 weeks, then tapering 5 mg every 2 weeks. Response to steroids helps make the diagnosis, with CT/​ERCP changes seen within 4 to 6 weeks. A nonresponse may indicate the wrong diagnosis but may also result from burnt-​out disease or a more fibrotic phenotype. Relapse is common and, if it occurs, can be retreated with steroids followed by azathioprine. Table 15.25.5  HISORt diagnostic criteria for IgG4-​related sclerosing cholangitis Histology of the bile duct

Lymphoplasmacytic sclerosing cholangitis Lymphoplasmacytic infiltrate with >104 IgG4 positive cells/​high powered field Storiform fibrosis Obliterative phlebitis

Imaging of the bile duct

Axial imaging reveals 1 or more strictures (intrahepatic, proximal extrahepatic, or pancreatic bile duct with thickening and inflammation) Fleeting or migratory strictures

Serology

IgG4 in serum (can be normal in up to 20%, can be elevated in other conditions, e.g. 9% of PSC)

Other organ involvement

Pancreas, kidney, salivary glands (sclerosing sialadenitis), lungs, pericardium, meninges, pituitary and encompasses retroperitoneal fibrosis, Reidel’s thyroiditis and Mikulicz’s disease

Response to steroid therapy

Normalization of liver enzymes or resolution of stricture

15.25  Diseases of the gallbladder and biliary tree

Secondary sclerosing cholangitis Secondary sclerosing cholangitis develops in response to an identifiable process involving biliary obstruction, including chronic obstruction of any cause, stones, parasites, surgical trauma of biliary tree, ischaemic cholangitis (e.g. after transarterial chemoembolization), and recurrent pancreatitis.

Cholangiocarcinoma Cholangiocarcinoma is discussed in Chapter 15.24.6.

Gallbladder cancer Except when discovered incidentally after laparoscopic cholecystectomy, when the cancer is often confined to the gallbladder wall and metastatic spread is minimal, gallbladder cancer often presents at an advanced stage with direct invasion into bile duct, liver, duodenum, or colon, and spread to local nodes, or liver metastases. It is often asymptomatic until obstructive symptoms arise. On imaging, gallbladder cancer appears as irregular thickening of the gallbladder wall or an intraluminal mass with enhancement after intravenous contrast. In patients with symptoms of biliary disease, ultrasonography is often the first test used. This may show the mass and will detect dilated ducts. However, cross-​sectional imaging using CT or MRI is best, obtaining good views of masses, dilated ducts and enlarged lymph nodes. MRI allows excellent views of hepatobiliary anatomy and when combined with an MRCP shows ductal involvement, demonstrates hilar vascular involvement, and is also good for viewing liver metastases. MRI is not as good as CT

TYPE 1

TYPE 3

for identifying distant metastases, and in clinical practice both are commonly used. Treatment is by surgical resection if possible, with extensive lymphadenectomy to clear the hepatoduodenal ligament and resection of the adjacent liver segments (4 and 5). Some surgeons advocate clearance of bile duct and lymph nodes from the hepatoduodenal ligament, to leave only skeletonized hepatic arteries and portal vein. When gallbladder cancer is discovered incidentally after laparoscopic cholecystectomy, the patient should be referred urgently to a hepatobiliary surgeon for consideration of early repeat operation to resect segments 4 and 5 of the liver with lymph node clearance. This policy greatly improves the chance of cure, and the BILCAP trial has also shown survival benefit for adjuvant capecitabine after surgical resection of gallbladder cancer

Congenital disorders of the bile ducts Choledochal cysts These are rare congenital abnormalities of the bile ducts, most commonly diagnosed in children and most prevalent in east Asian populations. They may be found incidentally or as a result of their complications which include malignant transformation, cholangitis, pancreatitis, and cholelithiasis. Adult patients typically present with biliary or pancreatic symptoms such as abdominal pain or jaundice. The cysts represent increased risk for stone disease during biliary stasis, and for biliary malignancy. Anomalous pancreaticobiliary duct union outside of the duodenal wall is present in 30 to 70%, with a long common channel

TYPE 2

TYPE 4

Fig. 15.25.16  Classification of choledochal cysts.

TYPE 5

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Table 15.25.6  Types of choledochal cyst Type

Comment

1

90% of cases. Cystic lesion of the bile duct. May present as a dilated common bile duct . Lacks biliary mucosa

2

Diverticulum of common bile duct

3

Intraduodenal (lined by duodenal mucosa)

4

Intra-​and extrahepatic duct involvement

5

Caroli’s disease. Intrahepatic saccular dilatations, communicating with bile ducts. Can be associated with extensive fibrosis

(>15 mm from the ampulla). This allows reflux of pancreatic juice into the biliary tree. It is thought that the enzymes may then contribute to cyst formation with inflammation of the cyst walls and hyperplasia. Intrahepatic cysts are associated with portal fibrosis and bile duct proliferation as well. Cysts are classified into five types depending on location and shape (Fig. 15.25.16, Table 15.25.6). Cholangiography is the most sensitive way to define ductal anatomy. Associations include double common bile duct, sclerosing cholangitis, hepatic cysts, and annular pancreas. Types 1 and 4 are most associated with cholangiocarcinoma (Fig. 15.25.17). Management of type 1 and 4 cysts is by excision, which depending on cyst involvement may include hepatic or Whipple’s resections. Types 2 and 3 are usually left alone. Type 5 (Caroli’s disease) may require transplantation due to recurrent sepsis and progressive liver failure.

FURTHER READING Johnson CD (2003). Arris & Gale lecture. Regulation and responses of gallbladder muscle activity in health and disease. Ann R Coll Surg Engl, 85, 297–​305. National Institute for Health and Care Excellence (NICE) (2014). Gallstone disease: diagnosis and management of cholelithiasis, cholecystitis and choledocholithiasis. NICE, London. Soares KC, et al. (2014). Choledochal cysts: presentation, clinical differentiation, and management. J Am Coll Surg, 219, 1167–​80.

Fig. 15.25.17  Type 1 choledochal cyst with anomalous pancreaticobiliary duct union (white arrow) complicated by cholangiocarcinoma (blue arrow).

15.26

Diseases of the pancreas

CONTENTS 15.26.1 Acute pancreatitis  3209 R. Carter, Euan J. Dickson, and C.J. McKay

15.26.2 Chronic pancreatitis  3218 Marco J. Bruno and Djuna L. Cahen

15.26.3 Tumours of the pancreas  3227 James R.A. Skipworth and Stephen P. Pereira

15.26.1  Acute pancreatitis R. Carter, Euan J. Dickson, and C.J. McKay ESSENTIALS Acute pancreatitis affects 300 to 600 new patients per million population per year and is most commonly caused by gallstones or alcohol. Careful imaging reveals that most so-​called idiopathic acute pancreatitis is due to small (1–​3-​mm diameter) gallstones. Diagnosis is made by a combination of a typical presentation (upper abdominal pain and vomiting) in conjunction with raised serum amylase (more than three times the upper limit of normal) and/​or lipase (more than twice the upper limit of normal). Several other acute abdominal emergencies can mimic acute pancreatitis and may be associated with a raised serum amylase. In equivocal cases, a CT scan is indicated to exclude other causes and confirm the diagnosis. Initial management is with (1)  analgesia, (2)  ensuring adequate oxygenation, and (3) intravenous fluid administration. The revision of the Atlanta classification separates patients clinically into (1) mild—​ with early resolution without complications, (2)  moderate—​local complications without organ failure, and (3) severe—​complications associated with organ failure. Mild acute pancreatitis responds to analgesia and intravenous fluids. If gallstones have been identified, then cholecystectomy

(or endoscopic retrograde cholangiopancreatography (ERCP) sphincterotomy where clinically appropriate) should be performed during the same admission, or at least within 2 to 4 weeks to prevent recurrent attacks. Severe acute pancreatitis carries a high mortality (up to 20%). Management in the early stages is centred on organ support (respiratory, circulatory, and renal failure). Later management involves surgical or radiological intervention for sepsis, usually within a specialist pancreatic unit. With regard to some specific aspects of management:  (1) there is no indication for a nasogastric tube or starvation:  enteral feeding of patients with prolonged illness is associated with fewer risks and side effects than total parenteral nutrition. (2)  Antibiotics should not be given until and unless a specific indication arises. (3)  ERCP—​occasionally cholangitis may be associated with hyperamylasaemia, in which case urgent biliary decompression at ERCP is indicated. (4) There are no pharmacological agents that benefit any form of acute pancreatitis. (5) The case for decompressive laparotomy for abdominal compartment syndrome remains unproven.

Epidemiology Population studies from Scotland and Finland have shown the incidence of acute pancreatitis is about 400 patients/​million per year. Incidence would appear to be rising, with a 100% increase in the hospitalization rate in the United States of America over the last 20  years, a 75% increase in admissions in the Netherlands, and a 3.1% yearly rise in incidence in the United Kingdom. The mean age at presentation is 53 years with a roughly equal sex distribution, although the largest increase in incidence has been among women under 35  years, which may reflect increasing obesity within the population. The disease was most prevalent in those with poorer socioeconomic status, especially where alcohol was the cause. Overall mortality is from 2.0 to 7.5%, highest in those who are over 70 years, obese individuals, and those with comorbidity at the time of onset. Prospective and retrospective studies record 45 to 50% of deaths as occurring in the initial week of the illness secondary to fulminant multiple organ failure.

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Clinical features Sudden onset of severe upper abdominal pain focused in the epigastrium with vomiting is the most common presentation. This tends to progressively lessen in severity over the first 48 to 72 h, and it is not usually a significant factor beyond this time. There may be upper abdominal tenderness and guarding, but these signs are often less marked than might be suspected from the severity of the pain, and bowel sounds are usually absent in the early stages. Vomiting is prevalent in the first 12 h of illness, contributing to hypovolaemia and hypotension. Clinical jaundice is rare on admission, although minor abnormalities of biochemical liver blood tests occur in 80% of patients with a biliary aetiology. Occasionally, hyperamylasaemia occurs in association with cholangitis, which if overlooked may result in irreversible multiple organ failure. The presence of jaundice and pyrexia on the day of admission is therefore an indication for urgent endoscopic retrograde cholangiopancreatography (ERCP) and biliary decompression.

Pathology The initial phase of acute pancreatitis is characterized by oedema and the development of an acute inflammatory infiltrate, rich in neutrophils, with tiny spots of fatty tissue necrosis, mainly on the surface but also in the intralobular fatty tissue. In mild cases, the changes are most marked in the peripancreatic tissue, but because the initial pancreatic histological change is within the intralobular fat, there is a relationship between extent of necrosis and the amount of fat within the pancreas. In severe disease, intravascular thrombosis and local enzymic necrosis leads to confluent areas of fat necrosis, which extends beyond the pancreas into the peripancreatic fat. Within the pancreas, disseminated ductal and periductal necrosis may be evident.

Diagnosis and assessment of severity The diagnosis is usually made from the clinical presentation of upper abdominal pain and vomiting associated with an elevation of serum amylase or lipase. A CT scan should be performed when the diagnosis is not clear. This often demonstrates pancreatic oedema and peripancreatic inflammatory stranding, fluid collections, and poor contrast enhancement of the gland (Fig. 15.26.1.1). Occasionally, the diagnosis may first be made at laparotomy, when simple washout and closure is all that should be done. The differential diagnosis is that of an acute abdomen (Box 15.26.1.1). A  raised amylase may be associated with several of these conditions, but the (near) universal availability of CT has simplified diagnosis when doubt exists.

Biochemical abnormalities A multitude of biochemical phenomena are found in acute pancreatitis. Various pancreatic enzymes are released that are useful as diagnostic markers. Acinar cell disruption leads to high serum levels of amylase, lipase, trypsin, chymotrypsin, phospholipase, elastase, trypsinogen activation peptide, and phospholipase activation

Fig. 15.26.1.1  CT scan 36 h from onset of pain showing reduced enhancement of neck and body, a perfused pancreatic tail, and peripancreatic stranding.

peptide. These are also elevated in peritoneal and retroperitoneal tissues as well as lymphatic fluid. C-​reactive protein, an acute-​phase reactant, is of most use for longitudinal monitoring of progress. Very high concentrations of circulating cytokines occur in the blood at an early stage in the disease, including tumour necrosis factor-​α, platelet activating factor, and interleukin 6 with maximal levels in those with severe pancreatitis: these are of research interest rather than clinical value.

Grading disease severity Many biochemical scoring systems attempting to objectively grade severity of an attack of acute pancreatitis have been developed, including the Glasgow and Ranson scoring systems. While there is value in directing less experienced clinicians to the multisystem organ dysfunction associated with a severe attack, none are sufficiently accurate to direct treatment, and the utility lies in assessing equipoise within clinical trials, with regard to which the APACHE II system has been shown to be useful in the stratification of severity of acute pancreatitis. CT scanning can be useful in demarcating location and extent of pancreatic injury, and a CT severity index has been developed, although CT is more commonly used to monitor the development of evolving complications. In practice, sequential physiological scoring systems (e.g. NEWS) can assist the

Box 15.26.1.1  Differential diagnosis of acute pancreatitis • Mesenteric ischaemia/​infarction • Small-​bowel obstruction/​perforationa • Renal failure • Macroamylasaemia • Dissecting aortic aneurysm • Diabetic ketoacidosis • Perforated duodenal ulcera • Acute cholangitisa • Acute cholecystitisa • Atypical myocardial infarctiona • Ectopic pregnancya a

Amylase is usually normal.

15.26.1  Acute pancreatitis

identification of clinical deterioration and are in common use in most surgical units.

Other factors affecting prognosis Other factors affecting prognosis include age and obesity. Many studies have shown that those aged over 70 years have a higher mortality. Chronic cardiorespiratory or renal impairment is common in this age group and further increases the risk of death. Acute pancreatitis carries a significantly higher mortality and morbidity in patients with a body mass index of more than 30  kg/​m2, mainly because of an increased risk of hypoxaemia, but also from other associated factors.

Aetiology Aetiological factors and rare associations of acute pancreatitis are listed in Boxes 15.26.1.2 and 15.26.1.3.

Major factors Biliary disease and alcohol abuse together account for over 80% of patients with acute pancreatitis in most prospective studies. Gallstones Gallstones are the predominant cause of acute pancreatitis and all patients should have an abdominal ultrasound examination to identify these, even where there is a history of alcohol excess. Smaller stones pass through the cystic duct more easily and are at increased risk of precipitating acute pancreatitis. Endoscopic ultrasonography (EUS) is more sensitive than transabdominal ultrasonography in identifying small gallstones (microlithiasis). This may be helpful in demonstrating gallstone aetiology in those patients previously labelled ‘idiopathic’.

Box 15.26.1.3  Rare associations with acute pancreatitis • Hypothermia • Coxsackie B virus • Mumps virus • Sclerosing cholangitis • α1-​Antitrypsin deficiency • Virus infection (non-​HIV) • Worm infestationa • Scorpion biteb • Duodenal duplication a

In South-​East Asia. b In Trinidad.

The mechanism by which gallstones induce acute pancreatitis is not certain, but increased back pressure in the pancreatic duct following transient impaction of a migrating gallstone at the ampulla of Vater is considered to be the likely initiating event. Subsequent intracellular events lead to activation of proteases within acinar cells, acinar cell injury, and a local inflammatory response. Alcohol The proportion of patients in whom pancreatitis is due to alcohol abuse is dependent on the population under study:  rates may be as high as 70 to 80% (in New York (United States of America) and Helsinki (Finland)). The risk is highest in young males who drink in excess of 80 g of alcohol per day. Smoking is a cofactor in the development of both acute and chronic pancreatitis. Many patients with a possible alcohol history also have gallstones and the diagnosis of alcohol-​induced acute pancreatitis should be one of exclusion. Alcohol probably causes acute pancreatitis through intracellular lysosomal release modulated by elevations in cytosolic and mitochondrial ionized Ca2+ concentration.

Minor factors Box 15.26.1.2  Aetiological factors in acute pancreatitis (according to frequency) Major • Biliary disease • Alcohol abuse Minor • After ERCP • Sphincter of Oddi dysfunction • Hyperparathyroidism • Hyperlipoproteinaemia • Blunt or surgical trauma • Autoimmune pancreatitis • Drugs • HIV-​associated pancreatitis • Hereditary (trypsinogen gene defects) • Ampullary or pancreatic tumour • Cancers metastatic to pancreas: Renal — — Stomach — Breast — Ovarian — Lung

Drugs The drugs most commonly implicated in causing acute pancreatitis are valproic acid, azathioprine, l-​asparaginase, and corticosteroids. There is equivocal evidence regarding thiazide and other diuretics. However, unless viral titres have been determined, together with adequate biliary investigations including endoscopic examination of the ampulla of Vater, it is unwise to ascribe acute pancreatitis to a particular drug. Repeat exposure to the same drug again causing acute pancreatitis is the strongest evidence of a direct association. Viral infection Viral infection, particularly mumps, Coxsackie B, and viral hepatitis, can cause acute pancreatitis. One clinical feature that may prove useful is prodromal diarrhoea, which is rare in all other types of acute pancreatitis. Of increasing importance are the effects of HIV infection, where acute pancreatitis may be associated with both the primary viral infection and treatment (antiretroviral drugs). Single combination agent therapy (tenofovir, lamivudine, and efavirenz) is considered the most pancreas friendly, but the evidence for favouring one agent over another is weak. Alcohol abuse is common in many HIV-​positive patients, particularly in Africa, and it may be difficult to define a specific causal agent.

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Benign pancreatic duct stricture

Hereditary

A focal area of pancreatic necrosis in a primary attack of acute pancreatitis can cause secondary fibrosis with main duct stricture formation and segmental ‘upstream’ recurrent attacks of pancreatitis as a consequence. Stricture dilatation or occasionally surgical decompression or distal pancreatectomy may be required. Congenital or developmental anatomical abnormalities can present with pancreatitis (choledochal cyst, duodenal duplication, anomalous pancreaticobiliary junction). Pancreas divisum (nonunion of main and accessory ducts) occurs in 3 to 5% of people and is not considered to be a primary cause of pancreatitis.

This condition is increasingly being studied since the discovery of genetic mutations of the cationic trypsinogen gene (PRSS1), which shed light on the mechanism of acute pancreatitis. A Europe-​wide study (EUROPAC) has tracked multiple families in the United Kingdom and Europe, and similar work in Japan and the United States of America is ongoing. The two most common mutations are R122H and N29I. An autosomal dominant pattern of inheritance is seen. Severe acute inflammatory changes are rare and diagnosis is often delayed. Patients usually have a long history of recurrent abdominal pain from childhood or adolescence. Changes of chronic fibrosis may be present at diagnosis. Typically, chronic pancreatitis is evident by the age of 20 to 40 years, and the risk of pancreatic carcinoma in those aged over 60 years is significantly increased. Mutations in the cystic fibrosis transmembrane conductance regulator gene (CTFR) and the pancreatic secretory trypsinogen inhibitor gene (SPINK1) are also linked to pancreatitis.

Periampullary or obstructive pancreatic tumours Periampullary adenoma or carcinoma resulting in upstream obstruction of the main pancreatic duct is an important association. Ampullary tumours are best diagnosed with side-​viewing endoscopic biopsy. With the increase in this approach to diagnosis, tumours at or close to the ampulla have been shown to cause 0.4% of cases of acute pancreatitis. Effective treatment of the tumour abolishes recurrent attacks. This usually involves surgical resection, but endoscopic laser therapy or endoscopic papillectomy can be effective in older and less fit patients. Carcinoma of pancreas can occasionally present with clinical acute pancreatitis and other primary tumours (such as neuroendocrine tumours) or tumours metastasizing to the pancreas (such as renal carcinoma) may present in this way, probably by causing pancreatic duct obstruction. Pancreatitis in association with a side branch intraductal papillary mucinous neoplasm is considered a risk factor for malignant transformation and requires assessment for potential resection following resolution. Hyperparathyroidism Hypercalcaemia secondary to hyperparathyroidism is now recognized to be an uncommon cause of acute pancreatitis. Removal of a parathyroid adenoma usually prevents further acute pancreatitis since persistent hypercalcaemia appears to be the provoking factor. Hyperlipidaemia Patients with type I  and type V hyperlipoproteinaemia may develop acute pancreatitis in the absence of alcohol ingestion when triglyceride levels exceed 11 mmol/​litre. Both subtypes are associated with chylomicrons, of which greater than 90% are triglycerides. Dietary restriction of lipids and various lipid-​lowering drugs are valuable in therapy. Hyperlipidaemia of any cause where triglyceride levels reach in excess of 2000 mg/​dl may cause acute pancreatitis, and acute pancreatitis may rarely complicate hyperlipidaemia of pregnancy or diabetic ketoacidosis. High triglyceride levels may be present during an attack of acute pancreatitis and identifying high fasting lipid levels following resolution is key to confirmation. Hypothermia This is an important association. In younger patients, this may be associated with alcohol abuse, particularly if patients fall asleep out of doors, or in the elderly in an unheated house. Management is directed at gradual warming and supportive measures for organ compromise.

Trauma Hyperamylasaemia may occur after blunt abdominal trauma, usually from a crush injury to the body of the pancreas against the vertebral column. The risk of associated injuries to surrounding organs is high, and in the acute phase these are usually more significant than the pancreatic injury. The identification of a pancreatic injury during a trauma laparotomy should be managed by simple drainage in most cases. When there is transection of the main pancreatic duct, therapeutic options include endoscopic transpapillary stenting and distal pancreatectomy. Late presentation is associated with pseudocyst formation due to leakage from the damaged pancreatic duct. Pancreatic manipulation during surgical mobilization for colonic, gastric, or splenic surgery may result in inflammation. Iatrogenic Surgical or endoscopic procedures involving the ampulla of Vater can induce pancreatitis. In recent years, diagnostic ERCP (2% risk of acute pancreatitis) has largely been replaced by noninvasive imaging modalities (EUS and magnetic resonance cholangiopancreatography). This has reduced the overall incidence of postprocedural acute pancreatitis, but EUS fine needle aspiration of pancreatic lesions, particularly close to the main duct, can itself result in pancreatitis. The risk of acute pancreatitis increases to 4 to 6% where a therapeutic endoscopic sphincterotomy has been performed and may be as high as 20% in high-​risk patients (sphincter of Oddi dysfunction). Iatrogenic perforation should be considered in all patients who develop pancreatitis after therapeutic ERCP, and patients with early organ dysfunction or abdominal signs should undergo a CT without delay if any doubt exists as this will affect management (antibiotics). Autoimmune pancreatitis This is a rare condition, which is considered part of the systemic IgG4-​related autoimmune disease spectrum and is associated with other autoimmune diseases (polyarteritis nodosa, systemic lupus erythematosus, other vasculitides) and inflammatory bowel disease (Crohn’s disease and ulcerative colitis). It may present as abdominal pain with obstructive jaundice more typical of chronic than acute pancreatitis. Other features may include (1)  an increased IgG4/​

15.26.1  Acute pancreatitis

IgG ratio in serum, (2)  homogeneous gland enlargement with a well-​defined halo on CT, (3) characteristic diffuse abnormality on EUS, and (4) periductal lymphoplasmacytic infiltrate on biopsy. The latter may also be associated with abnormalities in the extrahepatic biliary tree resembling sclerosing cholangitis (IgG4-​ associated cholangiopancreatopathy). Focal autoimmune pancreatitis may prove difficult to differentiate from carcinoma. A good response to steroids is diagnostic (HISORt criteria). Worm infestation Ascaris lumbricoides within the ampullary area may manifest as acute pancreatitis clinically, and other worms lodged in this area can produce the same effect.

Table 15.26.1.1  Grades of severity of pancreatitis (based on the clinical parameters of the presence or absence of organ failure and/​or complications Mild acute pancreatitis

• No organ failure • No local or systemic complications

Moderately severe acute pancreatitis

• Organ failure that resolves within 48 h (transient

Severe acute pancreatitis

• Persistent organ failure (>48 h): • Single organ failure • Multiple organ failure

Critical acute pancreatitis

In addition to the other three categories taken from the Atlanta revision, an additional ‘critical’ category (persistent organs failure and sepsis) was proposed by Petrov et al.

organ failure

Sphincter of Oddi dyskinesia Rarely, sphincter of Oddi dyskinesia can present with acute abdominal pain, although the more common presentation is one of chronic relapsing abdominal discomfort. The attacks associated with hyperamylasaemia are usually mild (except where pancreatitis follows an ERCP). With regard to functional gallbladder and sphincter of Oddi disorders (SODs), the Rome III diagnostic criteria for functional gastrointestinal disorders require episodes of pain in the epigastrium or right upper quadrant and all of the following: episodes lasting 30 min or longer; recurrent symptoms occurring at different intervals (not daily); the pain builds up to a steady level and is moderate/​severe enough to interrupt the patient’s daily activities or lead to a visit to the emergency department; the pain is not relieved by bowel movements, postural change, or antacids; and exclusion of other structural disease that would explain the symptoms. If these criteria are satisfied, then Rome III allowed further classification into functional gallbladder disorder (SOD I), where the gallbladder is present and biochemical tests are normal; functional biliary SOD (SOD II), where amylase and lipase are normal, but association of at least two episodes of pain with elevation of serum transaminases, alkaline phosphatase, or conjugated bilirubin is a supportive criterion; and functional pancreatic SOD (SOD III), characterized by elevation of serum amylase and/​or lipase. More recently, Rome IV, recognizing good evidence that sphincterotomy is no better than sham treatment in patients previously classified as having SOD III, discarded the use of this term and renamed SOD II ‘Functional Biliary Sphincter Disorder’. However, whether this exists as a clinical entity remains a matter of debate, and whether it is a potential cause of acute pancreatitis is controversial. Most clinicians would not recommend pancreatic sphincterotomy in the absence of ampullary stenosis.

organ failure) and/​or

• Local or systemic complications without persistent

heavily influenced by the degree of systemic disturbance, and this is reflected in an additional category of ‘moderately severe’ pancreatitis, where collections are present in the absence of organ dysfunction. In addition to disease severity, mortality is strongly associated with age and comorbidity. The significance of infection has been recognized in an addendum adding a category of ‘critical’, recognizing that those patients with sepsis and organ failure have the highest mortality. This classification further separates local complications/​collections on the basis of time from presentation (4 weeks) and on the presence of necrosis, leading to definitions aimed at permitting comparison of case series (Table 15.26.1.2). The ‘early’ phase is characterized by the initial host response to the pancreatitis, the severity being determined by the magnitude of organ disturbance/​ failure, and a ‘late’ phase typified by the persistence of organ dysfunction and the management of local or systemic complications. The vast majority of acute fluid collections without necrosis will resolve within 4 weeks, and a persistent fluid collection with minimal or no necrotic component (‘pseudocyst’) is very rare. Collections may be sterile or infected. Most clinically significant peripancreatic complications are therefore related to either acute necrotic collections (4 weeks). This temporal separation is somewhat arbitrary as the clinical management and surgical approach is determined by multifactorial individual patient factors. However, this does serve to provide a timeline beyond which, if appropriate, intervention should be delayed.

Management Classification of severity The original Atlanta classification of acute pancreatitis dichotomized clinical behaviour into mild or severe acute pancreatitis, and intervention for necrosis was often focused on early removal of sterile or infected necrosis, usually by open necrosectomy. This oversimplification proved inadequate in clinical practice and the Atlanta criteria were revised in 2013 to address the importance of early systemic organ dysfunction in determining disease severity and outcome (Table 15.26.1.1). The outcome following intervention for the management of local fluid or necrotic collections is also

General aspects The principles of organ support in critical illness should be followed, ensuring reversal of hypoxaemia, restoration of circulating volume, and maintenance of tissue perfusion ideally within a critical care environment. Early restoration of circulating blood volume is associated with an improved outcome. The combination of fluid lost from vomiting and loss of capillary integrity can be very substantial. The introduction of vasoconstrictor therapy should only be considered after establishing adequate volume resuscitation. Hypoxaemia reflects disease severity in acute pancreatitis, and while most patients

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Table 15.26.1.2  Local complications in acute pancreatitis (2012 Revised Atlanta Classification) Timescale

Necrosis absent

Necrosis present

4 weeks

Pancreatic pseudocyst (an encapsulated collection of fluid with a well-​defined inflammatory wall usually outside the pancreas with minimal or no necrosis)

Walled-​off necrosis (a mature, encapsulated collection of pancreatic or extrapancreatic necrosis that has developed a well-​defined inflammatory wall)

Infection

Each collection type may be sterile or infected

can be managed with supplemental humidified oxygen, assisted ventilation may be required in more severe cases. For initial resuscitation, Ringer’s lactate is recommended, with goal-​directed intravenous fluid (5–​10 ml/​kg per hour) to produce 0.5 ml/​kg of urine per hour. Renal replacement therapy by haemodialysis or haemofiltration may be required if renal failure becomes established. The more severe cases of acute pancreatitis are characterized by the development and persistence of a systemic inflammatory response syndrome, one aspect being the development of a swinging pyrexia. This is often inappropriately taken as evidence of sepsis but is usually a reflection of the inflammatory cascade and the presence of devitalized tissue in the retroperitoneum rather than bacterial infection.

Specific aspects

nutritional support is cheaper and is associated with fewer side effects than total parenteral nutrition. In addition, there is no difference in outcome with nasogastric compared to nasojejunal feeding. In clinical practice, therefore, the mode of nutritional support does not appear to influence the disease process, and the choice of delivery relates to tolerance and minimizing morbidity associated with the delivery system. Probiotics may be detrimental in acute pancreatitis and specifically supplemented nutrition should only be administered in the context of clinical trials. It has been suggested that nutritional support may help to preserve mucosal function and limit the stimulus to the inflammatory response. The experimental evidence supporting this has not been confirmed in clinical practice and there is no evidence that the mode of feeding alters disease progression.

ERCP

Other approaches

There is no role for early ERCP in mild disease. High fever within the first 24 h is rare and, if associated with jaundice, is suspicious of ascending cholangitis where the cholangitis, rather than any pancreatic inflammation, is driving organ dysfunction. This is the only unequivocal indication for ERCP and biliary decompression. The role of early ERCP remains controversial in all other circumstances. Several randomized studies and cohort series have looked at the role of early ERCP with endoscopic sphincterotomy compared with conservative management in acute gallstone pancreatitis. A  number of meta-​analyses have failed to demonstrate a definite benefit, and early ERCP is difficult to justify in patients who are not jaundiced.

Previous randomized studies have failed to provide sufficient evidence to recommend the use of antiproteases, antisecretory, anti-​ inflammatory agents, or antioxidant therapy in patients with acute pancreatitis. There is therefore no proven pharmacological therapy for the treatment of acute pancreatitis.

Antibiotics The dual peak in mortality in acute pancreatitis is well recognized. The late peak is determined by complications associated with necrosis, including the development of pancreatic or peripancreatic infection. The consensus of the most recent systemic reviews/​meta-​ analyses is that there is no evidence supporting the use of prophylactic antibiotics in either mild or severe acute pancreatitis, and the recommendation is to avoid their use, using targeted antibiotic therapy for episodes of proven infection. It is, however, reasonable to commence antibiotics in the deteriorating patient with radiological and clinical evidence of sepsis while awaiting culture confirmation. Nutrition support There is no benefit from enteral feeding in mild pancreatitis, and these patients need have no dietary restrictions. Assisted feeding may be required in severe acute pancreatitis to provide long-​term nutritional support. Randomized studies have shown that enteral

Intervention for postacute pancreatitis fluid and necrotic collections The definitions surrounding acute fluid-​predominant and acute necrotic collections have been detailed previously in Table 15.26.1.2. Due to the complexity and diversity of an individual patient’s clinical course, it is challenging to define specific triggers for intervention. Delayed intervention where possible, along with planned minimally invasive sepsis control, has become key to management in most pancreatic units. There is no role for early (week 1)  intervention unless vascular complications are suspected. Intervention is most commonly required for suspected or proven sepsis of acute necrotic collections or walled-​off necrosis after resolution of the initial inflammatory phase. Optimal management may involve a number or combination of techniques and require discussion with a specialist regional pancreatic centre. The indication for early (80 g/​day)   Increased (20–​80  g/​day)   Moderate (80 g/​day for some years in men, smaller amounts in women), or 2 History of increased alcohol intake (20–​80 g/​day for some years), or 3 History of moderate alcohol intake (200 μmol/​litre), the patient has biliary sepsis, there is diagnostic uncertainty, or there is likely to be a delay until surgery. In patients with locally advanced or metastatic disease, endoscopic biliary stenting may be required to relieve jaundice and prevent sepsis, and is associated with lower complication rates than percutaneous biliary drainage or surgical biliary bypass. Endoscopic stent insertion can be performed as soon as a treatment strategy is decided. Preoperatively (depending upon local availability and expertise), fully covered self-​expanding metal stents, rather than plastic stents, are preferred in patients who are deeply jaundiced or cholangitic, or in whom there is another reason for delaying surgery more than 1 to 2 weeks. Uncovered self-​expanding metal stents are generally reserved for patients with cytologically/​ histologically confirmed unresectable disease. Endoscopic stents carry a risk of endoscopic retrograde cholangiopancreatography-​ induced acute pancreatitis, stent migration, or later stent occlusion, but overall are associated with a low complication profile. If patients are found to have unresectable disease at operation, a surgical biliary bypass is often the management method of choice and can be combined with gastrojejunostomy for those patients in whom gastric outlet obstruction is suspected or imminent. Gastric outlet obstruction occurs in 10 to 20% of patients with locally advanced disease and those with successful endoscopic or percutaneous biliary drainage can be managed either by surgical bypass (open or laparoscopic) in patients with good performance status or via endoscopic stent insertion.

Fig. 15.26.3.2  Treatment algorithm for patients with pancreatic ductal adenocarcinoma.

15.26.3  Tumours of the pancreas

Surgical resection Most patients with pancreatic ductal adenocarcinoma present with distant metastases or locally advanced disease (involvement of nearby structures that would prevent a clear resection margin), hence only 10–​15% of patients are able to undergo surgical resection. Specific operative strategies depend upon the site and extent of disease: tumours in the head of the pancreas require pancreaticoduodenectomy, either via a classical Whipple’s procedure or via pylorus-​preserving pancreaticoduodenectomy (usually open but occasionally laparoscopic), whereas tumours in the body or tail can be resected via distal pancreatectomy with or without concurrent splenectomy (laparoscopic where possible; involvement of the spleen or splenic vessels is not a contraindication to surgery). All pancreatic surgery carries a potential risk of significant complications and patient selection is therefore crucial. Since the introduction of the National Cancer Plan in 2001 in the United Kingdom, all such resectional pancreatic surgery is now undertaken in regional specialized centres as there is good evidence that centralization of such services results in improved rates of morbidity and mortality (now 1–​2% in high-​volume centres), as well as oncological outcomes. There has been much recent discussion regarding the definitions of operable and locally advanced disease (inoperable but no progression to distant metastases), and the concept of borderline operable disease has recently been introduced (Table 15.26.3.5). The ESPAC-​5 trial (European Study group for Pancreatic Cancer—​ Trial 5F), a multicentre, prospective, randomized, feasibility phase II trial comparing neoadjuvant therapy to immediate surgical exploration in patients with borderline resectable pancreatic cancer, is currently recruiting.

Chemotherapy Advanced disease In patients with advanced disease, chemotherapy improves both survival and quality of life as compared to best supportive care alone. Overall, gemcitabine (a nucleoside analogue) is the most commonly used chemotherapeutic agent. The phase III, multicentre GemCap study randomized patients to receive gemcitabine alone or in combination with capecitabine (an oral prodrug enzymatically degraded to 5-​fluorouracil, a pyrimidine analogue) in 533 patients with advanced pancreatic ductal adenocarcinoma to demonstrate a trend towards improved survival in patients receiving combination therapy (7.1 vs 6.2 months overall survival; 1-​year survival 24.3% vs 22%; p = 0.077). The phase III randomized MPACT study demonstrated a significantly improved overall survival in patients administered

weekly nab-​paclitaxel (a mitotic inhibitor) with gemcitabine, as compared to gemcitabine alone (8.5 vs 6.7  months; p  =  0.0001). Gemcitabine-​based therapy is therefore a common combination regimen and has been shown to significantly improve progression-​ free and overall survival, as well as overall objective response rates, although this can be offset by the greater toxicity profile associated with combination therapy. Trials of biological agents have largely yielded disappointing results, although a Canadian phase III trial did demonstrate a small improvement in overall survival with the addition of erlotinib (an epidermal growth factor receptor inhibitor) to gemcitabine, as compared to gemcitabine alone (6.2 vs 5.9 months; p = 0.038). Other agents are under investigation. In a French multicentre study of FOLFIRINOX (oxaliplatin (platinum-​based chemotherapeutic agent), irinotecan (topoisomerase I  inhibitor), fluorouracil, and leucovorin (folic acid derivative)) or gemcitabine, there was improved survival in the FOLFIRINOX group (11.1 vs 6.8  months; p