Oxford Textbook of Medicine [3, 6 ed.] 0198746695, 9780198746690

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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

3

SECTIONS 16-21

Firth Conlon Cox ISBN 978-0-19-885346-6

9 780198 853466

INTERNATIONAL EDITION

Oxford Textbook of

SIXTH EDITION

1

2

2

Medicine SIXTH EDITION VOLUME 3

edited by

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

ONLY F O R 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 F O R 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 3: Sections 16–21

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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Preface

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.

Clinical skill 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.

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.

Patients and their expectations 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.

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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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.

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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 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 16.3 Clinical investigation of cardiac disorders  3294 16.3.1 Electrocardiography  3294 Andrew R. Houghton and David Gray 16.3.2 Echocardiography  3314 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 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

Section 16  Cardiovascular disorders

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

16.1

Structure and function

CONTENTS 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

16.1.1  Blood vessels and the endothelium Keith Channon and Patrick Vallance ESSENTIALS Anatomy of blood vessels The blood vessel wall consists of three layers:  the intima, media, and adventitia. Not all vessels have each layer, and the layers vary in size and structure between vessels. (1) The intima is made up of a single layer of endothelial cells on a basement membrane, beneath which—​depending on vessel size—​there may be a layer of fibroelastic connective tissue and an internal elastic lamina that provides both structure and flexibility. Embedded in the intima are pericytes. (2) The media is made up of smooth muscle cells, elastic laminae, and extracellular matrix. (3) The adventitia is the outermost part of the vessel, composed mainly of fibroelastic tissue but also containing nerves, small feeding blood vessels (the vasa vasorum), and lymph vessels. The adventitia is directly related to the surrounding perivascular adipose tissue.

Function of particular constituents of blood vessels Endothelial cells are metabolically very active and exert a profound influence on vascular reactivity, thrombogenesis and coagulation, and the behaviour of circulating cells. Endothelial cells sense blood flow through transduction of shear stress (viscous drag), and align with the direction of blood flow through cytoskeletal functions. They produce key vasodilator mediators:  nitric oxide, prostanoids, and hyperpolarizing factors. Although the predominant influence of the

healthy endothelium is as dilator, it also produces important vasoconstrictor factors, including endothelin, angiotensin-​ converting enzyme, certain prostanoids, and reactive oxygen species such as superoxide anion. The endothelium synthesizes and releases prothrombotic and antithrombotic factors, with antithrombotic factors predominating under basal conditions. The healthy endothelium allows leucocytes to roll along its surface, but prevents cells from adhering fully to the vessel wall. Vascular smooth muscle cells provide the contractile function of the vessel wall, but may adopt a range of other phenotypes:  they can enter a replicative state, undergo cell death through apoptosis, migrate into the intima, adopt a secretory phenotype that results in matrix deposition (including developing bone-​like features and calcification), and can contribute to inflammation within the vessel wall. The vessel is surrounded by adventitia and perivascular adipose tissue, which contain adipocytes, inflammatory cells, and fibroblasts. Evidence suggests that there is continuous cross-​talk between the vascular wall and perivascular tissues. Perivascular adipose tissue secretes a wide range of adipocytokines, which have paracrine effects on the vessel wall. The vessel and its perivascular adipose tissue are now considered to be closely interrelated, with perivascular adipose tissue playing important roles in vascular homeostasis and pathophysiology.

Integrated responses of blood vessels Blood flow elicits an endothelium-​dependent dilator tone due to the production of nitric oxide, which provides a physiological counterbalance to the constrictor tone of the sympathetic nervous system. Veins differ from arteries and arterioles, and do not seem to be actively dilated by continuous release of nitric oxide. Flow-​mediated dilatation is an autoregulatory property of blood vessels that tends to oppose classical myogenic autoregulation—​the process by which a blood vessel constricts in response to an increase in intraluminal pressure. There is a fourth-​power relationship between resistance to flow and the radius of a blood vessel, which means that relatively small changes in the thickness or contractile state of smooth muscle in small arteries and arterioles have big effects on systemic vascular resistance. There are important interactions between the sympathetic nervous, renin–​angiotensin, and endothelin systems, with these acting in concert to control constrictor tone, and with the endothelin system providing a slowly modulating background constrictor tone.

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Section 16  Cardiovascular disorder

Additional endocrine signals that modulate vascular tone and function include circulating cortisol and oestrogens.

Pathophysiology Several clinical conditions associated with increased cardiovascular risk—​ including atherosclerosis, hypertension, hypercholesterolaemia, and diabetes—​ are associated with reduced nitric oxide-​ mediated effects. Overproduction of nitric oxide may also contribute to disease, with induction of inducible nitric oxide synthase (e.g. in sepsis), leading to production of large amounts of nitric oxide and contributing to vascular paresis. Expression of adhesion molecules by the vascular endothelium is an important mechanism of cellular adhesion during inflammation and is also important in recruitment of monocytes in atherosclerosis. Impaired production and/​or function of endothelial progenitor cells, particularly with ageing, may contribute to the pathogenesis of endothelial dysfunction in disease, particularly in atherosclerosis and vascular injury, where endothelial cell turnover is increased.

Introduction Blood vessels range in size from microscopic capillaries to large vessels such as the aorta and vena cava, and vary in specialized function from tissue to tissue. They deliver oxygen and nutrients, remove waste, control the passage of cells and macromolecules from the blood into the tissues, and are equipped to sense and respond to physical and chemical signals. There are three basic layers to blood vessels—​the intima, the media, and the adventitia (Fig. 16.1.1.1). The intima comprises a single layer of endothelial cells on a basement membrane, beneath which—​depending on vessel size—​there may be a layer of fibroelastic connective tissue and an internal elastic lamina that provides both structure and flexibility. Embedded in the

intima are pericytes—​intriguing cells of smooth muscle cell lineage that make contact with multiple endothelial cells. The media is made up predominantly of smooth muscle cells and concentric elastic fibres making up the elastic laminae. The outermost part of the vessel is the adventitia, a less well-​defined layer composed mainly of fibroelastic tissue that provides structural integrity to the vessel, but also contains nerves, small feeding blood vessels (the vasa vasorum), and lymph vessels. However, the adventitia is also in continuity with perivascular adipose tissue (PVAT) that has paracrine relationships with the vascular wall. In simple terms, the intima may be considered as the layer that transduces signals from the lumen of the vessel to the rest of the vessel wall and controls the interface with the blood; the media is the mechanical workhorse of the vessel, and the adventitia links the vessel wall to the local and wider environment. Not all vessels have each layer, and the layers vary in size and structure between vessels. For example, capillaries are essentially endothelial cell tubes surrounded by pericytes, resistance vessels have a relatively thick media, and the large conduit arteries have a high proportion of elastic tissue and a rich vasa vasorum. In disease states, particularly atherosclerosis (see Chapter  16.13.1), the vessel wall may have a high content of inflammatory cells in the intima, media, and adventitia. All three layers coordinate to regulate the function of the blood vessel, and all three are involved in the pathogenesis of vascular disease. Large ‘conduit’ arteries perform the function of mass transport; smaller arteries and arterioles provide the predominate resistance to flow, and are therefore key determinants of blood pressure; capillaries are thin-​walled and contribute most to passage of nutrients, gases, and cells through to tissues; venules provide postcapillary resistance and help determine capillary pressure; and larger venules and veins dynamically regulate the total capacitance of the circulatory system.

Cellular constituents of blood vessels Endothelium

Fig. 16.1.1.1  Image of a human coronary artery, imaged in vivo using optical coherence tomography during coronary angiography. The asterisk denotes the circular cross-​section of the imaging catheter, and the dotted lines show the optical shadow cast by the coronary guide wire, adjacent to the imaging catheter. The vessel lumen appears black, with the vessel wall highlighted in yellow pseudocolour. The layers of the vessel wall—​intima (I), media (M), and adventitia (A)—​are shown in the magnified inset box.

A monolayer of endothelial cells lines the intimal surface of the entire vascular tree (Fig. 16.1.1.2) to form the largest endocrine/​ paracrine organ in the body. Endothelial cells are metabolically very active and exert a profound influence on vascular reactivity, thrombogenesis and coagulation, and the behaviour of circulating cells. Abnormalities of endothelial function have been implicated in a wide variety of diseases ranging from atheroma and hypertension to acute inflammation and septic shock. During early development, the endothelium forms the first layer of the circulatory system and extends to produce a network of interconnecting tubes. This ability of endothelial cells to form tube-​like structures is retained even when they are grown in vitro. In vivo the endothelial tubes differentiate into arteries, arterioles, capillaries, veins, and lymph vessels, and regional differences in function and structure evolve such that the properties of endothelial cells vary between arterial and venous beds, between micro-​ and macrovasculature, between organs, and between different parts of individual organs—​perhaps the most striking example being the specialized layer of endothelial cells and pericytes that forms the blood–​brain barrier. Although heterogeneity of vascular

16.1.1  Blood vessels and the endothelium

Fig. 16.1.1.2  Left panel: Immunostaining of an en face preparation of artery with CD31 (cell bodies red, nuclei blue), showing endothelial cells. Note that the endothelial cells are aligned in the direction of blood flow. Right panel shows a section of human internal mammary artery immunostained for endothelial nitric oxide synthase (red staining), demonstrating the endothelial cell layer on the luminal surface.

endothelium has long been recognized at the histological and immunocytochemical level, recent studies using microarray analysis of global gene expression have begun to define these differences at the molecular level and promise to have important implications for understanding physiology, pathophysiology, and therapeutics. Heterogeneity of endothelial cell function undoubtedly has such implications. For example, endothelial cell heterogeneity may provide strategies to target therapeutic agents or imaging markers to specific organs by coupling them with antibodies or ligands to vascular bed-​ specific endothelial proteins. However, endothelial cells also have many features in common and several pathologies, including those causing premature vascular disease, are associated with widespread changes in the behaviour of endothelial cells.

Anatomy of the endothelium Each endothelial cell is between 25 and 50 µm long, 10 to 15 µm wide, and up to 5 µm deep, and lies with its long axis aligned in the direction of the blood flow (Fig. 16.1.1.2). The underlying smooth muscle cells lie radially, are about 5 to 10 µm wide, and taper at either end so that a single endothelial cell can communicate with many smooth muscle cells, and vice versa. The endothelium also comes into intimate contact with circulating cells, and the total area of the luminal surface of the endothelium is in excess of 500 m2. This thin layer of cells is particularly susceptible to injury, and changes in endothelial cell morphology and turnover occur in experimental hypertension, diabetes, and atherosclerosis.

Signal detection by endothelial cells The endothelial cell membrane expresses many receptors for circulating hormones, local mediators, and vasoactive factors released from blood cells. Endothelial cells sense pressure, stretch, and blood flow via a number of different sensors that vary in different vessels, reflecting the differences in pressure and blood flow across different vascular beds. For example, shear stress (viscous blood flow force) varies from c.10 dyn/​cm2 in large conduit arteries such as the aorta, to c.50 dyn/​cm2 in resistance arterioles, c.20 dyn/​cm2 in post-​capillary venules, and c.1 dyn/​cm2 in large veins such as the vena cava. Endothelial cell mechanosensors on the luminal surface include G-​ protein-​coupled receptors (such as the sphingosine 1-​phosphate receptor 1 and the bradykinin B2 receptor), heterotrimeric G-​proteins,

ion channels (such as TRPV4, TRPP2, TRPC1, Piezo1, and Piezo2), and the glycocalyx, a c.500 nm thick layer of glycosaminoglycans on the endothelial surface containing syndecan-​1 and −4. Shear stress responses are also localized in microtubule-​based primary cilia (containing with the ion channels PKD1 and PKD1) and protein-​coated membrane ‘pits’ called caveolae, containing the proteins Caveolin 1–​3 and Cavin 1–​3. In addition, endothelial mechanosensors are present at cellular junctions, including PECAM-​1, VE-​cadherin, and VEGFR2, forming mechanosensory complexes that respond to shear stress. On the basal (outer) part of the endothelial cell, other mechanosensors such as the integrins interact with the intimal extracellular matrix (ECM). Rapid endothelial cell responses to shear stress include K+ and Ca2+ influx, activation of MAP kinases, Akt and eNOS, leading to nitric oxide (NO) production that causes vasodilatation and S-​ nitrosylation of endothelial cell proteins such heat shock proteins, as well as cytoskeletal components such as tropomyosin and vimentin. Small GTPases such as RhoA and Rac are highly sensitive to shear stress. RhoA is transiently downregulated within 5 min of onset of shear stress, allowing rearrangement of the actin cytoskeleton. Endothelial cell integrins modulate the response to shear stress, for example, by sensing the nature of connections with ECM components, and ensure spatial organization of focal adhesion complexes, microtubules, and intracellular signalling pathways such as p38 MAP kinase, JNK, and p21-​activated kinase. Downstream consequences of shear stress transduction include initial transcriptional activation of NF-​ kB target genes, such as ICAM-​1, but in areas of sustained laminar flow there is downregulation of NF-​kB and increased ‘atheroprotective’ gene expression, mediated by the transcription factor KLF2. In areas of disturbed flow (i.e. loss of laminar shear stress), NF-​kB and other inflammatory signalling are sustained, leading to ICAM-​ 1 and VCAM-​1 expression and enabling monocyte recruitment.

The endothelial cells in vascular damage and repair Vascular endothelial cells move in response to specific chemical signals and can migrate to recover areas of endothelial damage or denudation (Fig. 16.1.1.3). The basic mechanisms of movement share similarities with those required to form vessels during development

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and peripheral vascular disease. In general, the results of these early clinical experiments have been mixed, and there remain important unanswered questions regarding the optimum cell type, the timing and route of delivery (e.g. intracoronary vs. intravenous), and the precise mechanism of potential beneficial effects. Other therapeutic strategies have been aimed at increasing endogenous EPC number and/​or EPC function, either (e.g. using statin drugs) or acutely (by administration of erythropoietin, cytokines, or growth factors) in ischaemic events such as myocardial infarction.

Pericytes

Fig. 16.1.1.3  An endothelial cell moving. The front end of the cell with leading lamella is on the right, stress fibres of contractile elements are seen in the centre and these end in focal adhesions. The retracting rear end of the cell is on the left. Courtesy of Dr B. Wojciak-​Stothard.

(vasculogenesis) or during the process of formation of new vessels in adults (e.g. in tumour angiogenesis). Circulating endothelial progenitor cells (EPCs), derived from bone marrow, have been identified and are involved in the processes of vascular repair and the response to tissue injury. These progenitor cells are characterized by the expression of specific cell surface markers (CD34 and CD133) and can form colonies when cultured in vitro. There is also evidence that resident stem cells located in the vessel wall with properties of clonality, self-​renewal, and multipotentiality can replace local damaged or denuded endothelial cells. The relationship between the number of circulating endothelial cells and cardiovascular disease is complex. The number of circulating EPCs, typically estimated by colony growth in vitro from peripheral blood mononuclear cells, is thought to represent the restorative capacity of the vessel wall, with low numbers being indicative of disease progression and increased cardiovascular risk. Importantly, the number of circulating EPCs appears to decrease with age, and with known cardiovascular risk conditions such as diabetes, hence it is likely that the ability to increase EPCs in response to vascular damage is a key feature of a healthy cardiovascular system able to repair itself. Acute adverse events such as myocardial infarction are associated with a temporary increase in circulating EPC numbers. There is growing interest in the potential therapeutic delivery of EPCs—​or bone marrow-​derived cells capable of differentiating into EPCs and/​or endothelial cells—​for the treatment of cardiovascular disorders. For example, clinical studies have already been initiated in which autologous bone-​marrow-​derived cells have been administered to patients for the treatment of acute myocardial infarction

Pericytes are long cells (approximately 70 µm) with extending cytoplasmic processes around endothelial cells that make multiple cellular contacts (Fig. 16.1.1.4). In small capillaries, it also seems that pericytes may extend connections to more than one vessel, possibly exerting some sort of coordinating influence. The overall coverage of the endothelium by pericytes varies between vascular beds, from 10% to 50%. The junctions between pericytes and endothelial cells appear to be rich in growth factors (particularly epidermal growth factor) that are important in regulating endothelial cell growth and may be vital for angiogenesis and inflammation. Pericytes can also differentiate in to other cells, such as fibroblasts. The nature of the junction between pericytes and endothelial cells may be important for regulating permeability at specialized sites such as the blood–​brain barrier, and in the response to ischaemic injury. In other areas, the contractile function of pericytes may predominate. In the retina, where pericytes are particularly prevalent, their loss is associated with impaired hierarchical organization of vessels or even vessel regression, and this might contribute to diabetic retinopathy. In inflammation, neutrophil transmigration from venules is regulated by adhesion to pericytes. The only genetic disease

Endothelial cell

RBC

Pericyte

Fig. 16.1.1.4  Pericytes are observed outside small blood vessels in close association with endothelial cells. Reproduced with kind permission from the Department of Pathology and Laboratory Medicine, University of Pennsylvania.

16.1.1  Blood vessels and the endothelium

Box 16.1.1.1  Roles of pericytes • Contractility • Barrier function and regulation of permeability • Neutrophil transmigration in inflammation • Signalling to control endothelial growth and angiogenesis • Vascular stabilization • Sensors of hypoxia and hypoglycaemia • Transdifferentiation into fibroblasts in wound healing, cancer metastasis

to date in which pericyte loss has been implicated is Adams–​Oliver syndrome, a rare developmental disorder characterized by scalp and limb malformations, telangiectasia, and vascular problems. The potential roles of pericytes are listed in Box 16.1.1.1. These rather underinvestigated cells seem to retain a plasticity that enables them to differentiate into smooth muscle cells.

Vascular smooth muscle cells Smooth muscle cells lie mainly circumferentially in the vessel media to provide contractile function, which is influenced by hormonal, endothelial, neuronal, and intrinsic influences (‘myogenic tone’), with contraction being triggered by a wave of calcium release. The regulation of vascular smooth muscle cell (VSMC) Ca2+ signalling is complex and heterogeneous. Extracellular Ca2+ entry is regulated by activation of the plasma membrane voltage-​dependent L-​type Ca2+ channels (LTCC) and TRP channels. Intracellular Ca2+ release from the sarcoplasmic reticulum (SR) is regulated by agonist activation of SR-​bound inositol trisphosphate (IP3) or ryanodine receptors (RyR). Calcium signalling is highly compartmentalized such that large changes in intracellular Ca2+ may lead to VSMC contraction without activating other Ca2+-​dependent pathways, and vice-​versa. VSMC contraction is highly complex, but is effected by phosphorylation of smooth muscle actin at Ser 19 by myosin light chain kinase (MLCK). MLCK is a Ca2+-​calmodulin dependent kinase that is activated by VSMC Ca2+ signalling. Other important aspects of VSMC contractility, via the cytoskeleton and focal adhesion complexes, are regulated by complex networks of Ca2+ -​dependent pathways including the Ca/​CaM-​dependent kinase II (CaMKinase II) isoforms, protein kinase C (PKC), and MAP kinases. VSMC contraction is the key regulator of resistance to blood flow and hence blood pressure. There is a fourth-​power relationship between resistance to flow and the radius of the vessel, which means that relatively small changes in the contractile state of smooth muscle can produce large changes in the resistance offered by the vessel. This is particularly important for small arteries and arterioles, which are the major determinants of systemic vascular resistance. The relative thickness of the vessel wall compared to the size of the lumen is also an important determinant of resistance. As the wall:lumen ratio increases, there is a comparatively larger reduction in lumen size for every incremental shortening of the smooth muscle. In this way, smooth muscle hypertrophy or hyperplasia can lead to a functional hyperreactivity of the vessel wall, exemplifying the intimate connection between structure and function. Vascular smooth muscle cells are remarkably plastic and may adopt a range of phenotypes in response to local environmental changes. They may leave the quiescent contractile state and enter a replicative state, migrate into the intima, adopt a secretory

phenotype that results in matrix deposition (including the development of bone-​like features and calcification), and may, under certain conditions, contribute to inflammation within the vessel wall. Smooth muscle cells that replicate and secrete matrix contribute to the process of thickening of the vessel wall in vasculoproliferative syndromes including atherosclerosis, transplant vasculopathy, and the neointimal hyperplasia that characterizes vascular restenosis following arterial stent implantation. Phenotypic modulation of vascular smooth muscle cells is under coordinated transcriptional regulation. In the normal vessel wall, the contractile smooth muscle phenotype is maintained by a transcriptional pathway involving signalling from the actin cytoskeleton to SRF, a ubiquitous transcription factor that functions in a smooth muscle cell-​specific fashion by interacting with smooth muscle cell-​ restricted cofactors of the myocardin family. This actin–​SRF–​myocardin pathway directly regulates genes encoding contractile proteins such as smooth muscle myosin and SM22. However, in response to inflammatory and other pathological stimuli, the contractile transcriptional pathway is repressed, and alternate transcriptional pathways are activated that promote proliferation, production of inflammatory mediators, and synthesis of matrix proteins. Key mediators of the synthetic smooth muscle cell phenotype include the platelet-​ derived growth factor-​ BB (PDGF-​BB) and Notch signalling pathways, and many of the Ca2+-​ dependent pathways that also regulate VSMC contractility, cytoskeletal function, and interactions with the ECM. Recent evidence suggests that these transcriptional pathways are also regulated in an epigenetic fashion by smooth muscle cell-​specific programmes for modification of histones within the chromatin structure of smooth muscle-​restricted  genes. As in the case of endothelial cells, there is clear heterogeneity in vascular smooth muscle cell phenotype in various vascular beds. Indeed, subsets of vascular smooth muscle cells are derived from distinct embryological precursors; vascular smooth muscle cells of the proximal aortic arch and great vessels are derived from neural crest (i.e. ectoderm), whereas vascular smooth muscle cells in the rest of the circulation are derived from somatic mesoderm. In the adult, another important example of functional heterogeneity is that the pulmonary and systemic vasculature differ markedly in their response to hypoxia. Hypoxia produces modest vasodilatation in the systemic vasculature, but marked vasoconstriction in the pulmonary circulation. This is likely an adaptive mechanism to prevent ventilation–​perfusion mismatch in the presence of alveolar disease (e.g. pneumonia). However, chronic hypoxia (e.g. in the presence of chronic respiratory disease) can result in pulmonary hypertension and lead to right heart hypertrophy and failure. The precise molecular mechanisms regulating hypoxic pulmonary vasoconstriction are incompletely understood, but oxygen sensing mechanisms in the mitochondria and voltage-​gated potassium channels on the plasma membrane of pulmonary vascular smooth muscle cells appear to play important roles.

Control of vascular tone Endothelium extracts and inactivates circulating hormones, converts inactive precursors to active products, and synthesizes and releases a variety of vasoactive mediators (Fig. 16.1.1.5).

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Nerves

Shear stress Hormones Autocoids

Noradrenaline ATP Neuropeptide Y Nitric oxide Blood cells

Endothelial layer

Fig. 16.1.1.5  Vascular endothelial cells lie at the interface between blood and the smooth muscle cells. They detect chemical and physical signals in the lumen of the blood vessel and adjust their output of biologically active mediators accordingly. This provides a mechanism of local regulation of vascular function. Rapid adjustment of vascular tone is probably achieved through a balance of endothelium-​derived nitric oxide and neuronally derived noradrenaline. Endothelin provides a slowly modulating constrictor tone and angiotensin II has the capacity to fine-​tune neuronal, endothelial, and smooth muscle function. ACE, angiotensin-​converting enzyme.

Vasoconstrictor and vasodilator mediators allow the vessel to respond to changes in the local milieu, but the predominant background influence of the endothelium is dilator, with the removal of the endothelium leading to vasoconstriction. A  basal endothelium-​dependent dilator tone seems to provide a physiological counterbalance to the continuous constrictor tone of the sympathetic nervous system.

Vasodilators The endothelium produces at least three key vasodilation mediators (Fig. 16.1.1.5): nitric oxide (NO), prostanoids, and hyperpolarizing factors.

Nitric oxide Physiology The production of NO is responsible for endothelium-​dependent dilator tone that is generated by blood flow. NO is synthesized from the amino acid l-​arginine by the nitric oxide synthase (NOS) enzymes (Fig. 16.1.1.6; see also Fig 16.1.1.8). The vasodilator actions of NO are mediated through the second messenger cGMP, generated when NO activates soluble guanylate cyclase (sGC) by binding to the haem group in the enzyme. A similar mechanism mediates NO signalling by inhibition of cytochrome c oxidase, initially in a reversible manner, but irreversibly under certain conditions. Inhibition of this enzyme decreases oxygen utilization, and the release of NO by endothelial cells appears to be an important determinant of oxygen consumption in the vasculature. However, the signalling actions of NO are much broader than modification of enzyme function by haem binding. NO modifies protein functions through numerous chemical reactions involving nitrosylation of cysteine residues and nitration of tyrosines, including ion channels, enzymes, and transcription factors, leading to change such as reduced adhesiveness of the endothelial cell for circulating white cells. A key role for endothelium-​derived NO is the nitrosylation of haemoglobin, leading to changes in oxygen affinity, which appear to play a fundamental role in oxygen delivery in the microvasculature. The arterial circulation of animals and humans is vasodilated continuously and actively by endothelium-​ derived NO, and inhibition of the synthesis of NO with certain guanidino-​ substituted analogues of l-​arginine, including N-​G-​monomethyl-​ l-​arginine, leads to vasoconstriction, hypertension, and sodium retention. Shear stress—​the force caused by the viscous drag of flowing blood—​is an important physiological stimulus for the continuous production of NO. Shear stress increases NO production so the blood vessel relaxes and dilates, thereby reducing the shear stress and increasing flow and/​or reducing blood pressure.

Fig. 16.1.1.6  (a) Nitric oxide synthases (NOS) catalyse the conversion of l-​arginine and molecular oxygen to citrulline and NO. NOS enzymes are catalytically active as homodimers and require the binding of cofactors (flavin adenine dinucleotide, flavin mononucleotide (FMN), haem (Fe), and tetrahydrobiopterin (BH4)) and calmodulin (CaM) for optimal activity. Each NOS dimer coordinates a single atom of zinc. (b) Under conditions where NOS are ‘uncoupled’, the enzyme does not catalyse the conversion of l-​arginine to citrulline and NO, but instead generates superoxide or other reactive oxygen species (ROS) by reduction of molecular oxygen, driven by electron flow from NADPH via the flavin domain. Factors that cause NOS uncoupling include low levels of the cofactor tetrahydrobiopterin (BH4), inadequate levels of the substrate l-​arginine, or oxidative modification of the eNOS protein by glutathionylation (G) of specific cysteine residues.

16.1.1  Blood vessels and the endothelium

This process of flow-​mediated dilatation appears is a homeostatic mechanism to regulate blood flow and coordinate tissue perfusion. The autoregulatory action of flow-​mediated dilatation opposes classical myogenic autoregulation—​the process by which a blood vessel constricts in response to an increase in intraluminal pressure. Synthesis of NO is stimulated by acetylcholine, bradykinin, and substance P, and in many vessels the release of NO accounts for the vasodilator actions of these mediators, which are known as ‘endothelium-​ dependent vasodilators’. Circulating hormones, including insulin and oestrogens, may also act on receptors on or within the endothelial cell to stimulate the release of NO acutely or to alter the expression of endothelial NO synthase chronically. Endothelial NO synthase (NOS) is activated either by increases in intracellular calcium, which causes binding of calmodulin, or by phosphorylation of specific serine or threonine residues in the protein, for example, by the kinases Akt or PKC (Fig. 16.1.1.8). Phosphorylation can either activate or inhibit the enzyme, for example at serine 1179 or threonine 495, respectively. Phosphorylation of eNOS mediates the physiological effects of shear stress, and hormones such as insulin, oestrogen, and vascular endothelial growth factor (VEGF). Veins differ from arteries and arterioles in that they do not seem to be actively dilated by the continuous release of NO, although the venous endothelium releases NO when it is stimulated by acetylcholine or bradykinin, and veins are highly sensitive to NO-​ mediated vasodilatation. Furthermore, human veins do not release much NO in response to platelet-​derived mediators. Indeed, aggregating platelets constrict veins, due to the unopposed action of vasoconstricting platelet-​derived mediators on the vascular smooth muscle. The reasons for the arteriovenous difference in NO production are not fully understood, but one consequence is that the guanylyl cyclase in venous smooth muscle is relatively upregulated and veins respond to smaller amounts of NO than do arteries or arterioles. This is of therapeutic relevance; NO is the active moiety of glyceryl trinitrate and other nitrovasodilators, and the low basal synthesis of endogenous NO by venous endothelium accounts, in part, for the venoselective action of these drugs.

hypercholesterolaemia, even in the absence of angiographic evidence of atheroma in large vessels, is associated with abnormal endothelium-​dependent vasodilatation in coronary and peripheral arterioles. Modified low-​density lipoproteins appear to inhibit NO synthesis or accelerate its destruction, possibly by enhancing production of the superoxide anion. Basal endothelium-​dependent dilatation is also impaired in patients with essential hypertension and the degree of impairment increases with increasing blood pressure. It is not known whether the defect is a consequence or a cause of the raised pressure, but the fact that endothelial function appears to be restored by antihypertensive therapy argues in favour of such dysfunction being a response to raised pressure. Patients with diabetes show diminished endothelium-​dependent dilatation, and this defect does not reverse with treatment. Thus, patients with uncontrolled hypertension, diabetes, and hypercholesterolaemia all display defects of NO-​mediated vasodilatation and this could provide a common mechanism of vascular dysfunction in these diseases. Overproduction of NO may also contribute to disease. Bacterial endotoxin and some cytokines, including interleukin (IL)-​1 and interferon-​γ, induce expression of another NOS enzyme (inducible NOS, iNOS, or NOS2) in the endothelium, vascular smooth muscle, and inflammatory cells invading the vessel wall. Unlike the constitutive eNOS enzyme present in healthy endothelium, iNOS is not dependent upon agonist activation and produces large amounts of NO. In these quantities NO, either alone or in combination with superoxide, may contribute to tissue damage in addition to causing profound vasodilatation and hypotension such as that seen in septic shock. The NO pathway has been the basis for several important therapeutic approaches. Administration of glyceryl trinitrate, a NO donor that directly activates soluble guanylate cyclase, has been a longstanding therapy (notably since the time of Alfred Nobel) for coronary ischaemia and heart failure because of its ability to produce systemic venous and coronary arterial vasodilatation, respectively. Inhibitors of phosphodiesterase-​5 (e.g. sildenafil, vardenafil, and tadalafil), the enzyme that inactivates cGMP in VSMC, which is the key downstream signalling molecule for NO, were initially developed for hypertension, but have been much more widely used for erectile dysfunction because of their effects Pathophysiology on augmenting blood flow into the corpus cavernosum. PDE-​5 Loss of NO leads to arterial vasoconstriction, has the potential inhibitors are also used for the treatment of pulmonary hyperto enhance platelet and white cell adhesion, and, in experimental tension, and ongoing studies are exploring their efficacy in pamodels, may enhance atherogenesis. Several clinical conditions—​ tients with heart failure related to primarily systolic or primarily including atherosclerosis, hypertension, hypercholesterolaemia, diastolic dysfunction. Activators of soluble guanylate cyclase, the and diabetes—​ are associated with a functional loss of NO-​ enzyme that produces cGMP, have also been developed as potenmediated effects. tial therapies for systemic hypertension, pulmonary hypertenIn the coronary vasculature, loss of NO predisposes to vasospasm sion, and peripheral vascular disease (see Box 16.1.1.2). Other and may contribute to the onset of anginal symptoms. Atherosclerotic commonly used drugs, such as statins, may also exert some of coronary arteries constrict in response to the platelet-​derived me- their beneficial effects through ‘pleiotropic’ mechanisms that are diator serotonin (5-​hydroxytryptamine), whereas healthy vessels not primarily dependent upon cholesterol lowering but act to inare stimulated to produce more NO and dilate. Flow-​dependent crease NO bioactivity. dilatation is also lost in such vessels, and the response to sympathetic stimulation is converted from dilatation to unopposed con- Prostanoids striction. Endothelial dysfunction precedes the development of NO appears to be the dominant vasoactive factor released from endoovert atheroma, and there is a relationship between risk factors for thelial cells under basal conditions, but it is by no means the only ischaemic heart disease and impaired responsiveness of coronary mediator produced. The endothelium is a rich source of prostanoids, arteries to endothelium-​ dependent vasodilators. Furthermore, including the vasodilators prostacyclin and prostaglandins E2 and

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Box 16.1.1.2  PDE5 inhibitors, cGC activators, and ADMA

The pulmonary vasculature seems to be particularly sensitive to NO and the inhibition of NO synthesis causes pulmonary hypertension. These observations have been utilized therapeutically in the form of inhaled NO treatment, and amplification of NO signalling by inhibition of cGMP phosphodiesterase with sildenafil (see Chapter 16.15.2). Levels of VSMC cGMP are also increased by drugs that increasing the activity of soluble guanylate cyclase (sGC), either by activating the enzyme independently of the haem group (which can be oxidized or lost in pathophysiological states), or by stimulating the activity of the intact enzyme (e.g. riociguat). A naturally occurring amino acid, asymmetric dimethylarginine (ADMA), acts as an important endogenous inhibitor of NO synthesis, and the concentration of ADMA in blood is a predictor of cardiovascular risk. Accumulation of ADMA may be important in renal failure, providing a possible mechanism to link failing renal function with increased risk of atherothrombotic complications.

D2 (PGE2 and PGD2). However, whereas inhibition of NO leads to profound and widespread changes in vascular tone, inhibition of prostanoid synthesis with aspirin (or other non​steroidal anti-​ inflammatory drugs, NSAIDs) does not, excepting in the renal vasculature where dilator prostanoids do appear to be important in the regulation of basal renal blood flow: aspirin and other NSAIDs lead to vasoconstriction in the kidney, indicating tonic release of vasodilator prostanoids in this vascular bed. Furthermore, in the fetus and newborn, indometacin leads to the closure of the ductus arteriosus and a fall in cerebral blood flow suggesting a significant contribution of endothelium-​derived prostanoids to tonic vasodilatation in these beds, at least during development. The cerebral blood flow in adults also falls in response to indometacin, but not to aspirin and other cyclooxygenase (COX) inhibitors, and so the role of prostanoids is unclear. Vasodilator prostanoids are important in the vascular changes of inflammation, although whether these prostanoids derive exclusively from the endothelium is not known. The finding that the inhibition of COX-​II appears to be associated with increased cardiovascular risk is important and suggests that the balance of prostanoids in the vessel wall, and between endothelium and platelets, is a key determinant of the ‘stickiness’ of the endothelium to platelets and other circulating cells. Hyperpolarizing factors An endothelium-​derived hyperpolarizing factor has been identified in some animal and human blood vessels. Hyperpolarization of vascular smooth muscle cells leads to a fall in calcium entry and vascular relaxation. Increasing evidence suggests that endothelium-​ dependent hyperpolarization may be particularly important in small arteries and arterioles. The chemical identity of endothelium-​ derived hyperpolarizing factor has not been clearly established, but products of activity of cytochrome P450, the cannabinoid anandamide, and the potassium ion have all been suggested as possible candidates. Recent data also suggests that the C-​type natriuretic peptide accounts for this activity in some vessels. A picture is emerging that endothelium-​derived hyperpolarizing factor is not a single entity, but rather that hyperpolarization is a mechanism

utilized by different mediators that vary between vessels. In addition, direct contact through gap junctions also provides a means for endothelial cells to hyperpolarize smooth muscle cells. Without specific inhibitors, it is not yet clear what role the variations in endothelial cell hyperpolarization of smooth muscle cells plays in human disease.

Vasoconstrictors Although the predominant background influence of the endothelium is dilator, important vasoconstrictor factors are also synthesized and released. Endothelin The endothelins are a family of potent vasoconstrictor peptides of 21 amino acids, which are closely related to the snake-​venom toxin of the Israeli burrowing asp (Atractaspis engaddensis). Three types of endothelin have been described—​endothelin 1, 2, and 3—​and there are at least two endothelin receptors in human blood vessels, the endothelin A  and endothelin B receptors. Endothelins vasoconstrict and can promote the growth of vascular smooth muscle cells. Effects are mediated in part through the stimulation of increases in calcium and in part through calcium-​independent mechanisms, including activation of protein kinases. Endothelin 1 is synthesized from ‘big endothelin’ within human endothelial cells (Fig. 16.1.1.7). It is a potent and long-​ lasting constrictor of human blood vessels, and causes widespread vasoconstriction, hypertension, and sodium retention when infused into healthy volunteers. Antagonists of the endothelin A  receptor cause vasodilatation and can lower blood pressure, indicating that there is a tonic synthesis and release of endothelin A.  Several studies suggest that there may be important interactions between the sympathetic nervous system, the renin–​ angiotensin system, and the endothelin system, and that these may act in concert to control constrictor tone, with the endothelin system providing a slowly modulating background constrictor tone. Endothelins also exert an important influence on sodium reabsorption in the kidney. Although activation of endothelin B receptors on vascular smooth muscle causes constriction, activation of endothelial endothelin B receptors leads to the generation of vasodilator prostanoids and/​ or NO, hence endothelin can also produce transient vasodilatation in some circumstances. Binding of endothelin to endothelin B receptors also seems to be important to clear the peptide from the circulation. Stimuli for endothelin production include thrombin, insulin, ciclosporin, adrenaline, angiotensin II, cortisol, various proinflammatory cytokines, hypoxia, and shear stress. The concentrations of endothelins circulating in plasma are low and may not reflect local concentrations achieved within the vessel wall, making it difficult to interpret the elevated values reported in many conditions. Nonetheless, activation of the endothelin system has been implicated in the pathogenesis of certain cardiovascular conditions. For example, a role for endothelin in the pathogenesis of vasospasm associated with subarachnoid haemorrhage and some types of renal ischaemia is suggested by experiments in animals. In addition, the increased production of endothelin has also been clearly implicated in the pathogenesis of a very rare form of secondary systemic hypertension caused by malignant haemangioendothelioma, a vascular tumour characterized by intravascular proliferation of

16.1.1  Blood vessels and the endothelium

Lys-Arg

Lys-Arg C

N Dibasic-pair-specific endopeptidase Trp-Val

Big endothelin Endothelin-converting enzyme Endothelin-1

Activation of endothelin A and endothelin B receptors

Fig. 16.1.1.7  Endothelin-​1 (ET-​1), a cyclic (Cys1–​Cys15 and Cys3–​Cys11) 21-​amino acid peptide, is synthesized within the vascular endothelium as the product of an ‘inactive’ 39-​amino acid precursor known as ‘big ET-​1’, a conversion catalysed by a specific membrane-​bound zinc metalloproteinase endothelin converting enzyme (ECE). Big ET-​1, in turn, is the catalytic product of a larger (203 amino acids) precursor polypeptide termed ‘preproET-​1’ (a conversion that is believed to be mediated by a ‘furin-​like’ protease). The ECE-​mediated conversion of big ET-​1 to mature ET-​1 is an essential step in the expression of full biological activity. Upon release from the vascular endothelium, ET-​1 interacts with the underlying smooth muscle cells resulting in vasoconstriction. This action is mediated by two distinct G-​protein-​coupled receptors, ETA and ETB. Although the predominant action of ET-​1 is that of a vasoconstrictor, this effect is regulated by the concomitant release of vasodilatory factors (e.g. PGI2, NO) by the action of ET-​1 on endothelial ETB-​receptors. Although such an action tempers the contractile actions of ET-​1, it is postulated that endothelial dysfunction (e.g. diminished ability to synthesize and/​or release NO such as is seen in hypertension, atherosclerosis) results in aberrant ET-​mediated vasoconstrictor tone due to a loss in concomitant endothelial regulation.

atypical endothelial cells. In this condition, the degree of hypertension correlates with plasma levels of endothelin, and when the tumour is removed blood pressure and plasma endothelin levels fall. The role of endothelin in the pathogenesis of pulmonary hypertension and congestive heart failure has been studied most intensely. In pulmonary hypertension, selective ETA antagonists lower pulmonary vascular pressure in patients with advanced disease and have been approved for clinical use. However, the role of endothelin receptor antagonists in treating congestive heart failure is less clear. A  substantial body of preclinical evidence indicates that selective ETA or non​selective ETA/​ETB antagonists prevent ventricular remodelling and prolong survival in models of myocardial injury. However, although short-​term studies with endothelin antagonists produced beneficial hemodynamic effects in heart failure patients, long-​term studies failed to show significant effects on morbidity or mortality, and endothelin antagonists are not presently approved for heart failure. Angiotensin-​converting  enzyme Angiotensin-​converting enzyme (ACE) is located primarily on the luminal surface of the endothelium (see Fig. 16.1.1.5). This enzyme converts angiotensin I to angiotensin II and also metabolizes

bradykinin to inactive products. The pulmonary vasculature provides the largest area of endothelium and is important in the regulation of circulating levels of angiotensin II, but the activity of endothelial ACE in systemic vessels may be more important in determining the final concentrations of angiotensin II and bradykinin that reach the blood vessel wall. Furthermore, endothelial cells also have the ability to synthesize renin and its substrate. It seems, therefore, as though the enzymatic machinery for a complete renin–​ angiotensin system is present within the vessel wall. The activity of the renin–​angiotensin system is clearly important in cardiovascular diseases including hypertension and heart failure, but the relative importance of local, compared with systemic, regulation of angiotensin II production is not yet clear. Furthermore, the full clinical significance of bradykinin metabolism by endothelial ACE has yet to be determined. It has been demonstrated that at least part of the vasodilator action of ACE inhibitors in certain isolated blood vessels is due to accumulation of bradykinin, which stimulates NO synthesis. Bradykinin and many other vasoactive peptides (e.g. substance P and natriuretic peptides) are broken down by the metalloendopeptidase, neprilysin (particularly in the lung and kidney). Neprilysin is the target of neprilysin inhibitor drugs such as sacubitril, which has been combined with valsartan (an angiotensin II receptor antagonist) for the treatment of heart failure. Prostanoids The endothelium synthesizes thromboxane and the unstable prostaglandin endoperoxides PGG2 and PGH2. Overproduction of constrictor prostanoids by the endothelium has been implicated in animal models of diabetes and hypertension, but the significance of these findings for human disease remains uncertain. Reactive oxygen species Production of reactive oxygen species (ROS) influences blood vessel physiology by direct interactions with nitric oxide, and by modulating redox-​sensitive pathways such as gene expression and activity of key proteins by post-​translational oxidative modification. ROS such as the superoxide anion (O−2) are synthesized within the vascular wall by multiple enzyme systems within endothelial, vascular smooth muscle, and inflammatory cells (e.g. macrophages and neutrophils). A major source are the NADPH oxidases that can be defined by at least five classes of a catalytic subunit termed Nox1–​5. The Nox2 enzyme typified by the neutrophil NADPH oxidase (but also expressed in endothelial cells and other inflammatory cells) is a major source of vascular superoxide. Vascular smooth muscle cells, where Nox1 and Nox4 predominate, also contribute. Stimulation by angiotensin II increases superoxide generation by Nox2 NADPH oxidases, and is a key feature of vascular pathophysiology. Other important sources of ROS are mitochondria, xanthine oxidoreductase, and NOS. In addition to its important vasodilator properties, NO acts as a free radical scavenger. As is characteristic for such agents, NO itself is also a free radical (it has an unpaired electron in its outer orbit), and as such, reacts readily with other free radicals and ROS, resulting in the formation of the reactive nitrogen species peroxynitrite (ONOO−), and with other ROS to generate inorganic nitrite and nitrate (NO3−) in biological systems. Under certain physiological conditions (e.g. hypoxia), NO can be regenerated from nitrite by nitrite reductases such as xanthine oxidoreductase, or haemoglobin.

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eNOS can also generate ROS (see Fig.  16.1.1.6b). This aspect of eNOS function, termed ‘eNOS uncoupling’, occurs when levels of the cofactor for NOS, tetrahydrobiopterin (BH4), are lowered due to oxidation or reduced biosynthesis. Uncoupling is also caused by conformational changes in eNOS due to oxidative modification of cysteine residues on the enzyme by glutathionylation. The positive feedback loop created for generation of ROS is an important pathway resulting in endothelial dysfunction and other alterations in vascular redox signalling.

Regulation of platelet function and haemostasis The endothelium synthesizes and releases prothrombotic and antithrombotic factors. However, healthy endothelium presents a thromboresistant surface, indicating that the antithrombotic factors predominate under basal conditions.

Platelets Endothelial cells inhibit the aggregation and adhesion of platelets, and disaggregate aggregating platelets. Two mediators are of particular importance:  NO and prostacyclin (or PGE2 in the microvascular endothelium). These act synergistically through different second messenger systems: cGMP for NO and cAMP for prostacyclin. Thiols and sulphydryl-​ containing molecules react with NO to produce more stable adducts, including nitrosocysteine, nitrosoglutathione, nitrosoalbumin, and even nitrosohaemoglobin. Some of these compounds are formed in vivo and may enhance the antiplatelet effects of endothelium-​derived NO. Furthermore, interaction between NO and tissue plasminogen activator leads to the formation of nitroso-​tissue plasminogen activator, a molecule with fibrinolytic, antiplatelet, and vasorelaxant properties. It is not yet clear how important these NO adducts are in human physiology or pathophysiology. Deficient production of NO has been implicated in a wide variety of cardiovascular diseases (see ‘Nitric oxide’ section earlier), and abnormalities of prostanoid synthesis occur in experimental models of atherosclerosis and diabetes. In the presence of a quiescent healthy endothelium, loss of basal NO alone does not lead to significant systemic platelet activation. However, loss of NO and prostacyclin at sites of endothelial damage, dysfunction, or activation promotes the formation of platelet aggregates and may contribute to thrombosis and vessel occlusion. In animals, stenosed endothelium-​denuded vessels lead to cyclical variations in flow as platelets stick to the vessel wall and release vasoactive and proaggregant mediators. If this also occurs in human vessels in vivo, it might be an important mechanism of vasospasm and thrombosis. Under basal conditions the endothelium inhibits platelet activation, but in response to certain stimuli, proaggregant, proadhesive mediators may be synthesized and released. Unstable prostaglandin endoperoxides activate platelets, platelet activating factor may be produced, and von Willebrand factor—​which is synthesized and stored within endothelial cells—​increases platelet adhesion. These changes occur in response to inflammatory mediators and may also result from endothelial ‘injury’, such as those occurring during coronary artery angioplasty or stent implantation.

Coagulation Heparan sulphate is a glycosaminoglycan closely related to heparin, but less potent, which is found on the surface of endothelial cells. Antithrombin III is also expressed on the endothelial cell surface and, together with heparan sulphate, provides a mechanism for binding and inactivating thrombin. In addition, endothelial cells participate in the activation of the anticoagulant protein C, and secretion of protein S and thrombomodulin that is found on the cell surface. In the quiescent state, expression of anticoagulant factors predominates, but when activated the endothelium may promote coagulation. Receptors for clotting factors appear on the endothelial surface, von Willebrand factor is secreted, and tissue factor—​the principal cellular initiator of coagulation—​is expressed. Bacterial endotoxin, inflammatory cytokines, and glycosylated proteins activate the endothelium and shift the balance in favour of coagulation. This may occur in response to infection, inflammation, or endothelial injury. Circulating levels of von Willebrand factor are increased in some patients with diabetes or hypertension.

Fibrinolysis The endothelial cell surface has a fibrinolytic pathway. Urokinase and tissue plasminogen activator are secreted and there are specific binding sites for plasminogen activators and plasminogen. Thrombin, adrenaline, vasopressin, and stasis of blood may be physiological stimuli for the release of tissue plasminogen activator from human endothelium. Plasminogen activator inhibitor 1 is also synthesized and bound by endothelium, providing a pathway for local inhibition of the fibrinolytic system. Under basal conditions fibrinolysis is dominant, but the balance may be altered by a variety of local and circulating factors, including inflammatory cytokines and the atherogenic particle lipoprotein(a), which inhibits plasminogen binding and hence plasmin generation. In the presence of atherosclerosis, the fibrinolytic properties of the endothelium are diminished.

Other important aspects of vascular and endothelial biology Cellular adhesion The resting endothelium prevents cells from adhering fully to the vessel wall, but allows leucocytes to ‘roll’ along its surface. The regulation of rolling, adhesion, and migration is governed largely by specialized glycoproteins known as cell adhesion molecules, which are expressed in varying amounts on the endothelial cell surface and interact with complementary adhesion molecules on circulating cells. Endothelial-​leucocyte adhesion molecule 1 (ELAM-​1, also known as E-​selectin), vascular adhesion molecule 1 (VCAM-​1), intercellular adhesion molecule 1 (ICAM-​1), and P-​selectin (also known as GMP-​140) are all expressed on cytokine-​ activated endothelium. The degree of expression and the type of adhesion molecules expressed determines the ‘stickiness’ of the endothelium for different cell types. Expression of adhesion molecules is an important mechanism of cellular adhesion during inflammation and is also important in

16.1.1  Blood vessels and the endothelium

recruitment of T cells and monocytes in atherosclerosis. Increased expression of E-​selectin is seen in the coronary arteries of transplanted hearts, and has been implicated in the rapid development of atherosclerosis in these vessels. NO and prostacyclin inhibit the adhesion of white cells to the endothelium and this effect may be mediated by changes in the expression or configuration of adhesion molecules. Certain endothelial cell adhesion molecules are shed into the plasma:  changes in their concentration have been detected in a variety of cardiovascular diseases, but the significance of this is uncertain.

Proinflammatory cytokines Cytokines are released from activated leucocytes in response to infection and immunological stimulation and are also produced by the vessel wall itself; IL-​1, IL-​6, and IL-​8, and colony stimulating factors are synthesized by endotoxin-​stimulated endothelial cells, and tumour necrosis factor (TNF) by human smooth muscle cells. A  large number of cytokines and chemokines alter endothelial functions, upsetting the balance of vasoactive mediators, altering thrombotic activity and the expression of adhesion molecules, or initiating apoptosis (programmed cell death). IL-​1 and some other proinflammatory cytokines alter the synthesis of NO (see ‘Nitric oxide’ section earlier) and a variety of prostaglandins; enhance the generation of thrombin, platelet activating factor, von Willebrand factor, and plasminogen activator inhibitor; alter endothelial permeability; increase expression of ICAM-​1 and VCAM-​1; and may also cause endothelial cell damage and death. These findings are of direct relevance to the vascular changes occurring in inflammation and sepsis, and might also provide a link between acute or chronic immunological stimulation (e.g. infection) and the development of cardiovascular disease, including atherosclerosis or acute cardiovascular events. More recently it has been recognized that components of the innate immune pathway, such as Toll-​like receptors (TLRs), are expressed by cells in the vascular wall and play a role in the pathogenesis of cardiovascular disease. These receptors recognize specific, highly conserved structural motifs in non​host pathogens,

resulting in rapid activation of a coordinated innate immune response. However, TLRs may also be activated by damage-​associated molecular pattern molecules such as proteins released by injured or necrotic cells (e.g. heat shock proteins, HMBG1), and/​or modified by oxidation (e.g. oxidized LDL), by DNA released from the nucleus, or proteins that have been glycated in diabetes (advanced glycation end products, AGE), that are recognized by RAGE, the specific receptor for AGE. These innate immune mechanisms are important in the vascular wall in atherosclerotic plaques or in the myocardium following ischaemic injury, by initiation and amplifying the pathologic inflammatory response.

Cell growth and angiogenesis The endothelium of healthy differentiated vessels inhibits proliferation of the underlying smooth muscle. Endothelium-​derived vasodilator, antiplatelet, and antithrombotic mediators (e.g. NO, prostacyclin) tend to inhibit the growth of vascular smooth muscle cells, whereas vasoconstrictor and prothrombotic mediators (e.g. endothelin, angiotensin) tend to promote it. Thus, the basal state of the endothelium, in which dilatation and thromboresistance predominates, also prevents the growth of smooth muscle. The heparin-​ like molecules prevent cell growth and molecules similar or identical to platelet-​derived growth factor (PDGF) and fibroblast growth factor are endothelium-​derived growth promoters. Others such as transforming growth factor β (TGFβ), produced by endothelial cells, may either inhibit or promote cell growth, and the precise role of this molecule in vivo is unclear. The basal antiproliferative effects of the endothelium may retard the development of atherosclerosis and intimal proliferation. In addition to affecting the growth of underlying smooth muscle, endothelial cells are essential for the formation of new blood vessels. The ability of endothelial cells to initiate the formation of new vessels (angiogenesis and vasculogenesis; Fig. 16.1.1.8) is retained in adults, but the only place this occurs physiologically to any great extent is in the female reproductive tract. However, angiogenesis occurs in a wide range of disease states including atherosclerosis, rheumatoid arthritis, and tumour growth, and during wound

Fig. 16.1.1.8  Formation of new blood vessels. Endothelial cells grown in a matrix (Matrigel) form tube-​like structures. The right-​hand panel shows the effect of inhibiting angiogenic signals such as vascular endothelial growth factor (VEGF). Reprinted from Biochemical and Biophysical Research Communications, Vol 308, Issue 4, Smith CL et al., Dimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotype, pp. 984–​89. Copyright (2003), with permission from Elsevier.

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healing or in response to ischaemia. Positive and negative regulators of angiogenesis have been identified and a wide variety of cytokines, growth factors, and local autacoids can act alone or in concert to promote endothelial cell growth, migration, and tube formation. Of particular interest is VEGF, a growth factor produced by smooth muscle cells in response to hypoxia, inflammatory cytokines, and certain other growth factors. There is good evidence that VEGF can promote angiogenesis in a variety of animal models and in humans. Therapeutics that inhibit angiogenesis by targeting the VEGF pathway have shown clinical benefit in diabetic retinopathy and certain cancers. Intriguingly, it appears as though VEGF can increase the production of NO by endothelial cells, and this may be one of the effector molecules mediating some of the actions of this growth factor. In order to form endothelial tubes through tissues (i.e. angiogenesis), endothelial cells must degrade matrix and they are capable of synthesizing and releasing a variety of matrix metalloproteinases. Some of these matrix metalloproteinases may, in turn, affect endothelial function by regulating cell attachment, proliferation, and migration. Failure of endothelial cells to initiate appropriate angiogenesis in response to ischaemia may lead to tissue hypoxia, while excessive or inappropriate angiogenesis may contribute to a sustained inflammatory response in the vessel wall, disrupt vessel wall architecture, or lead to haemorrhage into atherosclerotic plaques.

Transport and metabolism The endothelium presents a permeability barrier for molecules in the bloodstream. Transfer of molecules from the bloodstream into the vessel wall across the endothelium can occur by transport through the endothelial cells or between them. The junctions between endothelial cells are maintained by specialized molecules, including cadherins, and are actively regulated. Transport between cells occurs when endothelial cells contract to leave intercellular gaps. This is an important mechanism for formation of localized oedema. Transport through cells occurs by transcytosis and is an important mechanism for the passage of some macromolecules, including insulin. In addition, specialized channels for transport of water have been identified—​the aquaporins. The endothelium is intimately involved in lipid metabolism. Lipoprotein lipase is bound to proteoglycans on the endothelial cell surface, and receptors for low-​density lipoproteins are present in varying amounts. In quiescent endothelium, lipoprotein lipase is active, but there are few low-​density lipoprotein receptors, indicating that healthy endothelium provides a barrier for the entry of low-​ density lipoproteins into the vessel wall. However, under conditions in which a low-​density lipoprotein is taken into the endothelium, modification by oxidation occurs and this step may stimulate atherogenesis.

Endothelial-​derived microvesicles Endothelial cell-​derived particles or cell fragments were first detected as presumed evidence of damaged or dead endothelial cell fragments (exosomes, microparticles, or apoptotic bodies). However, endothelium-​derived microvesicles have now been identified as a potential biomarker of endothelial function and cardiovascular disease, reflecting biological processes. Microvesicles are submicron-​sized particles shed from the plasma membrane of cells in response to cell activation, cell damage, or apoptosis.

The number of circulating microparticles appears to be increased in patients with cardiovascular disease such that it is possible that they play a role in pathogenesis, and it has been proposed that they are a biomarker of endothelial function and vascular health. Microvesicles contain proteins, active lipids, and nucleic acids that may provide additional biological and pathophysiological information, since these components are dependent on the nature and cause of microvesicle shedding. For example, microRNAs (e.g. miR-​ 126), which are endogenously expressed small non​coding RNAs that regulate gene expression at the post-​transcriptional level, have been implicated in regulating endothelial cell function and angiogenesis. Microvesicles are also a vehicle for cell-​to-​cell transfer of these signalling molecules, for example, between endothelial cells, platelets, and inflammatory cells such as monocytes. Specificity of cell-​to-​cell communication is mediated by cell surface proteins on microvesicles that are ligands for receptors on target cells.

The adventitia and perivascular adipose tissue Nerves supplying the vessel wall enter through the adventitia into the media to provide a key influence on the contraction of vascular smooth muscle cells. The sympathetic nervous system is, of course, of prime importance in determining the contractile state of the vessel. In addition, cholinergic innervation influences some vascular beds, as do purinergic nerves. Pharmacological observation suggests that not all vessels are equally affected by denervation or interruption of specific neuronal influences. Resistance vessels and capacitance veins seem to be particularly regulated by sympathetic tone, and blockade of the sympathetic system causes not only a fall in arterial pressure but also major venous dilatation that leads to postural hypotension. In the brain, local neuronal projections have been implicated in providing a link between cerebral activation and the consequent increase in blood flow. Lymph vessels also permeate the adventitia of large vessels and are important to remove fluid. A  network of small blood vessels, the vasa vasorum, is found in the adventitia of larger blood vessels. Vasa vasorum are found mainly in vessels that have relatively thick walls with many layers of vascular smooth muscle cells. An increase in vasa vasorum may be taken as an indication of vessel wall hypoxia. Stripping the vasa vasorum in large veins may contribute to both smooth muscle and endothelial dysfunction and damage, and, in the arterial system, can stimulate smooth muscle cell replication and promote an atherogenic type of lesion. The vasa vasorum responds to vasoactive agents, but the pharmacology of these vessels is relatively poorly understood. Infiltration of the adventitia with inflammatory cells may be an important feature of atherogenesis (see Chapter 16.13.1), and perivascular fat may interfere with vascular function through the generation of adipokines and inflammatory cytokines; this process has been implicated in the pathogenesis of cardiovascular disease in obese individuals. The adventitia surrounding the vascular wall also contains large numbers of adipocytes, forming the perivascular adipose tissue (PVAT). Although PVAT is typically in continuity with other surrounding adipose tissue, PVAT has particular cellular composition and pathophysiological roles that are distinct from other adipose tissue depots such as subcutaneous and visceral adipose tissue mediated by adipocytokines. PVAT has anticontractile properties on small vessels due to a variety of vasoactive molecules produced in this tissue, such as

16.1.2  Cardiac physiology

H2S, H2O2, and adipocytokines. Other infiltrating inflammatory cell types including T cells and macrophages have an equally important contribution. Most adipocytokines produced by the cells in PVAT have distinct paracrine effects on the vasculature. These can be proinflammatory/​pro-​atherogenic (e.g. resistin, IL-​6, TNFα, MCP-​1) or anti-​inflammatory/​antiatherogenic (e.g. adiponectin, omentin). The balance between pro-​and antiatherogenic adipokines is influenced by conditions such as obesity and diabetes. In human PVAT, PPAR​γ signalling is a major regulator of adipocytokine production, and its dysregulation in diabetes, obesity, and insulin resistance shifts the balance towards the production of proinflammatory mediators. Until recently, PVAT was considered to have mainly detrimental effects on vascular homeostasis. However, recent evidence suggests that it ‘senses’ proatherogenic changes in the underlying vascular wall (e.g. changes in ROS production), and can modify its biosynthetic profile by activating PPAR​γ signalling, leading to increased production of ‘antioxidant’ adipokines such as adiponectin and reduced production of ‘pro-​oxidant’ adipokines such as IL-​6. Therefore, increasing evidence suggests that healthy PVAT may provide local defence mechanisms against vascular injury, and its biosynthetic profile is regulated by complex interactions between PVAT, the underlying vascular wall, and systemic factors.

FURTHER READING Allt G, Lawrenson JG (2001). Pericytes:  cell biology and pathology. Cells Tissues Organs, 69,  1–​11. Armulik A, et al. (2005). Endothelial/​pericyte interactions. Circ Res, 97, 512–​23. Asahara T, et al. (1997). Isolation of putative progenitor endothelial cells for angiogenesis. Science, 275,  964–​6. Atkins GB, Jain MK (2007). Role of Krüppel-​like transcription factors in endothelial biology. Circ Res, 100, 1686–​95. Bonauer A, et  al. (2010). Vascular microRNAs. Curr Drug Targets, 11,  943–​9. Boos CJ, et al. (2006). Circulating endothelial cells in cardiovascular disease. J Amer Coll Cardiol, 8, 1538–​47. Channon KM, Guzik TJ (2002). Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors. J Physiol Pharmacol, 53, 515–​24. Chironi GN, et al. (2009). Endothelial microparticles in diseases. Cell Tissue Res, 335, 143–​51. Crabtree MJ, Channon KM (2011). Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease. Nitric Oxide, 25,  81–​8. Dhaun N, et al. (2006). The endothelin system and its antagonism in chronic kidney disease. J Am Soc Nephrol, 17, 943–​55. Earley S, Brayden JE (2010). Transient receptor potential channels and vascular function. Clin Sci (Lond), 119,  19–​36. Folkman J (2003). Fundamental concepts of the angiogenic process. Curr Mol Med, 3, 643–​51. Frantz S, et  al. (2007). Mechanisms of disease:  toll-​like receptors in cardiovascular disease. Nat Clin Pract Cardiovasc Med, 4, 444–​54. Furchgott RF, Zawadzki JV (1980). The obligatory role of endothelial cells in the relaxation of arterial smooth muscle. Nature, 288,  373–​6. Isner JM, Asahara T (1999). Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J Clin Invest, 103, 1232–​6. Kinlay S, et al. (2001). Endothelial function and coronary artery disease. Curr Opin Lipid, 12,  383–​9.

Margaritis M, et  al. (2013). Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation, 127, 2209–​21. Mason JC, Haskard DO (1994). The clinical importance of leucocyte and endothelial cell adhesion molecules in inflammation. Vasc Med Rev, 5, 249–​75. McDonald OG, Owens GK (2007). Programming smooth muscle plasticity with chromatin dynamics. Circ Res, 100, 1428–​41. Pasqualini R, et al. (2010). Leveraging molecular heterogeneity of the vascular endothelium for targeted drug delivery and imaging. Semin Thromb Hemost, 36, 343–​51. Rao RM, et al. (2007). Endothelial-​dependent mechanisms of leukocyte recruitment to the vascular wall. Circ Res, 101, 234–​47. Ross R (1999). Atherosclerosis—​an inflammatory disease. N Engl J Med, 340, 115–​26. Rust R, Gantner C, Schwab ME (2019). Pro- and antiangiogenic therapies: current status and clinical implications. FASEB J, 33, 34–48. Tse D, Stan RV (2010). Morphological heterogeneity of endothelium. Semin Thromb Hemost, 36, 236–​45. Vallance P, et al. (1997). Infection, inflammation and infarction: does acute endothelial dysfunction provide a link? Lancet, 349, 1391–​2. Vallance P, Leiper J (2004). Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol, 24, 1023–​30. Vane JR, et al. (1998). Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol, 38, 97–​120.

16.1.2 Cardiac physiology Rhys D. Evans, Kenneth T. MacLeod, Steven B. Marston, Nicholas J. Severs, and Peter H. Sugden ESSENTIALS The function of the heart is to provide the tissues of the body with sufficient oxygenated blood, substrates and metabolites, and removal of waste products, to meet the moment-​to-​moment needs as dictated by metabolism, physical activity and postural and emotional changes.

Functional anatomy of the cardiac myocyte Cardiac myocytes are the contractile cells of the heart and constitute the bulk of heart mass. There are structural and functional differences between the myocytes of the ventricles, the atria, and the conduction system: ventricular myocytes are elongated cells, packed with myofibrils (the contractile apparatus) and mitochondria (for ATP production). Myofibrils are repeating units (sarcomeres) made up of thin actin filaments anchored at the Z-​discs at either end of the sarcomere, and thick myosin filaments which interdigitate and interact with the thin filaments. Contraction results from sarcomere shortening produced by the ATP-​dependent movement of the thin and thick filaments relative to one another. Transverse (T-​) tubules facilitate extracellular Ca2+ entry into the cytoplasm (sarcoplasm) for contraction and signalling. Atrial myocytes differ from ventricular

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myocytes, having few T-​ tubules but more abundant caveolae. Myocytes of the conduction system are small and possess only a rudimentary myofibrillar structure. Myocytes are attached to adjoining cells and to the extracellular matrix to allow transmission of force. At some regions of contact (the intercalated discs), specialized structures (the gap junctions) contain channels which form contiguous electrical connections between a myocyte and its neighbours and allow passage of ions and small molecules. The sarcoplasmic reticulum surrounds the myofibrils and is a reservoir of the Ca2+ which participates in myofibrillar contraction. T-​tubules are deep, finger-​like indentations of the sarcolemma that abut the sarcoplasmic reticulum at junctional regions in register with the Z-​discs of the superficial sarcomeres.

Cardiac action potential A potential difference (the membrane potential) is maintained across the plasma membrane (sarcolemma) such that the inside of the cell is negative compared to the outside by about 90 mV. This is caused largely by the efflux of K+ down its concentration gradient from the cell through K+ channels and until the electronegative force retaining K+ in the cell balances the tendency for efflux. When a myocyte is electrically excited, Na+ channels open and Na+ enters the cell down its own concentration gradient, producing a rapid inward current and depolarizing the cell towards its equilibrium potential: the initial phase (phase 0) of the action potential. As the myocyte depolarizes, L-​type Ca2+ channels in the sarcolemma and T-​tubules open and Ca2+ enters the cell through its concentration gradient. A brief K+ efflux from the cardiomyocyte is associated with a small, transient repolarization (phase 1). The Na+ channels close rapidly, but the L-​type Ca2+ channels remain open for longer, maintaining depolarization: phases 1 and 2 of the action potential, where the tendency to depolarize is balanced by repolarizing outward current flow carried by a variety of K+ channels. The membrane potential in phase 2 is relatively stable and hence this phase is also known as the plateau phase. Ca2+ entry in close apposition to the junctional sarcoplasmic reticulum causes its Ca2+-​release channels (ryanodine receptors) to open, discharging about half of the sarcoplasmic reticulum Ca2+ reservoir into the cytoplasm (Ca2+-​induced Ca2+-​release). This increase in Ca2+ concentration (the Ca2+ transient) is sensed by a Ca2+-​binding protein (troponin C) that is a component of the thin filament regulatory complex (the troponin–​tropomyosin complex). This initiates myofibrillar contraction, which starts about halfway through phase 2. As the L-​type Ca2+ channels close, the outward current flow through + K channels predominates and the myocyte repolarizes towards the K+ equilibrium potential (phase 3). Ca2+ is removed from the cytoplasm and returned to the sarcoplasmic reticulum by active transport mediated by the sarcoplasmic/​endoplasmic Ca2+-​ATPase (SERCA2). Ca2+ is also expelled from the cell by the plasma membrane Na+/​ Ca2+ exchanger (NCX), which is electrogenic (three Na+ exchanged for one Ca2+) and tends to prolong the plateau phase. The behaviour of the Na+/​Ca2+ exchanger is complex because—​depending on the Na+ and Ca2+ concentrations and the membrane potential—​it can reverse, thus mediating Ca2+ entry and repolarization. This occurs at depolarized potentials, and more so when intracellular Na+ is increased. In phase 4, repolarization is complete and the myocyte is electrically quiescent, with membrane potential maintained by the sodium-​potassium pump, until the next depolarization.

Cardiac pacemaker and regulation of contractility The sinoatrial node (‘pacemaker’) in the right atrium contains modified myocytes that exhibit a different form of action potential from ventricular myocytes because of differences in the expression of ion channels. The cell depolarizes spontaneously and gradually during phase 4 until an action potential is produced. This partly results from the presence of hyperpolarization-​activated cyclic nucleotide-​gated channels which are absent from ventricular myocytes and which open at negative voltages and carry an inward-​depolarizing Na+ current (‘funny’ current). Depolarization is then mediated by Ca2+ channel opening. The stimulus is transmitted in a controlled manner via the conduction system (AV node; His–​Purkinje system) to all regions of the heart.

Whole organ physiology The strength of cardiac contraction is both an intrinsic function of the cardiomyocyte, dependent on the initial fibre length (precontraction loading), and on the intrinsic ‘contractility’ of the heart. Cardiac contractility is controlled largely by the sympathoadrenal system and the parasympathetic nervous system. β-​Adrenergic stimulation increases the tendency of the L-​type Ca2+ channel to open (positive inotropism). β-​ Stimulation also increases relaxation (positive lusitropism) by stimulation of SERCA2 and an increased rate of release of Ca2+ from the troponin complex (relaxation being an energy-​dependent process). The positive chronotropic (rate) effects of β-​stimulation result from increased hyperpolarization-​activated cyclic nucleotide-​gated channel opening, causing an increased frequency of pacemaker depolarization. These effects are all opposed by the (cholinergic) muscarinic receptors of the parasympathetic nervous system. The energy requirements of the heart during rest and exertion are influenced by ventricular volume, outflow resistance (hence blood pressure), venous return, and the activity of the autonomic nervous system. An increase in ventricular volume increases wall tension during contraction, and an augmented myocardial oxygen supply is then required to maintain the same systemic blood pressure and stroke volume. The normal integration of the venous return, heart rate, stroke volume, and arterial blood pressure ensures that there is an adequate supply of oxygen and nutrients to the tissues. The activities of the sympathetic and parasympathetic nervous systems contribute to the adjustment of cardiac performance to immediate needs—​the former by increasing heart rate and myocardial contractility during exertion and emotion, the latter by maintaining a relatively slow heart rate at rest. Parasympathetic (vagal) fibres in the heart are distributed mainly to the sinoatrial node and the atria; sympathetic innervation is to both the atria and the ventricles. There is a normal diurnal variation in autonomic function, with an increased sympathetic outflow in the mornings, soon after wakening. Coronary blood flow occurs largely in diastole. It is autoregulated to meet myocardial metabolic requirements and may increase five-​ or sixfold during strenuous exercise. The inner layers of the ventricular muscle normally receive a slightly greater blood flow than the outer layers. Haemodynamic and ventilatory responses during exercise take 2–​3 min to equilibrate and adjust to an increased workload and reach a new steady state. Regular exercise to at least 60% of maximal heart rate about three times a week improves effort tolerance. Measurement of the cardiovascular response to exercise provides an objective assessment of cardiac function.

16.1.2  Cardiac physiology

Introduction The function of the heart is to pump sufficient oxygenated blood containing nutrients, metabolites, and hormones to meet moment-​ to-​moment metabolic needs and preserve a constant internal environment. The heart has two essential characteristics—​contractility and rhythmicity. The nervous system and neurohumoral agents modulate relationships between the venous return to the heart, the outflow resistance against which it contracts, the frequency of contraction, and its inotropic (contractile) state; there are also intrinsic cardiac autoregulatory mechanisms. An understanding of the molecular mechanisms governing cardiac cell behaviour and the mechanical, electrical, and hormonal control of the heart at a whole organ level is essential for the understanding of cardiac pathophysiology.

Cardiac myocytes Cardiac myocytes (cardiomyocytes) are the contractile cells of the heart, and include ventricular and atrial myocytes, as well as cells specialized to provide the electrical impulse and conduction system. Myocytes constitute the bulk of the cellular volume, but because

they are large cells they are fewer in number, being outnumbered by endothelial cells, smooth muscle cells of the vasculature, and fibroblasts. Replication of ventricular myocytes is believed to decrease rapidly after birth in mammals, and occurs at an extremely low rate in adults, resulting in most cells being terminally differentiated; this is less clear for the atrial myocyte. Terminal differentiation has important consequences for the heart in terms of its limited ability to survive haemodynamic insults or stresses, but also means that the myocardium is essentially resistant to malignant transformation.

Morphology of the ventricular myocyte and its contractile machinery The ventricular myocyte is a large elongated cell (100–​150 µm long and 20–​35 µm wide) and is packed with striated myofibrils (the contractile elements) that alternate with rows of mitochondria (Fig. 16.1.2.1). Each myofibril is roughly cylindrical (2–​3 µm in diameter), stretches the length of the cell, and is anchored at each end in a fascia adherens junction. The myofibril comprises sarcomeres arranged in series. Sarcomeres consist of two arrays of filaments:  thin filaments, comprised predominantly of the protein actin, interdigitated with thick filaments of myosin. The characteristic striated appearance arises from the organization of these myofilaments within the myofibril (Fig. 16.1.2.1). The thick

mito

1 μm I band

A band

Z

I band

Z Sarcomere

H zone

M line Actin (thin filament)

Myosin (thick filament)

Fig. 16.1.2.1  Upper panel: electron micrograph of ventricular myocyte showing the structure of the myofibrils. Portions of two myofibrils are shown in the field, with a row of mitochondria (mito) between. Lower panel: diagrammatic representation of the arrangement of the thick and thin filaments in relation to the striated pattern seen in microscopy.

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Section 16  Cardiovascular disorders

filaments are confined to the A-​band at the centre of the sarcomere; the thin filaments extend out from either side of the Z-​disc (Z-​ line), crossing the I-​band, and penetrate partially into the A-​band, where they overlap and interact with the thick filaments. Each Z-​to Z-​disc repeat constitutes a sarcomere, and the distance between consecutive Z-​discs (the sarcomere length) is a measure of the contractile state of the myofibril. At the centre of the sarcomere lies the M-​line. Each myofibril contains 70–​80 sarcomeres. Myocytes have an irregular ‘branched’ morphology; through these branches, each ventricular myocyte typically connects to 10 or more of its neighbours to form the three-​dimensional branching, syncytium-​like structure of the myofibre.

Structure of the contractile apparatus Thick filaments The myosin molecule comprises two heavy chains (molecular mass c.200 kDa) and two pairs of light chains (mass 18–​28 kDa). The myosin heavy chains are arranged as dimers, with a tail and two heads (Fig. 16.1.2.2). The tails are packed together to form the shaft of the thick filament, while the heads protrude from the filament and lie close to the thin actin filaments. The myosin heads are the motor units of muscle: they bind and hydrolyse ATP to ADP and convert the free energy of ATP hydrolysis into mechanical work through their interaction with actin in the thin filaments (for details see ‘The mechanism of myofibrillar contraction’). Thin filaments Each thin filament comprises about 300 globular actin subunits (molecular mass 42 kDa). The actin monomers have sites for interaction with the myosin heads and with a regulatory protein complex that

Troponin T

α -Tropomyosin

Troponin C

Myosin light chain

confers Ca2+ sensitivity. The latter consists of the troponin complex (troponins I, C, and T) and the elongated protein α-​tropomyosin (Fig. 16.1.2.2). Troponin complexes are located at intervals along the actin filament. Tropomyosin forms two continuous strands along the thin filament and is responsible for cooperative propagation of regulatory signals. Other structural components of the sarcomere The thin filaments are attached to the Z-​discs in a regular array with filaments on each side in opposite orientation (Fig. 16.1.2.1). The main structural component of the Z-​disc is the actin cross-​linking protein α-​actinin. Z-​discs are also associated with the T-​tubules and costameres (see next) and contain several additional proteins believed to be associated with cell signalling. The M-​line (Fig. 16.1.2.1) contains the protein myomesin that cross-​links the thick filaments to maintain their orientation. In addition, the giant protein titin (connectin) extends from the M-​line to the Z-​disc. Titin contains multiple binding sites for several sarcomeric proteins, including myosin-​binding protein-​C (MyBP-​C; Fig. 16.1.2.2). It contributes to elasticity, passive tension, and thick filament positioning in the sarcomere. Intermediate filaments, costameres, and the plasma membrane skeleton The myofibrils are held in position by scaffold-​like webs of intermediate filaments made from a (non​contractile) protein, desmin, spanning the sarcolemma, mitochondria, and nucleus. Desmin filaments are anchored to costameres, which circumscribe the lateral plasma membrane. Apart from maintaining the spatial organization of the contractile apparatus, the costameres mechanically

Troponin I

β -Myosin heavy chain

Myosin-binding protein C

Myosin rod

Actin

Myosin head

Fig. 16.1.2.2  Structural arrangement of contractile proteins in the filament overlap zone of the sarcomere. Reproduced from Spirito et al. N Engl J Med 1997; 336: 775–​85. Copyright © 1997 Massachusetts Medical Society. All rights reserved.

16.1.2  Cardiac physiology

couple the cells laterally to the extracellular matrix. Associated with the costameres, but closely applied to the entire cytoplasmic aspect of the lateral plasma membrane, is the membrane skeleton, a peri­ pheral membrane protein network of dystrophin and spectrin. The costameres, membrane skeleton, and intermediate filaments are linked to the glycocalyx and extracellular matrix by sets of integral plasma membrane proteins, notably the integrins and the components of the dystrophin–​glycoprotein complex.

Connections between cardiac myocytes The myocyte can function as an autonomous contractile unit. To produce a heartbeat, the contractile capabilities of the c.3 billion myocytes that constitute the human heart have to be electromechanically synchronized. This requires both an orderly spread of the wave of electrical activation and the effective transmission of contractile force from one cell to the next, throughout the heart. This is achieved by the intercalated discs, formed from specialized regions of the plasma membrane where adjacent cells interact. Intercalated discs are situated at the blunted ends of the main body of the myocyte and its side branches (Fig. 16.1.2.4). Three types of cell membrane junction—​the gap junction, the fascia adherens, and the desmosome—​connect the adjacent membranes at the disc. The fascia adherens and desmosome are forms of anchoring junction which provide mechanical integrity between adjoining fibres; gap junctions contain clusters of connexons (Fig. 16.1.2.4). These gap junctions are clusters of intercellular channels which span two closely apposed plasma membranes and directly link adjacent cytoplasmic compartments of neighbouring cells. They form the sites of electrical coupling between individual cardiac myocytes and permit direct cell-​to-​cell transmission of chemical signals (ions and small molecules of 106 ions/​s), distinguishing them from other ion-​ transport proteins (e.g. the Na+/​K+-​ATPase or pump, and the Na+/​ Ca2+ exchanger (Na/​CaX); see ‘The Na+/​Ca2+ exchanger (Na/​CaX) and the Na+/​K+-​ATPase’, later on in this chapter) which move ions across plasma membranes several orders of magnitude more slowly. Hence cardiac excitation provides a means of coordinating the contractile activities of the four heart chambers and is the basis for the electrocardiograph (ECG; see Chapter 16.3.1). Origin of the membrane potential Cardiac membrane potential is determined by three factors:  (1) ionic concentrations across the sarcolemma; (2) the permeability (conductance) of the sarcolemma to specific ions; and (3) the activity of electrogenic pumps that maintain the ionic concentration gradients. When a ventricular myocyte is at rest (diastole), there is a potential difference of about −90 mV across the plasma membrane, the inside of the cell being negative with respect to the outside. This is principally caused by plasma membrane permeability to K+. The extracellular concentration of K+ (K+o) is about 4 mmol/​ litre, and the intracellular (cytoplasmic) concentration (K+i) is about 140 mmol/​litre, so K+ tends to diffuse out of the cell down its concentration gradient, resulting in the interior becoming negatively charged. An equilibrium is thus established where the electronegative force retaining K+ inside the cell (mostly derived from negatively charged intracellular proteins) balances its tendency to diffuse out of the cell down its concentration gradient. This is termed the equilibrium potential (E) and can be calculated from the Nernst equation (see Table 16.1.2.1 for E values of relevant

ions). At this potential, there will be no net flux of K+ ions through K+ channels and, if the membrane is only permeable to K+, then the membrane potential will be equal to EK. The membrane potential at any moment is dependent upon the equilibrium potentials for all permeant species and their relative permeabilities. The actual transmembrane potential difference at rest and the calculated EK are rarely the same owing to a small leakage, mainly of Na+ into the cell down its concentration gradient (Na+o = 140 mmol/​litre, Na+i = 7–​10 mmol/​litre). To counteract this leak and to maintain the concentration gradients of Na+ and K+ upon which the generation of the membrane potential depends, the plasma membrane Na+/​K+-​ATPase uses free energy derived from the hydrolysis of ATP to pump these ions against their concentration gradients. This process is electrogenic (three Na+ extruded for two K+ entering) and generates 3–​10 mV of the membrane potential.

The action potential The action potential is divided into five phases (Fig. 16.1.2.5). The currents that flow are described in Table 16.1.2.1, Table 16.1.2.2, and Fig. 16.1.2.5. Depolarization from the resting potential is mediated by inward cation current flow. Phase 0 of the action potential When a myocyte is electrically stimulated, Na+ channels (Nav1.5) open and allow Na+ ions to enter the cell. The channels open by sensing potential difference more positive than about −65 mV across the cell membrane (‘voltage gated’; Fig. 16.1.2.5). Excitation depolarizes the cell membrane slightly and this increases the probability of Na+ channel opening. A cardiac myocyte contains many thousands of Na+ channels, hence the current (I) generated by the movement of Na+ ions into the cell (INa) is the sum of the small currents that flow through each individual channel. Positive charge is taken into the cell, the membrane potential increases (becomes less negative) towards the equilibrium potential for Na+ (ENa = +70 mV, Table 16.1.2.1), and the cell depolarizes (Fig. 16.1.2.5). The Na+ current causes the rapid upstroke (phase 0) of the action potential. The propagation velocity of the action potential across the whole heart is related to the rate of the rapid upstroke. Following activation and opening, the channels close very rapidly, even though the myocyte remains depolarized, a process termed ‘inactivation’. Inactivated channels cannot open again until the cell repolarizes, causing the refractory period during which a further stimulus cannot evoke another action potential (Fig. 16.1.2.5).

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Section 16  Cardiovascular disorders

Membrane potential (mV)

+40

1

The inactivation of each channel decreases the total number of Na+ channels that are conducting such that INa almost entirely inactivates within the first 5 ms of the action potential (the overall action potential in humans at rest lasts c.350 ms). Some Na+ channels do not inactivate so rapidly, allowing a small inward current to persist during the plateau phase of the action potential (phase 2, see next). In late phase 0 some L-​type Ca2+ channels (Cav1.2) also start to open, resulting in Ca2+ influx into the cardiomyocyte.

2

0 0

3

−40 Absolute refractory period

−80

4 Relative refractory period

Phase 1 of the action potential

1.0 Ca transient (µM)

The characteristic notch observed in phase 1 of the action potential in ventricular myocytes (Fig. 16.1.2.5) is caused by a transient outward current (ITO), carried mainly by K+ ions flowing out of the cell (ITO1), but also by some Cl− current (ITO2), that partially repolarizes the membrane. The current inactivates within 30–​40 ms but is important in determining action potential duration. A  component of ITO appears to be dependent upon intracellular Ca2+ concentration (raised Ca2+o increases ITO):  this is the probable mechanism underlying action potential shortening during tachycardia.

0.1

outward

K currents

ITo

IKr

IK1

IKs

outward inward

Ca and Na/CaX current

3260

INaCa

ICa

time

Fig. 16.1.2.5 Ca2+ transient, membrane potential, K+ currents, and Ca2+-​related currents during a ventricular myocyte action potential. The inward Na+ current that produces the rapid upstroke of the action potential (depolarization) is not shown. Top panel: phases of the ventricular myocyte action potential. Upper middle panel: changes in cytoplasmic Ca2+ concentration during the action potential (Ca2+ transient). For a period between phase 0 and about midway through phase 3, cardiac muscle cannot be excited with another stimulus: the absolute refractory period. From about halfway through phase 3 until just before the end of phase 3, cardiac muscle is in its relative refractory period, when a stronger stimulus than normal is required to initiate an action potential. The states of refractoriness are related to the ability of ion channels to recover from a stimulus. This recovery is both voltage-​and time-​dependent. Lower middle panel: K+ currents during one action potential. All K+ currents (ITO, IKs, IKr, and IK1) repolarize the myocyte because of outward K+ movement. Bottom panel: Ca2+-​related currents during one action potential. Because of the inward movement of Ca2+, Ca2+ current (ICa) is depolarizing. The Na/​CaX produces both outward and inward current (INa,Ca) depending on the phase of the action potential. The inward Na+ current is roughly 8–​10 times the size of the Ca2+ current and has largely inactivated by the time of the peak Ca2+ current.

Phase 2 of the action potential Several currents flow during phase 2 (the action potential plateau), including ICa (Fig. 16.1.2.5). L-​type (‘long-​lasting’) Ca2+ channels, which take longer to activate and inactivate than Na+ channels, open within 3–​5 ms of the start of the upstroke and allow Ca2+ to flow into the cell (ICa). L-​type Ca2+ channels activate at more positive voltages than Na+ channels (around −35 mV). The influx of Ca2+ maintains depolarization (Fig. 16.1.2.5, Tables 16.1.2.1 and 16.1.2.2), and initiates Ca2+-​induced Ca2+-​release (CICR) from the SR through the SR Ca2+-​release channels (ryanodine receptors), causing the myocyte to contract and hence crucial for excitation–​contraction coupling (see next). Hence, Ca2+ has a role in both membrane potential and signal transduction/​inotropy. In addition, a slow delayed rectifier K+ current (IKs) exports K+ in phase 2. The plateau phase (phase 2) of the action potential (Fig. 16.1.2.5) is prolonged in ventricular myocytes because of the properties of several types of K+ channel that give rise to several different K+ currents. The main repolarizing current, IK, is composed of two distinct ‘rectifier’ currents, one activating more rapidly (IKr) than the other (IKs) (see Table 16.1.2.2). Both channels open at positive membrane potentials and close (deactivate) at negative potentials. Hence the plateau of the action potential is the result of a balance of inward (Ca2+) and outward (K+) current flow. Phase 3 of the action potential The final phase of repolarization begins with the termination of ICa and progressively increasing K+ current (IKr and IKs) (Fig. 16.1.2.5). As repolarization proceeds, the sodium-​calcium exchanger Na/​CaX responds to the increase in cytoplasmic Ca2+ concentration and produces an inward current (INa,Ca) through the exchange of three Na+ entering the cell for one Ca2+ expelled; by producing an inward current, the Na/​CaX slows repolarization and prolongs the plateau. In ventricular myocytes, complete repolarization and a return to a negative resting membrane potential is eventually achieved by (the large) IK1 (the ‘inward rectifier’; Fig. 16.1.2.5; Table 16.1.2.2). The channel through which this current flows possesses peculiar characteristics. Normally, because of the relative concentrations of K+ inside and outside the cell, there is outward movement of K+ ions that becomes

16.1.2  Cardiac physiology

Table 16.1.2.2  Plasma membrane currents in the cardiac myocyte Current

Name/​Ion

Activated by

Blocked by

Gene

Protein

Function

Inward currents

INa

(Fast) Na+ current; Na+

Depolarization

Tetrodotoxin, local anaesthetics

SCN5A

Nav1.5

Rapid upstroke of action potential (phase 0)

ICa,L

L-​type Ca2+ current (‘long-​lasting’); Ca2+

Depolarization

Verapamil, Cd2+, dihydropyridines

CACNA1C

Cav1.2

Ca2+ influx that activates CICR, provides some Ca2+ for contraction (phase 0–​2)

ICa,T

T-​type Ca2+ current (‘transient’); Ca2+

Activates on depolarization but at more negative potentials than L-​type current

Ni2+, mibefradil

CACNA1G CACNA1H

Cav3.1 Cav3.2

Channel density high in pacemaker and conducting tissue so may contribute to pacemaker activity (phase 4). Role in ventricular cells unclear (phase 2)

If

Hyperpolarization-​ activated, cyclic nucleotide-​gated cation channel; Na+, K+

Hyperpolarization, noradrenaline, cAMP, autonomic nervous system

Cs+, ZD7288, ivabradine, zatebradine, cilobradine

HCN2 HCN4

HCN2 HCN4

Exists in sinoatrial node and Purkinje fibres bringing membrane potential slowly to threshold (phase 4); also known as ‘funny’ current

Ca2+i (Na+)

Ni2+, KB-​R7943

NCX1 SLC8A1

NCX

3Na+-​1Ca2+ exchange. Expels Ca2+ from the cell, maintains inward current flow near end of action potential, at positive potentials may reverse and mediate Ca2+ influx (phase 3, 4)

4-​Aminopyridine

KCNA4 KCND2 KCND3

Kv1.4 Kv4.2 Kv4.3

Early repolarization (phase 1; notch)

Inward and outward (reversible) current

INa/​Ca

Na/​CaX current; Na+, Ca2+

Outward currents

ITO

Transient outward current; K+ (ITO1); Cl-​ (ITO2)

Depolarization

ICl

Chloride current; Cl-​

cAMP

CFTR

Early repolarization

ICl,Ca

Ca2+-​activated chloride current

Ca2+

CLCA1

Early repolarization

IKur

Ultra-​rapid delayed rectifier; K+

Depolarization

Tetraethylammonium, Cs+, Ba2+, 4-​ aminopyridine, flecainide, nifedipine, diltiazem, bupivacaine, propafenone, quinidine

KCNA5

Kv1.5

Repolarization of cell (phase 1, 3)

IKr

Rapid delayed rectifier; K+

Depolarization

Tetraethylammonium, Cs+, Ba2+, E-​4031, dofetilide, D-​sotolol, cisapride, BRL32872

KCNH2 hERG

hERG, Kv11.1

Repolarization of cell (phase 2, 3)

IKs

Slow delayed rectifier; K+

Depolarization

Chromanol 293B

KCNQ1

KvLQT1 Kv7.1

Repolarization of cell (phase 2, 3)

IK1

Inward (anomalous) rectifier; K+

Depolarization from EK Conductance of channel increases then decreases to zero at 0 mV

Cs+, Rb+, Ba2+, intracellular Mg2+, spermidine, spermine

KCNJ2 KCNJ12

Kir2.1 Kir2.2

Prolongs action potential duration, background K+ conductance. (phase 3, 4)

Ip

Na+/​K+ pump current (INaK); Na+, K+

Na+i, K+o

Cardiac glycosides

ATP1A1

IK,ACh

Acetylcholine-​ activated K+ current (inward rectifier); K+

ACh, parasympathetic nerves

Ba2+

KCNJ3 KCNJ5

Kir3.1 Kir3.4

Muscarinic receptor-​coupled. Activates additional K+ channels so slowing pacemaker potential (phase 3, 4)

IKATP

ATP-​activated K+ current; K+

ATP, nicorandil

KCNJ11

Kir6.2 (SUR2A)

Cardiac ATP homeostasis and metabolic matching (phase 1, 2); SUR subunits are sulphonylurea receptors

larger the more positive the displacement from EK. However, the IK1 current flows through a channel that first increases its conductance but then decreases it as the cell depolarizes away from EK (anomalous rectification). Thus, there is outward flow of repolarizing current only over a narrow voltage range (around −30 to −80 mV)—​another reason for the prolonged cardiac action potential because a large, rapid, outward K+ current does not flow despite the membrane potential approaching 0 mV during the plateau phase.

3Na+-​2K+ ATPase exchanger. Maintains low [Na+]i

IK1 is responsible for the main (background) flow of K+ giving rise to the membrane potential. The channels through which IK1 flows are numerous in ventricular cells, fewer in atrial cells, and absent in pacemaker cells. The current is therefore large in ventricular cells and this is the reason that the resting membrane potential of ventricular myocytes lies near EK, whereas atrial cells have a more positive (less negative) resting membrane potential, and SA nodal cells do not have a stable resting potential.

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Section 16  Cardiovascular disorders

Phase 4 of the action potential This phase relates to the membrane potential during the electrically silent period between excitatory events in ventricular myocytes (Fig. 16.1.2.5); phase 4 is stable in these cells. Besides the underlying IK1 activity, it is accompanied by an electrogenic active sodium-​ potassium exchange giving rise to a Na+/​K+ pump current (IP). Differences in ion channel distribution alters the stability of phase 4 due to differing ionic currents and leading to spontaneous depolarization associated with pacemaker activity (‘pacemaker potential’). Regional variations in action potential The configuration of the cardiac action potential differs regionally within the heart (Fig. 16.1.2.6) because ion channel expression varies between cells. In the sinoatrial node, INa is very small and the main current responsible for the depolarizing upstroke is ICa, carried mainly by L-​type Ca2+ channels (ICa,L). The only repolarizing current is IK. IK1 is absent and, as mentioned earlier, this partially explains why sinoatrial node cells have a more depolarized ‘diastolic’ potential than ventricular myocytes. Sinoatrial node cells depolarize spontaneously during phase 4 (Fig. 16.1.2.6), owing to the absence of IK1 and the presence of a current activated on hyperpolarization called the ‘funny’ current (If), carried mainly by Na+ through hyperpolarization-​activated cyclic nucleotide-​gated (HCN) channels, but also current (ICa,T) resulting from an influx of Ca2+ through voltage-​dependent T-​type (‘transient’) Ca2+ channels (abundant in these cells; see Table 16.1.2.2). Phase 4 is often termed the ‘pre-​or pacemaker potential’ in nodal cells and is caused by the gradual decrease in IK and increase in If and ICa,T (Fig. 16.1.2.6). Once the cell has depolarized to a voltage at which L-​type Ca2+ channels open (the threshold), a more rapid depolarization (caused by ICa,L) occurs, forming the upstroke (phase 0) of the sinoatrial node action potential. Acetylcholine (ACh) activates IK,ACh, which helps drive the membrane potential towards EK and slows the rate of depolarization, while β-​adrenergic stimulation increases the slope of the pacemaker potential and heart rate through an effect on If, affecting heart rate (Fig. 16.1.2.7).

Membrane potential (mV)

Adrenergic stimulation

Normal rate

0

Threshold – 50

Pacemaker potential Cholinergic stimulation

Membrane potential (mV)

3262

Normal rate

0

Threshold – 50

Fig. 16.1.2.7  Change in heart rate produced by altering the phase 4 slope of the pacemaker potential in the sinoatrial (SA) node. β-​Adrenergic stimulation increases (increased If), and cholinergic stimulation decreases (increased IK, ACh), the slope of the pacemaker potential, affecting the time taken to reach threshold.

Atrial and ventricular myocytes do not have pacemaker potentials and spontaneously discharge only when injured or when there is abnormal ionic balance. The longest action potential is in Purkinje fibres (Fig. 16.1.2.6) and this acts as a ‘gate’ preventing retrograde activation by depolarization of adjacent ventricular myocytes.

The mechanism of myocyte contraction

Sinoatrial node 0 mV

Excitation–​contraction coupling –50 mV Threshold potential 0 mV

–80 mV Atrial muscle

Atrioventricular node

Purkinje fibre

Ventricular muscle

Fig. 16.1.2.6  Regional configurations of the action potential. In the sinoatrial (SA) and atrioventricular (AV) nodes, the cells spontaneously depolarize during diastole (phase 4 depolarization). When the membrane potential reaches a threshold, the complete action potential is initiated. Because the SA nodal cells have the fastest phase 4 depolarization, they act as the cardiac pacemaker.

The electrical events throughout the heart initiate and regulate contraction (Fig. 16.1.2.5). Coupling of the electrical excitation of the heart to contraction (termed excitation–​contraction coupling or EC coupling) by Ca2+ ions involves the interaction of several proteins involved in Ca2+ homeostasis (Fig. 16.1.2.3). The T-​tubules carry depolarization deeply into the cell. During diastole (phase 4), when cytoplasmic Ca2+ concentrations are low (c.0.1 µmol/​litre), Ca2+ is sequestered by the Ca2+-​buffering protein calsequestrin within the JSR. Depolarization (phase 0)  then opens the L-​type Ca2+ channels in the T-​tubule and plasma membrane allowing influx of Ca2+ (Figs. 16.1.2.3 and 16.1.2.5) and producing ICa (Fig. 16.1.2.5). Ca2+ influx increases the local cytoplasmic Ca2+ concentration around clusters of SR Ca2+-​release channels in the JSR sufficiently to open them (i.e. CICR), the number of channels activated in this way being mainly, though not exclusively, determined by the size of the Ca2+

16.1.2  Cardiac physiology

current. CICR provides amplification, as the small ‘trigger’ Ca2+ influx through the L-​type Ca2+ channels evokes a much larger release of Ca2+ from the SR into the cytoplasm; also, the release of Ca2+ from the SR is under precise control as it is closely matched to the amount of Ca2+ influx. Cytoplasmic Ca2+ concentration rises to between 1 and 3 µmol/​litre (Fig. 16.1.2.5). The release of Ca2+ eventually ceases because the L-​type Ca channels inactivate, so the trigger influx declines, leading to closure of SR Ca2+ release channels.

Action potential Force

The mechanism of myofibrillar contraction

Ca transient

Ca2+ release from the SR activates the contractile apparatus of the sarcomere (Figs. 16.1.2.2 and 16.1.2.8). The temporal relationship between the action potential, the Ca2+ transient, and the subsequent development of tension is shown in Fig. 16.1.2.9. Sarcomere shortening is caused by the interaction of motor protein myosin in the thick filaments with actin in the thin filaments (Fig. 16.1.2.8). Myosin heads bind and hydrolyse ATP, retaining bound ADP and phosphate, and trapping the free energy of hydrolysis within the myosin molecule. The myosin–​ ADP–​ phosphate complex then binds to actin, leading to the release of the stored energy by a conformational change that moves the actin filament by about 10 nm relative to the thick filament. This is known as the cross-​bridge cycle (Fig. 16.1.2.8) and results in the sliding of the thin filament past the thick filaments, and sarcomere shortening. If the muscle is under load, the cross-​bridge cycle generates force and work is done (the maximum efficiency is more than 60% in intact muscle). The mechanical characteristics of contracting muscle can be described in terms of the relationship between shortening speed and force, and

(b)

(a)

(c)

Pi Pi ADP

ADP

ATP (e)

ATP

(d) actin filament myosin head myosin filament

Fig. 16.1.2.8  The cross-​bridge cycle. Exchange of ATP with ADP (a) on either a load-​bearing (b) or a resting-​length myosin head (c) results in a conformational change in the myosin head, causing a rapid dissociation of the myosin head from actin ((b) to (d) and (c) to (d), respectively). Following detachment from actin, the ATP is hydrolysed to ADP and Pi, both of which remain tightly bound to the myosin head (e). Hydrolysis is accompanied by a major conformational change which represents the reversal or a repriming of the power stroke. If an actin site is within reach of the myosin head, it will bind rapidly and reversibly to the actin site (a). When the myosin head binds actin, the interaction can promote a major change in conformation (the power stroke) which is accompanied by the dissociation of Pi ((a) to (b)). This step approximates to isometric contraction (no relative movement of actin and myosin), whereas the (a) to (c) steps approximate to an isotonic contraction (relative movement, with a release of the myosin ‘spring’). This power stroke consists of a reorientation of part of the myosin head that results in the displacement of the tip by up to 10 nm. Reproduced with permission from S. Weiss and M. A. Geeves.

Fig. 16.1.2.9  The relationship between the ventricular action potential, the Ca2+-​transient and the generation of force. The peak of force production is not achieved until near the end of the plateau phase of the action potential and lags behind the peak of the Ca2+-​transient, reflecting the time required for Ca2+-​induced Ca2+-​release and cross-​bridge cycling.

between sarcomere length and force (Fig.  16.1.2.10a). Maximum force is produced under isometric conditions, while maximum shortening speed is observed in unloaded muscle. Power output is the product of force and velocity and is optimal at about 30% of maximum shortening speed (Fig. 16.1.2.10a). The isometric force produced by a muscle depends on the sarcomere length, being optimal at 2.00–​2.25 µm where the overlap of thick and thin filaments is optimal and such that all the myosin cross-​bridges can interact with actin (Fig. 16.1.2.10b). In the heart, the sarcomere length is generally less than optimal, with ‘preload’ stretching the sarcomere to 2.1 µm at the end of diastole and the sarcomere shortening to 1.6 µm during systole. In this length range, stretching the cardiac muscle when it is relaxed leads to increased force in the subsequent contraction. This characteristic is responsible in part for the Frank–​Starling mechanism of the heart.

Control of contraction by Ca2+ Muscle contraction is initiated by an increase in cytoplasmic Ca2+, which binds to the troponin complex of the thin filament. Troponin comprises three subunits. Troponin C is a Ca2+-​binding protein; in cardiac myocytes, the thin filament is activated when a single Ca2+ ion binds to troponin C. Troponin I is the inhibitory subunit. In relaxed muscle, the Ca2+ concentration is low and troponin I  binds to a site on actin which blocks the binding of myosin cross-​bridges, thus preventing cross-​bridge cycling. In the presence of activating Ca2+ concentrations, Ca2+ binds to troponin C which then binds troponin I, preventing its interaction with actin, permitting actin–​myosin interaction. The third component, troponin T, binds to troponin C and troponin I and also to tropomyosin, independently of the Ca2+ concentration, thereby anchoring the regulatory complex on the thin filament (Fig. 16.1.2.2). There are cardiac-​specific isoforms of troponin I  and troponin T, while troponin C is present in heart as the isoform found in skeletal muscle. The tropomyosin lies in a groove between actin filaments, inhibiting interaction between actin and

3263

Section 16  Cardiovascular disorders

(b)

(a)

1

100%

2

3

4

Tension Power

1.0 Force

3264

0.5

0% 1.0

1.5

2.0

2.5

3.0

3.5µm

1 2

0

0

0.5

1.0

Velocity

3 4

Fig. 16.1.2.10  Force–​velocity–​power relationship in cardiac muscle. (a) Force–​velocity relationship (red symbols, black line). Maximum force is produced under isometric conditions (velocity V = 0), while maximum shortening speed is observed in unloaded muscle (force P = 0). The power-​velocity relationship (blue symbols, green line) is a parabola with maximum power being produced at an intermediate force and velocity. (b) Length–​tension relationship in cardiac muscle. At sarcomere length greater than 2.0 µm (­examples 2, 3), isometric tension depends on the amount of overlap between myosin cross-​bridges and actin filaments. At shorter sarcomere lengths (down to 1.6 µm; ­example 1), tension is reduced because of interference of thin filaments from opposite ends of the sarcomere. Below 1.6 µm sarcomere length, myosin filaments interfere with the Z-​line and tension falls rapidly. The range of sarcomere lengths during a normal cardiac cycle is shown in blue. Actin filaments: grey; myosin filaments: red.

myosin heads. Ca2+ binding to troponin C induces a conformational change, resulting in a shift of the tropomyosin in the actin groove and exposing the myosin head-​binding sites. The Ca2+-​sensitivity of cardiac myocytes is increased by stretch, promoting relaxation at the start of diastole (short sarcomere lengths) and activating contraction at the start of systole (long sarcomere lengths). Moreover, this ‘stretch activation’ is delayed so that the enhanced contractility is synchronized with systole, thus contributing to the Starling effect.

Termination of contraction Sarcoplasmic/​endoplasmic reticulum ATPase type 2 (SERCA 2) Contraction is terminated predominantly by Ca2+ reuptake into the SR by activation of SERCA2, an ATP-​requiring Ca2+ pump expressed in the network of non​junctional SR surrounding the myofibrils (Fig. 16.1.2.3a). SERCA2 activity is regulated by the extent of phosphorylation of the SERCA2-​associated protein phospholamban associated with the activities of protein phosphatase-​1, inhibitor-​1 and PKCα, together with covalent modification by SUMOylation and acetylation. The Na+/​Ca2+ exchanger (Na/​CaX) and the Na+/​K+-​ATPase The sarcolemmal Na/​CaX antiporter contributes to lowering cytoplasmic Ca2+ during the latter part of the action potential (phases 3 and 4) and during diastole (Fig. 16.1.2.5 and Table 16.1.2.2). Its activity is regulated by Ca2+i through a large intracellular loop containing two Ca2+-​binding domains. The Na/​CaX utilizes the energy associated with the concentration and electrical gradients for Na+ to expel Ca2+ from the cell. It is electrogenic, promoting depolarization under these conditions. The exchange is sensitive to Na+i concentration: when membrane potential is near its diastolic level and Na+i is at normal physiological concentration, the Na/​CaX will eject Ca2+ from the cell; if Na+i increases by a few mmol/​litre and

the membrane potential becomes depolarized, the exchanger can reverse and mediate Ca2+ entry. The sarcolemmal Na+/​K+-​ATPase is responsible for Na+i extrusion. Cardiac glycosides (e.g. digoxin) inhibit the Na+/​K+-​ATPase, preventing Na+ extrusion, which indirectly reverses the Na/​CaX into Ca2+o uptake mode. Under these conditions, Ca2+ uptake by the SR may be increased, thereby augmenting the cardiac Ca2+ pool and facilitating CICR. The net effect of the cardiac glycosides is to increase the cytoplasmic concentration and availability of Ca2+ resulting in an increased force of contraction (positive inotropy). Ventricular myocytes possess other minor systems to decrease cytoplasmic Ca2+ concentrations, including the plasma membrane Ca2+ ATPase and mitochondrial Ca2+ uptake. SERCA2 and Na/​CaX contribute about 70% and 25%, respectively, towards relaxation, though these figures vary greatly between species.

Whole organ physiology The cardiac cycle Electrical events initiate the cardiac cycle with depolarization of the sinoatrial (SA) node in the upper right atrium (Fig. 16.1.2.11). Cardiac muscle acts as a functional syncytium. Communication between neighbouring cells is mediated by gap junctions which form arrays of cell-​to-​cell channels. The generated action potential spreads from the sinoatrial node across the functional syncytium at a speed of 1.0–​1.2 m/​s. The first mechanical response is atrial systole. The atria comprise a single functional syncytium, and the ventricles also comprise a single, separate, syncytium. These two syncytia are not contiguous with each other and not capable of activating each other directly. The conduction of the electrical impulse from atrium to ventricle normally occurs only through the atrioventricular (AV) node (Fig. 16.1.2.11), a region of slow conductance at 0.02–​0.1 m/​s. This delays activation of the cells of the bundle of His

16.1.2  Cardiac physiology

Superior vena cava

Aorta

Left bundle branch

Sinoatrial node

Anterior fasicle

Atrioventricular node Purkinje system

Bundle of His

Posterior fasicle Right bundle branch

Fig. 16.1.2.11  Diagram of the heart showing the impulse-​generating and impulse-​conducting systems. From Junqueira LC, Carneiro J, (2005). Basic histology, 11th edn. McGraw-​Hill, New York.

arising from the AV node and allows time for completion of ventricular filling. The conduction velocity in the bundle of His is from 1.2 to 2.0 m/​s. The impulse passes via the right bundle branch and the two branches (anterior and posterior) of the left bundle, and spreads rapidly (2.0–​4.0 m/​s) through the Purkinje fibres and each muscle cell to produce an orderly sequence of ventricular contraction (Fig. 16.1.2.11). Atrial and ventricular depolarization (P wave and QRS complex, respectively) and repolarization (T wave) can be recorded on the ECG (Fig. 16.1.2.12). While the recorded ECG is a summation of all the individual action potentials of the myocytes, the ECG voltage is much less than

VAT

1.0

R

10 mm

PR segment

ST segment

0.5

T

P

P

U

P–R interval

0.04

Isoelectric line

Q S QRS interval

Voltage (in mV)

1 mm

0

Q–T interval

0

0.2

0.4 Seconds

0.6

0.8

1.0

Fig. 16.1.2.12  Diagram of electrocardiographic complexes, intervals, and segments. VAT, ventricular activation time. From Goldschlager N, Goldman MJ (1989). Principles of clinical electrocardiography, 13th edn. Appleton and Lange, East Norwalk, CT.

direct action potential recordings (about 1 mV compared to about 100 mV) because of the resistance of body tissues between the heart and the ECG electrodes. The specialized cells of pacemaker tissue have an inherent rhythmicity (unstable phase 4 membrane potential) that is shared by the sinoatrial node, the atrioventricular node, and Purkinje tissue. Unlike other myocardial cells, these cells do not maintain a diastolic intracellular potential of about −90 mV but tend to depolarize spontaneously. Because the sinoatrial node has the fastest inherent discharge (depolarization) rate, and because there is a brief period after depolarization of the whole heart during which a further stimulus is ineffective—​the absolute refractory period—​the sinoatrial node is normally the pacesetter for the heart. However, if this does not occur, pacemaker tissue in the atrioventricular node, the bundle of His, or the Purkinje system will assume this role, in which case the heart rate is then considerably slower.

Mechanical events The mechanical events following depolarization of the atrial and ventricular muscle and their timing in relation to the ECG, to pressure and flow changes, and to heart sounds are shown in five phases in Fig. 16.1.2.13. After the P wave, and coinciding with atrial systole, ‘a’ waves appear in left atrial and right atrial pressure tracings due to atrial contraction, and an ‘a’ wave can be seen in the jugular venous pulse. Atrial contraction increases ventricular filling by about 10% (phase 1). The onset of ventricular contraction coincides with the peak of the R wave of the ECG; a rapid rise in intraventricular pressure closes the mitral and tricuspid valves, causing the first heart sound; mitral valve closure slightly precedes tricuspid valve closure and two components of the first heart sound may be heard (M1-T1). During this short isovolumetric period (phase 2 of Fig. 16.1.2.13), the pressure rises rapidly in the ventricles. When ventricular pressures exceed those in the pulmonary artery and aorta, the outflow valves open and ventricular ejection follows. The highest flow rate is in early systole, and pressures in the aorta and pulmonary artery rise. Normally, between 50 and 70% of the ventricular volume is ejected during systole (the ejection fraction), and this can be seen in the volume curve included in Fig. 16.1.2.13 (phase 3). The jugular venous pulse, during ventricular contraction, has a positive deflection in early systole, the ‘c’ wave, due to right ventricular contraction and bulging of the tricuspid valve into the right atrium. Descent of the tricuspid ring caused by ventricular contraction then produces a negative ‘x’ descent, but as atrial inflow continues the pressure rises in the atria and great veins, producing the ‘v’ wave. This reaches its peak just before the opening of the tricuspid valve, declining during early ventricular filling as the negative ‘y’ descent. The changes in the pulmonary veins and left atrium are similar. As the strength of ventricular contraction declines in late systole, coinciding with the end of the T wave, the aortic and pulmonary valves close, producing the dicrotic notch seen on both aortic and pulmonary artery pressure tracings in Fig. 16.1.2.13. Aortic closure slightly precedes pulmonary closure, and together these are responsible for the two components of the second heart sound (A2-​P2). A short period of further rapid decline in ventricular pressure ensues without change in the ventricular volume (the period of isovolumetric ventricular relaxation, phase 4), and at the end of this the mitral and tricuspid valves open. Valve opening is not normally audible. There is a pressure gradient from atrium to ventricle so that a period of

3265

Section 16  Cardiovascular disorders

0

0.2 0.4 0.6 0.8 Time (s) Diastole

Atrial systole Ventricular systole

3266

Normal volumes, pressures, and flows

P R T

U

4 1

2 3

Ventricular 120 and 80 aortic pressure 40 (mm Hg) 0 130 Ventricular volume (ml) 65

Electrocardiogram

c

o

Heart sounds (phonocardiogram) Aortic pressure (at o, the aortic valve opens; at c, it closes) Left ventricular pressure

o′

Left ventricular volume (at c′ , the mitral valve closes; at o′ , it opens)

c′

0 Aortic blood flow (l/min)

5 3 0

a

c

Right atrial pressure (left is similar)

v

Jugular venous pressure, showing a, c, and v waves

n n Pressure 30 (mm Hg) 15 0

Carotid pressure (n = dicrotic notch) Radial pressure Pulmonary arterial pressure Right ventricular pressure

12 3 4

ventricular function, with increased end-​diastolic pressure. A fourth heart sound precedes the Q wave of the ECG, which must be distinguished from a normal splitting of the two components of the first heart sound. The latter occurs after the Q wave (Figs. 16.1.2.12 and 16.1.2.13).

5

Phases of cardiac cycle

Fig. 16.1.2.13  Events of the cardiac cycle at a heart rate of 75 beats/​ min. The phases of the cardiac cycle, identified by the numbers at the bottom, are: (1) atrial systole; (2) isovolumetric ventricular contraction; (3) ventricular ejection; (4) isovolumetric ventricular relaxation; and (5) ventricular filling. Note that aortic pressure actually exceeds left ventricular pressure in late systole, but the momentum of the blood keeps it flowing out of the ventricle for a short time before the aortic valve is eventually forced shut, causing the second heart sound. The pressure relationships in the right ventricle and pulmonary artery are similar. The jugular venous pulse is similar in form to that seen in the right atrial pressure tracing. The ‘c’ wave interrupts the ‘x’ descent of the ‘a’ wave. The decline in pressure from the peak of the ‘v’ is the ‘y’ descent; the rate of decline reflects speed of ventricular filling. Modified with permission from Ganong WF (2005). Review of medical physiology, 22nd edn. McGraw-​Hill, New York.

rapid ventricular filling follows, which coincides with the timing of the third heart sound. The rapid ventricular filling is reflected in the shape of the ventricular volume curve and is followed by a period of slower filling (phase 5), with a final sudden small increment from the next atrial contraction as ventricular diastole ends (phase 1). Third heart sounds are normally audible in children and young adults, but over the age of about 40 years this usually indicates elevation of ventricular end-​diastolic pressure (most frequently in the left ventricle). The myocardium and valvular structures become stiffer with ageing, and large increases in ventricular end-​diastolic pressure are then required to tense valvular structures and generate audible vibrations. A fourth heart sound usually indicates abnormal

The blood volume in normal adults is about 5 litres (haematocrit 45%), and, of this, about 1.5 litres are in the heart and lungs—​the central blood volume. The pulmonary arteries, capillaries, and veins contain about 0.9 litres, with only about 75 ml being in the pulmonary capillaries at any one instant. The volume of blood in the heart is about 0.6 litres. Left ventricular end-​diastolic volume is about 140 ml, stroke volume about 90 ml, and end-​systolic volume around 50 ml, reflecting an ejection fraction (stroke volume/​end-​ diastolic volume) of between 50 and 70%. The right ventricular ejection fraction is similar. Of the 3.5 litres in the systemic circulation, most—​at least 60% of the total blood volume—​is in the veins. The systemic veins containing most of the blood volume are thin-​walled and easily distensible, and input of blood into the contracting heart is associated with only small changes in venous pressure: they act as a blood volume reservoir or ‘buffer’. By contrast, ejection of blood into the much less distensible arterial tree produces large pressure changes. The normal values for pressures generated in the heart and great vessels during the cardiac cycle are shown in Table 16.1.2.3. Pressures are measured with reference to a zero pressure empirically set at 5 cm below the sternal angle with the patient recumbent. ‘Normal’ arterial blood pressure is considered later (see next, ‘Regulation of systemic arterial blood pressure’). Cardiac output is the product of stroke volume and heart rate (stroke volume = end-​diastolic volume –​end-​systolic volume). It is related to body size and is best expressed as litre/​min per m2 of body surface area: the ‘cardiac index’. The mean cardiac index under resting and relaxed conditions is 3.5 litre/​min per m2, and values below 2 and above 5 are abnormal. The cardiac index declines with age. In persons of average size, resting whole body oxygen consumption is about 240 ml/​min, and the difference in oxygen content between arterial and mixed venous blood is about 40 ml/​litre (arteriovenous oxygen difference), giving a basal cardiac output of 6 litre/​min. In normal subjects, the arteriovenous difference in oxygen content at rest is maintained within narrow limits, from 35 to 45 ml/​litre; values of 55 ml/​litre and above are always abnormal. Pulmonary or systemic vascular resistance is estimated by dividing the difference between mean inflow pressure (pulmonary artery or aortic) and mean outflow pressure (left atrial or right atrial, usually in mm Hg) by the flow (usually in litre/​min) through the respective circulations. In normal subjects and patients without intracardiac shunts, this flow is the cardiac output. Normal pulmonary vascular resistance is less than 2 mm Hg/​litre per min (hybrid resistance units, Wood units; equivalent to 16 MPa.S.m−3, 160 dyn.S.cm–​5). Arterial blood pressure is the product of cardiac output and total peripheral (systemic) resistance. Stroke work is the integral of instantaneous ventricular pressure with respect to stroke volume, but is usually estimated as the product of stroke volume and mean ejection pressure. The orderly sequence of contraction in the normal cardiac cycle coordinates changes in

16.1.2  Cardiac physiology

Table 16.1.2.3  Normal resting values for pressures in the heart and great vessels Site

Systolic pressure (mm Hg)

Diastolic pressure (mm Hg)

Mean pressure (mm Hg)

Right atrium

‘a’ up to 7, ‘v’ up to 5

‘y’ up to 3, ‘x’ up to 3

Less than 5

Right ventricle

Up to 25

End pressure before ‘a’ up to 3; end pressure on ‘a’ up to 7

Not applicable

Pulmonary artery

Up to 25

Up to 15

Up to 18

Left atrium (direct or indirect pulmonary artery/capillary wedge)

‘a’ up to 12, ‘v’ up to 10

‘x’ up to 7, ‘y’ up to 7

Up to 10

Left ventricle

120

End pressure before ‘a’ up to 7; end pressure on ‘a’ up to 12

Not applicable

Myocardial mechanics When a muscle is activated to contract, it develops a potential for doing work. In isolated skeletal and heart muscle preparations, the stretching force applied to the muscle—​and therefore the length of the muscle—​can be varied before contraction; this is the preload. The activated muscle will begin to shorten when it has generated a force sufficient to overcome that exerted by the attached weight or load against which it contracts. When the force exerted by the load is so arranged that it is not applied to the relaxed muscle and is applied only after the muscle has begun to develop tension, it is termed the afterload. If this load is so large that the activated muscle is unable to overcome it, and so cannot shorten, the contraction produces tension only, and the contraction is isometric. When shortening does occur, external work is done. If the load is constant during the shortening, the contraction is said to be isotonic; if it changes, it is auxotonic. The tension produced by both skeletal and cardiac muscle during contraction depends on initial fibre length; during afterloaded isotonic contractions from a particular length, the amount and the speed of fibre shortening, and the tension developed, all depend upon the afterload. Over a range of loads the initial velocity of muscle shortening is most rapid and the most extensive shortening occurs when the load is smallest. The inverse relationship between initial velocity of fibre shortening and load in an isotonic contraction is a fundamental one for both skeletal and cardiac muscle. There is, however, a major difference between the two types of muscle in that the relationship at any one given length is constant in a skeletal muscle, whereas in cardiac muscle there are variations in inotropic state that are accompanied by considerable changes in the relationship between force and velocity. A  positive inotropic effect produces a more extensive contraction from the same initial length and afterload, and a faster maximum velocity of shortening (Vmax). An increase in initial fibre length with no increase in inotropic state increases the force of contraction but does not, however, change the maximum velocity of shortening. This means that the force of contraction of cardiac muscle varies with fibre length ((pre-​)loading)—​for example, heterometric regulation, an aspect of the Frank–​Starling relationship—​but contractile force also independently varies with the ‘intrinsic’ contractility of the cardiac muscle fibre (inotropy)—​homeometric regulation. This is illustrated in Fig. 16.1.2.14.

The contraction of the intact heart can be visualized as being similar mechanically to the afterloaded contraction of an isolated muscle strip. For the left ventricle, the preload is the distending force which stretches the muscle fibres in end-​diastole (i.e. a function of ventricular filling), and the initial afterload is the force the ventricle must generate in order to open the aortic valve and eject blood against the systemic vascular (total peripheral) resistance. At the end of ejection, the ventricular muscle is isolated from the peripheral circulation, with the afterload then supported by the competent aortic valve, and the muscle relaxes against a comparatively small force. Relaxation of the heart is an active process due to ATP-​dependent withdrawal of calcium ions from the cytoplasm surrounding the myofibrils. ‘Active’ relaxation is still proceeding in the ventricular wall when the atrioventricular valves open, and, if it is delayed—​as in the hypoxic heart—​the slower relaxation increases the stiffness of the ventricular wall and impedes filling. Wall thickness is also a determinant of compliance and relaxation rate. For this reason, filling pressures are higher for the thicker and stiffer left ventricle than for the thinner and more distensible right ventricle (Table 16.1.2.3). When the left ventricle is hypertrophied

Velocity of shortening

instantaneous pressure and flow, so maximizing the transfer of energy to the circulation. Normal left ventricular work output at rest is about 6 kg/​m2 per min.

Vmax

a

b

Force (afterload)

c

Poa

Pob

Poc

Fig. 16.1.2.14  Idealized relationships between velocity of fibre shortening and afterload or force developed during contraction of a strip of cardiac muscle under three different conditions. Curves a and b were obtained with the muscle in the same inotropic state but with a longer initial fibre length (greater preload) for curve b. Curves b and c were obtained with initial fibre length the same but with contractility increased in c by the addition of a drug producing a positive inotropic effect. The terms Vmax and P0 describe, respectively, a hypothetical maximum shortening velocity in the absence of any load (hence the broken lines), and the force developed in an isometric contraction. An increase in initial fibre length increases P0 but not Vmax; a positive inotropic change increases both P0 and Vmax.

3267

Section 16  Cardiovascular disorders

due to chronic pressure overload, as in systemic hypertension or aortic stenosis, it becomes stiffer and filling pressures may then be abnormally high.

Myocardial metabolism The heart depends on oxidative metabolism to synthesize sufficient ATP to supply its energetic needs, including the generation of ionic gradients and cross-​bridge cycling. In the normal myocardium about 70% of energy is derived from lipid oxidation and about 30% from glucose oxidation, with glycolysis contributing relatively minor amounts of ATP anaerobically. Of plasma lipids utilized for oxidation by the heart, non​esterified (‘free’) fatty acids (NEFA) are an important energy source, especially in starvation and exercise when their plasma concentration is increased, but substantial fatty acid supply is also derived from circulating triacylglycerols (triglycerides; TAG) in plasma, including those contained in very low density lipoprotein and, in the post-prandial state, chylomicrons. Lipolysis of TAG in the lipoprotein particles is achieved by activity of the enzyme lipoprotein lipase (LPL), expressed in high copy number in the myocardium. LPL monomers are synthesized in the cardiomyocytes but are translocated in their active (dimerized, glycosylated) forms to their physiological site of action on the luminal surface of coronary endothelium, to which they are attached by a GPIHBP1 (glycosylphosphatidyl inositol-HDL binding protein 1)-heparan sulphate proteoglycan anchor (and from which they can be detached by heparin). Fatty acids liberated from TAG by LPL are assimilated into the underlying cardiomyocyte via fatty acid transporters (including fatty acid translocase; FAT/​CD36), possibly by the same route as NEFA, where they undergo mitochondrial β-​oxidation for ATP production. Besides fatty acids and glucose, the heart can also readily oxidize lactate (in the presence of adequate oxygen provision) and ketone bodies (acetoacetate, 3-​hydroxybutyrate) as well as amino acids. The cardiomyocyte is rich in mitochondria (Fig. 16.1.2.1). Cardiac substrate selection is partly a function of plasma substrate concentration and plasma metabolic hormonal milieu, but it changes characteristically in cardiac and metabolic disease. In ventricular hypertrophy, myocardial metabolism reverts to a more fetal pattern of increased glucose utilization and diminished lipid oxidation. A similar pattern may also be seen in cardiac failure of diverse aetiologies. An explanation for this phenomenon is that since fatty acid molecules are more reduced and glucose molecules more oxidized (and some ATP can be derived from glucose by anaerobic substrate-​level phosphorylation in glycolysis), greater amounts of oxygen are required to oxidize lipids than carbohydrates (glucose:  3.7 mol ATP/​mol O2; palmitate:  2.8 mol ATP/​mol O2), hence switching from fatty acid to glucose utilization may increase myocardial oxidative efficiency. By contrast, in diabetes mellitus lack of insulin or its signalling results in decreased glucose uptake (myocardium expresses insulin-​sensitive GLUT-​4 as well as GLUT-​1 glucose transporters) and oxidation by cardiomyocytes, with increased reliance on fatty acid utilization in keeping with the increased circulating lipids. This may lead to decreased efficiency of the diabetic myocardium and has been suggested as the mechanistic basis of diabetic (non​ischaemic) cardiomyopathy. By contrast to cardiomyocytes, the conducting system of SA and AV nodes and the His–​Purkinje cells relies more on anaerobic glycolysis for its energy provision.

Regulation of cardiac function Four essential factors determine the performance of the heart: (1) venous return, (2) outflow resistance (afterload), (3) inotropic state or contractility, and (4) heart rate. Changes in cardiac performance are accomplished by mechanisms that alter these four determinants.

Venous return, preload, and the Frank–​Starling relationship The relationship described independently by Frank and Starling between end-​ diastolic fibre length and force of contraction is shown in Fig. 16.1.2.15 and is the mechanism underlying the intrinsic ability of the heart to eject whatever blood volume (within limits) it is presented with, and hence to match RV output precisely with LV output. When the ventricle ejects against a constant pressure, variations in venous return alter the degree of stretch of the muscle fibres in diastole, and this determines contraction strength and work output. The number of active force-​generating sites in each fibre increases as it lengthens so that, within limits, the force of contraction and stroke work are positively related to end-​diastolic fibre length (heterometric regulation). The relationship is curvilinear when stroke work is plotted against end-​diastolic pressure as an index of preload, reflecting the exponential relationship between end-​diastolic pressure and end-​diastolic volume. When stroke work is plotted against end-​diastolic volume, the relationship between stroke work and preload is linear. The response of the heart at any particular time depends upon: (1) the intrinsic contractile state of the muscle (i.e. the biochemistry and contractile machinery); (2) the prevailing neurohumoral state (e.g. increased sympathetic outflow produces a more forceful contraction (positive inotropic effect) at any given end-​diastolic fibre length); (3) extrinsic inotropic influences—​drugs which have either positive or negative inotropic effects.

Stroke work (force of contraction)

3268

Positive inotropic effect

Negative inotropic effect

End-diastolic fibre length

Fig. 16.1.2.15  The Frank–​Starling relationship: the relation between left ventricular end-​diastolic fibre length and left ventricular stroke work. Also shown, the displacement upward and to the left with an increase in contractility and downward and to the right with a reduction in contractility. Similar but not identical curves are obtained by plotting left ventricular stroke work as one measure of the force of contraction against ventricular end-​diastolic pressure or volume (see text). Similar function curves may be obtained from both ventricles and both atria.

16.1.2  Cardiac physiology

End-​diastolic fibre length is determined by the force distending the ventricle at end-​diastole, and end-​diastolic pressure provides a reasonable indication of this force when the ventricle has normal distensibility or compliance; this is the preload. The systemic venous return and the elastic properties of the myocardium produce the end-​diastolic distending pressure for the right ventricle, and the pulmonary venous return and myocardial elasticity that for the left ventricle. For clinical purposes, it is convenient to equate venous return with preload because, as it changes from beat to beat, it adjusts the strength of the subsequent ventricular (and atrial) contraction by varying the force stretching the relaxed cardiac muscle and changing end-​diastolic fibre length.

Outflow resistance or afterload Pulmonary and aortic valve opening pressures are determined largely by the pulmonary and systemic vascular resistances, as shown for the latter in Fig. 16.1.2.16. These resistances, together with an inertial component dependent upon the mass of blood within the vessels, the compliance (stiffness) of the vessels, and the physical characteristics of each vascular tree combined with the pulsatile nature of the flow, constitute the impedance to ventricular outflow. This is the load against which the ventricle must contract and shorten. As this load is not applied in diastole to the relaxed muscle, it then being supported by competent aortic and pulmonary valves, it is described clinically as the afterload: it becomes applied to the muscle only after the ventricle has begun to develop tension. Regulation of systemic arterial blood pressure The regulation of the systemic circulation is well adapted to the vital function of maintaining constant, adequate tissue perfusion. There is a need to maintain a relatively constant arterial blood pressure when there are changes in posture and circulating blood volume. Systemic blood pressure is necessarily relatively high because selective tissue

Pressure (mm Hg)

120

Systolic

80 TA

Diastolic 40

Vena cava

Veins

Venules

Capillaries

Arterioles

Arteries

Aorta

0

Fig. 16.1.2.16  Diagram of the changes in pressure as blood flows through the systemic circulation. The total cross-​sectional area of the vessels (TA) increases from 4.5 cm2 to 4500 cm2 in the capillaries. The major resistance to flow is at the arteriolar level, associated with the greatest decrease in blood pressure. Modified and reproduced with permission from Ganong WF (2005). Review of medical physiology, 22nd edn. McGraw-​Hill, New York.

arteriolar tone is used to direct the available systemic blood flow to organs requiring augmented supply of substrate and oxygen as a result of increased work and metabolism; this demands a high tonic arteriolar tone and hence high systemic vascular resistance. Systemic BP = CO × SVR, hence BP is regulated by those factors affecting CO (stroke volume, heart rate), as well as SVR (principally resistance vessel radius). The baroreceptors mediate rapid responses to alterations in aortic pressure, while a variety of hormonal and physical factors regulate the circulating blood volume. Baroreceptors The baroreceptor regulatory system comprises two groups of mechano-​(stretch) receptors, which are widespread in the thoracic cardiovascular system, with high pressure cardiopulmonary baroreceptors located in the systemic arterial system, and low-​pressure volume receptors found in the large systemic veins of the thorax. Of the former, one group is clustered in the carotid sinuses near the bifurcations of the common carotid arteries in the neck, and a second group is located in the arch of the aorta. These respond to an increase in central arterial pressure by the firing of impulses, which pass by the glossopharyngeal (IX) and vagus (X) cranial nerves to the solitary tract nucleus in the medulla and inhibit sympathetic efferent outflow. Efferent impulses from these central connections pass via the right vagus nerve mainly to the sinoatrial node, and via the left vagus mainly to the atrioventricular node. The effect is to decrease the heart rate and the force of atrial contraction. There is also attenuation of sympathetic discharge to arteriolar smooth muscle in the limbs and visceral circulation, resulting in a release of peripheral arteriolar constriction and, therefore, peripheral vasodilatation. Thus, the immediate response to a rise in arterial pressure is slowing of the heart rate, reduced force of atrial contraction, and reduced vascular resistance. The net effect of this negative feedback system is to offset the elevation in blood pressure. Conversely, lowering blood pressure diminishes stimulation of the stretch receptors and reduces afferent traffic to the solitary tract nucleus, resulting in reduced inhibition of sympathetic outflow. There is, then, a quickening of the heart rate together with peripheral vasoconstriction so that the blood pressure increases. The changes in heart rate take place within 1 to 2 s and changes in vasomotor control within 5 to 6 s. Baroreceptor mechanisms effectively modulate the responses of blood pressure to postural change. Additionally, they adapt to maintain the normal circadian variation in blood pressure (see ‘Diurnal variation in autonomic function’, later on in this chapter). They also maintain elevated arterial blood pressure in systemic hypertension: the baroreflex acts around a ‘set point’ of blood pressure, and this is altered in systemic hypertension. Sensory input to the reflex is reduced in disorders of the autonomic nervous system (e.g. autonomic neuropathy), and in the prolonged weightlessness of space flight. Blood volume The circulating blood volume is relatively small, and a large proportion is contained in the veins (capacitance vessels; Fig. 16.1.2.16) so that any change in blood volume will affect venous return and, therefore, cardiac output and blood pressure. When blood volume is large and the veins full, there is little reduction in venous return on standing and cardiac output is maintained. However, when effective blood volume is reduced and the veins are relatively empty,

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on standing there is pooling of blood in the veins of the legs and a reduction in venous return and cardiac output, so that arterial blood pressure falls. Baroreceptor responses become evident within a few beats, the heart rate increases, and cardiac output and blood pressure are restored. Circulating blood volume is kept relatively constant by a combination of mechanisms which include systemic venous stretch (volume) receptors in the great veins and atria, together with the actions of natriuretic peptides, the renin–​angiotensin–​aldosterone system, vasopressin (ADH; AVP), and osmolality. Natriuretic peptides The discovery of secretory granules in the atria of the heart, and the demonstration in 1981 that they produce a natriuretic factor that inhibits the reabsorption of sodium in the distal tubule of the kidney, enhanced understanding of the regulation of blood volume and cardiac performance. Three natriuretic peptides, all containing a similar 17 amino acid ring structure, have subsequently been identified. • Atrial natriuretic peptide (ANP) is a 28 amino acid peptide present in the circulation, and concentrations increase during volume expansion. ANP release is also stimulated by vasoconstrictors, atrial tachycardia, endothelin, and sympathetic stimulation of β-​receptors. The right atrium contains about 2–​4 times as much activity as the left, and release of the hormone is mediated largely by atrial wall distension. The effect is to produce a diuresis and to reduce cardiac and circulating blood volume and hence central venous pressure (i.e. the opposite effect to aldosterone). ANP also has a vasodilator action and opposes the vasoconstricting effects of noradrenaline and angiotensin II (inhibits renin and aldosterone release). • The second natriuretic peptide was identified in brain tissue and is now referred to as B-​type natriuretic peptide (BNP). It is a 32 amino acid peptide, large amounts of which are found in the ventricles of the human heart, and circulating levels are increased in ventricular hypertrophy and cardiac failure. B-​type and ANP have similar actions. The half-​life of B-​type is about twice that of ANP, making it easier and more reliable to measure in blood, whence it may be used to diagnose and monitor heart failure. • The third natriuretic peptide to be identified was C-​type natriuretic peptide. This is distributed widely in tissues, but circulating concentrations are low, hence while ANP and BNP have an essentially endocrine role, CNP is considered to be a paracrine effector. It is released by cardiac endothelium and exerts a local vasodilator effect in complement with the NO and PGI2 systems, thereby constituting at least part of the endothelium-​derived hyperpolarization relaxant activity. It also acts as a paracrine growth/​trophic factor and has anti-​inflammatory activity. In brief summary, natriuretic peptides contribute to the regulation of cardiac and circulating blood volume and of blood pressure. Both B-​type natriuretic peptide and N-​terminal pro-​brain natriuretic peptide (NT-proBNP: an inactive 76 amino acid product of the BNP prohormone, released on BNP cleavage and release) are useful adjuncts to the clinical evaluation of dyspnoeic patients in that levels are elevated when breathlessness is due to cardiac failure. Renin–​angiotensin  system The renin–​angiotensin–​aldosterone (RAA) system, which is both local and systemic, is of major importance in the regulation of

circulating blood volume and the maintenance of normal blood pressure. Enhanced activity of systemic renin and angiotensin increases the production of aldosterone, which promotes reabsorption of sodium by the kidney and expansion of circulating blood volume. All components of the renin–​angiotensin system are distributed widely throughout tissues—​including the brain and the heart—​and increased activation of the system increases the risk of cardiovascular events. Angiotensin II is a potent vasoconstrictor that has a number of additional important actions on the vasculature (Fig. 16.1.2.17). The angiotensin-​converting enzyme (ACE) inhibitors in clinical use diminish angiotensin II production locally and in the circulating blood, resulting in vasodilatation and decreased blood pressure. They may be used to offload the failing heart (decrease afterload). Both local and general effects appear important in mediating the benefits that accrue from the use of these drugs in the management of hypertension and congestive cardiac failure, and in the reduction in rates of recurrence of coronary events in ischaemic heart disease by retarding the rate of atherosclerosis. The mechanisms mediating the latter include antioxidant effects, decreasing oxidative stress by a reduction in the production of potentially damaging free radicals (effects which are independent of blood pressure), anti-​inflammatory effects, and augmentation of the profibrinolytic effects of bradykinin. Angiotensin II receptor-​blocking drugs have also been shown to produce similar outcomes. Regulation of nitric oxide production A recently recognized contribution to endothelial function, which affects the afterload, is related to nitric oxide production, and its inhibition by asymmetric dimethylarginine (ADMA). Asymmetric dimethylarginine is produced by the physiological degradation of methylated proteins. ADMA inhibits the production of nitric oxide, which is derived directly from l-​arginine, present in all cells. ADMA levels are regulated by the balance between its production and its metabolism. The balance may be disrupted in clinical situations, for example, in renal impairment. Reduced renal function increases the level of ADMA and this reduces endothelial dilatation. ADMA concentrations are also increased by low density lipoprotein (both native and oxidized), hence ADMA-​induced blunting of NO-​mediated vasodilatation potentially aggravates dyslipidaemic coronary artery disease. Ventricular volume and afterload Ventricular volume also has a major effect on afterload, as pressure is equal to force per unit area. The force acting radially on the inner surface of the whole ventricle at any time during systole is the product of the intraventricular pressure and ventricular surface area at that time. If the left ventricle is assumed to be a sphere (surface area  =  πd2), the force opposing ejection at any time during contraction is the product of the intracavity pressure and πd2 at that time. Thus, a doubling in left ventricular diameter from a normal value of 5–​10  cm would result in a fourfold increase in the force opposing ejection for the same intracavity systolic pressure; the ventricle would need to develop greatly increased wall tension to overcome that force. Because wall tension developed during systole is the major determinant of myocardial oxygen consumption, the contraction will clearly be much less efficient in the larger heart for the same stroke volume and ejection pressure (stroke work).

16.1.2  Cardiac physiology

Hypotension Decreased sodium delivery Sympathetic stimulation

Renin

Angiotensinogen

Angiotensin I

Chymase

Angiotensin converting enzyme

Angiotensin II

Aldosterone

Increased blood volume

Renal salt and water retention Reduced collagen turnover

Angiotensinases

Angiotensin III

Vasoconstriction, increased blood pressure Vascular smooth muscle cell proliferation Endothelial dysfunction Inhibition of PAI-1 and PAI-2 Myocyte hypertrophy, ventricular remodelling Vasopressin secretion Extracellular matrix formation Renal tubular sodium reuptake

Fig. 16.1.2.17  The renin–​angiotensin system.

During a normal heartbeat, the afterload is greatest at the beginning of ejection (rapid rise in pressure and maximum volume; Fig. 16.1.2.13), but decreases thereafter as the pressure reaches a plateau and then declines as the ventricle becomes smaller (i.e. its diameter increases). There is, therefore, a matching of the afterload to the declining intensity of the contraction as it proceeds to completion (end-​systole), and fibres shorten at a relatively constant rate. This is less obvious in a large heart with low ejection fraction, where the volume change during ejection is a smaller proportion of the total ventricular volume. The end-​diastolic volume is influenced by preload, afterload, circulating blood volume, the inotropic state of the ventricle, heart rate, and neurohumoral influences. It is smaller in the erect than in the horizontal position because of reduced venous return, and it decreases with a moderate increase in heart rate because of an associated positive inotropic effect. The proportion of end-​diastolic volume ejected during systole, the ejection fraction (normal 50–​70%), is a useful index of overall left ventricular function and is easily measured non​invasively by nuclear gated blood-​pool scanning, two-​ dimensional echocardiography, and magnetic resonance imaging techniques. The ejection fraction is found to increase with exercise and with positive inotropic interventions. Values for normal right ventricular ejection fraction are of the same order as those for the left side of the heart.

Role of the sympathoadrenal system in normal and failing hearts Catecholamines have positive inotropic, lusitropic, chronotropic, and dromotropic effects on the normal heart. The inotropic effect of catecholamines on the force of contraction is achieved by a protein kinase-​A (PKA)-​mediated phosphorylation of the L-​type Ca2+ channel, which increases the probability of channels opening when

the cell is depolarized, thus increasing ICa. Positive lusitropism (myocardial relaxation) occurs by a PKA catalytic subunit-​ mediated phosphorylation of phospholamban which inhibits SERCA2 in its hypophosphorylated state (Fig.  16.1.2.3a):  phosphorylated phospholamban does not inhibit SERCA2. The effect of phospholamban phosphorylation is thus to activate SERCA2 and stimulate Ca2+ reuptake into the SR, and augment myofibril relaxation. In addition, PKA phosphorylates cardiac troponin I, and this increases the rate of dissociation of Ca2+ from troponin C, increasing the rate of dissociation of myosin cross-​bridges from actin (i.e. stimulating relaxation). Positive chronotropism is achieved by increasing the frequency of depolarization in the sinoatrial node. Upon stimulation of the sympathoadrenal system, If (generated by HCN channels; Table 16.1.2.2) is activated to depolarize the membrane to the threshold level more rapidly and increase the rate of production of action potentials. The positive chronotropism of the sympathoadrenal system is in part mediated by the binding of PKA-​ derived cAMP to these HCN channels. This shifts their voltage dependence of activation to more depolarized potentials and increases both the rate of channel opening and the maximal current level. The net result is an increased frequency of depolarization and the heart rate increases. Sympathomimetic agents speed conduction in the AV node (positively dromotropic). In heart failure, the myocyte becomes relatively unresponsive to β-​adrenergic agonists, and consequently phosphorylation of the proteins responsible for the control of contractility is diminished. The β1-​adrenergic receptor abundance is downregulated and the expression of proteins which antagonize β1-​receptor signalling is increased, thus the efficacy of β-​agonism is diminished. Many drugs that mitigate heart failure are targeted at the proteins that regulate the inotropic state. There is evidence also that SERCA2 expression is decreased, and this may contribute to the elevated cytoplasmic Ca2+

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concentrations sometimes seen in diastole during heart failure, with slowed cross-​bridge dissociation kinetics. This forms the mechanistic basis for the poor relaxation and diastolic dysfunction characteristic of diastolic heart failure, associated with hypophosphorylation of PKA and PKG sites on cardiac titin (connectin, the giant c30,000 amino acid protein responsible for the passive elasticity of the muscle fibre), and the worsened mechanical function of the heart in this condition. Myocardial function is greatly altered by changes in inotropic state or contractility. Positive inotropic effects are thought to be mediated by activation of excitation–​contraction coupling mechanisms and are associated with an increased influx of calcium ions into cardiomyocytes and a more powerful contraction. Changes in the intensity of excitation–​contraction coupling (homeometric) are independent of the Frank–​Starling (heterometric) mechanism. Increases in the intensity shift the curve upwards and to the left, and decreases shift it downwards and to the right (Fig. 16.1.2.15). With a positive inotropic effect, the force of contraction, however measured, is increased for a given end-​diastolic fibre length and, if the afterload is the same, the initial velocity of fibre shortening is also increased (Fig. 16.1.2.14). In the intact heart there is more complete emptying during systole and hence a lower end-​systolic volume and higher stroke volume. Positive inotropy is achieved by increased PKA/​ cAMP activity, associated with phosphorylation of phospholamban (though with altered lusitropy), sensitization of troponin C to Ca2+, and phosphorylation of L-​type Ca2+ channels. Increased sympathetic stimulation, some drugs, calcium, and an increase in heart rate itself (the staircase or Bowditch phenomenon; post-​ectopic potentiation, see ‘Heart rate’, next section) have positive inotropic effects. An increase in afterload can also cause a small increase in inotropy. Myocardial depressants, such as hypoxia and most anaesthetic drugs, have negative inotropic effects. Increased parasympathetic stimulation produces acetylcholine-​mediated negative inotropic effects that are confined almost entirely to the atria because of the anatomical distribution of vagal cholinergic endings in the myocardium. It is difficult to measure inotropic changes accurately in the human heart because changes in the intensity of excitation–​contraction coupling and changes in the Frank–​Starling relationship, though separate, are nevertheless closely interlinked. The peak rate of change of intraventricular pressure (peak dP/​dt) is a useful index of change in contractility (with changes in the maximum rate of pressure rise (+dP/​dtmax) relating to inotropy and changes in the maximum rate of pressure fall (–​dP/​dtmax) relating to lusitropy), provided that preload, afterload, and heart rate remain constant.

Heart rate Frequency of contraction is the fourth essential determinant of cardiac performance. Normal heart rate is 60–​100 beats/​min, but varies with age. Tachycardia may be defined as HR more than 100 beats/​min and bradycardia as HR less than 60 beats/​min. Heart rate is regulated by intrinsic and extrinsic mechanisms. The former includes the increased heart rate observed with increased venous return and right atrial stretch (Bainbridge reflex). The latter may be considered as either neural (i.e. based on the autonomic supply to the heart through the two cardiac plexi at the base of the heart, with sympathetic stimulation being positively chronotropic and parasympathetic stimulation being negatively chronotropic) or humoral (e.g. catecholamines, thyroid hormones, and calcium

acting as positive chronotropes and muscarinic alkaloids and potassium acting as negative chronotropes). Heart rate during rest and exertion may vary from 45 to 200 beats/​min in the healthy young adult. As changes can occur within seconds, an increase in heart rate is the usual and most effective way of producing a rapid increase in cardiac output. It plays the major role in the response to exercise, during which stroke volume does increase (more so in athletes and when in the erect, rather than the supine, position) but the changes are less marked than those of rate. In addition, an increase in contraction frequency itself produces a positive inotropic effect, whereby the force of contraction increases and reaches a new steady state within a few beats. This is termed the ‘positive staircase’, Treppe, or Bowditch effect. It may be a consequence of an augmented movement of calcium ions into myocardial cells with increased frequency of action potentials, combined with diminished time for outward movement of calcium between beats. More forceful contractions also follow premature beats—​the phenomenon of post-​extrasystolic potentiation—​and the mechanism is probably the same. The extrasystole occurring prematurely is a weak contraction because of decreased filling time and an uncoordinated activation of the ventricle when the ectopic focus is within the ventricle. The next beat is delayed because of the refractory period of the extrasystolic beat, but is a more powerful contraction because of increased filling time and ventricular volume, and increased contractility. Calcium-​dependent changes similar to those of the Bowditch effect are probably responsible for the latter, and the increased contractility is independent of volume loading effects. Recently it has become clear that intrinsic circadian clocks are involved in the control of heart rate, with time-​of-​day dependent oscillations in clock gene expression. The cardiomyocyte circadian clock influences many myocardial processes, including ion channels.

Coronary blood flow Coronary blood flow accounts for about 4% of the cardiac output. The heart extracts most (70%) of the oxygen carried in the coronary circulation under resting conditions, the arteriovenous difference for oxygen across the heart being about 110 ml/​litre, while that for the whole body is only about 40 ml/​litre under resting conditions. Therefore, large increases in myocardial oxygen requirements must be met largely by increases in coronary blood flow, and this may increase five-​or sixfold during strenuous exercise. The greater part of this flow is to the left ventricle, of which at least two-​thirds occurs during diastole because of the throttling effect systole has on myocardial perfusion. The main coronary arteries are on the superficial (epicardial) surface of the heart, and because of this, and the hindrance to coronary flow during systole, the subendocardial region of the left ventricle is more vulnerable to perfusion deficits in relation to oxygen need than the outer two-​thirds of the muscle wall. Despite these mechanical problems, flow is normally evenly distributed throughout the myocardium so that when regional coronary blood flow is measured experimentally using injected radioactive microspheres (in dogs), the ratio of endocardial to epicardial flow is approximately unity. In fact, the inner layers of the heart probably receive slightly more blood (up to 10%) than the outer layers. This is consistent with the subendocardium developing more tension than

16.1.2  Cardiac physiology

the subepicardium, and is evidence for a greater rate of myocardial oxygen consumption in the inner layers. Myocardial oxygen requirements and coronary blood flow are finely adjusted and matched, with coronary vascular resistance subject to autoregulation.

The nervous system and the heart The heart is richly supplied with sympathetic adrenergic nerves, whose terminals reach atrial and ventricular muscle fibres and impinge upon all pacemaker tissue, including the sinoatrial and atrioventricular nodes and Purkinje fibres. Sympathetic stimulation leads to an increase in myocardial contractility and heart rate, and in the rate of spread of the activation wave through the atrioventricular node and the Purkinje system. This is mediated by local noradrenaline release, which interacts with β-​adrenergic receptors. The key elements in these regulatory mechanisms are calcium ions and cAMP. The activated β-​receptor increases adenyl cyclase activity and the conversion of ATP to cAMP. Non​adrenergic non​cholinergic cotransmitters have recently been isolated and recognized as important adjuncts to autonomic efferent transmission. These include non​peptides such as ATP, dopamine, and (at least in the enteric system) GABA and 5-hydroxytryptamine (5-​HT), but also peptides. Peptide cotransmitters released with noradrenaline and acetylcholine have now been isolated and shown to influence autonomic function, and include neuropeptide Y (NPY), GnRH, and substance P. Neuropeptide Y is a peptide of 36 amino acids that is colocated with noradrenaline in most sympathetic nerves and is released with sympathetic stimulation. It is a powerful pressor agent with direct arteriolar vasoconstrictor action and also potentiates the pressor action of noradrenaline. The distribution of parasympathetic fibres is much more limited in the heart, being confined to the sinoatrial and atrioventricular nodes and the atria, with few, if any, fibres reaching the ventricles in humans, except perhaps in anatomical relation to coronary arteries and Purkinje tissue. The effects of parasympathetic nerve stimulation are mediated by local acetylcholine release, which slows the heart rate and speed of conduction through the atrioventricular node and Purkinje tissue, and depresses atrial contractility. The negative inotropic effects are associated with a lowering of the concentration of intracellular cAMP. The effect of the nervous system on the heart at any one time is the sum of the activities of these two opposing control systems. They usually vary reciprocally. Under resting conditions, vagal inhibitory effects predominate, maintaining a slow heart rate, there being virtually no sympathetic outflow. With exercise, there is withdrawal of vagal activity and an increase in sympathetic outflow. Afferents from stretch receptors in the carotid sinus and aortic arch—​the baroreceptors—​also have a considerable effect on cardiac performance, this effect being mediated via the adrenergic nervous system and vagal withdrawal. A fall in blood pressure reduces stretching in the carotid sinus and inhibitory afferent traffic so that the sympathetic outflow increases. As a consequence of this combined vagal and sympathetic effect, there is a quickening of the heart rate within one or two beats, a positive inotropic effect, and also a constriction of systemic veins and arterioles that increases preload and afterload. Elevation of pressure in the carotid sinus has the reverse effect. In

cardiac failure, there is reduced variability in heart rate due to these autonomic mechanisms as there is then a predominance of adrenergic activity. There are also mechanoreceptors in all four chambers of the heart (identified in dogs) and in the coronary vessels, which give rise to depressor reflexes. Their clinical relevance is uncertain, but they may contribute to the bradycardia and hypotension occurring in some patients with acute myocardial infarction—​in particular to the syncope that patients with critical aortic stenosis may experience with the onset of exercise when there is sudden left ventricular distension. Vagal afferents from reflexogenic areas in the infarcting left ventricle may be responsible for the bradycardia, gastric distension, nausea, and vomiting which frequently occur with the onset of inferior or posterior myocardial infarction, but not usually of anterior infarction, which is generally associated with a marked increase in sympathetic activity. The cardiac receptors connected to afferent fibres running in cardiac sympathetic nerves, however, are very important because they are responsible for the perception of cardiac pain. Receptors have also been identified (in animals) at the junction of pulmonary veins with the atrial wall. These respond to mechanical distension with increased sympathetic outflow to the sinus node and inhibition of secretion of antidiuretic hormone from the posterior lobe of the pituitary gland. The result is a quickening of the heart rate and diuresis.

Autonomic efferent activity The autonomic outflow to the heart is controlled by multiple integrative sites within the central nervous system, with complex interactions between afferent and central inputs. Autonomic responses are mediated through the suprapontine and bulbospinal pathways—​ both those arising ‘reflexively’ and those arising from various types of volitional or central ‘command’. Nevertheless, intrinsic mechanisms are sufficient for adequate cardiac function in the absence of autonomic control, as prolonged survival after cardiac transplantation has shown. But in the denervated heart, dependent on intrinsic and humoral mechanisms, there is blunting of the normally rapid physiological adjustments mediated by the autonomic nervous system. Diurnal variation in autonomic function Variations in vascular tone and control of blood pressure and of hormone secretion and platelet function occur in a predictable way throughout the 24-​h cycle. In normal subjects, there is a circadian rhythm of blood pressure changes that is not seen in patients after cardiac transplantation, who have denervated hearts. There is a decline in both blood pressure and heart rate at night, and increases in both soon after wakening. This is due to a normal adrenergic surge in the early morning, which results in increased vascular tone and blood pressure. Increased forearm vascular resistance in the morning, with a reduction in the afternoon and evening, can be clearly identified in humans by assessing responses to α-​adrenergic blockade. It is likely that this occurs in coronary vessels as well. Measurable early morning increases in circulating catecholamines and in the propensity for platelets to aggregate can also be documented. The circadian rhythm of autonomic function is correlated with a significant tendency for myocardial infarction and sudden cardiac death to occur more frequently in the morning, soon after wakening.

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There is also an increase in the occurrence of angina pectoris in the early morning, independent of the level of physical activity.

Exercise and the heart: Cardiac reserve The heart responds to exercise with an increase in cardiac output, and values of 30 litres/​min may be achieved in a trained athlete. Exercising muscles extract more oxygen from the blood, but the response of the cardiac output is the principal determinant of delivery of oxygen to tissues and is the limiting factor for aerobic exercise. The cardiac response to exercise involves all the mechanisms already discussed. Interaction within the central nervous system between higher and autonomic centres augments sympathetic discharge, and there is a withdrawal of vagal parasympathetic outflow. The heart rate increases immediately, and redistribution of peripheral flow increases venous return and preload (increased end-​diastolic volume). There is venoconstriction, particularly in the large-​volume splanchnic circulation, and vasoconstriction and increased oxygen extraction in inactive parts. In active parts, there is vasodilation. This is most evident in the vascular beds of the exercising skeletal muscles and of the heart itself. The overall effect is a marked lowering of total peripheral vascular resistance, which reduces afterload and encourages greater systolic emptying of the left ventricle (decreased end-​systolic volume). Stroke volume increases during exercise in the upright position. During light to moderate exercise (running or cycling), for up to about 80% of maximum exercise capacity there is an almost linear relationship between work intensity and heart rate response, cardiac output, and oxygen uptake. With further exercise, the heart rate and cardiac output responses level off while additional increases in oxygen consumption occur by increased oxygen extraction and a greater widening of the arteriovenous difference for oxygen. The venous return increases in relation to the elevated cardiac output. Vasodilation in the working muscles that receive the bulk of the redirected blood permits high flow rates into the systemic venous capacitance vessels. Because of adrenergically mediated venoconstriction, the capacity of this system is reduced, so that blood moves rapidly into the right atrium. Venous return is also enhanced by the pumping action of the rhythmically contracting working muscles, by a decrease in intrathoracic pressure with forced inspiration, and by an increase in intra-​abdominal pressure. The augmented pulmonary blood flow results in only slight increases in pulmonary artery pressure because of the distensibility of the large pulmonary arteries, an increased area of the pulmonary capillary bed due to the recruitment of more capillaries, and the low resistance offered by the normal pulmonary circulation (see Table 16.1.2.3), that is, the response of the pulmonary vasculature to increased RV output (CO) and increased PA pressure is to dilate pulmonary blood vessels and decrease pulmonary vascular resistance. Since the pulmonary circulation is in series with the right and left sides of the heart, this is a vital mechanism to permit the increased CO to traverse the lungs and explains why the RV does not need to maintain such high pressures as the LV, and hence is much thinner. The elevated cardiac output and larger stroke volume result in increased systolic blood pressure and pulse pressure, even though the afterload itself is reduced. Enhanced neurohumoral activity from adrenergic stimulation of the heart and the adrenal glands (increased circulating adrenaline and noradrenaline) effect positive inotropic changes, to which tachycardia also contributes because of the

Bowditch effect. There is a shift in the Frank–​Starling relationship to the left, increased speed and force of cardiac contraction, and elevated ejection fraction and stroke volume. Peak +dP/​dt is increased, and there is a rapid rise in coronary blood flow to meet myocardial oxygen requirements that increase linearly with the product of systolic blood pressure and heart rate. However, the increased heart rate is achieved by a shortened diastolic interval, leaving less time for coronary flow to occur. This may become limiting at very high heart rates. During moderate exercise, these changes together result in a decreased or unaltered end-​diastolic volume and decreased end-​systolic volume. With severe exercise, end-​diastolic dimensions and end-​diastolic fibre length are slightly increased and the Frank–​ Starling mechanism then operates and further augments the force of contraction. The haemodynamic and ventilatory responses evoked by an increase to a new steady workload take about 2–​3 min to equilibrate and adjust oxygen supply to the greater demand. Protocols for exercise testing are therefore usually based on work increments at 3-​ min intervals to allow time for a new ‘steady state’ to occur (e.g. in the standard Bruce exercise protocol). A steady state becomes progressively more difficult to maintain as maximal exercise capacity is approached. Glycogen is used by the working skeletal muscles as a source of stored energy, and the anaerobic metabolism which ensues produces lactic acidosis and thereby further increases ventilation. As all cardiopulmonary transport mechanisms reach maximum levels, shortness of breath, fatigue, and muscle pain become limiting symptoms; motivation then becomes a determinant of the duration of exercise. Ageing reduces the efficacy of cardiopulmonary transport mechanisms and, hence, exercise capacity. The heart rate response at peak exercise reflects this. In healthy individuals aged 20 years it is about 200 beats/​min, and at 65 years about 170 beats/​min. When exercise stops, the cardiopulmonary and metabolic changes return rapidly to resting levels, the rate following an exponential pattern in the first few minutes; the excretion and metabolism of lactate and other substances, and the dissipation of heat generated take longer (time constant of about 15 min or more). Reduced circulatory function slows the recovery rate. Training effects Regular exercise to about 60% of maximal heart rate for 20–​30 min three times a week is the minimum requirement for improved effort tolerance due to a training effect. The resting heart rate becomes slower, while the cardiac output is maintained by an increased end-​diastolic volume and ejection fraction, and therefore stroke volume. In a ‘trained’ exercising individual, there is a reduced heart rate response to a standard submaximal workload, and systemic blood flow is more effectively distributed away from visceral and skin circulations to working muscles. Changes in muscle mitochondria permit increased oxygen consumption. There is suggestive animal evidence that prolonged endurance training increases the calibre of coronary arteries and enlarges capillary surface area relative to cardiac muscle mass. Myocardial protein synthesis increases. Adrenergic mechanisms appear to be involved in mediating this trophic response. Rhythmic exercise (e.g. running) and isometric exercise (e.g. weightlifting) have different physiological effects. The blood pressure rises disproportionately during the latter. The mechanisms are partly reflex and partly mechanical from the contracting

16.1.2  Cardiac physiology

muscles. Isometric exercise training is not recommended for cardiac patients because of the increased afterload it imposes. Regular exercise has other effects:  it increases feelings of well-​ being and lowers blood pressure in normotensive and mildly hypertensive subjects. There are also diverse exercise-​related hormonal changes, including increased insulin sensitivity and the reduction of glucose-​stimulated insulin secretion—​of particular relevance to patients with type 2 diabetes. Regular exercise also improves the availability of nitric oxide, with its important vascular effects. These are considered elsewhere. To summarize, changes in the four essential determinants of cardiac function—​preload, afterload, heart rate, and contractility—​ combine to augment cardiac output and oxygen delivery during exercise. Measurement of the cardiovascular response to exercise is essential for the objective assessment of cardiac function.

FURTHER READING Abdel-​Aleem S, Lowe JE (2012). Cardiac metabolism in health and disease. Kluwer Academic Publishers, New York, NY. Bers DM (2001). Excitation-​contraction coupling and cardiac contractile force, 2nd edition. Kluwer, Dordrecht. Durgan DJ, Young ME (2010). The cardiomyocyte circadian clock: emerging roles in health and disease. Circ Res, 106, 647–​58. Ganong WF (2005). Review of medical physiology, 22nd edition. McGraw-​Hill, New York. Herring N, Paterson DJ (2018). Levick’s introduction to cardiovascular physiology, 6th edition. CRC Press, Boca Raton, FL. Houser SR, Margulies KB (2003). Is depressed myocyte contractility centrally involved in heart failure? Circ Res, 92,  350–​8.

Ieda M, Zimmerman W-​H (2017). Cardiac regeneration (cardiac and vascular biology). Springer, New York, NY. Kaestner L (2012). Calcium signalling: approaches and findings in the heart and blood. Springer Science Media, Berlin. Kardami E, et al. (2010). Cardiac cell biology. Springer Science Media, Berlin. Katz AM (2006). Physiology of the heart, 4th edition. Lippincott Williams and Wilkins, Philadelphia, PA. Ko Y-​S, et al. (2004). Three-​dimensional reconstruction of the rabbit atrioventricular conduction axis by combining histological, desmin, and connexin mapping data. Circulation, 109, 1172–​9. Libby P, et al. (ed.) (2008). Braunwald’s heart disease: a textbook of cardiovascular medicine, 8th edition. Saunders Elsevier, Philadelphia, PA. Opie LH (2013). Stunning, hibernation and calcium in myocardial ischemia and reperfusion. Kluwer Academic Publishers, Boston, MA. O’Rourke B (2010). Be still, my beating heart: never! Circ Res, 106, 238–​9. Pappano AJ, Wier WG (2019). Cardiovascular physiology, 11th edition. Mosby Physiology Series, Elsevier, Philadelphia, PA. Severs NJ (2000). The cardiac muscle cell. BioEssays, 22, 188–​99. Severs NJ, et al. (2004). Gap junction alterations in human cardiac disease. Cardiovasc Res, 62, 368–​77. Solaro RJ, Tardiff JC (2013). Biophysics of the failing heart: physics and biology of heart muscle. Springer Science Media, Berlin. Willis MS, Homeister JW, Stone J (2014). Cellular and molecular pathobiology of cardiovascular disease. Academic Press–​Elsevier, Amsterdam. Young ME (2006). The circadian clock within the heart: potential influence on myocardial gene expression, metabolism, and function. Am J Physiol Heart Circ Physiol, 290,  1–​16. Zipes DP, Jalife J (2013). Cardiac electrophysiology, 6th edition. Saunders Elsevier, Philadelphia, PA.

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16.2

Clinical presentation of heart disease

CONTENTS 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

16.2.1  Chest pain, breathlessness, and fatigue

low sensitivity; basal inspiratory crackles are suggestive of pulmonary oedema but have low sensitivity and specificity.

Other considerations The cardiovascular history routinely includes assessment of risk factors and those aspects of the patient’s past medical history that make cardiovascular disease more likely. The presence of numerous risk factors may, on occasion, prompt the physician to proceed to further investigation even in the face of a relatively unconvincing history. Most diagnoses are made on the basis of patient history, and the physician is always compelled to return to the initial history and examination to put the findings of any investigations into context and to plan therapy appropriate for the individual patient.

Jeremy Dwight Introduction ESSENTIALS Chest pain, breathlessness, and fatigue are common diagnostic challenges, with a broad differential diagnosis that includes several life-​threatening pathologies.

Chest pain The most reliable discriminating feature for angina, as opposed to other causes of chest pain, is its constricting nature, a fixed and predictable relationship to exertion, and that is relieved, within a few minutes, by rest or glyceryl trinitrate. The pain in acute coronary syndromes is similar to exertional angina, but usually more severe and usually reaches maximal intensity over the course of a few minutes: pain reaching its maximum intensity instantaneously suggests an alternative cause. Specific clues in history and physical examination are critical for diagnosis of aortic dissection and pericarditis.

Breathlessness and fatigue Most patients find it impossible to distinguish between cardiac and pulmonary causes of dyspnoea. In the diagnosis of left ventricular failure the most helpful features in the history are exertional breathlessness, orthopnoea, paroxysmal nocturnal dyspnoea, or a history of myocardial infarction. A  displaced apex on palpation is helpful and relatively specific; a third heart sound has a high specificity but

The symptoms of chest pain, breathlessness, and fatigue present a frequent diagnostic challenge in the outpatient and acute medical departments, as well as the emergency department. They have a broad differential diagnosis that includes several life-​threatening pathologies. As with all clinical presentations, the initial presenting symptom will prompt a differential diagnosis that the physician must narrow down, using a thorough history, to one or two possibilities. The onset, nature, and precipitating causes of symptoms need to be accurately defined, with carefully directed questions used to assess their relevance. The process involves a partnership between the patient and their doctor and is enhanced by explaining the reasoning behind the questions asked and their relevance to making a diagnosis. In this way history-​taking is a useful opportunity to assist the patient to a better understanding of their symptoms and to improve their compliance with any management plan. The cardiovascular history routinely includes assessment of risk factors such as age, occupation, diabetes, hypertension, smoking, hypercholesterolaemia, drugs (both therapeutic and recreational), and a family history. It should also record those aspects of the patient’s past medical history that make cardiovascular disease more likely, such as stroke, transient ischaemic attack, claudication, vascular surgery, renal disease, or connective tissue disease. The presence of numerous risk factors may, on occasion, prompt the

16.2.1  Chest pain, breathlessness, and fatigue

physician to proceed to further investigation even in the face of a relatively unconvincing history. Armed with a differential diagnosis obtained from the history, the physical examination is directed to identifying further supporting evidence. In isolation, however, there are surprisingly few examination findings that will provide a definitive diagnosis. The cardiologist has a large armamentarium of diagnostic tools available to assist in making a diagnosis—​ ECG, echocardiography, coronary angiography, MRI, and so on. These may appear to threaten to displace history-​taking with the allure of high-​definition images and impressive software. However, most diagnoses are made on the basis of patient history, and the physician is always compelled to return to the initial history and examination to put the findings of any investigations into context and to plan therapy appropriate for the individual patient.

Chest pain Chest pain accounts for up to 20% of all medical consultations and is one of the commonest presentations to the emergency department. In the community setting musculoskeletal or gastrointestinal causes are most common, whereas cardiac causes are more frequent in the emergency department (Table 16.2.1.1).

The circumstances of chest pain Chest pain on exertion: Angina pectoris They who are afflicted with it are seized while they are walking (more especially if it be uphill and soon after eating) with a painful and most disagreeable sensation of the breast, which seems as if it would extinguish life, if it were to increase or continue, but the moment they stand still, all this uneasiness vanishes. (Heberden, 1768) Unfortunately for the physician, the descriptors used by patients with angina are highly variable and include burning, heaviness,

tightness, pressure, squeezing, aching, and strangling. Patients may not describe pain and it is preferable to ask for symptoms of discomfort in the chest. Most patients with angina recognize the pain as being worrying or serious. The location of the discomfort is usually retrosternal and may radiate to the arms, neck, and jaw (Fig. 16.2.1.1). Less commonly, the pain may be felt in the back and upper abdomen. The most reliable discriminating feature for angina as opposed to other causes of chest pain is a fixed and predictable relationship to exertion that is relieved within a few minutes by rest or glyceryl trinitrate (nitroglycerin). The discomfort characteristically occurs when walking up an incline and compels the patient to stop. In some cases, the characteristic symptoms occur at the start of exertion and then ease, which is termed ‘walk-​through angina’. Surprisingly, patients may still be able to perform substantial anaerobic exercise without limitation. Angina is often worse in cold weather, in a cold wind, or after eating. Occasionally the pain is only present at the start of the day, when the patient is shaving or brushing their teeth. Symptoms of chest discomfort occurring after rather than during exertion, or which are present continuously throughout the day, are not due to angina. Taking a careful history of the time course of relief with rest and glyceryl trinitrate is important. Many patients mistakenly report a response to glyceryl trinitrate when their pain has taken more than 15 min to resolve, but a response to glyceryl trinitrate is only helpful diagnostically when it occurs within a few minutes. Oesophageal spasm also responds to glyceryl trinitrate and may produce similar discomfort, but the pain is not related to exertion and is nearly always associated with symptoms of reflux. The three key clinical features of anginal pain are that it is (1) a constricting discomfort in the front of the chest, neck, shoulders, jaw, or arms; (2) precipitated by exertion; (3) relieved by rest or GTN within about 5 min. These features are used to identify patients with typical angina (all three features), atypical angina (two features), or non​cardiac pain (one or none of these features). In the United Kingdom this classification has been incorporated into National Institute for Health and Care Excellence (NICE) guidelines for management of recent onset chest pain. Chest pain at rest

Table 16.2.1.1  Cardiovascular causes of chest pain and differential diagnoses Frequency as cause of chest pain

Cardiovascular

Non​cardiovascular

Common

Angina

Oesophageal reflux

Acute coronary syndromes

Pleurisy

Pericarditis

Musculoskeletal, including osteochondritis

Pulmonary embolism Syndrome X Uncommon

Valvular heart disease

Pneumothorax

Pulmonary hypertension

Herpes zoster

Aortic dissection

Peptic ulcer disease

Myocarditis

Pulmonary or mediastinal tumours

Takotsubo cardiomyopathy

Mediastinitis

Chest pain due to ischaemia that occurs at rest has a broader differential diagnosis. The important life-​threatening differential diagnoses are myocardial infarction, aortic dissection, and pulmonary embolism. Rest pain due to angina without infarction is usually accompanied by a history of exertional angina, but there are a few exceptions. Arrhythmias (e.g. paroxysmal atrial fibrillation) may precipitate angina at rest and a history of palpitations should be sought in those with unpredictable symptoms. Emotional stress may also precipitate an attack. An important example of this is Takotsubo cardiomyopathy, where chest pain is accompanied by a characteristic pattern of left ventricular damage in the absence of significant coronary disease. Nocturnal angina may be precipitated by nightmares or the onset of pulmonary oedema, but a history of exertional angina is nearly always present. Where nocturnal chest pain is present in the absence of exertional symptoms, a history of acid reflux (relief on sitting up or with antacids, and discomfort on drinking hot fluids) should be sought. Reflux symptoms are common and may coexist with angina, and the patient may find it impossible to differentiate between the two.

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RETROSTERNAL Myocardial ischaemic pain Pericardial pain Oesophageal pain Aortic dissection Mediastinal lesions Pulmonary embolization

SHOULDER Myocardial ischaemic pain Pericarditis Subdiaphragmatic abscess Diaphragmatic pleurisy Cervical spine disease Acute musculoskeletal pain Thoracic outlet syndrome

INTERSCAPULAR Myocardial ischaemic pain Musculoskeletal pain Gallbladder pain Pancreatic pain

ARMS Myocardial ischaemic pain Cervical/dorsal spine pain Thoracic outlet syndrome

RIGHT LOWER ANTERIOR CHEST Gallbladder pain Distention of the liver Subdiaphragmatic abscess Pneumonia/pleurisy Gastric or duodenal penetrating ulcer Pulmonary embolization Acute myositis Injuries

EPIGASTRIC Myocardial ischaemic pain Pericardial pain Oesophageal pain Duodenal/gastric pain Pancreatic pain Gallbladder pain Distention of the liver Diaphragmatic pleurisy Pneumonia

LEFT LOWER ANTERIOR CHEST Intercostal neuralgia Pulmonary embolization Myositis Pneumonia/pleurisy Splenic infarction Splenic flexure syndrome Subdiaphragmatic abscess Precordial catch syndrome Injuries

Fig. 16.2.1.1  Differential diagnosis of chest pain according to location and radiation. Serious intrathoracic or subdiaphragmatic diseases are usually associated with pains that begin in the central or left anterior chest, left shoulder or upper arm, the interscapular region, or the epigastrium. The scheme is not all inclusive (e.g. intercostal neuralgia occurs in locations other than the left lower anterior chest area). From Miller AJ (1988). Diagnosis of chest pain. New York, Raven Press (LWW), p. 175.

Particular causes of chest pain Acute coronary syndromes The term ‘acute coronary syndrome’ encompasses myocardial infarction and unstable angina, conditions which are usually caused by a common pathology—​the rupture or erosion of an atheromatous plaque. Because of the need for rapid assessment and treatment, the ECG is often used to triage patients with chest pain on admission to the emergency department. Where there are classic features of ST elevation infarction, treatment is commenced with thrombolysis or angioplasty after a brief confirmatory history (see Chapter 16.13.4). However, patients with ST elevation represent only a small fraction of those presenting with chest pain, and those without ST elevation present the greater diagnostic challenge. Some will simply have dyspepsia or musculoskeletal pain, whereas those at the other end of the spectrum will be at imminent risk of myocardial infarction. The history has two important roles: first to establish whether the pain is cardiac, and secondly to contribute to the risk stratification process that determines the nature and time course subsequent therapy and investigation. The character of pain in acute coronary syndromes is similar to exertional angina, but usually more severe. It usually reaches maximal intensity over the course of a few minutes. Pain reaching its maximum intensity instantaneously suggests an alternative cause, in particular, aortic dissection. The patient should be asked to describe exactly what they were doing at the onset of the pain: sudden onset during a specific movement will suggest a musculoskeletal origin. The classical description of the pain of myocardial infarction is of a heavy, crushing, or constricting pain. In comparison to angina

the duration of pain in myocardial infarction is longer (>15 min), and with increasing duration myocardial infarction is more likely, but the pain rarely lasts more than a few hours. Infarction is more likely to be associated with systemic symptoms (breathlessness, sweating, nausea, and vomiting) and does not respond to glyceryl trinitrate. About one-​half of patients will have a history suggestive of worsening exertional angina, or short-​lived episodes of chest pain at rest before presentation. The pain of an acute coronary syndrome usually discourages the patient from attempting any exertion and does not improve with exercise. Although the history alone cannot definitively rule out myocardial infarction, it can be used to assess the probability of this condition (Box 16.2.1.1). During the examination, the patient should be asked to map out the distribution of the pain. Pain radiation to both arms is suggestive of acute coronary syndrome. Highly localized pain of less than a few centimetres in distribution is unlikely to ischaemic in origin. Tenderness on palpation of the chest wall or pain exacerbated by rotation of the thorax or passive movements of the arms or neck suggest musculoskeletal pain but does not infallibly rule out cardiac ischaemia. Components of the history, the ECG, and markers of myocardial damage are used in non-​ST elevation acute coronary syndromes to determine the risk of subsequent events in the TIMI (Thrombolysis in Myocardial Infarction) risk score (Table 16.2.1.2) and a scoring system based on the GRACE (Global Registry of Acute Coronary Events) registry. Great emphasis has been placed on the use of troponin estimation in determining the risk of subsequent events in these patients and this is undoubtedly a useful tool. However, in the absence of definitive ECG changes or troponin rise, the patient may still score 5 on the TIMI risk score from the history alone, giving

16.2.1  Chest pain, breathlessness, and fatigue

Box 16.2.1.1  Risk stratification for acute myocardial infarction and acute coronary syndrome according to components of the chest pain history Low risk: • Pain that is pleuritic, positional, or reproducible with palpation, or is described as stabbing Probably low risk: • Pain not related to exertion or that occurs in a small inframammary area of the chest Probably high risk: • Pain described as pressure, is similar to that of a prior myocardial infarction or worse than prior anginal pain, or is accompanied by nausea, vomiting, or diaphoresis High risk: • Pain that radiates to one or both shoulders or arms or is related to exertion

a risk of 25% of major cardiovascular adverse events in the next 14 days. For further discussion, see Chapter 16.13.4. There are no specific findings on cardiovascular examination in acute coronary syndromes. In the context of severe coronary disease the patient may present with the clinical features of left ventricular failure (see ‘Particular causes of breathlessness’) or cardiogenic shock. Features of increased sympathetic tone, pallor, tachycardia, and sweating are often present in infarction, but are also features of all causes of severe chest pain. A pansystolic murmur may indicate the development of a ventricular septal defect or papillary muscle rupture and severe mitral regurgitation, complications which are usually associated with haemodynamic compromise and left ventricular failure. The presence of peripheral vascular disease increases the probability of coexistent coronary disease and the patient should be examined for carotid, femoral, and renal bruits and an abdominal aortic aneurysm. The foot pulses should also be assessed. The presence of neck and/​ or chest wall tenderness will point to alternative diagnoses such as cervical spondylopathy, costochondritis, or nerve entrapment. Hypochondrial tenderness suggests a gastrointestinal cause (e.g. peptic ulcer disease, pancreatitis, or gallstones). Table 16.2.1.2  TIMI risk score for non-​ST elevation acute coronary syndromes Clinical feature

Points

Age ≥65 years

1

At least three risk factors for coronary diseasea

1

Prior demonstration of significant coronary artery stenosis

1

ST deviation on ECG

1

Severe anginal symptoms (e.g. ≥2 anginal events in the last 24 h)

1

Use of aspirin in previous 7 days

1

Elevated cardiac markers (e.g. troponin)

1

a Family history, hypertension, hypercholesterolaemia, diabetes, current smoking. From Antman EM et al. (2000). The TIMI risk score for unstable angina/​non-​ST elevation MI: a method for prognostication and therapeutic decision making. JAMA, 284, 835–​42.

Coronary spasm, Prinzmetal’s angina, syndrome X, atypical angina Patients with unpredictable angina due to the occurrence of coronary spasm, either in the context of coronary disease or with normal coronary arteries, have been described. The diagnosis should only be considered in the patient with a classical description of ischaemic chest pain that usually responds rapidly to glyceryl trinitrate, preferably in the context of ECG changes (ST elevation in the case of Prinzmetal’s angina). Cocaine abuse is a frequent cause of this presentation to the emergency department. Syndrome X, as its name suggests, is poorly understood. This label (whether it can properly be called a diagnosis is debatable) is often attached to patients with cardiac-​sounding chest pain and a normal angiogram. This finding is more common in women. The pain often has features atypical of angina. It is often of submammary location or radiation, and precipitating factors are highly variable. This diagnosis should only be considered after other causes of chest pain have been carefully excluded, since it may expose the patient to a lifetime of inappropriate treatment and anxiety. The term ‘atypical chest pain’ is meaningless (especially for the patient) and is best avoided. There are, however, many patients for whom a confident diagnosis cannot be made. Serious pathology can be excluded and the patient reassured that they have an excellent prognosis. It is better to leave the diagnosis at ‘chest pain-​type symptom’ than to inappropriately label the patient as having ‘atypical angina’ or syndrome X.

Aortic dissection Aortic dissection is a rare but important cause of chest pain: up to one-​half of all patients with an untreated proximal aortic dissection die within 48 h. The pain of aortic dissection is very sudden in onset, is usually described as tearing or ripping, and the patient may report that it migrates from the front to the back of the chest. There should be a particularly high index of suspicion when chest pain is associated with neurological features such as hemiplegia or paraplegia due to involvement of the carotid vessels and spinal arteries, but these are present in less than 20% of cases. Risk factors in the history include hypertension, Marfan syndrome, a bicuspid aortic valve, previous aortic valve replacement, cocaine usage, and the third trimester of pregnancy. Of the clinical features (see Box 16.2.1.2) aortic pain (as described earlier), loss of

Box 16.2.1.2  Clinical features associated with aortic dissection • Sudden onset tearing, ripping chest pain that migrates to the back • Loss of peripheral pulses • Blood pressure difference more than 20 mm Hg between arms • Hemiparesis • Paraparesis • Diastolic murmur • Pleural effusion (usually left-​sided) • Hoarseness • Horner’s syndrome • Bilateral testicular tenderness • Pulsatile sternoclavicular joint • Superior vena cava obstruction • Pulsus paradoxus (with pericardial tamponade)

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peripheral pulses, blood pressure difference between the two arms (>20 mm Hg), and mediastinal widening on the chest radiograph are the most helpful. In the absence of these features the incidence of aortic dissection is less than 5%. The absolute level of blood pressure in unhelpful in discriminating aortic dissection from other causes of chest pain. Pericarditis Pericarditis occurs most commonly following a myocardial infarction or viral infection. The patient may describe a preceding viral illness with fever and cough. The pain is usually sharp and precordial. The onset is often sudden. It is characteristically worse on inspiration and relieved by sitting up and leaning forward, and it can be accompanied by classic pleuritic pain. A less typical description occurs when a pericardial effusion has developed and the pain arises from pericardial distension, when the pain may be a dull retrosternal ache or pressure. Radiation of pericarditic pain occurs to all those areas associated with myocardial infarction, but radiation to the trapezius ridges is pathognomonic of the diagnosis. The patient is usually well and not compromised haemodynamically (except where there is pericardial tamponade). Clinical examination may initially be normal. A pericardial friction rub heard over the sternum may be positional and appear and disappear within hours. Repeated examination may be helpful, including auscultation of the patient lying flat in expiration. The ECG finding of concave ST

elevation in multiple lead is helpful, but ECG findings are equivocal or normal in 40–​50% of cases.

Breathlessness and fatigue Breathlessness (or dyspnoea, derived from Greek words meaning painful or difficult breathing) is the endpoint of a variety of pathologies and is mediated by a series of neural pathways, the sensory inputs of which originate in the lungs, chest wall, and peripheral and sensory chemoreceptors (see Fig. 16.2.1.2). Patients may describe the sensation of breathlessness as tightness, wheeze, ‘inability to get enough air’, sighing, choking, or suffocating. Heart failure, asthma, and chronic obstructive airways disease account for about three-​ quarters of hospital admissions with breathlessness in industrialized nations. Symptom clusters have been described for these pathologies, but most patients find it impossible to distinguish between cardiac and pulmonary causes of dyspnoea. The time course of the illness is an important aid to the diagnosis in patients with dyspnoea but must be interpreted in the context of the patient’s day-​to-​day activities. Even when the disease progresses gradually the patient may report a recent onset of symptoms because they have (often subconsciously) adapted their lifestyle over the course of many months. This is particularly true of patients with chronic heart failure.

Afferent signals

Efferent signals Motor cortex

Effort

Chemoreceptors

Sensory cortex Effort?

Air hunger

Upper airway

Brain stem Upper airway

Chest tightness

Ventilatory muscles

Chest wall

Fig. 16.2.1.2  Efferent and afferent signals that contribute to the sensation of dyspnoea. The sense of respiratory effort is believed to arise from a signal transmitted from the motor cortex to the sensory cortex coincidently with the outgoing motor command to the ventilatory muscles. The arrow from the brainstem to the sensory cortex indicates that the motor output of the brainstem may also contribute to the sense of effort. The sense of air hunger is believed to arise, in part, from increased respiratory activity within the brainstem, and the sensation of chest tightness probably results from stimulation of vagal-​irritant receptors. Although afferent information from airway, lung, and chest wall receptors most likely passes through the brainstem before reaching the sensory cortex, the dashed lines indicate uncertainty about whether some afferents bypass the brainstem and project directly to the sensory cortex. From Manning HL, Schwartzstein RM (1995). Pathophysiology of dyspnea. New England Journal of Medicine, 333, 1547–​53. http://​content.nejm.org/​cgi/​content/​extract/​333/​23/​1547.

16.2.1  Chest pain, breathlessness, and fatigue

Table 16.2.1.3  New York Heart Association classification of breathlessness according to severity Class I

No limitation—​ordinary physical activity does not cause undue fatigue, dyspnoea, or palpitation

Class II

Slight limitation of physical activity—​comfortable at rest, but ordinary physical activity results in fatigue, dyspnoea, or palpitation

Class III

Marked limitation of physical activity—​comfortable at rest, but less than normal activity produces symptoms

Class IV

Inability to carry out any physical activity without discomfort

Until relatively recently, symptoms of fatigue and breathlessness in heart failure have been assumed to be due purely to a combination of poor cardiac output and pulmonary congestion. However, in patients with heart failure the correlation between symptoms and left ventricular ejection fraction is very poor. Changes in skeletal and respiratory muscle function appear to contribute significantly to symptoms, a hypothesis that is supported by the response observed to exercise training programmes in patients with chronic heart failure, and which may account for part of the considerable variability in disability in patients with similar haemodynamic and echocardiographic findings. Because of the contribution of fatigue, it is more helpful to ask about a change in exercise tolerance in patients with suspected heart failure, since this may correlate more closely with the underlying pathology. The New York Heart Association (NYHA) classification is used to classify the extent of disability (Table 16.2.1.3). The time course of onset of breathlessness can be particularly useful in determining the underlying pathology (Table 16.2.1.4). Breathlessness of dramatic onset (over minutes) is suggestive of pulmonary embolism, pulmonary oedema, upper airway obstruction, or a pneumothorax. Chronic dyspnoea presents in the context of worsening breathlessness over a period of months or years is typical

of chronic obstructive airways disease, interstitial lung disease, or anaemia, but may also be a feature of heart failure. Acute or chronic dyspnoea indicates an exacerbation of breathlessness in a patient with established disease. Chronic obstructive airways disease, asthma, and heart failure are common in the population of industrialized countries and most elderly patients presenting to the emergency department with breathing difficulties will have a prior history of pulmonary or cardiac disease. However, it is important not to automatically attribute any deterioration in symptoms as being due to progression of their underlying disease process. Alternative causes should be considered, and this situation is often a major diagnostic challenge. A common example is a sudden deterioration in the patient with long-​standing well-​controlled heart failure, which should prompt consideration of further pathology such as a silent myocardial infarction, pulmonary embolism, or arrhythmia. Breathlessness at rest occurs in pulmonary embolism or pulmonary oedema, and with a pneumothorax. Exertional dyspnoea occurs in left ventricular failure and chronic obstructive airways disease. Psychogenic breathlessness is frequently present at rest and is associated with sighing, features of hyperventilation such as perioral or peripheral paraesthesiae, and chest tightness. The presence of breathlessness at rest but not on exertion strongly suggests a functional origin.

Particular causes of breathlessness Left ventricular failure The incidence of left ventricular failure in the community is 1–​2%. It is important to attempt to identify the cause during the initial assessment. A history of ischaemic or valvular heart disease, alcohol abuse, smoking, diabetes, hypertension, and a family history are important. Patients with left ventricular failure commonly present to the outpatient clinic, but may present for the first time to the emergency

Table 16.2.1.4  Conditions causing breathlessness classified by the rate of onset Acute

Acute on chronic

Chronic

Asthma

Infective exacerbation of COPD

COPD

Myocardial infarction

Decompensated chronic heart failure

Cardiac failure

PE

PE complicating congestive cardiac failure or COPD

Anaemia

Cardiogenic pulmonary oedema (secondary to ischaemia, valvular disease, arrhythmias)

Pneumothorax complicating COPD or asthma

Pulmonary vascular disease (PE, pulmonary hypertension)

Pneumonia

Atrial fibrillation/​flutter complicating COPD or cardiac failure

Parenchymal lung disease, e.g. UIP, sarcoid

Non​cardiogenic pulmonary oedema

Chordal rupture in chronic non​rheumatic mitral regurgitation

Pleural disease, e.g. effusion, asbestosis

Pulmonary haemorrhage

Chest wall disease, e.g. kyphosis, ankylosing spondylitis

Spontaneous pneumothorax

Neuromuscular disorders, e.g. muscular dystrophy, polio, myasthenia gravis

Chest trauma

Malignancy

Upper airway obstruction

Obesity/​deconditioning

Hyperventilation syndrome

Sleep apnoea Silent myocardial ischaemia

COPD, chronic obstructive pulmonary disease; PE, pulmonary embolism; UIP, usual interstitial pneumonia.

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department. An acute presentation is more likely when there has been a rapid rise in the left atrial pressure generating pulmonary oedema. In severe cases this is associated with haemoptysis in the form of frothy pink sputum. This type of presentation occurs with myocardial infarction, mitral valve papillary muscle or chordal rupture, malignant hypertension, tachyarrhythmias, and endocarditis with major valve destruction. Where a rise in left atrial pressure occurs over a longer time course, sustained elevated left atrial pressures are compensated for by increased lymphatic drainage and structural changes in the pulmonary capillary and alveolar basement membrane and patients more commonly present with fatigue, exertional breathlessness, and orthopnoea. Prolonged increases in left atrial pressure are associated with pulmonary hypertension and the associated clinical features of right ventricular enlargement, tricuspid regurgitation, and a loud pulmonary second sound. This type of presentation is more frequently a feature of patients with an idiopathic, ischaemic, hypertensive, or alcoholic cardiomyopathy. Clinical findings that help in assessing impaired left ventricular function or elevated left atrial filling pressures are shown in Table 16.2.1.5. The most helpful features in the history are exertional breathlessness, orthopnoea, paroxysmal nocturnal dyspnoea, or a history of myocardial infarction. Breathlessness that is worse on lying flat and relieved promptly on sitting up is characteristic for orthopnoea. Patients with chronic obstructive airways disease may also describe orthopnoea, but this is usually present only in the setting of severe disease and chronic breathlessness at rest. Paroxysmal nocturnal dyspnoea is due to the development of interstitial oedema and typically occurs 2–​4 h after the onset of sleep. The patient usually stands up or sits on the side of the bed and symptoms resolve over the course of 10–​15 min. This is usually a frightening and memorable experience for the patient, and to avoid these symptoms they will sleep propped up on pillows or, in severe cases, in a chair. However, a history of paroxysmal nocturnal dyspnoea or orthopnoea is only present in 20% of patients with heart failure and its absence does not exclude the diagnosis. Ankle oedema is supportive of a diagnosis of heart failure, but dependent oedema is often present in older people and in patients with chronic obstructive airways disease, and the astute physician should avoid the common mistake of assuming that ‘ankle oedema means cardiac failure means diuretic prescription’. The clinical examination findings are used to support a suspected diagnosis of heart failure, but they are not always helpful.

Table 16.2.1.5  Helpful and relatively specific clinical findings for predicting heart failure in patients presenting with dyspnoea History

Examination

Orthopnoea

Elevated jugular venous pressure

Paroxysmal nocturnal dyspnoea

Cardiomegaly

Recent onset peripheral oedema

Third or fourth heart sound

Prior history of heart failure

Basal crepitations

Previous myocardial infarction

Positive hepatojugular reflux Peripheral oedema beyond mid-​calf

Source data from Badgett RG, Lucey CT, Mulrow CD (1997). Can the clinical examination diagnose left-​sided heart failure in adults? JAMA, 277, 1712–​19.

Tachycardia, cyanosis, and an elevated jugular venous pressure are features of heart failure, but they are also features of the major differential diagnoses, pulmonary embolism, and chronic obstructive airways disease. Although jugular venous pressure correlates with left atrial pressure it may be misleading in the presence of isolated right ventricular dysfunction, tricuspid regurgitation, and pulmonary hypertension. A displaced apex on palpation is helpful and relatively specific. Basal inspiratory crackles (rales) are suggestive of pulmonary oedema but can be present in fibrotic lung disease infection and chronic airways disease and have a sensitivity and specificity as low as 13% and 35%, respectively. The third sound is a low-​pitched sound heard in mid-​diastole, best with the bell of the stethoscope placed lightly over the apex. It can be confused with a split second sound but is later in diastole and has a much longer duration. It has a high specificity (90–​97%) but low sensitivity (31–​ 51%) for detecting left ventricular dysfunction. Fever and purulent sputum usually point to a diagnosis of an infective exacerbation of chronic bronchitis or chest infection. In older people, however, a chest infection may precipitate decompensation of heart failure. Left ventricular failure is highly unlikely in the presence of a genuinely normal ECG. Evidence of a previous myocardial infarction on the ECG, in particular the presence of Q waves in the anterior chest leads is highly predictive of left ventricular dysfunction. The most useful finding on chest radiography is cardiomegaly, but heart size may be normal, particularly in diastolic heart failure. Changes of pulmonary venous distension, pulmonary oedema, and pleural effusion are more common in acute presentations, but are frequently absent in patients presenting with chronic breathlessness. Following clinical assessment, including ECG and chest radiography, there may still be considerable uncertainty about the diagnosis of the cause of breathlessness, particularly in patients presenting to the emergency department. Measurement of blood brain natriuretic peptide (BNP) may assist in a more rapid and accurate diagnosis in this circumstance, a level below 100 pg/​ml (>300 pg/​ml for NT-​ proBNP) making the diagnosis of left ventricular failure highly unlikely and alternative diagnoses should be considered. High levels (>500 pg/​ml) are strongly suggestive of heart failure. Intermediate levels are more difficult to interpret as there are certain confounding factors for BNP measurement (Table 16.2.1.6) As with troponin, BNP levels (see Chapter 16.5.3) must be interpreted in the context of the history, clinical findings, and other investigations. Scoring systems have been devised using BNP and other clinical and investigation findings in acute dyspnoea (Fig. 16.2.1.3). Given the relatively poor predictive value of the clinical history and physical signs in the diagnosis of left ventricular failure, open access to echocardiography may appear superior to clinical assessment. However, there are important arguments for careful clinical assessment. Firstly, echocardiography is not always available in the emergency setting. Secondly, cardiac and non​cardiac causes of dyspnoea, particularly chronic obstructive pulmonary disease (COPD), often coexist, and where there is dual pathology, deciding which treatment to escalate is more dependent on the appropriate interpretation of the symptoms, clinical signs, and chest radiographic findings than echocardiographic parameters. Thirdly, heart failure is frequently present in the presence of apparently preserved systolic function on echocardiography.

16.2.1  Chest pain, breathlessness, and fatigue

Table 16.2.1.6  Confounding factors in the interpretation of BNP measurements

be a feature of chronic CO2 retention. Although often cited as a cause of the clinical features of right heart failure in COPD, true right ventricular failure is relatively uncommon, and the mechanism of fluid retention is complex. COPD and heart failure often coexist. The chest radiograph may be unhelpful and patients with emphysema and left ventricular failure may not have any radiological features of pulmonary congestion or oedema. In these situations, systolic heart failure can only be ruled out by echocardiography.

Increased BNP

Decreased BNP

Increasing age

Obesity

Female sex

Cardioactive drugs

Pulmonary disease

ACE inhibitors

Systemic hypertension

Spironolactone

Hyperthyroidism

β-​Blockers (long term)

Pulmonary embolism

Cushing’s syndrome

Diuretics

Pulmonary embolism is a common differential diagnosis in patients with breathlessness and should be considered in any presenting with breathlessness without clinical signs of left ventricular failure. The acute presenting symptoms are of breathlessness (usually of sudden onset), chest pain (classically pleuritic, but central with large pulmonary emboli), and less commonly haemoptysis, cough, and syncope. The differential diagnosis depends on the predominant presenting feature, such as pleuritic pain (chest infection with pleurisy, pericarditis), central chest pain (myocardial infarction), dyspnoea (COPD), or heart failure. Chronic pulmonary embolic disease and pulmonary hypertension present with exertional breathlessness, and patients may complain of central chest pain that is due to right ventricular subendocardial ischaemia. The diagnosis of pulmonary embolism cannot easily be excluded without investigation and the exclusion of an alternative, more likely, cause of breathlessness is crucial to the initial assessment. Most patients with acute pulmonary embolism are breathless or tachypnoeic (respiratory rate >20/​min) and in the absence of these findings, haemoptysis and pleuritic chest pain are usually due to another cause. See Chapter 16.16.1 for further discussion of examination findings and diagnostic strategy in patients with suspected pulmonary embolism.

Glucocorticoid usage Conn’s syndrome Hepatic cirrhosis with ascites Renal failure Paraneoplastic syndrome Subarachnoid haemorrhage

Airways disease The clinical features of heart failure and airways disease are often difficult to distinguish. Patients with lung disease tend to use the terms ‘chest tightness’ or ‘restriction’, whereas the patient with heart failure is more inclined to describe the sensation of ‘not being able to get enough air’. Patients are more likely to have COPD if they have a self-​reported history of COPD, wheezing on examination (although this can be a feature of heart failure), a forced expiratory time of 9 s or more, and laryngeal descent. Clearly COPD is very unlikely in the absence of a smoking history and in patients under 45 years of age. Patients with COPD and left ventricular failure may suffer from a chronic cough, although in the case of heart failure this is usually a dry cough and more prominent at night. Fluid retention giving rise to an elevated jugular venous pressure and ankle oedema can occur in association with hypoxia, but only if saturations are persistently less than 93%. Ankle oedema may also

% of patients with CHF

100

Derivation population Validation population

80 60 40 20 0 4-​week interval), high risk, and recurrent syncope. Tilt testing When the history is suggestive of vasovagal syncope, the tilt test may be of value in confirming the diagnosis, but a negative test does not exclude the diagnosis. Adjuvant provocation (isoprenaline or nitrate) may increase the sensitivity, but the incidence of false positive tests with tilt testing has been reported as 5–​20%. As such, its use is

probably best limited to investigation of recurrent symptoms with an atypical history in patients in whom there are no features to suggest cardiac syncope. Electrophysiological testing Abnormal sinus node function or evidence of atrioventricular conduction disease may be elicited by electrophysiological testing, but demonstrating bradycardia during ambulatory monitoring more reliably makes both of these diagnoses. In patients with structural heart disease in whom arrhythmia is suspected, programmed electrical stimulation of the ventricles can induce sustained monomorphic ventricular tachycardia. This is a relatively specific response which shows that the patient is at risk of recurrent ventricular arrhythmia and makes an arrhythmic origin of syncope likely. However, recent guidelines on device implantation suggest that an electrophysiological study is no longer routinely required in a patient with impaired ventricular function and syncope likely to be cardiac in origin. If there is enough clinical suspicion, then implantable cardioverter defibrillators can be offered to these patients without electrophysiological testing. It is important to note that the diagnostic yield of electrophysiological testing is low in patients with a structurally normal heart. Other investigations Assessment for structural heart disease is important. Physical examination will detect most significant valve disease, but other diagnoses, such as hypertrophic cardiomyopathy or atrial myxoma, may produce little in the way of clinical signs. An echocardiogram is therefore worthwhile in cases where the diagnosis remains unclear. Exercise testing is useful in patients with a history of syncope during or immediately after exercise. Exercise testing is diagnostic if Mobitz II second-​degree or third-​degree atrioventricular block develop during exercise even without syncope. Troponin measurement is not indicated in patients with syncope in the absence of features suggestive of an acute coronary syndrome. Approximately 10% of patients over the age of 60 presenting to the emergency department with syncope will have an elevated troponin, and although this is an independent risk factor for subsequent serious events, the finding rarely changes management appropriately or contributes to the final diagnosis. A strong suspicion of diagnoses other than syncope should lead to other investigations, including electroencephalography and brain imaging, but these have a low diagnostic yield in patients with syncope and should not be routine.

Management Neurocardiogenic syncope may require no treatment other than reassurance and avoidance of provocative factors. Syncope has several effects on lifestyle. Simple lifestyle measures may be employed to improve symptoms in specific situations: for example, increased fluid and salt intake. Where there is warning before syncope occurs this may be used to prevent injury or complete syncope by adopting a position lying down or with feet elevated. It is crucial for those who suffer syncope to avoid situations that might put them at harm, such as swimming alone or bathing (showering is preferred). Management of vasovagal syncope, bradycardia, and cardiac arrhythmia are discussed in Chapters 16.4 and 24.5.4. In up to one-​third

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of patients, the aetiology of syncope may not be found: these patients have a good outcome unless they have underlying heart disease.

Palpitation The symptom of palpitation is defined as an awareness of one’s heart beating. This may be due to an awareness of an abnormal heart rhythm, but it may also be due to an abnormal awareness of normal rhythm. A  careful and detailed history can provide a likely diagnosis. The most important aim in investigation is to correlate symptoms with cardiac rhythm.

History A description of the symptom should include an estimate of heart rate, duration of symptom, regularity of rhythm, suddenness of onset and offset. It may be helpful to ask the patient to tap with their finger to describe their palpitation. Trigger factors, including exercise, and aggravating factors such as alcohol and caffeine should be detailed. The length of history may be of interest. Sinus tachycardia An awareness of a rapid heart rate of gradual onset and offset is often associated with feelings of alarm and panic in patients with anxiety. Premature/​ectopic  beats Symptomatic atrial and ventricular premature or ectopic beats commonly occur in normal individuals, and often generate considerable anxiety resulting in consultation. In the absence of coronary disease, premature ventricular ectopic beats (PVCs) at a frequency of 1 per hour or more were recorded during Holter monitoring in the Framingham study in 33% of men and 32% of women. PVCs have also been recorded in 0.8% of a healthy military population during a standard 12-​lead ECG. These are important factors to remember when discussing their significance with the patient. The patient may describe ‘missed beats’ or forceful beats. These symptoms relate to the pause that follows a premature beat. The premature beat produces a short diastolic filling interval and the low ventricular volume results in reduced ventricular contraction with a small stroke volume. However, the subsequent pause provides a long diastolic filling period and the resultant stretching of the ventricular walls is associated with an increased and forceful systolic contraction. The combination of the diminished premature beat and the enhanced postextrasystolic beat is responsible for the symptoms. Benign ectopy is indicated by the absence of a history of other cardiovascular symptoms or family history of sudden death, their occurrence at rest and resolution with exercise, and a normal clinical cardiovascular examination and resting ECG. Multifocal ventricular ectopy, and PVCs at a frequency of more than 20 000 in 24 h, are more indicative of potentially significant cardiac pathology and require further investigation. Atrial fibrillation This common arrhythmia may produce a variety of symptoms depending on ventricular rate, irregularity, and persistence. Paroxysmal atrial fibrillation is characterized by self-​terminating episodes of atrial fibrillation, when there may be a rapid and irregular ventricular response. The patient is aware of an increased heart rate

and often describes the irregular nature of the symptom. The variations in diastolic interval produce symptoms by similar mechanisms to that described earlier for premature beats, with ‘missed’ and ‘forceful’ beats. Patients with sinoatrial dysfunction may be most symptomatic on termination of the atrial fibrillation, which can be followed by sinus bradycardia or prolonged sinus pauses. Atrial fibrillation may be persistent or permanent, and the severity of symptoms will be related to the ventricular rate and irregularity. Paroxysmal supraventricular tachycardia A history of sudden-​onset, rapid, regular palpitation in a healthy patient with no underlying structural heart disease is suggestive of paroxysmal supraventricular tachycardia. It may stop spontaneously or with vagotonic manoeuvres, or the patient may have had to attend hospital for intravenous therapy. In addition to palpitation, patients commonly report fatigue, malaise, light-​headedness, or dyspnoea, but because they have normal hearts such episodes of tachycardia are usually well tolerated. Polyuria is a common associated symptom, which results from the release of atrial natriuretic peptide secondary to atrial stretch. Ventricular tachycardia Ventricular arrhythmias can present with the symptom of palpitation, but more severe symptoms such as syncope or cardiac arrest also occur. Characteristically the symptom of palpitation would be the sudden onset and offset of a rapid regular heart rhythm. A history of structural heart disease should be sought.

Investigation Electrocardiogram The first aim is to document cardiac rhythm during symptoms. This may be possible with a standard ECG if the arrhythmia is sustained or persistent. Atrial or ventricular premature beats, or evidence of structural heart disease (e.g. myocardial infarction), may be documented. The presence of pre-​ excitation indicates the diagnosis of Wolff–​ Parkinson–​White syndrome and suggests symptoms due to episodes of atrioventricular re-​entry tachycardia. Other ECG signs indicative of primary electrical heart disease are: a corrected QT interval greater than 460 ms or less than 320 ms (long or short QT syndrome); right bundle branch block with ‘coved’ ST elevation (Brugada syndrome); epsilon waves and/​or T wave inversion with QRS duration greater than 100 ms in the right precordial ECG leads (arrhythmogenic right ventricular cardiomyopathy); and high voltages in the precordial leads with Q wave formation and ST changes (hypertrophic cardiomyopathy). Ambulatory monitoring The success of ambulatory monitoring in documenting the rhythm during symptoms will be dependent on the frequency of symptoms. If they occur daily, then a 24 or 48 h Holter recording should suffice. However, palpitation is often infrequent and other patient-​activated devices can be of more value. These include hand-​held, patient-​ activated event recorders that allow the telephonic transmission of recordings. These devices do not allow retrospective recording and require symptoms of sufficient duration to allow their use. However, there are now devices producing high quality single lead ECG recording that can be used with a smartphone and purchased directly by the patient. Shorter episodes may also be captured using loop recorders: the newest devices are the size of a large plaster, are attached

16.2.2  Syncope and palpitation

on the left upper part of the chest, can record for up to 2 weeks, and are waterproof. Ultimately, implantable loop recorders may be helpful where symptoms are infrequent, and they may also be effective in monitoring therapy once implanted for diagnostic purposes. The most recent devices are small enough to be classed as ‘injectable’, and they may even be implanted in the outpatient clinic setting. Other investigations Thyroid function and a full blood count are of particular importance in patients with atrial arrhythmias or sinus tachycardia, respectively. Electrolytes are routinely analysed. In patients with paroxysmal symptoms, a history of hypertension, sweating, and anxiety during attacks, urinary metanephrines for the investigation of phaeochromocytoma are indicated. Echocardiography is performed in most patients with palpitations and documented arrhythmias: in patients with ventricular ectopy, however, it is usually indicated only in those with suspected structural heart disease, a very high burden of ectopy, or those at a high risk of development of serious ventricular arrhythmias or sudden cardiac death. Electrophysiological studies Invasive studies are of most value in determining the mechanism of a previously documented tachyarrhythmia, particularly with a view to treatments such as radiofrequency catheter ablation.

Management Documentation of the cardiac rhythm during palpitation allows appropriate management, with reassurance as the only treatment in those with sinus tachycardia or premature beats. The treatment of other cardiac arrhythmias is discussed in Chapter 16.4. Lifestyle advice Advice regarding lifestyle with palpitations revolves around reassurance where it is felt to be benign and avoiding precipitants

where these can be identified. Although caffeine, other stimulants, alcohol, and stress are often quoted as potential triggers (and this may be true of ectopy, for example), it is much more common for many arrhythmias to occur without any avoidable trigger. Exercise as a trigger for palpitations is unusual and may signify adrenaline-​ dependent arrhythmias such as some forms of ventricular tachycardia (see Chapter 16.4). Driving restrictions may apply for both palpitations and syncope. In the United Kingdom clear guidance is provided by the Driver and Vehicle Licensing Agency (DVLA) as to who can and cannot drive with these symptoms, investigations that are required, and the duration of driving bans for both a normal driving licence and heavy goods/​passenger vehicle licences.

FURTHER READING Benditt DG, Sutton R (2005). Tilt-​table testing in the evaluation of syncope. J Cardiovasc Electrophysiol, 16,  356–​8. Brignole M, et al. (2018). 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J, 39, 1883–948. Brignole M, et al. (2018). Practical instructions for the 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J, 39, e43–e80. Grubb BP (2005). Neurocardiogenic syncope and related disorders of orthostatic intolerance. Circulation, 111, 2997–​3006. NICE (2010). Transient loss of consciousness. Clinical guideline. https://​ www.nice.org.uk/​guidance/​cg109 Raviele A, et al. (2011). Management of palpitations: a position paper from the European Heart Rhythm Association. Europace, 13, 920–​34. Shen W-​K, et  al. (2017). ACC/​AHA/​HRS Guideline for the evaluation and management of patients with syncope:  a report of the American College of Cardiology/​ American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. Circulation, 136(5), e60–​e122.

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16.3

Clinical investigation of cardiac disorders

CONTENTS 16.3.1 Electrocardiography  3294 Andrew R. Houghton and David Gray

16.3.2 Echocardiography  3314 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

16.3.1 Electrocardiography Andrew R. Houghton and David Gray ESSENTIALS The resting 12-​lead ECG The ECG has been recognized as a valuable diagnostic tool since the end of the 19th century. The normal ECG waveform consists of P, QRS, and T waves (and sometimes U waves)—​P waves result from atrial depolarization, QRS complexes from ventricular depolarization, and T waves from ventricular repolarization. The standard 12-​ lead ECG utilizes four limb electrodes and six precordial electrodes to generate 12 leads or ‘views’ of the heart’s electrical activity. There are six limb leads (termed I, II, III, aVR, aVL, and aVF) and six precordial leads (termed V1, V2, V3, V4, V5, and V6). Supplementary ‘views’ can be obtained by using additional leads, such as V7, V8, and V9 to assess the posterior aspect of the heart and right-​sided chest leads to look for a right ventricular myocardial infarction. Assessment of the 12-​lead ECG—​this should be done in a methodical manner, working through each aspect in turn. Conventionally, the heart rate, rhythm, and axis are assessed before inspection of each component of the waveform—​the P wave, PR interval, QRS complex, ST segment, T wave, QT interval, and U wave, with each component having its own range of normal attributes.

Myocardial hypertrophy—​the ECG can be a specific but generally insensitive tool for detecting myocardial hypertrophy: (1) left ventricular hypertrophy can be assessed using certain diagnostic criteria, including the Cornell criteria and the Romhilt–​Estes scoring system; (2) right ventricular hypertrophy is indicated by a dominant R wave in lead V1 with right axis deviation; (3) left atrial hypertrophy is indicated by broad, bifid P waves; and (4) right atrial hypertrophy by tall P waves. Conduction blocks—​(1) left anterior hemiblock results from a block of conduction in the anterosuperior fascicle and is a cause of left axis deviation; (2) left posterior hemiblock results from a block of conduction in the posteroinferior fascicle and is a cause of right axis deviation; (3) left and right bundle branch blocks both cause broadening of the QRS complexes by prolonging ventricular depolarization, and both exhibit characteristic diagnostic features. Ventricular pre-​excitation—​causes shortening of the PR interval and can result from Wolff–​Parkinson–​White-​type pre-​excitation, short PR-​type pre-​excitation, or Mahaim-​type pre-​excitation.

Acute coronary syndromes The ECG is the most useful bedside triage tool in acute coronary syndromes, with utility in diagnosis, in location of the site of ischaemia/​ infarction, and as a prognostic indicator. ST elevation myocardial infarction—​the first indication of infarction on the ECG is usually ST segment elevation, which occurs within a few hours. The J point (the origin of the ST segment at its junction with the QRS complex) is elevated by 1 mm or more in two or more limb leads, or by 2 mm in two or more precordial leads. The ST segment returns to the baseline over the next 48–​72 h, during which Q waves and symmetrically inverted T waves appear. Some patients develop left bundle branch block, either transiently or permanently. The ECG of a completed infarct shows new Q waves greater than 2  mm, R waves reduced in size or absent, and inverted T waves. Non-​ST-​elevation myocardial infarction—​ECG changes are more variable than in ST-​elevation myocardial infarction. The ECG may be normal on first presentation and remain unchanged throughout the acute admission; there may be transient ST segment depression indicative of myocardial ischaemia; in 20–​30% the only change will be T-​wave inversion. Difficulties in interpretation of the ECG in acute coronary syndromes—​ the ECG diagnosis of acute myocardial infarction can pose challenges in the setting of right ventricular infarction, atrial infarction, coronary

16.3.1 Electrocardiography

artery spasm, reciprocal changes, ‘stuttering’ infarction, non​infarct ST segment elevation, late presentation, left bundle branch block, prior infarction, pre-​excitation, and T-​wave inversion. Clinical decision-​making—​incorrect interpretation of an ECG can lead to inappropriate patient triage, either missing the opportunity to provide appropriate reperfusion therapy, or leading to inappropriate treatment with attendant risk. Up to 12% of those with a high-​ risk ECG are missed on admission to the emergency department, yet pressure to provide treatment promptly to fulfil audit ‘targets’, for example, door-​to-​balloon time for primary percutaneous coronary intervention, should not replace accuracy in diagnosis. It is sometimes better to repeat the ECG than to make an incorrect diagnosis. It is easy to place too much reliance on minor changes on the ECG; it is gross changes of ST elevation or depression within the parameters just outlined that should determine treatment.

Exercise ECG testing Exercise ECG testing is better as an indicator of prognosis than as a diagnostic tool. The sensitivity of exercise ECG testing, the proportion with coronary disease correctly identified by the test, is 68% (range 23–​100) and specificity, the proportion free of disease correctly identified by the test, is 77% (range 17–​100). In multivessel disease, these figures are 81% (range 40–​100) and 66% (range 17–​100), respectively. This means that exercise testing frequently yields both false-​positive results—​incorrectly diagnosing disease when coronary arteries are normal or minimally diseased—​and false-​negative results—​missing coronary disease when a flow-​limiting, even critical left main stem, coronary stenosis is present. Appearance of symptoms or ECG changes early in an exercise test is generally associated with more severe and extensive coronary disease and a poor prognosis. Changes within the first 3 min usually indicate severe coronary disease affecting the left main stem or the proximal segments of at least one major coronary artery. Multivessel coronary disease is more likely with ST segment down-​sloping, delayed ST normalization after exercise, increased number of leads affected, and lower workload at which ECG changes appear.

The resting 12-​lead ECG

Switzerland, in 1889. Although Einthoven made considerable improvements to the technique of recording ECGs with the capillary electrometer, it was only with his invention of the string galvanometer at the turn of the century that high-​quality ECG recording became possible. Within a decade of Einthoven’s publication of the first string galvanometer ECG recordings in 1902, a commercial ECG machine became available. Manufactured by the Cambridge Scientific Instrument Company, the first machine was delivered to Sir Thomas Lewis, who would play a major role in developing the clinical application of electrocardiography. Einthoven’s invention led to him being awarded the Nobel Prize in 1924. Einthoven was also the first to use the PQRST notation to describe the ECG waveforms. In the early ECG recordings, the waveforms were named ABCD (four deflections were recognized). Mathematical correction, using differential equations, was used to correct and improve ECG recordings, and it was traditional that mathematical notation used letters from the latter half of the alphabet. The letters N and O were already used elsewhere, so it was decided to begin the notation at P. Over the following years further refinements were undertaken, most notably in the 1930s when the use of the chest leads was first described. At around the same time Frank Wilson invented the ‘indifferent electrode’ (also known as the ‘Wilson central terminal’). This led to the development of the ‘unipolar’ limb leads VR, VL, and VF (‘V’ stands for ‘voltage’). In 1942 the American cardiologist Emanuel Goldberger increased the voltage of these leads by 50%, leading to the term ‘augmented’ leads (aVR, aVL, and aVF), and the 12-​lead ECG which remains familiar today finally took shape. Although the format of the 12-​lead ECG has remained essentially unchanged since that time, there have nevertheless been other significant developments in electrocardiography over more recent years. Ambulatory ECG recorders and implantable cardiac monitors have gained a central role in the investigation of patients with suspected arrhythmias, and the use of intracardiac ECG recording has enabled the rapid development and widespread use of electrophysiological studies.

Normal ECG appearances The ECG waveform

History The first electrocardiogram (ECG), of an exposed frog’s heart, was performed by Marey in 1876 using the mercury capillary electrometer that had recently been invented by Gabriel Lippmann. Two years later the British physiologists John Burdon Sanderson and Fredrick Page demonstrated that recordings of the frog heart’s electrical activity consisted of two phases (which were subsequently to become known as the QRS complex and T wave). The first human ECG was published in 1887 by Augustus D Waller, who had worked under Sanderson in the Department of Physiology at the University College of London. While working at St Mary’s Hospital, London, Waller used a capillary electrometer to record the ECG of a laboratory technician, Thomas Goswell. Electrocardiography was developed further by the Dutch physiologist Willem Einthoven, who witnessed a demonstration by Waller at the First International Congress of Physiology in Basle,

The three fundamental deflections on the normal ECG are termed the P wave, the QRS complex, and the T wave (Fig. 16.3.1.1). The origins of each deflection are as follows.

P wave The P wave results from depolarization of the atrial myocardium. Depolarization of the sinoatrial node itself, which triggers normal atrial depolarization, cannot be seen on the surface ECG (although it can be identified in intracardiac recordings). However, the presence of a P wave with normal morphology and orientation is generally taken to infer normal sinoatrial node depolarization. Repolarization of the atrial myocardium is represented on the ECG by the Ta wave (the atrial equivalent of the ventricular T wave). The Ta wave is seen as a small asymmetrical deflection after the P wave, with an opposite polarity to the preceding P wave. The Ta wave is often hidden within the QRS complex and is therefore not easily

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Fig. 16.3.1.1  Basic ECG waveform.

seen—​in fact, it is unusual to be able to appreciate the Ta wave at all. However, it can extend right through to the following ST segment, where it can be mistaken for the ST segment depression of myocardial ischaemia (particularly because the Ta wave is most likely to be seen extending into the ST segment during exercise-​induced sinus tachycardia). There is one case report of a positive Ta wave (after an inverted P wave) giving the erroneous impression of an acute ST segment elevation myocardial infarction.

QRS complex The QRS complex represents depolarization of the ventricular myocardium. Of all the deflections, the QRS complex can exhibit the greatest variability in appearance. As a result, the individual components of the QRS complex can be labelled in upper case (Q, R, or S) or lower case (q, r, or s) to represent the relative size of the component. For example, QRS complexes with a small Q wave deflection can be termed qRS complexes, and those QRS complexes with no Q wave component and a small R wave component can be termed rS complexes.

The augmented unipolar leads measure the voltage between a single positive electrode and a ‘central’ point of reference generated from the other limb electrodes. Thus, aVR uses the right arm electrode as the positive terminal, aVL uses the left arm electrode, and aVF uses the left leg electrode. The three bipolar leads and the three augmented unipolar leads together comprise the six limb leads that view the heart in the frontal plane. The unipolar chest leads measure the voltage between six electrodes placed across the surface of the chest and a central point of reference, providing a view of the heart that is perpendicular to the frontal plane leads. For all 12 ECG leads, it is conventional that a wave of depolarization moving towards a lead generates a positive (upward) deflection on the ECG recording and vice versa.

The six limb leads (frontal plane leads) Because the limbs act as linear conductors, it does not matter whereabouts the limb electrodes are attached on each limb. The six limb leads provide general spatial information (being less localized than the six chest leads). Fig. 16.3.1.2 shows the orientation of the six

T wave The T wave (together with the preceding ST segment) represents repolarization of the ventricular myocardium.

The 12 conventional ECG leads aVR

Lead nomenclature It is important to emphasize that the term ‘lead’ does not refer to the electrode connecting the ECG machine to the patient. For a standard 12-​lead ECG recording, 10 electrodes are used to generate the 12 conventional ECG leads. The 12 leads can be categorized as limb (or frontal plane) leads (I, II, III, aVR, aVL, aVF) and chest (or precordial) leads (V1, V2, V3, V4, V5, V6). The 12 leads can also be categorized as bipolar (I, II, III) or unipolar (aVR, aVL, aVF, V1, V2, V3, V4, V5, V6). The leads aVR, aVL, and aVF can be further described as ‘augmented’ leads, as they are modified versions of the original VR, VL, and VF leads, having a voltage amplification of 50%. The bipolar leads are generated by measuring the potential (voltage) between two electrodes. One electrode acts as a positive terminal and the other as a negative terminal. For instance, lead I measures the potential between the left arm electrode (positive) and right arm electrode (negative). Lead I is obtained by subtracting the right arm vector from the left arm vector. Similarly, lead II measures the potential between the left leg electrode and the right arm electrode, and lead III measures the potential between the left leg electrode and the left arm electrode.

aVL I

Right

III

aVF

Left

II

Fig. 16.3.1.2  The six limb leads and their ‘view’ of the heart. Note that leads II, III, and aVF are inferior to the heart, I and aVL are anterolateral to the heart, and aVR looks into the cavity of the heart.

16.3.1 Electrocardiography

• The V4 electrode is placed at the left midclavicular line in the fifth intercostal space • The V5 electrode is placed at the left anterior axillary line in a horizontal line with V4 • The V6 electrode is placed at the left midaxillary line in a horizontal line with V4 and V5

Reading a normal 12-​lead ECG V1

V2 V3 V4

V6

V5

Fig. 16.3.1.3  Surface positions of the chest electrodes.

limb leads in relation to the heart. In simple terms, one can visualize lead aVR as ‘looking’ at the heart from the right shoulder, lead aVL from the left shoulder, and lead aVF from the feet. Lead I ‘looks’ at the heart from the left horizontal position. Similarly, the ‘views’ of leads II and III are shown in Fig. 16.3.1.2.

The six chest leads (precordial leads) For the chest (precordial) leads, each of the six electrodes is attached to a particular site on the chest wall. The chest electrodes act as positive terminals, and the indifferent terminal is formed from a combination of leads R, L, and F. The location of each electrode is important, in contrast to the limb leads. The surface positions of the chest electrodes are shown in Fig. 16.3.1.3, and the relation between the chest leads and the heart in Fig. 16.3.1.4. The electrodes are placed as follows: • The V1 electrode is placed at the right sternal edge in the fourth intercostal space • The V2 electrode is placed at the left sternal edge in the fourth intercostal space • The V3 electrode is placed midway between the V2 and V4 electrodes

Fig. 16.3.1.5 shows a normal 12-​lead ECG. As is conventional, this shows the leads arranged in four columns, each column containing three leads. In addition, a rhythm strip runs along the bottom of the ECG across its whole width. This is conventionally lead II, but any one of the 12 leads can be used for the rhythm strip as required. The ECG is recorded at a paper speed of 25 mm/​s, and at a sensitivity of 10 mm/​mV. The speed and sensitivity settings can also be adjusted on most ECG machines, if required, and so it is important that the actual recording speed and sensitivity are always noted on the ECG for future reference. In the following paragraphs we will describe the appearances of the normal ECG, looking at each wave, interval, and segment in turn. We will assume that the patient is in normal sinus rhythm, and that a standard paper speed (25  mm/​ s) and calibration (10 mm/​mV) have been used—​this should always be checked before reading any ECG.

Identification details Before reading the ECG, check the patient’s details (the patient’s name and at least one other form of identification, such as date of birth or identification number, should be recorded on the ECG) and the date and time on which the ECG was recorded. It is good practice to note on the ECG any relevant clinical features. For instance, a note that the patient was experiencing chest pain or palpitations at the time the ECG was recorded can prove invaluable later on. Indeed, ECG interpretation should always take into account the appropriate clinical context. For instance, the ECG shown in Fig. 16.3.1.5 can be interpreted as showing normal sinus rhythm in a patient who is well. However, in a patient who is unconscious and pulseless, the same ECG would be interpreted as showing pulseless electrical activity, a cardiac arrest rhythm. Before interpreting any ECG, it is therefore appropriate (and important) to ask, ‘How is the patient?’ Rate

V6

V5

V1

V4 V2

V3

Fig. 16.3.1.4  The chest leads and their anatomical relationship to the heart. Return to the top.

A normal heart rate is between 60 and 100 beats/​min. A rate below 60 beats/​min is termed bradycardia; a rate greater than 100 beats/​ min is termed tachycardia. Heart rate normally applies to the ventricular rate, as shown on the ECG by the rate of QRS complexes. However, the atria have their own rate, as shown by the P wave rate. The atrial and ventricular rates are usually the same, and there is a 1:1 ratio between P waves and QRS complexes. However, the rates can differ; for instance, in complete heart block (Fig. 16.3.1.6), the atrial rate is usually greater than the ventricular rate, and both rates should therefore be quoted. Ventricular rate can be calculated in two different ways. One method necessitates counting the number of large (5 mm) squares between two adjacent QRS complexes. This figure is then divided into 300 to give the ventricular rate per minute. For instance, if there are five large squares between QRS complexes, the ventricular rate is 300/​5 = 60

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Fig. 16.3.1.5  A normal 12-​lead ECG.

beats/​min. The same method can be used to calculate atrial rate, counting the large squares between two consecutive P waves. If the heart rhythm is irregular, the square-​counting method is not so useful. An alternative method is to count the number of QRS complexes in a certain time period, and then multiply the number up to obtain a rate per minute. Traditionally one counts the number of QRS complexes in a period of 30 large squares, which equates to 6 s of recording (a paper speed of 25 mm/​s covers five large squares per second, or 300 large squares per minute). One then multiplies the result by 10 to obtain the rate per minute. Thus, if there are 8 QRS complexes within 30 large squares, then the ventricular rate is 8 × 10 = 80 beats/​min. Once again, the same method can be used to calculate atrial rate. Rhythm A detailed description of arrhythmias can be found in Chapter 16.4. In general terms, the assessment of rhythm on the ECG requires careful attention to the following: • Whether there is ventricular activity (QRS complexes) and what is the ventricular rate; • Whether there is atrial activity (P waves) and what is the atrial rate; • Whether the heart rhythm is regular or irregular; • Whether the QRS complexes are normal or broad (broad complexes indicating either a ventricular origin to the rhythm or aberrant conduction of a supraventricular rhythm); • Whether there is a relationship between P waves and QRS complexes. Assessing the ECG along these lines will provide a basis upon which to describe the rhythm and begin to identify the nature of the arrhythmia.

Axis The concept of axis is often regarded as one of the hardest principles to grasp when learning ECG interpretation. The concept is, nonetheless, straightforward: axis refers to the overall direction in which the wave of depolarization travels. There is a QRS (ventricular) axis, which is what most people refer to when discussing cardiac axis, but the P wave has its own axis too, representing the overall direction of depolarization in the atria. The T wave also has an axis, in this case referring to the overall direction of the wave of repolarization. In this section the discussion is confined to the QRS (ventricular) axis, but the same principles apply to P wave and T wave axes too. As the ventricles depolarize, the wave of depolarization travels through the atrioventricular node, into the bundle of His, and then to the ventricular myocardium via the Purkinje fibres. The overall direction of this depolarization wavefront is usually towards the apex of the heart. If, by convention, we regard the ‘view’ that lead I has of the heart (a horizontal line to the left of the heart) as 0°, and any angle clockwise from that line is positive (and any angle anticlockwise from that line is negative), then the normal ventricular depolarization wavefront travels through the ventricles at an angle of approximately +60° (Fig. 16.3.1.7). As Fig. 16.3.1.7 illustrates, the six limb leads ‘view’ the heart from different angles. Lead I is taken as the horizontal reference point, 0°. Moving in a clockwise (positive) direction, lead II views the heart from an angle of +60°, lead aVF from an angle of +90°, and lead III from an angle of +120°. Moving anticlockwise from lead I, lead aVL views the heart from an angle of −30°, and lead aVR from an angle of −150°. This system of looking at axes, using the six limb leads, is known as the hexaxial reference system. The shaded area in Fig. 16.3.1.7 shows the normal range for the QRS axis, which lies between −30° and +90°. This does vary with

Fig. 16.3.1.6  Complete heart block: complete dissociation of atrial (P waves) and ventricular (QRS complexes) rate.

16.3.1 Electrocardiography

−90 −60

−120 aVR

aVL −150

−30

0

180

I

30

150

60

120 III

90

II

aVF

Fig. 16.3.1.7  The standard convention for describing the orientation of cardiac axis, and the corresponding ‘views’ of each of the six limb leads. The shaded area represents the normal range for the QRS axis.

body morphology—​tall, slim individuals tend to have axes towards the rightward (+ 90°) end of the normal range; short, overweight individuals have axes towards the leftward (−30°) end of the normal range. An axis more negative (anticlockwise) than −30° is abnormal and termed left axis deviation. Similarly, an axis more positive (clockwise) than + 90° is abnormal and termed right axis deviation. Left axis deviation is seen in left anterior hemiblock (see next), inferior myocardial infarction, and also in ostium primum atrial septal defect. Right axis deviation is seen in left posterior hemiblock, right ventricular hypertrophy, lateral myocardial infarction, ostium secundum atrial septal defect, and Wolff–​Parkinson–​White (WPW) syndrome. There are several ways to calculate the QRS axis. One method is to look for which of the six limb leads has a QRS complex in which the R wave and S wave are closest to being equal (i.e. in which the positive and negative deflections cancel each other out). The QRS axis will be at right angles to this ‘equipolar’ lead, but could be pointing in either direction. For instance, if the equipolar lead is lead III (which looks at the heart from + 120°), then the QRS axis will be at right angles to this, namely either + 30° or −150° (refer back to Fig. 16.3.1.7). Next, find which lead is at right angles to the equipolar lead—​in this example, the answer would be lead aVR. Now, if the QRS axis is −150°, then you would expect a positive QRS complex in lead aVR (because the wave of depolarization would be travelling directly towards it). If, however, the QRS complex in lead aVR is negative, the depolarization must be moving away from it and the QRS axis must be therefore be + 30°. This method works whichever limb lead is equipolar, as every limb lead has another lead at right angles to it.

An alternative and quick method of checking whether the QRS axis is within the normal range is simply to look at leads I and II. If the QRS complex in lead I is positive (or at least equipolar), then the QRS axis must lie somewhere in the range of −90° to + 90°. Similarly, if the QRS complex in lead II is positive, then the QRS axis must lie somewhere in the range −30° to + 150°. Therefore, we can say that if the QRS complexes in leads I and II are both positive then the QRS axis must lie somewhere in the range −30° to + 90°. Thus, a positive QRS complex in leads I and II means the QRS axis is within the normal range; a positive QRS complex in lead I and a negative QRS complex in lead II indicate left axis deviation; a negative QRS complex in lead I and a positive QRS complex in lead II indicate right axis deviation. More precise calculations of the QRS axis can be made by measuring the individual R and S waves in each of the limb leads and using vector analysis to plot out the overall direction of depolarization, but this degree of precision is usually unnecessary. P wave The P wave represents atrial depolarization. P waves are usually upright except in leads aVR and V1 (and sometimes V2), where they can be inverted (or biphasic). P waves are seen most clearly in lead II and this is usually the lead of choice for the rhythm strip so that atrial activity can be assessed clearly. P waves can be inverted in other leads, indicating that atrial depolarization has been initiated somewhere other than the sinoatrial node. For instance, an ectopic focus of depolarization near the atrioventricular node will give rise to inverted P waves in the inferior leads (II, III, and aVF) as the wave of atrial depolarization will spread upwards rather than downwards. P waves are normally no broader than three small squares (0.12 s) and no taller than 2.5 mm. The features of atrial hypertrophy are discussed later. PR interval The PR interval is measured from the beginning of the P wave to the beginning of the QRS complex. A  normal PR interval is between 0.12 s and 0.20 s in adults. A long, fixed PR interval is termed first-​degree atrioventricular block and results from a delay in conduction between the atria and ventricles (Fig. 16.3.1.8). In second-​degree atrioventricular block the PR interval may gradually increase with each beat before a P wave is not conducted (Mobitz type I  or Wenckebach phenomenon) or may be fixed and long (or normal) with intermittent non​conduction of P waves (Mobitz type II). In third-​degree atrioventricular block and also in atrioventricular dissociation, the PR interval will vary because of the absence of any association between atrial and ventricular activity. See Chapter 16.4 for further discussion.

Fig. 16.3.1.8  First-​degree atrioventricular block (long PR interval).

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Fig. 16.3.1.9  A prolonged QT interval. Measurement can be difficult since the precise beginning and end of the interval may not be easy to determine, particularly if the end of the T wave is obscured by a superimposed U wave or the following P wave.

A short PR interval is seen in ventricular pre-​excitation (see next) or when the focus of atrial depolarization arises not from the sinoatrial node but from the vicinity of the atrioventricular node. QRS complex The QRS complex represents ventricular depolarization. The first negative deflection of the complex is termed the Q wave and the first positive deflection the R wave (whether or not it follows a Q wave). A negative deflection after an R wave is termed an S wave. If the deflections are small, lower-​case letters (q, r, and s) are used. Thus, it is possible to have QRS complexes, qRS complexes, rS complexes, and so on. Normal ‘physiological’ q waves are usually narrow (no more than 0.04 s in duration) and small (less than 25% the amplitude of the following R wave) and result from the left to right depolarization of the interventricular septum (‘septal q waves’). Larger Q waves may be pathological, although can be normal in leads III and aVR, and may also been seen in lead aVL if the QRS axis is greater than + 60°. The normal QRS complex duration is less than 0.12 s. The amplitude of the QRS complex varies normally from lead to lead and, in the precordial leads, normally increases progressively from lead V1 to V6. At least one R wave in the precordial leads must be at least 8 mm in height, and the tallest R wave should be no more than 27 mm (and the deepest S wave no more than 30 mm), and the sum of the tallest R wave and the deepest S wave should be no more than 40 mm. In the limb leads, the R wave height should be no more than 13 mm in lead aVL and 20 mm in lead aVF. ST segment The ST segment should be horizontal and should not normally deviate by more than 1 mm above or next the isoelectric line (which is the line between end of the T wave and the start of the subsequent P wave). T wave T waves in the limb leads are normally concordant—​if the QRS complex is positive, the subsequent T wave is upright, and vice versa. The T wave is normally inverted in lead aVR and upright in leads I and II. With regard to the precordial leads, normal T waves are always upright in leads V4 to V6. A flat or inverted T wave is found in lead V1 in 20% of adults, and in lead V2 in 5% of adults (in which case, the T wave should be inverted in lead V1 as well). An inverted T wave in lead V3 can, rarely, be found in normal young adults. T waves should not change their orientation—​an inverted T wave is not normal if previous ECGs show that it was previously upright. There are no strict criteria for normal T wave size, so ‘tall’ and ‘small’ T waves are not well defined and deciding on their presence tends to be a subjective judgement. ‘Tall’ T waves can occur in early acute myocardial infarction (‘hyperacute’ T waves) and in hyperkalaemia (‘tented’ T waves). Small T waves can be seen in hypokalaemia.

QT interval The QT interval is measured between the start of the QRS complex and the end of the T wave. The normal range for the QT interval varies according to heart rate. It is therefore convenient to correct the measured QT interval to what it would be if the heart rate were 60 beats/​min. This is done most commonly using Bazett’s formula, in which the measured QT interval (in seconds) is divided by the square root of the RR interval (in seconds), to give the corrected QT interval (QTc). The normal range for the QT interval at a heart rate of 60 beats/​min, and thus for the QTc, is between 0.35 s and 0.45 s (men) or 0.46 s (women) (Fig. 16.3.1.9). U wave The T wave is occasionally followed by a U wave, most clearly seen in the right precordial leads, which has the same orientation as the T wave and is usually no more than one-​third of its size. The physiological origin of the U wave is still debated but is often said to relate to after depolarizations in the ventricles.

Myocardial hypertrophy Left ventricular hypertrophy Evidence of left ventricular hypertrophy on the ECG is a significant risk factor for cardiovascular morbidity and mortality. Several diagnostic ECG criteria for left ventricular hypertrophy have been developed which, in general, are relatively specific (>90%) but not very sensitive (20–​60%). The diagnostic criteria shown in Box 16.3.1.1 are commonly used. The Cornell criteria involve measuring the S wave in lead V3 and the R wave in lead aVL. Left ventricular hypertrophy is indicated by a sum of more than 28 mm in men and more than 20 mm in women. The Romhilt–​Estes scoring system allocates points for the presence of certain criteria, with a score of five indicating left ventricular hypertrophy and a score of 4 indicating probable left ventricular hypertrophy. Points are allocated as follows: • 3 points for (a) R or S wave in limb leads of 20 mm or more; (b) S wave in right precordial leads of 25 mm or more; or (c) R wave in left precordial leads of 25 mm or more; • 3 points for ST segment and T wave changes (‘typical strain’) in a patient not taking digitalis (1 point with digitalis); • 3 points for P-​terminal force in V1 greater than 1 mm deep with a duration greater than 0.04 s; • 2 points for left axis deviation (beyond −15°); • 1 point for QRS complex duration greater than 0.09 s; • 1 point for intrinsicoid deflection (the interval from the start of the QRS complex to the peak of the R wave) in V5 or V6 greater than 0.05 s.

16.3.1 Electrocardiography

Box 16.3.1.1  Diagnostic criteria for left ventricular hypertrophy Limb leads • R wave >11 mm in lead aVL • R wave >20 mm in lead aVF • S wave >14 mm in lead aVR • Sum of R wave in lead I and S wave in lead III >25 mm Precordial leads • R wave of ≥25 mm in the left precordial leads • S wave of ≥25 mm in the right precordial leads • Sum of S wave in lead V1 and R wave in lead V5 or V6  >35  mm (Sokolow–​Lyon criteria) • Sum of tallest R wave and deepest S wave in the precordial leads >45 mm

A left ventricular ‘strain’ pattern (ST-​T wave abnormalities) is associated with around double the risk of myocardial infarction and stroke as left ventricular hypertrophy in the absence of strain. Left ventricular hypertrophy cannot be assessed reliably using the ECG in patients with bundle branch block, previous myocardial infarction, or WPW syndrome; visualization via echocardiography or cardiac MRI is required. An example of left ventricular hypertrophy is shown in Fig. 16.3.1.10.

Right ventricular hypertrophy As with left ventricular hypertrophy, the ECG criteria for right ventricular hypertrophy tend to be relatively specific but not very sensitive. Right ventricular hypertrophy shifts the QRS complex axis rightwards as well as producing higher-​voltage QRS complexes in the right precordial leads. ECG criteria include: • a dominant R wave (R wave ≥ S wave) in lead V1, in the presence of a normal QRS duration; • a QRS complex axis of greater than + 90°. These criteria are supported by: • ST segment depression and T-​wave inversion in the right precordial leads; • deep S waves in the lateral precordial and limb leads.

Fig. 16.3.1.10  Left ventricular hypertrophy.

It is not essential for all these criteria to be present, but the greater the number of features present, the greater the likelihood of right ventricular hypertrophy. It is prudent to remember that a dominant R wave in lead V1 can also be seen in right bundle branch block, WPW syndrome, and a posterior wall myocardial infarction.

Atrial hypertrophy Left atrial hypertrophy Left atrial depolarization is responsible for the terminal portion of the normal P wave. Left atrial hypertrophy increases the voltage and duration of this depolarization, and thus usually evidences itself by abnormalities of the terminal portion of the P wave. The P wave duration is prolonged, and it becomes bifid in lead II and biphasic, with a predominant negative component, in lead V1. So-​called ‘P mitrale’ can be seen in the left atrial enlargement that results from mitral valve stenosis (hence the term) and also in association with conditions that cause left ventricular hypertrophy, such as hypertension (most commonly) and aortic stenosis (Fig. 16.3.1.11).

Right atrial hypertrophy Right atrial hypertrophy increases the voltage, but not the duration, of the P wave, and this is usually best seen in the inferior and right precordial leads. A P wave height greater than 2.5 mm is regarded as abnormal. So-​called ‘P pulmonale’ can result from right ventricular hypertrophy or from tricuspid valve stenosis (Fig. 16.3.1.12).

The hemiblocks The left bundle branch divides into anterosuperior and postero­ inferior fascicles. A block of either fascicle (hemiblock) causes a deviation of the QRS axis.

Left anterior hemiblock A block of the anterosuperior fascicle leads to a left anterior hemiblock. This causes a leftward shift in the QRS axis, as the

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Fig. 16.3.1.11  Left atrial hypertrophy (‘P mitrale’).

These findings may be accompanied by ST segment depression and T-​wave inversion in the lateral precordial and limb leads, broad QS waves in the right precordial leads and broad R waves in the lateral leads, and R wave notching (‘M-​shaped’ QRS complexes). An example of LBBB is shown in Fig. 16.3.1.13. The extensive nature of the ECG changes means that further interpretation of the QRS complexes, ST segments, or T waves cannot be made. The difficulties of diagnosing myocardial infarction in the setting of LBBB are discussed later.

Right bundle branch block right/​inferior region of the left ventricle depolarizes first (via the posteroinferior fascicle) and then the wave of depolarization spreads to the left/​superior region. Although this hemiblock introduces a minor delay in ventricular depolarization, the QRS duration remains within the normal range (up to 120 ms). The QRS axis shifts to the left (beyond −30°). As a similar axis shift can result from an inferior myocardial infarction, the diagnosis of an left anterior hemiblock requires the presence of left axis deviation in the absence of an abnormal q wave in lead aVF.

Left posterior hemiblock Block of the posteroinferior fascicle leads to left posterior hemiblock. This causes a rightward shift in the QRS axis, as the left/​superior region of the left ventricle depolarizes first (via the anterosuperior fascicle) and then the wave of depolarization spreads to the right/​inferior region. As with a left anterior hemiblock, the QRS duration remains within the normal range (up to 120 ms). The QRS axis shifts to the right (beyond + 90°). However, right axis deviation can occur in several conditions (most commonly right ventricular hypertrophy, but also in lateral myocardial infarction and WPW syndrome). It is therefore not possible to diagnose left posterior hemiblock with certainty from the 12-​lead ECG alone.

Bundle branch block Left bundle branch block A left bundle branch block (LBBB) leads to a delay in left ventricular depolarization, as the left ventricle is depolarized via the right-​sided Purkinje system. In addition, the interventricular septum depolarizes from right to left instead of the usual left to right. Thus, in LBBB: • The QRS duration is prolonged (≥120 ms); • The normal ‘septal’ q waves usually seen in the lateral leads are absent; • A secondary r wave is not seen in lead V1 (this distinguishes LBBB from right bundle branch block (RBBB) with clockwise cardiac rotation).

RBBB leads to a delay in right ventricular depolarization, as the right ventricle is depolarized via the left-​sided Purkinje system. However, the normal left to right activation of the interventricular septum is preserved. The ECG changes seen in RBBB are therefore not as extensive as in LBBB. The QRS duration is prolonged (≥120 ms) and the right ventricular leads contain a second positive wave (and, conversely, the left ventricular leads contain a second negative wave). Thus, in RBBB: • the QRS duration is prolonged (≥120 ms); • lead V1 contains a second positive wave (rsR); • lead V6 contains a second negative wave (qRs). These findings may be accompanied by deep slurred S waves in the lateral precordial and limb leads, and abnormal ST-​T wave changes in the right precordial leads. An example of RBBB is shown in Fig. 16.3.1.14.

Ventricular pre-​excitation The normal progression of a wave of depolarization is from the sinoatrial node through the atria to the atrioventricular node, and then through the bundle of His and the Purkinje fibres to the ventricular myocardium. However, approximately 1 in 1000 of the population has an accessory pathway—​an alternative pathway from atria to ventricles that bypasses part of this normal route. Such a pathway initiates depolarization of the ventricles at a slightly earlier stage in the cardiac cycle than would otherwise be the case, hence the term ‘ventricular pre-​excitation’. This is because the accessory pathway lacks the inherent delay to conduction that is normally found in the atrioventricular node, thus allowing faster conduction of the wave of depolarization from atria to ventricles. There are several types of pathway that can give rise to ventricular pre-​excitation.

WPW-​type pre-​excitation WPW-​type pre-​excitation is exemplified by WPW syndrome. In WPW syndrome an accessory pathway, the bundle of Kent, connects

Fig. 16.3.1.12  Right atrial hypertrophy (‘P pulmonale’).

16.3.1 Electrocardiography

Fig. 16.3.1.13  Left bundle branch block.

the atria to the ventricles and bypasses the atrioventricular node altogether. This shortens the time between the onset of atrial depolarization and the onset of ventricular depolarization, and hence one of the ECG features of WPW syndrome is a short PR interval (2 mm

16.3.1 Electrocardiography

Table 16.3.1.1  Location of infarction and affected coronary artery ECG leads affected

Site of infarction

Most likely artery occluded (positive predictive value)

V3 and V4 I, aVL and V1 to V6 (in extensive infarction)

Anterior

Left anterior descending (96%)

V1 and V2

Septal

V1 to V4

Anteroseptal

I, aVL, and V3 to V6

Anterolateral

II, III, and aVF

Inferior

Right coronary (80%) Right or circumflex (94%)

I, aVL and V6 I and aVL (high lateral)

Lateral

Circumflex (75%)

ST depression in V1 and V2 followed by development of prominent R waves in lead V1 or V2

Posterior

Circumflex (75%)

Lateral or posterior

Right or circumflex (94%)

II, III, and aVF with aVL, V5, and V6

Inferolateral

Right coronary (93%)

in two contiguous leads) is associated with an increased risk of death at 1 year. The presenting ECG and probability of acute coronary syndrome New, or presumed new, ST segment deviation greater than 0.1 mV, however transiently, or T-​wave inversion in multiple precordial leads, is highly indicative of ACS. Q waves, ST segment depression of 0.05–​ 0.1 mV, or T-​wave inversion greater than 0.1 mV have an intermediate probability of ACS. T-​wave flattening or inversion less than 0.1 mV (in leads with dominant R waves) or a normal ECG has a low probability of ACS. The likelihood of NSTEMI is increased threefold in chest pain with ST segment depression in three leads or more than 0.2 mV.

Fig. 16.3.1.16  Evolution of STEMI over several days.

The presenting ECG and triage The presenting ECG can be used to triage patients with acute cardiac-​sounding chest pain: • ST elevation present—​immediate reperfusion should be considered, by primary percutaneous coronary intervention (PCI) (or by intravenous thrombolysis if primary PCI unavailable). • ST elevation not evident—​immediate treatment with antiplatelet drugs and anti-​ ischaemic drugs, with consideration of coronary angiography where appropriate. Risk stratification using tools such as GRACE or TIMI scoring, can help identify those most likely to benefit from early coronary angiography and revascularization.

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ST segment elevation myocardial infarction The ECG changes of myocardial infarction, first described in 1920, reflect myocardial ischaemia, injury, and myocyte necrosis. Within an hour or so of occlusion of a coronary artery, the T wave becomes more prominent, exceeding one-​half the height of the preceding R wave in the ECG leads subtending the infarcted area (see Fig. 16.3.1.16). Many patients present later than this, so these changes may pass unnoticed. In up to 50%, the presenting ECG is normal. The first documented indication of infarction is usually ST segment elevation which occurs within a few hours. The J point (the origin of the ST segment at its junction with the QRS complex) is elevated by 1 mm or more in two or more limb leads, or by 2 mm in two or more precordial leads. The ST segment returns to the baseline over the next 48–​72 h, during which Q waves and symmetrically inverted T waves appear. Some patients develop LBBB, either transiently or permanently. The ECG of a completed infarct shows new Q waves greater than 2  mm, R waves reduced in size or absent, and inverted T waves. This classical evolution of STEMI is seen in about 50–​66% of patients.

Reperfusion therapy, by primary PCI (or thrombolysis where primary PCI is unavailable) may alter this natural sequence of changes in the ECG. If treatment is given with thrombolysis, then an ECG performed 90 min after initiation should show that ST elevation has been reduced by at least 50% from pretreatment levels (Fig. 16.3.1.17). If chest pain persists and the ST segments remain elevated, coronary angiography and rescue PCI should be considered. Where available, primary PCI should be offered in preference to thrombolysis. Resolution of ST segment elevation predicts 30-​day mortality. With greater than 70% ST segment resolution, mortality is 2.1%; with 30–​70% ST segment resolution 5.2%; with no ST segment resolution 5.5%; and with worsening ST segment elevation 8.1%. Non-​ST elevation myocardial infarction ECG changes in NSTEMI are more variable than in STEMI. The ECG may be normal on first presentation and remain unchanged throughout the acute admission. There may be transient ST segment depression indicative of myocardial ischaemia. In 20–​30%, the only change will be T-​wave inversion. Risk-​scoring systems have

(a)

(b)

Fig. 16.3.1.17  (a) Acute inferolateral ST segment elevation myocardial infarction. (b) Substantial (but not complete) resolution of ST segment elevation 90 min after the initiation of thrombolysis.

16.3.1 Electrocardiography

been developed, for example, by the Trials In Myocardial Infarction group (http://​www.timi.org), for use in patients with ACS. These are described in Chapter 16.13.4: with regard to NSTEMI, ST segment deviation greater than 0.5 mm is one of the recorded parameters. The extent of ST depression identifies those who are most likely to benefit from early revascularization (FRISC II trial). Mortality with early invasive therapy is 4% with ST segment depression, 2% with no ECG changes, and 0.2% with T-​wave inversion.

Difficult diagnoses in acute myocardial infarction Right ventricular infarction The ECG provides prognostic as well as diagnostic information. An inferior infarction generally carries a good prognosis unless it is associated with a right ventricular infarction, when there is a sixfold increased risk of a major in-​hospital complication, including

ventricular fibrillation, reinfarction, and death. The right ventricle is involved in about 50% of those with an inferior infarction, occurring with occlusion of the right coronary artery, causing a transmural infarct of the inferoposterior wall and the posterior septum. To determine whether the right ventricle is involved in an inferior infarction, an ECG should be recorded with the anterior chest leads placed on the right side of the chest, in equivalent (but mirrored) positions to a standard 12-​lead ECG. The right ventricle is involved if there is greater than 1 mm ST segment elevation in chest lead ‘right V4’ (RV4); this has a sensitivity of 100%, specificity of 87%, and positive predictive value of 92% for occlusion of the right coronary artery proximal to the right ventricular branch. If these changes are absent, the right ventricle has been spared (Fig. 16.3.1.18).

Atrial infarction This occurs in up to 10% of myocardial infarcts in conjunction with ventricular infarction. A  clue to its presence is PR segment

(a)

(b)

Fig. 16.3.1.18  (a) Inferior ST segment elevation myocardial infarction. (b) Inferior ST segment elevation myocardial infarction with right ventricular involvement (note the right ventricular chest leads, with ST segment elevation in lead RV4).

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displacement but there may also be an abnormal P wave. It can cause rupture of the atrial wall and is frequently associated with atrial arrhythmias including atrial fibrillation, atrial flutter, and atrioventricular nodal rhythm.

Coronary artery spasm The pain of Prinzmetal’s or variant angina is not usually triggered by exercise, emotion, cold, or a meal but tends to occur at rest, accompanied by transient, marked ST segment elevation. This rapidly reverts to normal when the pain resolves spontaneously or with glyceryl trinitrate. Atrioventricular block or ventricular arrhythmia may accompany spasm-​induced myocardial ischaemia. Spasm sufficient to cause myocardial ischaemia, myocardial infarction, and sudden death can follow cocaine use.

Reciprocal changes—​septal ischaemia or posterior infarction? ST or ‘reciprocal’ depression may be seen in leads remote from the site of a STEMI. For example, ST depression may be seen in leads V1 to V4 in an inferior STEMI. There are two explanations. First, in a right-​dominant system (70% of the population), the right coronary artery supplies the posterior interventricular septum, which becomes ischaemic with an inferior STEMI; the ischaemia resolves within a few days as septal perforating arteries from the left anterior descending artery dilate in response to ischaemic stress. Second, in a left-​dominant system, the circumflex supplies the posterior interventricular septum; if this occludes, a ‘true posterior infarction’ follows.

Difficulties in diagnosing STEMI ‘Stuttering’ infarction Symptoms of myocardial infarction are usually severe and of sudden onset. Occasionally, the onset of symptoms is not so clear cut and chest pain may resolve but recur at intervals over several hours. The time of arterial occlusion is at best a guess, but for practical purposes is taken as the time that symptoms increase or are at their worst.

Non​infarct causes of ST segment elevation Pericarditis may mimic the pain of myocardial infarction but is usually relieved by sitting forward and is accompanied by a pericardial rub. The ST segments are elevated diffusely, do not fit the usual lead pattern for an inferior or anterior infarction, and, unlike the convexity of STEMI, are concave upwards (Fig. 16.3.1.19). Prinzmetal’s angina, caused by coronary artery spasm, can also mimic myocardial infarction. This usually occurs at rest, with marked ST elevation during pain and a brisk response to glyceryl trinitrate. The ST segment can be elevated chronically in left ventricular aneurysm, left ventricular hypertrophy, LBBB, hypertrophic cardiomyopathy, acute cor pulmonale, hypothermia, and cocaine abuse. A  normal variant is so-​called ‘high take-​off ’ where serial ECGs show consistent ST elevation across most ECG leads; patients should be given a copy of the ECG to show to medical personnel to avoid unnecessary investigations and treatment. Late presentation Patients who present to hospital outside the 12-​h time limit for reperfusion are sometimes diagnosed as ‘missed infarction’. The ECG may show signs characteristically seen later in the infarction process, with ST segments only slightly elevated, with established Q waves and inverted T waves. Over the next few days, the ST segment fully returns to baseline and Q waves and T waves deepen. LBBB Recognition of acute STEMI in pre-​existing LBBB is challenging, but the Sgarbossa criteria help. Five points are scored for ST elevation 1 mm or greater in at least one lead with a positive QRS complex, 3 points for ST depression 1 mm or greater in leads V1–​V3, and 2 points for 5 mm or greater ST elevation in leads with a negative QRS complex. A score of 3 points or greater has a 90% specificity (but a poor sensitivity) for acute myocardial infarction. ECG changes of ‘old’ infarction Q waves, once formed, usually persist indefinitely and so are a reliable indicator of a previous myocardial infarction (Fig. 16.3.1.20).

Fig. 16.3.1.19  Widespread elevation of the ST segments (concave upwards) in a case of pericarditis.

16.3.1 Electrocardiography

Fig. 16.3.1.20  ‘Old’ inferior myocardial infarction: pathological Q waves in leads II, III, and aVF.

However, there are several other causes of a Q wave that may cause confusion, the most common being hypertrophic cardiomyopathy and idiopathic cardiomyopathy. Rarer causes include myocarditis, cardiac amyloid, neuromuscular disorders (e.g. muscular dystrophy, myotonic dystrophy, Friedreich’s ataxia), scleroderma, sarcoidosis, and an anomalous coronary artery. Pre-​excitation WPW syndrome makes interpretation of the ECG more complicated. It may mask a myocardial infarction if conduction via the bypass tract is towards the left ventricle, as a Q wave will not be apparent. WPW may also simulate an infarction due to a negative δ-wave in the inferior leads producing Q waves. Serial or previous ECGs will reveal the true diagnosis. Patients with WPW syndrome should be given a copy of their ECG to avoid confusion and unnecessary future investigations. T-​wave inversion Atypical ECG features are seen in up to half of all infarctions in the early stages. Alone, these changes are not diagnostic. They can occur in ventricular aneurysm, electrolyte abnormalities, myocarditis, and subarachnoid haemorrhage, and with some drugs. Serial ECGs are necessary to establish a firm diagnosis. Deep, symmetrical ‘arrowhead’ T waves developing during an infarction are most often due to proximal occlusion of the left anterior descending coronary artery (Fig. 16.3.1.21).

Where errors occur Incorrect interpretation of an ECG leads to inappropriate patient triage and misses the opportunity to provide reperfusion therapy, whether by angioplasty or thrombolysis. In the worst-​case scenario, inappropriate thrombolysis might lead to a haemorrhagic stroke or ruptured aneurysm. Up to 12% of those with a high-​risk ECG (i.e. ST segment elevation of at least 0.1 mV, ST segment depression of at least 0.05 mV, or T-​wave inversion of at least 0.2 mV in two or more contiguous leads) are missed on admission to the emergency department. The ECG provides a ‘snapshot’ of electrical events within the heart, when the clinician really needs a ‘movie’ to monitor the dynamic changes of an acute coronary syndrome. If a diagnosis cannot be made on the presenting ECG but the history suggests an acute coronary syndrome, the patient should be admitted to a monitored area, a review by a specialist should be arranged, and the ECG should be repeated if symptoms get worse or if ST segment changes are seen on the monitor. This will ensure prompt and appropriate treatment. While it may be important to provide treatment promptly to fulfil audit targets (e.g. door-​to-​balloon time for primary PCI), speed should not replace accuracy in diagnosis. It is sometimes better to repeat the ECG than to make an incorrect diagnosis. It is easy to place too much reliance on minor changes on the ECG; it is clear changes of ST elevation or depression within the aforementioned parameters, that should determine treatment.

Fig. 16.3.1.21  Recent anterior ST segment elevation myocardial infarction with ‘arrowhead’ T-​wave inversion.

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Exercise ECG testing ECG changes on exercise were first reported in patients with chronic stable angina in the early 1900s. Exercise testing was adopted into routine clinical practice soon after a standardized exercise protocol was developed.

Cardiovascular responses to exercise in normal subjects and in coronary disease Normally on treadmill exercise, heart rate increases as a result of diminished vagal and increased sympathetic outflow. Heart rate increases on commencing exercise and reaches a plateau during each stage of the exercise test. A rapid increase may be due to lack of fitness, prolonged bed rest, anaemia, or dehydration. Systolic blood pressure increases in line with increased cardiac output, while diastolic pressure is near constant or falls slightly due to vasodilatation. On stopping the test, heart rate slows within a few minutes to pretest levels and both systolic and diastolic blood pressure falls, often to below pretest levels, as a result of vasodilatation. With cardiac disease, the maximum cardiac rate may be attenuated (even in the absence of a β-​blocker) due to sinus node disease, coronary heart disease, or postinfarction (with or without β-​ blockade). Failure to achieve the maximum predicted heart rate, calculated as 220 minus age, is suggestive of cardiac disease. Brady-​and tachyarrhythmias including atrial fibrillation may occur. Exercise-​induced hypotension, even a transient fall in blood pressure at (near-​)maximum heart rate, is indicative of severe heart disease and increases the risk of ventricular fibrillation. On stopping exercise, systolic pressure falls to resting levels (or lower) within minutes, where it may remain for several hours. In some, venous pooling may cause a precipitous drop in systolic pressure. ECG changes with exercise in normal subjects and in coronary disease In normal subjects, exercise-​induced tachycardia causes shortened PR, QRS, and QT intervals, increased P wave amplitude, and

down-​sloping of the PR segment. R waves and T waves may diminish, and S waves increase at maximum exercise. The J point (the isoelectric point where the S wave reaches the baseline) may become depressed in all leads and the ST segment may become up-​sloping. The most helpful ECG marker of exercise-​induced myocardial ischaemia is the ST segment which becomes depressed with increasing heart rate. This is due to shortening of the action potential due to ischaemia, setting up electrical gradients between endocardium and epicardium. Horizontal or down-​sloping ST depression, measured 60–​80 ms after the J point, of 1 mm (0.10 mV) or more for 80 ms in at least three complexes is considered significant (Fig. 16.3.1.22), but the leads in which ST depression appear do not reliably localize the site of myocardial ischaemia. Other indicators of myocardial ischaemia include: • ST segment elevation—​ this indicates severe ischaemia due to proximal disease or coronary spasm, or an aneurysmal or dyskinetic left ventricle. Unlike exercise-​induced ST segment depression, the ECG site of ST segment elevation is relatively specific for the coronary artery involved. • T-​ wave inversion—​ this may occur with exercise-​ induced hyperventilation. • Normalization of an inverted T wave—​this alone is not indicative of coronary disease. • U wave inversion—​this is relatively specific for coronary artery disease but is relatively insensitive; in precordial leads, it usually indicates left anterior descending coronary artery disease.

Exercise protocols Various protocols have been developed but the most widely used are the following. Bruce protocol This is a multistage test with 3-​min walking periods during which a steady state is reached before the workload is increased by increasing the speed and slope of the treadmill. It is clearly only suitable for

Fig. 16.3.1.22  ECG recorded during an exercise treadmill test, showing anterolateral ST segment depression after 3 min of exercise using the Bruce protocol.

16.3.1 Electrocardiography

Table 16.3.1.2  Table of MET equivalents Occupation

METs

Activity

METs

Receptionist

1–​2

Carrying a suitcase

7

Professional (active)

1.5–​2.5

Cleaning floor

4

Homemaker

1.5–​4

Washing clothes

5

Farm worker

3.5–​7.5

Cooking

3

Construction worker

4–​8.5

Gardening

4

Miner

4–​9

Push mower

5

Postal carrier

2.5–​5

Sex

5

Bed-​making

5–​6

those whose walking is not limited by other considerations (e.g. musculoskeletal or neurological). For older patients or those with limited exercise capacity, the test can be modified to include two stages with lower workload demands. Bicycle ergometry This is often combined with radionuclide imaging (see Chapter 16.3.3), which increases the sensitivity and specificity of the test. Cycling avoids motion artefact, and so ECG recordings are clearer. The patient pedals at a comfortable speed of between 60 and 80 revolutions/​ min; the test is terminated if speed cannot be maintained above 40 revolutions/​min. Exercise workload begins at 25 W and resistance is increased every 2 min in 25-​W increments by applying either an electronic or mechanical brake. The workload achieved during exercise is measured in metabolic equivalents or METs. This allows comparison of different protocols. A MET is 3.5 ml/​min per kg, the resting Vo2 for a 40-​year-​old 70 kg male. METs equivalent to normal daily activities have been estimated (Table 16.3.1.2).

Conducting the exercise test Who should have an exercise test? Deciding who should and who should not undergo an exercise test requires clinical judgement and the test should not be organized as a routine. Exercise testing is used to: • assess functional capacity and estimate prognosis in the evaluation of chest pain; • assess patients with known coronary artery disease; • establish prognosis after myocardial infarction either predischarge (submaximal test) or 4–​6 weeks post-​discharge (symptom-​limited); • assess the effectiveness of coronary revascularization; • assess patients with symptoms of exercise-​ induced cardiac arrhythmia; • risk-​stratify before non​cardiac surgery in patients with or at high risk of coronary disease; • determine the efficacy of rate-​responsive pacemakers.

Exercise testing may also be indicated in selected asymptomatic individuals: • in specific occupations for licensing purposes (e.g. airline pilots, bus, or heavy goods vehicle drivers); • with more than two cardiovascular risk factors for risk stratification; • wishing to commence a strenuous exercise programme; • to assess cardiovascular risk due to prior to major surgery. Who should not have an exercise test? In its 2016 guideline on assessing chest pain of recent onset, the National Institute for Health and Care Excellence (NICE) recommended that exercise testing should no longer be used to diagnose or exclude stable angina in those without known coronary artery disease. Some conditions are considered to be absolute contraindications to exercise testing but even in these patients a submaximal test may be informative. Exercise testing is inappropriate: • in healthy individuals with a low-​risk factor profile—​the false-​ positive rate is increased (see next); • with unstable medical conditions such as unstable angina; severe congestive cardiac failure; uncontrolled ventricular or supraventricular arrhythmia; myocarditis; severe pulmonary hypertension; drug toxicity; haemodynamic instability; symptomatic aortic stenosis; active thromboembolic disease; hypertension with systolic blood pressure more than 200  mm Hg or diastolic blood pressure more than 110 mm Hg; • in extreme obesity; • when taking specific medication—​digoxin depresses the ST segment (Fig. 16.3.1.23); type 1 antiarrhythmics and tricyclic antidepressants may be proarrhythmic; • in vasoregulatory disorders—​pulse and blood pressure changes are unpredictable. Patients with aortic stenosis may fail to report symptoms of angina, breathlessness, and syncope. Although severe symptomatic aortic stenosis is considered an absolute contraindication to exercise testing, a medically supervised symptom-​limited test in those who appear to be asymptomatic during their everyday activities may identify those who warrant cardiac catheterization and valve replacement. Who should supervise an exercise test—​cardiac technician, specialist nurse, or physician? Patients with new or recent-​onset chest pain thought to be angina are often referred to a rapid-​access chest pain clinic for assessment, where a specialist nurse carries out an initial assessment and then an exercise test. Experience shows that this approach is safe, provided a physician is available for consultation and advice. There are some high-​risk situations where the test, if it must be carried out, should

Fig. 16.3.1.23  Depression of the ST segments caused by digoxin.

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be supervised by a physician. These include patients whose symptoms are unstable, aortic stenosis, known severe coronary disease, severe or moderate systemic or pulmonary hypertension, severe left ventricular dysfunction, congestive or hypertrophic cardiomyopathy, or a history of ventricular tachycardia, or second or third-​ degree atrioventricular block.

Risks of exercise testing Exercise testing is generally considered a safe procedure but full resuscitation facilities, including defibrillator, emergency drug kit, airways management equipment, and oxygen are essential. Serious complications are rare. The risk of myocardial infarction and sudden death is less than 1 in 1000, more when testing patients after myocardial infarction or with malignant ventricular arrhythmia. When to stop an exercise test Reasons for stopping a test include: • achieving 90% of the maximum predicted heart rate; • symptoms—​establish if these are typical symptoms of chest pain or breathlessness; exercise may continue provided that symptoms are not distressing or severe; • systolic blood pressure—​if systolic blood pressure falls below baseline levels or if systolic increases to greater 250 mm Hg or diastolic to greater than 115 mm Hg; • change in ECG—​if more than 2 mm ST segment depression or more than 1 mm ST segment elevation; or if LBBB (this may look remarkably like ventricular tachycardia at fast heart rate) or arrhythmia develops; • clinical signs—​if signs of poor peripheral perfusion such as cyanosis appear; • symptoms of central nervous system dysfunction—​dizziness, near syncope, or ataxia; • serious arrhythmia—​ventricular tachycardia, multifocal ectopics, ventricular couplets; • technical difficulties—​failure of blood pressure recording or poor ECG trace; • patient request—​distressing symptoms of fatigue, breathlessness, wheeze, or claudication; maximal patient effort; or inability to maintain speed of treadmill. Recovery period It is important to observe the patient into the recovery period until the pretest heart rate and blood pressure have been restored. Minor ECG abnormalities early in recovery are common but late changes usually indicate myocardial ischaemia.

Interpreting the results of an exercise test Like all medical tests, the exercise test is not a perfect indicator of the presence or absence of disease. Nevertheless, a test is often described as: • positive—​chest pain develops with or without ST displacement; blood pressure falls; arrhythmia occurs; the patient fails to complete the first two stages of the Bruce protocol or reach 90% of predicted maximum heart rate;

• negative—​the patient completes uneventfully three stages of the Bruce protocol or reaches 90% of predicted maximum heart rate; • indeterminate—​90% predicted heart rate is not reached; symptoms occur which are not typical of cardiac pain with a normal ECG throughout. A positive test does not necessarily mean that the patient has coronary disease, nor does a negative test mean the patient has some other, non​cardiac, cause for chest pain. The exercise test has limited use as a diagnostic test for coronary disease.

Limitations and strengths of the exercise test The exercise test as a diagnostic tool The sensitivity of the exercise test, the proportion with coronary disease correctly identified by the test, is 68% (range 23–​100) and specificity, the proportion free of disease correctly identified by the test, is 77% (range 17–​100). In multivessel disease, these figures are 81% (range 40–​100) and 66% (range 17–​100), respectively. This means that exercise testing frequently yields false-​positive results, incorrectly diagnosing disease when coronary arteries are normal or minimally diseased; and false-​negative results, missing coronary disease when a flow-​limiting, even critical left main stem, coronary stenosis is present. Selection of patients for exercise testing is important as a false-​ positive result is more likely when an individual has few predisposing risk factors for coronary disease or the prevalence of coronary disease prevalence in the population is low. Example 1 A positive test in a middle-​aged man with multiple coronary risk factors (smoking, dyslipidaemia, hypertension, diabetes mellitus, and family history) and typical chest pain on exertion (who is highly likely to have coronary disease) is most likely to be correct. Example 2 A positive test in a young woman with atypical chest pain and few or no cardiovascular risk factors is likely to be incorrect and may lead to other, more invasive tests including coronary angiography. The prevalence of coronary disease is lower in women than men and the specificity of exercise testing is lower in women, which means that the test is more likely to be positive in the absence of coronary disease, possibly due to increased catecholamine secretion during exercise contributing to coronary vasoconstriction. The exercise test as an indicator of prognosis Although the exercise test is of limited value as an aid to diagnosis, it is more reliable as a marker of prognosis. Generally, appearance of symptoms or ECG changes early in the test is associated with more severe and extensive coronary disease and a poor prognosis (Table 16.3.1.3). Changes within the first 3 min usually indicate severe coronary disease affecting the left main stem or the proximal segments of at least one major coronary artery. Multivessel coronary disease is more likely with ST segment down-​sloping, delayed ST normalization after exercise, increased number of leads affected, and lower workload at which ECG changes appear.

16.3.1 Electrocardiography

Table 16.3.1.3  Prognostic indicators on treadmill testing

ST segment

Indicators of a good prognosis

Indicators of a poor prognosis

No displacement or up-​sloping

2 mm or more depression in stage 1 Bruce-​within 3 minutes Down-​sloping or horizontal

Duration of exercise

9 minutes (>9 METs)

Unable to complete stage 2 Bruce or equivalent (120/​min off β-​blocker

Systolic BP response

Maintained or increased

Sustained decrease >10 mm Hg or failure to rise with exercise

Changes on exercise

No changes

Ventricular tachycardia U wave inversion T wave normalization

Recovery

Recovers normal heart rate 10 min

Symptoms

None or atypical

Test terminated due to increasing angina on exercise

Difficulties with exercise testing Baseline ECGs that make interpretation of the exercise test difficult ECG patterns that may make exercise-​induced changes hard to recognize include: • ST depression or elevation at rest • Ventricular strain patterns—​left and right ventricular hypertrophy; • T wave changes—​inversion secondary to previous infarction or ‘strain’ • Conduction abnormalities—​LBBB affects ST segment and T wave; RBBB affects ST segment and T wave changes in V1, V2, and V3 • Prolonged QT interval Alternative tests that do not rely on the ECG to identify myocardial ischaemia are dobutamine stress echocardiography, radionuclide thallium, or myocardial perfusion imaging (MIBI) stress test, or cardiac MRI (see Chapters 16.3.2 and 16.3.3). Medication and exercise testing β-​Blockers and rate-​modifying calcium antagonists may mask myocardial ischaemia by limiting exercise-​induced tachycardia and so delay the appearance of ST depression. Blood pressure-​ lowering medication may blunt the normal exercise-​induced rise in pressure. Digoxin may induce or accentuate ST depression on the resting ECG. Medication may be continued if the indication for exercise testing is to assess the efficacy of treatment but should be temporarily stopped in all other circumstances. Specific rules apply if assessing for driving licensing purposes—​always check local rules, but generally, antianginal drugs must be stopped at least 48 h prior to the assessment. ST segment depression in the absence of symptoms Asymptomatic, exercise-​induced ST segment depression, or ‘silent ischaemia’, is seen in 60% of patients with coronary disease but does not increase the risk of cardiac death compared with those who report angina. Technical issues Current ECG machines filter out motion and muscle artefact to facilitate measurement of the ST segment. Because leads placed

on the limbs produce motion artefact, moving these to the torso exaggerates the degree of change and increases the amplitude of the R wave, potentiating exercise-​induced ST segment changes. It can be difficult to identify ST segment depression during exercise. If there is any doubt about the extent of ST segment depression on the running ECG, most automated machines will provide a filtered 12-​lead ECG for comparison with baseline.

Exercise testing in special groups Peri-​and post-​myocardial infarction Exercise testing after myocardial infarction may be performed for risk stratification and selection for revascularization. A submaximal predischarge test to identify residual ischaemia appears to be safe, with 0.05% morbidity and 0.02% mortality. An abnormal blood pressure response or low exercise capacity predicts a poor outcome and is an indication for urgent revascularization. Evidence of myocardial ischaemia, especially at low workload, is an indication for referral for coronary angiography. Elderly patients Advanced age alone is not a contraindication to exercise testing, provided that the individual can walk at a reasonable speed. If mobility is limited, dobutamine stress echocardiography, radionuclide thallium, or MIBI stress test, or cardiac MRI are alternative means of identifying ischaemia (see Chapters  16.3.2 and 16.3.3). Asymptomatic individuals Testing may be undertaken in asymptomatic individuals, generally a low-​risk population, as part of health screening, for insurance purposes, or for risk stratification. Up to 12% of middle-​aged men and up to 30% of women will have an abnormal exercise test in the absence of symptoms; the risk of a cardiac event is low unless the test result indicates a poor prognosis. The presence of cardiovascular risk factors increases the likelihood of coronary disease. Cardiac arrhythmia Exercise testing can be useful in evaluating cardiac arrhythmia, supplementary to ambulatory monitoring and electrophysiological studies. In about 10%, it may provoke an arrhythmia.

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FURTHER READING Bruce, RA, Fisher LD (1987). Exercise-​enhanced assessment of risk factors for coronary heart disease in healthy men. J Electrocardiol, 20 (Suppl. October), 162. Cura FA, et al. (2004). ST segment resolution 60 minutes after combination treatment of abciximab with reteplase or reteplase alone for acute myocardial infarction (30-​day mortality results from the resolution of ST segment after reperfusion therapy substudy). Am J Cardiol, 94, 859–​63. Einthoven W (1912). The different forms of the human electrocardiogram and their signification. Lancet, 1, 853–​61. Gianrossi R, et  al. (1989). Exercise-​ induced ST segment depression in the diagnosis of coronary artery disease:  a meta-​analysis. Circulation, 80,  87–​98. Hancock EW, et  al. (2009). AHA/​ ACCF/​ HRS recommendations for the standardization and interpretation of the electrocardiogram:  part V:  electrocardiogram changes associated with cardiac chamber hypertrophy. J Am Coll Cardiol, 53, 992–​1002. Houghton AR, Gray D (2014). Making sense of the ECG, 4th edition. Hodder Arnold, London. Joint European Society of Cardiology/​American College of Cardiology Committee (2000). Myocardial infarction redefined—​a consensus document of the joint European Society of Cardiology/​American College of Cardiology Committee for the Redefinition of Myocardial Infarction. Eur Heart J, 21, 1502–​13. Kligfield P, et  al. (2007). Recommendations for the standardization and interpretation of the electrocardiogram: part I: the electrocardiogram and its technology. J Am Coll Cardiol, 49, 1109–​27. Knaapen P, van Loon RB, Visser FC (2005). A rare cause of ST segment elevation. Heart, 91, 188. Levy D, et  al. (1990). Determinants of sensitivity and specificity of electrocardiographic criteria for left ventricular hypertrophy. Circulation, 81, 815–​20. Lloyd Jones DM, et al. (1998). Electrocardiographic and clinical predictors of acute myocardial infarction in patients with unstable angina pectoris. Am J Cardiol, 81, 1182–​6. Marey EJ (1876). Des variations électriques des muscles et du coeur en particulier étudiés au moyen de l’electromètre de M Lippman. C R Acad Sci (Paris), 82,  975–​7. Mason JW, et  al. (2007). Recommendations for the standardization and interpretation of the electrocardiogram:  part II: electrocardiography diagnostic statement list. J Am Coll Cardiol, 49, 1128–​35. Mueller C, et  al. (2004). Prognostic value of the admission electrocardiograph in patients with unstable angina/​ST segment elevation myocardial infarction treated with very early revascularisation. Am J Med, 117, 145–​50. National Institute of Health Care Excellence (2016). Chest pain of recent onset. Clinical guideline. https://​ w ww.nice.org.uk/​ guidance/​c g95 Rautaharju PM, et  al. (2009). AHA/​ACCF/​HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval. J Am Coll Cardiol, 53, 982–​91. Savonitto S, et al. (1999). Prognostic value of the admission electrocardiogram in acute coronary syndromes. JAMA, 281, 707–​13. Sharma S, et al. (2017). International recommendations for electrocardiographic interpretation in athletes. J Am Coll Cardiol, 69, 1057–75.

Surawicz B, et al. (2009). AHA/​ACCF/​HRS recommendations for the standardization and interpretation of the electrocardiogram:  part III: intraventricular conduction disturbances. J Am Coll Cardiol, 53, 976–​81. Wagner GS, et al. (2009). AHA/​ACCF/​HRS recommendations for the standardization and interpretation of the electrocardiogram:  part VI: acute ischemia/​infarction. J Am Coll Cardiol, 53, 1003–​11. Waller AD (1887). A demonstration on man of electromotive changes accompanying the heart’s beat. J Physiol (Lond), 8, 229–​34.

16.3.2 Echocardiography James D. Newton, Adrian P. Banning, and Andrew R. J. Mitchell ESSENTIALS Ease of use, rapid data provision, portability, and safety mean that echocardiography has become the principal investigation for almost all cardiac conditions. A  modern transthoracic echocardiography examination combines real-​time two-​dimensional imaging of the myocardium and valves with information about velocity and direction of blood flow obtained by Doppler and colour-​flow mapping. A complete examination can be performed in most patients in less than 30 min. Valvular heart disease—​echocardiography has revolutionized the diagnosis and follow-​up of patients with these conditions. Serial cardiac catheterization to assess severity and progress of valvular stenosis has been completely superseded by Doppler echocardiography, and the role of invasive investigation is increasingly limited to the assessment of the coronary arteries prior to revascularization. Transoesophageal echocardiography—​this is now a routine investigation in many centres. Under sedation, an ultrasound probe is passed into the oesophagus to a position behind the heart, producing excellent resolution of cardiac structures. It is used diagnostically in many emergency situations, including aortic dissection and suspected prosthetic mechanical valve dysfunction, and as an additional method of monitoring cardiac performance during cardiac and noncardiac surgery. Other technological developments—​ these include (1)  stress echocardiography—​used to detect occult coronary disease and predict cardiac risk; (2) use of contrast agents—​these improve visualization of the endocardium in patients with poor acoustic windows and allow some estimation of myocardial perfusion; and (3)  real-​time three-​dimensional imaging—​this is available on modern platforms and allows detailed assessment of myocardial and valve function. Recent developments in assessing myocardial mechanics by quantifying strain offer new insights into early pathological changes, and progressive miniaturization of platforms including fully portable systems have further increased the utility of echocardiography in the assessment of cardiac structure and function.

16.3.2 Echocardiography

History of echocardiography The timeline of key discoveries and inventions is as follows: • 1842—​Christian Doppler observed that the pitch of a sound varies if the source is moving. • 1880—​first piezoelectric crystals developed. • 1912—​Richardson develops sonar technique using sound waves to detect underwater objects. • 1929—​ Sokolov uses ultrasound to identify flaws in metal components. • 1954—​ heart visualized with ultrasound by Carl Herz and Inge Edler. • 1960s—​ multielement scanners lead to development of two-​ dimensional (2D) echocardiography. • 1970s—​ Doppler colour-​ flow mapping used to evaluate valve disease. • 1970s—​transoesophageal and stress echocardiography developed. • 1980s—​ultrasound contrast agents developed. • 1990s—​intracardiac and intracoronary ultrasound in wider use. • 2000s—​development and refinement of three-​dimensional (3D) echocardiography and advances in myocardial deformation imaging.

Principles of echocardiography The transducer used for most echocardiographic examinations contains piezoelectric crystals that emit ultrasound frequencies of 2.5–​5 MHz. Most of the sound energy is scattered or absorbed, but reflection occurs at interfaces between tissues of different acoustic impedance (e.g. between blood and muscle). The transducer collects these reflections and the time delay between emission and reception is calculated. This allows the depth of the reflection to be derived and its position to be displayed on a screen as a dot (pixel). The brightness of the dot is related to the magnitude of the reflected signal. In general, higher-​frequency transducers allow better discrimination between structures, but the increased attenuation leads to reduced penetration. There are three main echocardiographic techniques:  two-​ dimensional (cross-​sectional), M-​mode, and Doppler.

Fig. 16.3.2.1  Parasternal long-​axis view of the heart using 2D echocardiography. The sector images through the right ventricle (RV) to the left ventricle (LV). In this view, 2D echocardiography provides useful data on the structure and function of the aortic valve (AV) and mitral valve (MV).

reflections from cardiac structures being displayed as horizontal lines, with superficial structures at the top of the screen and the deeper structures at the bottom (Fig. 16.3.2.2). These data are interpretable when one knows which structure each line represents. The technique has excellent spatial resolution and temporal resolution; hence, with the advent of 2D echocardiography and Doppler, M-​mode is now principally used for measurement of cardiac chamber dimensions and observation of the relative movement of cardiac structures to each other; for example, the relationship of the anterior leaflet of the mitral valve to the septum in hypertrophic cardiomyopathy.

Doppler echocardiography The Doppler principle allows the velocity and direction of movement of an object (blood or myocardium in the case of cardiac ultrasonography) to be calculated from the shift in the frequency of a reflected waveform relative to the observer. Cardiac imaging employs pulsed-​ wave, continuous-​ wave, and colour Doppler techniques. Pulsed-​wave Doppler allows information about flow to be obtained from a defined point within the heart. The range of detectable velocities is limited, and the technique is used for sampling normal and low velocities (e.g. mitral valve flow).

Two-​dimensional echocardiography (cross-​sectional) Cross-​sectional images are constructed as the ultrasound beam sweeps across the heart in a sector (Fig. 16.3.2.1). Between 50 and 100 cross-​sections are presented each second, giving the impression of a moving picture. These images are readily interpretable by an observer with knowledge of cardiac anatomy, and this technique is the cornerstone of modern echocardiography.

M-​mode echocardiography M-​mode echocardiography preceded modern 2D imaging. Unlike 2D imaging, which uses a series of sweeps across the heart, M-​mode uses a single static beam of ultrasound pulses at a very high frequency. The narrow beam is analogous to a vertical mineshaft passing through various layers of rock. Displayed in real time, this results in

Fig. 16.3.2.2  M-​Mode view of the left ventricle. The high imaging frequency of M-​mode allows accurate measurements of structures to be made, in this case the diastolic (D) and systolic (S) cavity size.

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Fig. 16.3.2.3  Continuous-​wave Doppler of the aortic valve showing aortic regurgitation (flow towards the probe above the line). Calculations can be performed using on-​machine software to instantly provide useful haemodynamic data.

Continuous-​wave Doppler identifies the peak velocity encountered along the whole of the ultrasound beam and is particularly valuable for measuring high-​velocity jets such as those in aortic valve disease (Fig. 16.3.2.3). It is important to remember, however, that failure to align the transducer exactly parallel to flow results in measurement of artefactual low velocities and potentially an underestimation of valvular stenosis. Colour Doppler allows a dynamic representation of the direction and velocity of flow to be superimposed on to a 2D image of the heart. Velocities towards the transducer are usually coded in red and velocities away in blue (Fig. 16.3.2.4). Turbulent and high-​velocity flow produces variable velocities and results in a mosaic pattern that is ideal for characterization of regurgitant lesions. This technique is now so sensitive that it can detect trivial regurgitation during the closure of many normal heart valves. Tissue Doppler echocardiography uses the same principles but by changing the settings the direction and velocity of the myocardium is encoded rather than the blood pool. Pulse-​wave Doppler can then be used to interrogate a specific part of the myocardium and

Fig. 16.3.2.5  Tissue Doppler of the basal interventricular septum allowing measurement of the systolic contraction (S) and early passive relaxation (E′) phase.

provide detailed information on myocardial mechanics in both systole and diastole (Fig. 16.3.2.5).

Transthoracic echocardiography Imaging is performed using dedicated echocardiography equipment with the patient lying on their left hip in the left lateral position and with their left arm behind their head to open the rib spaces. Ultrasound cannot travel through bone and thus cardiac imaging is performed via intercostal spaces to the left of the sternum and at the apex of the heart in the axillary line. These ‘echo windows’ provide standard views described as the parasternal short and long axis and apical two-​, four-​, and five-​chamber views. Useful additional views can also be obtained from the subcostal and suprasternal approach in some patients. A standard echocardiography examination involves 2D imaging from the parasternal, apical, and subcostal approaches supported by M-​mode measurements, continuous, pulsed, and colour Doppler and tissue Doppler imaging.

Valvular heart disease Transthoracic echocardiography is the investigation of choice for patients with suspected valvular heart disease. All four cardiac valves can be visualized and interrogated by Doppler and 2D echocardiography. Concomitant abnormalities in ventricular performance can be assessed simultaneously. Aortic stenosis

Fig. 16.3.2.4  Colour-​flow mapping of mitral regurgitation. There is high-​velocity flow in systole from the left ventricle into the left atrium through the mitral valve.

Two-​dimensional echocardiography can usually image the aortic valve cusps; if they are thin and freely mobile, it is unlikely that there is significant aortic stenosis. However, if the valve cusps are thickened and calcified, interrogation by continuous-​wave Doppler is mandatory. The severity of aortic stenosis is usually expressed as the peak pressure difference (or gradient) across the valve, and is calculated from the maximum flow velocity (V) using the modified Bernoulli equation (pressure gradient = 4 V2). In patients with normal left ventricular systolic function, a peak gradient measured by Doppler of over 65 mm Hg or a mean gradient of over 40 mm Hg suggests significant aortic stenosis. The aortic valve area can be estimated using the continuity equation which requires measurement of the left ventricular outflow tract diameter on 2D echo and

16.3.2 Echocardiography

Fig. 16.3.2.6  Continuous-​wave Doppler through the aortic valve. The peak velocity is 503 cm/​s. This equates to a peak pressure gradient (A0 max PG) of 101 mm Hg. Previous measurements of the left ventricular outflow tract diameter and velocity allow a calculated aortic valve area to be derived, in this case 0.57 cm2.

the velocity at this point using pulse-​wave Doppler (Fig. 16.3.2.6). Severe stenosis usually equates to a valve area of less than 1.0 cm2 but should be indexed to the patient’s body surface area. When chronic critical outflow obstruction results in declining left ventricular function and reduced cardiac output, the gradient produced by any degree of valve obstruction also falls. Doubt about the severity of the stenosis can usually be resolved by enhancing left ventricular function by administering intravenous dobutamine and evaluating the gradient during increased flow. Aortic regurgitation

Fig. 16.3.2.7  Pulse-​wave Doppler at the mitral valve leaflet tips in a patient with severe mitral valve stenosis. The pressure half-​time is calculated as 368 ms, giving an estimated valve area of 0.6 cm2.

estimating the area of the valve orifice either by direct planimetry on a 2D short-​axis image or from the Doppler pressure half-​time (mitral valve area = 220/​pressure half-​time). A valve area of less than 1.0 cm2 usually indicates severe mitral stenosis (Fig. 16.3.2.7). The mean gradient across the valve can also be measured by Doppler and is typically more than 10 mm Hg in severe stenosis. Transthoracic echocardiography is also used to assess the suitability of the mitral valve for balloon dilation, although transoesophageal imaging is necessary to exclude left atrial thrombus.

Assessment of the mechanism and severity of aortic regurgitation requires a combination of all three echocardiography modalities. M-​mode may demonstrate fluttering of the anterior leaflet of the mitral valve and, in the setting of acute severe aortic regurgitation, may reveal premature closure of the mitral valve. Two-​dimensional echocardiography will occasionally demonstrate prolapse of one more of the aortic cusps, but even severe aortic regurgitation can occur through an aortic valve that appears to be structurally normal. The severity of aortic regurgitation can be estimated using continuous-​ wave and colour Doppler (see Chapter  16.6, Figs. 16.14.1.3 and 16.14.1.4), although assessment can be difficult as it is influenced by left ventricular function and blood pressure. Doppler-​ derived pressure half-​time and measurement of regurgitant fraction and/​or flow convergence zone are valuable when there is uncertainty over lesion severity. M-​mode and colour Doppler can be combined and, when the regurgitant jet fills more than 50% of the left ventricular outflow tract, the regurgitation is classified as severe. Flow within the descending thoracic aorta can be measured using pulse-​ wave Doppler and in severe aortic regurgitation there is typically holodiastolic flow reversal—​analogous to the collapsing pulse. In patients with severe asymptomatic aortic regurgitation, serial increase in left ventricular dimensions or a progressive fall in ejection fraction are indications for surgery. However, any increase in ventricular dimension should be at least 0.5 cm before it is regarded as significant, given the limited reproducibility of echocardiographic parameters.

Mitral regurgitation

Mitral stenosis

Fig. 16.3.2.8  Apical four-​chamber view with colour-​flow demonstrating an eccentric jet of mitral regurgitation from the left ventricle (LV) to the left atrium (LA). In this case, the leak is due to prolapse of the posterior mitral valve leaflet.

Mitral valve stenosis is well visualized using either M-​mode or cross-​sectional echocardiography. Its severity can be determined by

Transthoracic echocardiography will usually demonstrate the mechanism and severity of mitral regurgitation. Two-​dimensional imaging identifies abnormalities of the valve leaflets and colour-​ flow shows jet direction and area (Fig. 16.3.2.8). Severe mitral regurgitation is suggested by increased left ventricular end-​diastolic dimension and hyperdynamic function due to volume overload.

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Table 16.3.2.1  Classification of mitral regurgitation Mild

Severe

Specific signs of severity Vena contracta Jet size PISA radius

0.7 cm

1.2 m/​s)

CW trace

Soft and parabolic

Dense and triangular

LV and LA

Normal size LV if chronic MR

Enlarged LV and LA if no other cause

CW, continuous wave; LA, left atrium; LV, left ventricle; PISA, proximal isovelocity surface area.

Precise quantification of the amount of regurgitation is demanding as it is influenced by left ventricular function, the direction of the jet, and left atrial size. Various algorithms have been devised to improve quantification of mitral regurgitation, including measurement of the flow convergence zone and the proximal isovelocity surface area (PISA) method, but most centres simply classify the extent of regurgitation as mild, moderate, or severe (Table 16.3.2.1). Pulmonary and tricuspid valve disease In adults, 2D imaging of the pulmonary valve may be difficult, particularly if there is lung disease. Despite this, accurate Doppler information is usually obtainable. Tricuspid stenosis is very uncommon, but some degree of tricuspid regurgitation is detectable even in healthy individuals. Measurement of the peak velocity of tricuspid regurgitation (V) is valuable as, in the absence of pulmonary valve disease, it can be used to estimate pulmonary artery (PA) systolic pressure: PA systolic pressure (mm Hg) = 4V2 + right atrial pressure    (usually 5−10 mm  Hg). Prosthetic valves Transthoracic echocardiography is commonly performed as part of the routine follow-​up of prosthetic valves. It is usually able to assess biological valves accurately, but for mechanical mitral valve prostheses, attenuation artefact produced by the metal may be problematic. Transoesophageal imaging is recommended when transthoracic imaging is suboptimal or if improved resolution is required, for example, in patients with suspected prosthetic valve endocarditis.

Haemodynamic assessment Using Doppler to evaluate flow across all four cardiac valves and the great vessels, the pressure within each cardiac chamber can be estimated and a comprehensive description of the current haemodynamic status provided (Fig. 16.3.2.9). This can be extremely helpful in the setting of intensive cardiorespiratory support,

although obtaining clear and accurate images in critically ill patients can be very challenging.

Abnormal left ventricular function In most patients, a full transthoracic echocardiography study will confirm or refute a clinical suspicion of left ventricular dysfunction and identify the likely aetiology of any abnormality. Systolic and diastolic left ventricular function can be assessed, and a variety of methods can be used to derive an estimate of left ventricular ejection fraction. The most accurate methods use imaging in two orthogonal planes or a 3D technique to model the whole left ventricle (Fig. 16.3.2.10). The normal ejection fraction (calculated from the end-​diastolic and end-​systolic volumes) is greater than 55%. An ejection fraction of 45–​54% equates to mild left ventricular dysfunction, 30–​44% to moderate dysfunction, and less than 30% to severe dysfunction. However, ejection fraction as a single measure of systolic function can be misleading as it is influenced by both preload and afterload, and can be preserved even with significant myocardial pathology. Advances in image processing have facilitated the advent of speckle tracking, whereby unique patterns of ultrasound reflections within the myocardium are tracked frame by frame and used to derive measures of myocardial deformation. The most robust of these is global longitudinal strain, with a value of  –​20% being considered normal and abnormal values being closer to 0%. There is emerging evidence that this parameter changes before ejection fraction and is more reproducible. In patients with ischaemic heart disease, assessment of regional wall motion is valuable. Segments may be described as normokinetic, hypokinetic, akinetic, dyskinetic, or aneurysmal. Detection of a regional wall motion abnormality in patients presenting with left ventricular systolic dysfunction supports an ischaemic aetiology. The echocardiographic assessment of diastolic dysfunction is complex, but increasingly important in the assessment of patients with heart failure presenting with a normal ejection fraction. Impaired diastolic filling is indicated by a combination of echocardiographic findings routinely measured. Measurements of early

16.3.2 Echocardiography

Fig. 16.3.2.9  An example of the haemodynamic parameters that can be estimated with a standard transthoracic echocardiography data set.

Fig. 16.3.2.10  Apical four-​chamber and two-​chamber views in end diastole and end systole with an overall ejection fraction derived from the change in volume.

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diastolic filling E (the peak early diastolic flow velocity) compared to that associated with atrial filling (A) giving an E/​A ratio greater than 1.0 are often used as an indicator of diastolic dysfunction but rely on the patient being in sinus rhythm and can be misleading in severe diastolic dysfunction where pseudo normalization may occur. The ratio of tissue Doppler measurement of peak early diastolic mitral annular tissue velocities (e′) in combination with peak early diastolic filling (E) providing a ratio (E/​e′) is also used as an indicator of diastolic dysfunction. A ratio greater than 15 is strongly supportive of diastolic dysfunction. The presence of an enlarged left atrium is an important discriminator as left atrial size is rarely normal in the presence of significant diastolic dysfunction. These parameters are often abnormal in older people and only support a diagnosis of diastolic heart failure in conjunction with appropriate clinical features. Pulmonary artery pressure Estimation of pulmonary artery pressure from a tricuspid regurgitant jet is possible in most echocardiographic examinations (see earlier). Causes of an elevated pulmonary artery systolic pressure (>35 mm Hg) include left heart failure, valvular disease (particularly mitral valve disease), pulmonary embolic disease, chronic obstructive airways disease, and pulmonary vascular disease. Left ventricular hypertrophy Left ventricular hypertrophy is detected by echocardiography and a measurement of left ventricular mass can also be derived. Transthoracic echocardiography may also detect intracardiac thrombus, particularly in patients with impaired systolic ventricular function (Fig. 16.3.2.11). Minor concentric left ventricular hypertrophy is common in patients with hypertension. In hypertrophic cardiomyopathy, 2D imaging may demonstrate asymmetrical septal hypertrophy with disproportionate thickening of the interventricular septum compared with the left ventricular free wall, or dramatic concentric hypertrophy with left ventricular cavity obliteration. Other characteristic features of hypertrophic cardiomyopathy include systolic anterior motion of the mitral valve and partial midsystolic closure

Fig. 16.3.2.11  Apical four-​chamber view showing the left ventricle (LV), left atrium (LA), right ventricle (RV), and right atrium (RA). There is a large thrombus attached to the left ventricular apical septum.

of the aortic valve, which usually correlates with the presence of outflow tract obstruction. In the absence of conditions that may induce ventricular hypertrophy (e.g. aortic stenosis), these findings are diagnostic of hypertrophic cardiomyopathy. Colour Doppler can demonstrate turbulence in the outflow tract and continuous-​ wave Doppler may detect characteristic ‘dynamic’ gradients that increase in severity as systole progresses. Other associated echocardiographic abnormalities in hypertrophic cardiomyopathy include mitral regurgitation and severe diastolic dysfunction.

Atrial fibrillation Most patients with atrial fibrillation should undergo echocardiography as it excludes a structural cause for atrial fibrillation (e.g. mitral stenosis) and facilitates thromboembolic risk stratification. It also allows measurement of left atrial dimensions, which can guide treatment as the success of cardioversion falls as the left atrium enlarges. Identification of left ventricular hypertrophy can guide the choice of antiarrhythmic drug therapy. Transoesophageal echocardiography can be useful to facilitate cardioversion in patients with atrial fibrillation of unknown duration by excluding intracardiac thrombus, particularly in the left atrial appendage (Fig. 16.3.2.12).

Following an embolic event or stroke Echocardiography is the investigation of choice when a cardiac source of an embolus is suspected. It should be considered in all patients presenting with embolic occlusion of a peripheral artery, or thromboembolic episodes in more than one vascular territory. Echocardiography should not, however, be performed in circumstances when the result is unlikely to influence patient management. In patients with ischaemic stroke and a low likelihood of atheromatous arterial disease, an echocardiogram can be considered as, occasionally, it will detect occult abnormalities such as a cardiac thrombus or atrial myxoma (Fig. 16.3.2.13). Enhancement of the right heart with non​transpulmonary contrast such as agitated saline should be considered to exclude paradoxical embolism through a cardiac shunt, and include Valsalva manoeuvres

Fig. 16.3.2.12  Transoesophageal echocardiography of a patient with atrial fibrillation. There is a large thrombus filling (and extending from) the left atrial appendage (LAA). LA, left atrium; LV, left ventricle.

16.3.2 Echocardiography

and have subtle abnormalities on mitral and tricuspid valve inflow Doppler patterns.

Pulmonary embolism Echocardiography can be useful in patients with pulmonary embolism as it can demonstrate right ventricular dilation and/​or impaired right ventricular systolic function. Tricuspid regurgitant velocity can be used to estimate pulmonary artery systolic pressure, although it is unusual for this to be more than 70 mm Hg acutely. Exceptionally, 2D imaging may show a thrombus within the right heart or the proximal pulmonary arteries. Although echocardiography is diagnostically useful when it demonstrates features consistent with pulmonary embolism, it cannot exclude the diagnosis.

Infective endocarditis Fig. 16.3.2.13  Transoesophageal echocardiography revealing a large myxoma in the left atrium (LA) and close to the mitral valve.

to augment any right to left shunt. In patients with a high clinical suspicion of a cardiac source of embolus, in whom transthoracic echocardiography is normal, transoesophageal echocardiography is recommended.

Pericardial disease Echocardiography is not routinely indicated in patients with uncomplicated pericarditis. It can, however, diagnose the presence of pericardial fluid and is useful when a pericardial effusion is suspected and percutaneous drainage is being considered. Echocardiographic signs of pericardial tamponade include exaggerated respiratory variation in the mitral valve Doppler, presystolic closure of the aortic valve, and (particularly) right atrial and right ventricular diastolic collapse (Fig. 16.3.2.14). Constrictive pericarditis is a difficult diagnosis to make using standard echocardiographic techniques. Patients may complain of episodic breathlessness and fluid retention, have characteristic abnormalities of the venous pressure,

Fig. 16.3.2.14  Apical four-​chamber view demonstrating a large pericardial effusion. There is collapse of the right ventricle, suggesting cardiac tamponade.

Echocardiography cannot be used to exclude endocarditis but is valuable when endocarditis is suspected clinically while there is insufficient data to make a formal diagnosis. Under these circumstances, a typical vegetation (Fig. 16.3.2.15) detected by an experienced observer is regarded as a major criterion in the Duke diagnostic classification, and this may facilitate appropriate management. Transoesophageal echocardiography should be performed when there is a suspicion of aortic root abscess, if prosthetic endocarditis is suspected, or occasionally, in cases where there is persistent diagnostic doubt and the additional sensitivity and spatial resolution of transoesophageal echocardiography might be valuable.

Congenital heart disease Echocardiography is the diagnostic modality of choice for patients with suspected congenital heart disease. Detailed transthoracic cardiac imaging is possible in cooperative infants and children, but occasionally sedation or a short anaesthetic may be required. Rates of cardiac catheterization have been reduced by miniaturization of transoesophageal probes that facilitate diagnosis and follow-​up of complex congenital heart disease. Fetal echocardiography is performed when surveillance obstetric ultrasound is abnormal, or in cases where previous history suggests a possible cardiac problem.

Fig. 16.3.2.15  Apical four-​chamber view demonstrating a large vegetation involving the mitral valve.

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Transoesophageal echocardiography Transoesophageal echocardiography is now available in many centres (Fig. 16.3.2.16). The ultrasound probe is like an endoscope used for upper gastrointestinal investigation, except that there are no optical fibres. Transoesophageal echocardiography is an invasive procedure for which the patient’s written consent is (usually) required. After fasting for a minimum of 4 h, a local anaesthetic spray (10% lidocaine) is applied to the upper pharynx and the patient is usually sedated, typically with a short-​acting intravenous benzodiazepine (e.g. midazolam 2 mg). The probe is manipulated into the oesophagus where its position behind the heart produces excellent resolution, particularly of posterior cardiac structures. Blood pressure and oxygen saturation are monitored throughout, and both resuscitation equipment and the benzodiazepine antagonist flumazenil should be readily available. Even though transoesophageal echocardiography is commonly performed in high-​risk, haemodynamically unstable patients, the rate of serious complications (aspiration and oesophageal rupture/​ tears) is less than 1%. Absolute contraindications to transoesophageal echocardiography include oesophageal tumours, strictures, diverticula, and varices.

Who should have a transoesophageal echocardiogram? The indications for transoesophageal echocardiography are listed in Box 16.3.2.1. The principal advantages over transthoracic imaging are improved spatial resolution and the ability to image posterior structures such as the left atrium and descending aorta. It is valuable in many emergency situations, including suspected aortic dissection, prosthetic mechanical valve failure, and possible endocarditis. Transoesophageal echocardiography may be used to image the heart in patients in whom data from transthoracic imaging is unsatisfactory due to obesity, lung disease, or chest deformity. Other indications include screening for left atrial thrombus before cardioversion of atrial fibrillation, and monitoring cardiac performance during cardiac and some non-​ cardiac surgery.

Box 16.3.2.1  Principal indications for transoesophageal echocardiography Valve disease • Mitral stenosis—​ to assess suitability for percutaneous balloon commisurotomy and exclude left atrial thrombus • Mitral regurgitation—​to assess anatomy, severity, and suitability for surgical repair • Prosthetic valves—​particularly to assess prosthetic mitral regurgitation Infective endocarditis • Possible aortic root abscess • Failure to respond to antibiotics, or recurrent fever in a patient with endocarditis • High clinical suspicion of endocarditis with no diagnostic abnormality on transthoracic imaging • Possible prosthetic valve endocarditis Aortic disease • Possible acute aortic dissection • Follow-​up of patients with known aortic pathology • Imaging aortic atheroma before surgery or patients with possible cholesterol embolization Potential cardiac source of embolism • Before elective cardioversion of atrial fibrillation • Patients with valvular heart disease and a definite embolic episode despite anticoagulation • Patients with a definite embolic episode and a ‘normal heart’ on transthoracic imaging Incomplete or impractical transthoracic imaging • Chest deformity or pulmonary disease • Patients undergoing mechanical ventilation • Congenital heart disease • Perioperative imaging of cardiac function and surgical procedures

Valve disease Patients with mitral stenosis are at increased risk of thromboembolism, and transthoracic echocardiography has limited sensitivity for the detection of left atrial thrombus. Transoesophageal echocardiography is recommended in those patients with mitral stenosis if embolic events occur despite therapeutic anticoagulation, and may demonstrate spontaneous echocardiography contrast (smoke-​like echoes produced by the interaction of erythrocytes and plasma proteins under conditions of stasis). This is an independent predictor of left atrial thrombus and cardiac thromboembolic events. Transoesophageal echocardiography is also used to assess anatomy and exclude left atrial thrombus before balloon valvuloplasty in patients with mitral stenosis and to assess anatomy, severity, and suitability for surgical repair in patients with mitral regurgitation. In patients with mitral prostheses, reverberation artefact overlying the left atrium limits the ability of transthoracic imaging to detect paraprosthetic regurgitation. Transoesophageal imaging provides excellent visualization of the left atrium and is particularly recommended under these circumstances. Endocarditis

Fig. 16.3.2.16  Transoesophageal echocardiography.

Characteristic vegetations or evidence of abscess formation identified by echocardiography are increasingly used as diagnostic criteria in patients with possible endocarditis. The excellent spatial resolution (10 mm) and assessing patency of the foramen ovale (Fig. 16.3.2.19). However, the clinical relevance of such atrial septal abnormalities can be questionable as the relationship to the thromboembolic event is commonly speculative. Currently, anticoagulation is the usual management following an otherwise unexplained, single, embolic event, but occasionally percutaneous or surgical correction of the defect is recommended.

Aortic disease Transthoracic imaging of the aorta is limited to the proximal aortic root and the arch in most patients. Using transoesophageal imaging, most of the ascending and the entire descending thoracic aorta can be visualized and image quality is improved. This is particularly useful in patients with suspected acute aortic dissection and, in many cases, it is the only imaging necessary before emergency surgery (see Chapter 16.14.1, Figs. 16.14.1.8 and 16.14.1.9). Large, mobile, or pedunculated aortic atheromas in the descending aorta which can be associated with ischaemic stroke may be detected by transoesophageal echocardiography (Fig. 16.3.2.18). Transoesophageal imaging of the aorta has also been recommended in suspected cases of cholesterol embolization and to assess thromboembolic risk prior to cardiac intervention or surgery. Thromboembolism In patients with thromboembolism, there has been extensive debate over the value of imaging with transoesophageal echocardiography. Clinical examination, electrocardiography, and transthoracic echocardiography provide sufficient information to determine optimal management in the majority. However, transoesophageal echocardiography is indicated when embolic events occur in anticoagulated patients with native or prosthetic valvular heart disease, especially if endocarditis is suspected, or when transthoracic images are inconclusive. In patients with unexplained or cryptogenic ischaemic

Fig. 16.3.2.19  Transoesophageal echocardiography of the interatrial septum. The flap of the patent foramen ovale can be seen where the septum primum is overlapped by the septum secundum. There is colour-​flow through it (arrowed) from the left atrium (LA) to the right atrium (RA).

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Stress echocardiography Diagnosis of reversible ischaemic myocardial dysfunction is now possible using echocardiography. Imaging can be performed either during or immediately after exercise, but more commonly an intravenous infusion of dobutamine is used to mimic the cardiac response to exercise. Development of reversible systolic regional wall motion abnormalities suggests coronary artery disease. Stress echocardiography also has an increasing role in risk stratification before general surgical procedures and in assessing myocardial viability before revascularization. The use of transpulmonary contrast agents to opacify the left ventricle and enhance endocardial definition greatly reduces the number of inconclusive scans, allowing more accurate assessment of left ventricular function and some measure of myocardial perfusion (Fig. 16.3.2.20).

Intracardiac echocardiography Miniaturization of echocardiography probes has led to the development of echocardiography from within the heart. Small, flexible catheters with ultrasound transducers (Fig. 16.3.2.21) can be manoeuvred within the heart to provide very high-​resolution images of intracardiac structures. This has been particularly useful during percutaneous closure of atrial septal defects and during radiofrequency ablation procedures (Fig. 16.3.2.22).

Fig. 16.3.2.21  Comparison of an intracardiac echocardiography probe with a standard transoesophageal echocardiography probe with a close-​up view of the tip of the probes. The intracardiac probes are for single use only; the transoesophageal probes are sterilized after each procedure.

Three-​dimensional echocardiography Real-​time, 3D image acquisitions with both transthoracic and trans­ oesophageal echocardiography are now available on most high-​end echocardiography machines. Some systems acquire a series of gated images to reconstruct the entire heart during a cardiac cycle. This image can then be manoeuvred and slices cut away to visualize the area of interest (Fig. 16.3.2.23). Regional wall tracking can also allow a 3D model of left ventricular function to be acquired and provides

Fig. 16.3.2.20  A sequence of apical two-​chamber images during a stress echo. At peak stress a wall motion abnormality in the inferior apex is evident, which persists into the recovery phase.

Fig. 16.3.2.22  Intracardiac echocardiography from the right atrium (RA). An atrial septal defect is being closed using a percutaneous approach. The disc in the left atrium (LA) has been deployed and is about to be pulled tight to the interatrial septum.

Fig. 16.3.2.23  3D transoesophageal echocardiography of the mitral valve. The images show prolapse of the central portion of the posterior leaflet with three ruptured chordae. The whole of the mitral valve is in view and oriented to mimic the view of the cardiac surgeon at the time of mitral valve repair.

16.3.2 Echocardiography

Fig. 16.3.2.24  3D transthoracic echocardiography of the left ventricle. The whole of the left ventricle is captured over four cardiac cycles and stitched together to create a single volume of data. Corrections for foreshortening can be made, the volume traced over time, and a 3D ‘model’ of the left ventricle created with each segment shaded a different colour.

an accurate assessment of left ventricular function (Fig. 16.3.2.24) as well as identifying areas of left ventricular dys-​ synchrony. Transthoracic 3D acquisition is limited by frame rate and image quality in the same way as 2D echocardiography. Transoesophageal 3D echocardiography usually produces clear 3D images, particularly of the mitral valve and is excellent for examination of prosthetic mitral valves (Fig 16.3.2.25). It is particularly helpful in displaying and communicating pathology, as views familiar to cardiac surgeons can be recreated and displayed.

Fig. 16.3.2.25  3D transthoracic echocardiography of a mechanical prosthetic mitral valve. The sutures placed by the surgeon are visible as a row of dots around the sewing ring.

Echocardiography in the emergency setting Echocardiography equipment increases in sophistication but also continues to miniaturize, and now several small portable ultrasound devices are available (Fig. 16.3.2.26). These are increasingly available in emergency and intensive care departments. A  hand-​held ‘screening ultrasound’ can be performed in a matter of seconds to exclude pericardial effusion, recognize left ventricular dysfunction

Fig. 16.3.2.26  Hand-​carried ultrasound allows rapid assessment of cardiac function and can exclude a pericardial effusion.

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or pulmonary embolism, and to diagnose most valvular abnormalities. This is proving extremely useful in the management of critically ill patients. Transducers compatible with smartphones further increase the availability of immediate ultrasound assessment; a rechargeable and fully wireless platform linked to a smartphone app by Bluetooth or Wi-​Fi has recently been released. It is important to recognize that these devices cannot perform a full echocardiogram and a more detailed study is needed if the screening scan is abnormal or inconclusive. In critically ill patients with sepsis or severe metabolic derangement, left ventricular function is often abnormal; however, this does not always imply that left ventricular dysfunction is the cause of the presentation. Repeat examination following treatment of the underlying illness often reveals that this finding is transient and is not always an indication of primary cardiac disease. The advent of portable ultrasound has prompted the development of several types of emergency ultrasound including: • FAST scan—​focused assessment with sonography for trauma • FEEL scan—​focused echocardiography in emergency life support • FICE scan—​focused intensive care echocardiography • FATE scan—​focused transthoracic echocardiography Each of these require specific training, mentoring, and accreditation to become proficient. Full training in transthoracic echocardiography typically requires 2 years and over 500 scans performed and reported.

Feigenbaum H (2004). Feigenbaum’s echocardiography. Lea & Febiger, Philadelphia, PA. Flachskampf FA, et  al. (2001). Recommendations for performing transesophageal echocardiography. Euro J Echocardiol, 2, 8. King A, et  al. (2016). Global longitudinal strain:  a useful everyday measurement? Echo Research and Practice, 3,  85–​93. Leeson P, Augustine D, Mitchell ARJ, Becher H (2012). Echocardiography, 2nd edition. Oxford University Press, Oxford. Rimington H, Chambers J (2016). Echocardiography: a practical guide for reporting and interpretation, 3rd edition. CRC Press, Florida, US. Zoghbi WA, et  al. (2003). Recommendations for evaluation of the severity of native valvular regurgitation with two-​dimensional and Doppler echocardiography. J Am Soc Echo, 16, 777.

16.3.3  Cardiac investigations: Nuclear, MRI, and CT Nikant Sabharwal, Andrew Kelion, Theodoros Karamitos, and Stefan Neubauer ESSENTIALS Myocardial perfusion scintigraphy

Limitations of echocardiography Despite the rapid and substantial advances in ultrasound technology and the widespread use of echocardiography, it is important to recognize and understand the limitations of the technique. These include reliance on acoustic windows (clear images are impossible in some patients), evaluation at rest (most echo studies are performed with the patient resting, so dynamic lesions such as outflow tract gradients of mitral regurgitation can be underestimated), subjective assessments (precise quantification of cardiac function and valve disease can be challenging and often a more subjective opinion is required, which depends critically on the operator’s experience and training), evaluation of complex structures such as the right ventricle remains a major challenge (3D techniques are showing promise but are not in mainstream use), and the fact that the scope of an ‘echo’ is broad (to measure every parameter possible would take more than 60 min). Like any other test, echocardiography is most powerful when the pretest probability has been considered and a specific question asked; for example, ‘Is there important aortic stenosis to explain symptoms and signs?’

FURTHER READING Cheitlin MD, et  al. (2003). ACC/​AHA/​ASE guideline update for the clinical application of echocardiography:  summary article. Circulation, 108, 1146. Douglas PS, et al. (2011). ACCF/​ASE/​AHA/​ASNC/​HFSA/​HRS/​SCAI/​ SCCM/​SCCT/​SCMR 2011 appropriate use criteria for echocardiography. J Am Soc Echo, 24, 229.

Myocardial perfusion scintigraphy provides physiological information about the coronary circulation, in contrast to the anatomical information provided by angiography. Three radionuclide-​labelled perfusion tracers are routinely used in single photon emission computed tomography (SPECT) imaging: thallium-​201 and the technetium-​99m-​labelled complexes sestamibi and tetrofosmin. Imaging is performed following tracer injection during stress (exercise or pharmacological) and at rest; comparison allows determination of whether regional perfusion is normal, or if there is inducible hypoperfusion or infarction/​scar. Myocardial perfusion imaging is minimally invasive, and—​in contrast to other methods of investigation—​can be performed regardless of overall exercise capacity, abnormalities of the resting electrocardiogram (ECG), pacemakers, obesity, claustrophobia, renal dysfunction, iodine allergy, or acoustic windows. In the investigation of a patient with possible coronary artery disease, a normal SPECT study is very reassuring, predicting a very low chance of cardiac death or non​fatal myocardial infarction over the following few years (10% of myocardium), transient ischaemic left ventricular dilatation, left ventricular ejection fraction (LVEF) less than 0.4 (see ‘Assessment of left ventricular volume and function’), and lung uptake (only with thallium-​201). SPECT is also able to add prognostic data when risk scores such as the Duke treadmill score are applied to exercise ECG variables (Fig. 16.3.3.2), and can stratify risk in specific populations such as patients after myocardial infarction or with diabetes mellitus, women, and patients with an abnormal ECG (e.g. left bundle branch block). More recent data have emphasized the value of MPS even in patients with proven coronary artery disease. In a large retrospective study from Cedars-​ Sinai Hospital (Los Angeles, California), patients managed conservatively had higher event rates than those managed with revascularization if they had inducible hypoperfusion that was more extensive than 10% of the left ventricular myocardium (see Fig. 16.3.3.3). The COURAGE trial failed to show any prognostic benefit of percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) over OMT alone. However, a nuclear substudy suggested that PCI was better at reducing inducible hypoperfusion than OMT alone, and that event rates were lower for patients with greater decreases in inducible hypoperfusion. Further research is ongoing to identify if MPS could be used to identify a subgroup of patients in whom, despite OMT, the prognosis could be improved by PCI. Nuclear techniques are well suited to the identification of myocardial viability, which predicts functional recovery (identified by hard events/year (%) 9 8 7 6

SPECT result normal mild-abnormal >mild abnormal

5 4 3 2 1 0 low

intermediate

high risk

Result of exercise ECG (Duke treadmill score)

Fig. 16.3.3.2  Incremental value of myocardial perfusion imaging over exercise ECG: hard event rates per year as a function of exercise SPECT in patients initially stratified by low, intermediate, and high Duke treadmill scores.

Fig. 16.3.3.3  Annualized cardiac death rate according to ischaemic burden and treatment strategy. Increasing ischaemia appears to be better treated with revascularization in this retrospective study. From Hachamovitch, R. et al. (2003). Comparison of the short-​term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation, 107, 2900–​7.

echocardiography) in approximately 80% of dysfunctional segments after revascularization. Comparative studies with low-​dose dobutamine echocardiography (see Chapter 16.3.2), positron emission tomography (PET), and cardiovascular magnetic resonance (CMR) have been performed. Each test is broadly similar in its ability to predict functional recovery. SPECT has also been used to assess success of revascularization procedures. In the acute setting, resting SPECT may be performed in patients attending the emergency department with chest pain and a non-​ diagnostic initial ECG. A normal perfusion scan is associated with a low risk of future events, lower likelihood of requiring cardiac catheterization, and lower costs owing to the shorter hospital stay and fewer subsequent investigations.

Non​perfusion uses of SPECT techniques Myocardial perfusion imaging for the investigation of suspected or known coronary disease is by far the most commonly performed nuclear cardiology investigation. However, scintigraphic imaging using other radiopharmaceuticals is increasingly performed to answer specific physiological questions in several other cardiac diseases. It has been recognized for almost 40 years that some patients with cardiac amyloidosis exhibit myocardial uptake of phosphate bone tracers. More recently, it has become apparent that this phenomenon tends to be limited to those with transthyretin-​type (ATTR) cardiac amyloidosis, as opposed to those with the light-​chain-​type (AL). Cardiac planar and SPECT imaging using bone tracers such as technetium-​99m-​3,3-​diphosphono-​1,2-​propanodicarboxylic acid (DPD—​Europe) or technetium-​99m-​pyrophosphate (PYP—​USA) can therefore be used to confirm a diagnosis of ATTR-​amyloid with very high positive predictive value, thereby obviating the need for cardiac biopsy. Iodine-​ 131-​ meta-​ iodobenzylguanidine (mIBG) is a false-​ transmitter analogue of norepinephrine and can be used to image the state of cardiac sympathetic innervation, which can become abnormal in patients with heart failure. Reduced cardiac uptake and increased washout of mIBG is associated with increased mortality, heart failure progression, and re-​admission, independent of

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left ventricular (LV) ejection fraction and brain natriuretic peptide (BNP) level. There is interest in using mIBG scintigraphy to stratify the risk of sudden arrhythmic death to help gauge the likely benefit of an implantable cardioverter-​defibrillator (ICD). The increasing use of implantable cardiac devices (pacemakers, ICDs, prosthetic valves) has led to a rise in the number of patients presenting with suspected device-​related infection. Echo imaging, even transoesophageally, is not always diagnostic, and scintigraphic imaging using the patient’s own labelled white cells may have a role. This technique is less sensitive but more specific than fluorine-​18-​fluorodeoxyglucose (FDG), and can be particularly useful within three months of valve replacement when false-​ positive FDG scans are common due to non​infective post-​surgical inflammation.

Assessment of left ventricular volumes and function using nuclear techniques Nuclear cardiology techniques have been used for the non​invasive assessment of left ventricular function since the early 1970s. Three radionuclide techniques are available for assessing left ventricular function:  first-​ pass radionuclide ventriculography, equilibrium radionuclide ventriculography, and gated myocardial perfusion SPECT. The first is rarely performed nowadays and will not be considered further. Equilibrium radionuclide ventriculography This investigation, also affectionately (but inaccurately) known as multigated acquisition (MUGA), is performed following labelling of red blood cells with technetium-​99m-​pertechnetate. This is usually performed in vivo following a preceding injection of stannous pyrophosphate. For a simple assessment of LVEF, gated planar imaging of the blood pool is performed in a LAO 45° projection to optimize separation of the left and right ventricular cavities. This method is independent of left ventricular geometry, and hence very accurate and reproducible. The wide availability of echo (with its lack of radiation exposure) has led to a substantial decrease in the number of equilibrium radionuclide ventriculography studies performed. However, the radionuclide method can still be valuable when a quick and reproducible assessment of LVEF is required, for example in the monitoring of patients undergoing chemotherapy with anthracyclines or trastuzumab. ECG-​gated myocardial perfusion SPECT SPECT acquisition during MPS can be gated at no extra inconvenience, cost, or risk to the patient. Tomographic slices are reconstructed for each of 8 or 16 frames and can be played as a cine for visual assessment. Left ventricular volumes and LVEF can be derived following endomyocardial border definition. Gated SPECT (Fig. 16.3.3.4) can be very useful in identifying attenuation artefacts (which appear as fixed perfusion defects but demonstrate normal wall motion). Indices of left ventricular function (ejection fraction and end-​systolic volume) provide independent prognostic information and are powerful predictors of cardiac death. Importantly, changes in regional and global function from post-​stress to rest imaging can help unmask multivessel ischaemia which has been underestimated by the visible regional perfusion defects.

Fig. 16.3.3.4  Gated SPECT to assess left ventricular systolic function at rest in a patient with an extensive anteroapical and septal infarct and poor left ventricular systolic function. Left column: end-​diastolic frame showing (from top to bottom) apical, mid, and basal short-​axis slices, horizontal, and vertical long-​axis slices. Right column: end-​systolic frame showing corresponding slices. Right column: calculated volumes and ejection fraction (middle panel), with time-​volume curve (bottom panel).

Positron emission tomography PET scanners employ coincidence detection of 511-​keV photons travelling 180° apart following annihilation of a positron with an electron. Cardiac PET studies are no longer confined to research centres, mainly due to the rapid increase in availability of combined PET/​CT scanners driven by developments in oncological practice. Myocardial perfusion can be assessed with nitrogen-​13-​ammonia (requiring an on-​site cyclotron) or rubidium-​82 (from a generator), but is best done with oxygen-​15-​water (though this tracer requires a cyclotron and does not permit myocardial imaging). Myocardial viability in terms of metabolic integrity is assessed with fluorine-​18-​ fluorodeoxyglucose (FDG), which has become widely commercially available with the growth of oncological PET. FDG-​PET is increasingly used to image intracardiac infection and inflammation as it is avidly taken up by metabolically active white cells. For this indication, careful patient preparation is essential to suppress myocardial FDG uptake using a carbohydrate-​restricted diet followed by fasting. FDG-​PET has a high sensitivity for identifying cardiac device-​related infection, though white cell scintigraphy is more reliable within three months of valve surgery. Its role in cardiac sarcoidosis is also well-​established, especially for disease monitoring. Sodium fluoride-​18 (NaF) PET is an interesting research tool for imaging microcalcification in coronary atheromatous plaques, which may identify those most likely to become unstable causing an acute coronary syndrome.

16.3.3  Cardiac investigations

Comparison of nuclear techniques with other imaging modalities For physiological assessment of known or suspected coronary artery disease, the alternatives to SPECT and PET are exercise electrocardiography, stress (exercise or dobutamine) echocardiography, and stress CMR (with vasodilator stress for perfusion or dobutamine for wall motion). The exercise ECG is inferior, mainly due to its dependence on exercise ability and the poor sensitivity and specificity of ECG changes. Stress echocardiography is a good alternative technique, with a slightly lower sensitivity but higher specificity in comparative studies. It is physician-​intensive and operator-​dependent, but harmonic imaging and microbubble contrast agents have greatly improved image quality. An important advantage over the radionuclide techniques is the avoidance of ionizing radiation, which makes it particularly attractive for younger patients. Cardiac MRI can assess regional and global left ventricular systolic function during a dobutamine infusion, similar to stress echocardiography. Alternatively, gadolinium can be used as a first-​pass myocardial perfusion tracer during vasodilator stress, with late-​ enhancement used to identify infarction. A large multicentre comparative study has suggested that CMR is an equivalent alternative to SPECT. In practice, the different modalities should be regarded as largely interchangeable, with local clinical expertise being more important than any marginal differences in technical performance between them. Functional imaging, however performed, is recommended in the latest National Institute for Health and Care Excellence (NICE) guidelines for the assessment of patients with chest pain of recent onset.

Cardiac MRI Introduction Cardiovascular MRI (CMR) has undergone significant advancement in terms of imaging capabilities, ease of use, and speed of acquisition over the past 20 years. A study of cardiovascular anatomy, left and right ventricular function, and viability/​fibrosis (late gadolinium enhancement) with a modern CMR scanner can be performed in less than 30 min by an experienced operator. These improvements have led to the widespread adoption of CMR in clinical practice.

How CMR works MRI is typically based on the magnetic properties of the hydrogen nucleus, though other nuclei can also be used. Hydrogen nuclei (protons), which are abundant in the human body, behave like small spinning magnets that have an alignment (magnetic moment) parallel to the direction of the external magnetic field and a rotation (precession) frequency proportional to the strength of the field. Radio waves in the form of a radiofrequency pulse transmitted into the patient cause the alignment of the protons to change, that is, the magnetic moments in that region are flipped out at an angle (flip angle) to the magnetic field (excitation). When this radiofrequency pulse is turned off, the protons in the patient’s body return to their neutral position (relaxation), emitting their own weak radio-​wave signals, which are detected by receiver coils and used to produce

an image. The contrast between tissues (e.g. heart muscle and fat) depends on the tissue density of hydrogen atoms (proton density), and on two distinct MR relaxation processes that affect the net magnetization: the longitudinal relaxation time (T1), and transverse relaxation time (T2). The differences in these parameters in distinct tissues are used to generate contrast in MR images. Image contrast can also be modified by modulating the way the radiofrequency pulses are played out (the MR sequence): for example, in so-​called T1-​weighted images, myocardial tissue is dark whereas fat is bright. On the other hand, T2-​weighted images highlight unbound water in the myocardium and are used to demonstrate myocardial oedema due to inflammation or acute ischaemia. CMR requires advanced technology, including a high-​field superconducting magnet which produces a homogeneous and stable magnetic field (1.5 or 3.0 Tesla), gradient coils within the bore of the magnet which generate the gradient fields, a radiofrequency amplifier to excite the spins with radiofrequency pulses, and a radiofrequency antenna (coil), which receives the radio signals coming from the patient. A computer and specific software are also needed to control the scanner and generate (reconstruct) the images. To prevent artefacts from cardiac motion, most CMR images are generated with ultrafast sequences gated to the R wave of the ECG. Respiratory motion, which is another factor that can produce artefacts, is eliminated by acquiring most CMR images in end-​ expiratory breath-​hold. When acquisition is long and cannot be completed within one breath-​hold, special free-​breathing sequences that track the diaphragm’s position (navigators) are used.

CMR safety MRI scan subjects and operators are not exposed to ionizing radiation and there are no proven detrimental biological side effects of MRI, if safety guidelines are followed. Ferromagnetic objects can be attracted by the scanner, becoming projectiles that could lead to significant patient or operator injury and also damage the scanner. The presence of certain medical implants and devices (e.g. most pacemakers and defibrillators, cochlear implants, cerebrovascular clips) is a contraindication for routine MR scanning, but nearly all prosthetic cardiac valves, coronary and vascular stents, and orthopaedic implants are safe in a 3-​T (or less) MR environment. MRI conditional pacemakers and defibrillators (generator and leads) are now available. Whenever there is uncertainty regarding a particular device or implant, the CMR operator should consult a more detailed source of information, such as reference manuals, dedicated websites (e.g. http://​www.mrisafety.com), or the manufacturer’s product information. Claustrophobia may be a problem for a few patients, and mild sedation usually helps to overcome this. Gadolinium contrast agents are safe for most patients (safer than iodine-​based contrast), but gadolinium-​containing contrast agents have been linked with the development of a rare systemic disorder called nephrogenic systemic fibrosis. The patients at risk for developing this disease are those with acute kidney injury or chronic kidney disease (glomerular filtration rate 60 ms in V1 RBBB pattern: qR, Rs, or Rr in V1 Axis > +90 or < −90 **Features favouring VT

QRS atypical for RBBB or LBBB*

V>A rate • Ventricular tachycardia

*Atypical features of BBB favouring VT

Yes

Atrial activity visible

No

RP > PR No

Yes

In 12-lead ECG: Fusion or capture beats Extreme axis deviation In precordial leads: Concordance (all either positive or negative) Absence of RS pattern in any chest lead Onset R to nadir of S > 100ms

Fig. 16.4.16  Algorithm for diagnosis of tachycardia from 12-​lead ECG. A, atrial rate; AF, atrial fibrillation; Afl, atrial flutter; AT, atrial tachycardia; AVNRT, atrioventricular nodal re-​entrant tachycardia; AVRT, atrioventricular re-​entrant tachycardia; BBB, bundle branch block; LBBB, left bundle branch block; PJRT, permanent junctional reciprocating tachycardia; PR, PR interval; RBBB, right bundle branch block; RP, RP interval; V, ventricular rate; VT, ventricular tachycardia. See text for details.

failings and misconceptions, the commonest being that the clinical context is not considered:

to transient AV nodal blockade with adenosine will assist diagnosis in many patients (Table 16.4.5).

• Age of the patient—​middle-​aged or older individuals presenting with a recent history of broad-​complex tachycardia, and who give a history of myocardial infarction or congestive heart failure, are more likely to have ventricular than supraventricular tachycardia. However, ventricular tachycardia can also arise in young patients. • Haemodynamic status of the patient—​it is often assumed that ventricular tachycardia should cause haemodynamic collapse, whereas patients may in fact be haemodynamically stable if the rate is not excessively fast or if underlying cardiac function is good. Conversely, supraventricular tachycardias may cause syncope, hypotension, or shock if sufficiently rapid, or if there is underlying heart disease. • Nature of the episodes of palpitation—​it is often not appreciated that ventricular tachycardia can present with a typical history of paroxysmal self-​terminating episodes, just as in the case of supraventricular tachycardia.

General principles of management

The importance of making a correct diagnosis in broad-​complex tachycardia is twofold. First, inappropriate acute therapy of the tachyarrhythmia can be avoided. In particular, the use of verapamil in ventricular tachycardia misdiagnosed as supraventricular tachycardia is associated with a high risk of haemodynamic collapse as a result of its negative inotropic effect, coupled with its lack of efficacy in terminating ventricular tachycardia. Secondly, if the original arrhythmia has been misdiagnosed, then the adverse prognostic significance of ventricular tachycardia will be overlooked. Appropriate investigation and long-​term management may not be instituted. It is therefore important that a diagnosis of SVT with aberration is made only if the ECG displays typical left or right bundle branch block with none of the features suggestive of VT listed in Fig. 16.4.16. In addition to attention to the history and 12-​lead ECG, the response

Many cardiac arrhythmias are benign and require no intervention. The main indications for treatment are to relieve symptoms, or to prevent complications such as myocardial ischaemia, cardiac failure, embolism, or arrhythmic sudden death. Precipitating factors such as myocardial ischaemia/​infarction, infection, thyrotoxicosis, alcohol, electrolyte disorders, or drug toxicity must be sought and treated if possible. The therapy indicated will commonly be influenced by the presence of underlying structural heart disease such as myocardial ischaemia/​infarction or left ventricular dysfunction and can include drug therapy, device implantation, or radiofrequency ablation. Acute management of tachycardia An algorithm for the treatment of tachyarrhythmias is shown in Fig. 16.4.17. Assessment of the patient’s cardiorespiratory status takes precedence. R-​ wave synchronized, direct current (DC) Table 16.4.5  Diagnostic use of intravenous adenosine Arrhythmia

Response

Atrial tachycardia Atrial flutter Atrial fibrillation

Transient AV block reveals atrial arrhythmia Rarely terminated

AVNRT AVRT

Terminates tachycardia by anterograde (AV) block

Ventricular tachycardia

Not terminated 1:1 VA conduction may be blocked, revealing AV dissociation

For abbreviations, see Fig. 16.4.16.

16.4  Cardiac arrhythmias

Haemodynamic compromise Yes DC cardioversion

Persistent or re-initiated

* Caution with broad complex tachycardias or known pre-excitation. Adenosine is contraindicated in pre-excited AF and asthma

No

Vagal manoeuvres IV adenosine*

** Use only one drug from list *** If clinically appropriate, e.g. frequently recurring tachycardia

Persistent or re-initiated

Terminated

QRS 1 procedure

Permanent AF

AV node

+++

Requires permanent pacing, does not cure AF

Scar-​related ventricular tachycardia

Re-​entry circuit

+

High recurrence rate

Focal ventricular tachycardia

Site of origin

++

Especially RVOT focus

AVRT, atrioventricular re-​entry tachycardia; AF, atrial fibrillation; AVNRT, atrioventricular nodal re-​entry tachycardia; LA, left atrial; CHB, complete heart block; TVA, tricuspid valve annulus; IVC, inferior vena cava; RVOT, right ventricular outflow tract.

interval, or, if sufficiently premature, complete failure of conduction (Fig. 16.4.22b). Non​conducted atrial extrasystoles must be distinguished from sinus arrest or second-​degree AV block. An atrial extrasystole will commonly reset the sinoatrial node, such that the next sinus beat occurs earlier than expected with respect to the preceding sinus beat, and the pause is less than compensatory. Atrial extrasystoles are a common finding in healthy people, particularly with increasing age, but are more frequent in the presence of increased atrial pressure or stretch such as in cardiac failure or chronic mitral valve disease. Patients should be reassured that the arrhythmia is benign, and that drug treatment is rarely necessary. If treatment is required on symptomatic grounds, β-​adrenergic blockers may be used, but class I antiarrhythmic drugs should be avoided in view of their proarrhythmic risk. Junctional extrasystoles Junctional extrasystoles are identified by the appearance of a premature, normal QRS complex in the absence of a preceding P-​wave. The atria as well as the ventricles may be activated, resulting in an inverted P-​wave simultaneous with the QRS complex, or inscribed within the ST segment. The significance and management of junctional extrasystoles are similar to those of atrial extrasystoles. (a)

Ventricular extrasystoles Ventricular extrasystoles are identified by the appearance of a bizarre, wide QRS complex not preceded by a P-​wave (Fig. 16.4.23). There is commonly ST-​segment depression and T-​wave inversion. Ventricular extrasystoles may be intermittent or occur with a fixed relationship to the preceding normal beats, that is, 1:1, 1:2 (bigeminy or trigeminy). Ventricular extrasystoles occur in otherwise normal hearts but are found particularly in the presence of structural heart disease. Benign ventricular ectopy is common and indicated by the following:  normal resting 12-​lead ECG, structurally normal heart on echo, absence of other cardiac symptoms, resolution with exercise, and the absence of a family history of early cardiac disease or sudden cardiac death. Ventricular ectopics occur commonly in the acute phase of myocardial infarction, but are also seen in the postinfarction phase, and in the presence of severe left ventricular hypertrophy or dysfunction of whatever cause. While the presence of frequent ectopy following myocardial infarction conveys an adverse prognosis, their suppression with class  I  agents (flecainide) actually increases mortality. Extrasystoles may produce symptoms that require treatment in a minority of cases. The safest option is β-​blockade.

Atrial arrhythmias Atrial fibrillation Mechanisms Studies of patients with paroxysmal atrial fibrillation suggest that the arrhythmia may be triggered by one or more rapidly discharging foci, which are commonly situated in the pulmonary veins.

(b)

Fig. 16.4.22  Atrial extrasystoles. (a) An atrial extrasystole, with an abnormal P-​wave at the end of the preceding T-​wave, occurs following a sinus beat. (b) Blocked atrial extrasystoles. In the same patient, atrial extrasystoles occur following each sinus beat. They are earlier than those in (a), and the AV node is refractory because of the proximity of the atrial extrasystoles to the preceding beat, and conduction is blocked.

Fig. 16.4.23  Ventricular extrasystole (open circle). No retrograde atrial activation occurs, and the P-​wave sequence is undisturbed (arrowed).

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In the presence of a heterogeneous substrate, it is thought that such a trigger gives rise to high frequency re-​entry in certain areas (rotors) which perpetuate fibrillatory conduction. Rapid atrial activation induces a process of electrical remodelling, which renders cardioversion and maintenance of sinus rhytshm more difficult (‘atrial fibrillation begets atrial fibrillation’). The initial mechanism of remodelling is thought to be intracellular calcium overload resulting in shortening of the atrial refractory period, although more prolonged atrial tachyarrhythmias result in downregulation of calcium entry and dedifferentiation of atrial myocytes. Structural changes, including interstitial fibrosis, also occur and further perpetuate the arrhythmia. Classification and aetiology Atrial fibrillation is a common arrhythmia affecting 1% of the population, the incidence increases with advancing age to 5–​10% in very elderly individuals. It is classified as paroxysmal (self-​terminating episodes 48 h/​no defined onset, with haemodynamic instability, and no intercurrent illness Oral digoxin loading pending urgent echocardiographic assessment, then β-​blockade if required (in the absence of cardiogenic shock or severe LV dysfunction or aortic stenosis on echo). Consider IV amiodarone and TOE-​guided cardioversion in patients failing to respond (emergency cardioversion may be required without TOE in patients in imminent danger of cardiorespiratory arrest). 4 Rapidly conducted atrial fibrillation in conjunction with intercurrent illness In the context of a prior diagnosis of well-​controlled permanent atrial fibrillation, treatment should be directed at the underlying illness and continuing the current rate of control medication. Patients with new-​onset atrial fibrillation should be treated with rate control (as aforementioned) and anticoagulation with LMWH. Where haemodynamic compromise is felt to be due to atrial fibrillation rather than the underlying illness, chemical or electrical cardioversion may be attempted depending on the duration of the arrhythmia (see earlier); however, the early recurrence rate is high. LMWH, low molecular weight heparin; LV, left ventricular; TOE, trans­ oesophageal echocardiography.

syndrome, implantation of a permanent pacemaker may be required to control bradycardia and to allow antiarrhythmic therapy for the treatment of tachycardia. Catheter ablation may be considered as first line or for those in whom pharmacological therapy has failed. The goal of catheter ablation is to achieve electrical isolation of the pulmonary veins; clinical success rates are 70–​80% from a single procedure. Persistent atrial fibrillation Persistent atrial fibrillation is not self-​terminating, usually requires electrical cardioversion to achieve sinus rhythm, and has a high recurrence rate even after successful cardioversion. The key decision is whether to employ a rhythm or rate control strategy. The AFFIRM trial showed no overall mortality benefit of a rhythm-​ control strategy in patients in whom a rhythm-​control strategy in not indicated on the basis of symptoms. In general, a rate control strategy should be employed in asymptomatic or mildly symptomatic individuals, in older people, and in those with contraindications to antiarrhythmic therapy or cardioversion. This group should be treated as having permanent atrial fibrillation. In more severely

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symptomatic or younger patients, or in those with atrial fibrillation due to a treated precipitant, a rhythm-​control strategy may be more appropriate. However, treatment choice has to be tailored to the individual and both options should be discussed with the patient. In patients with multiple comorbidities (e.g. chronic obstructive pulmonary disease, heart failure, ischaemic heart disease), the contribution of atrial fibrillation to the patient’s limitation may not be immediately clear. In such cases an attempt at restoring sinus rhythm may be worthwhile to clarify whether a rhythm-​control strategy is justified. Prophylaxis of thromboembolism should be considered in both groups. If a rhythm-​control strategy is adopted, elective cardioversion should be scheduled. Given that cardioversion may be associated with embolism, patients undergoing this procedure should be treated with warfarin or a non-​VKA oral anticoagulants (NOAC) for at least 3 weeks beforehand, and this should be continued long term if warranted according to risk stratification, and for at least 4 weeks in those at low risk of thromboembolism, otherwise long-​ term anticoagulation is indicated irrespective of the apparent success of rhythm control. There is a high risk of recurrent atrial fibrillation (up to 50% at 1  year) and antiarrhythmic prophylaxis should be considered. First-​line therapy is often a simple β-​ blocker followed by a class Ic agent if there is no structural heart disease. Amiodarone may also be considered, and treatment prior to cardioversion increases the likelihood of its success. Finally, radiofrequency ablation may be employed but this requires more extensive left atrial ablation compared to paroxysmal atrial fibrillation (Fig. 16.4.25), with a lower success rate, and often requires more than one procedure.

Permanent atrial fibrillation In permanent atrial fibrillation, restoration of sinus rhythm is not feasible or is unsuccessful and chronic management involves control of ventricular rate. Traditionally, the mainstay of treatment has been digoxin, at a dose titrated to achieve adequate slowing in the ventricular rate at rest, with therapeutic plasma concentrations. Despite adequate rate control at rest, patients commonly have an uncontrolled heart rate on exercise. Control of rate response with other AV nodal blocking drugs such as β-​blockers or verapamil is associated with improved rate control which is especially important if the duration of diastole is critical, as in mitral stenosis or ischaemic heart disease. Often a combination of AV nodal blocking drugs is required. In cases where adequate rate control cannot be achieved despite combination therapy, radiofrequency ablation of the AV node and implantation of a permanent pacemaker (or cardiac resynchronization pacemaker) is an option, although this commits the patient to lifelong pacing therapy. Prevention of thromboembolism Atrial fibrillation patients have a fivefold increased risk of stroke compared to age-​and gender-​matched peers without atrial fibrillation. However, individual stroke risk varies and is dependent upon the presence of other stroke risk factors such as increasing age, previous stroke, or transient ischaemic attack (TIA), hypertension, heart failure, diabetes mellitus, vascular disease (peripheral artery disease, myocardial infarction), and female gender; the more risk factors that are present, the greater the risk of stroke. Importantly, when stroke occurs in the presence of atrial fibrillation, the severity is greater, survival is poorer, residual neurological deficit is greater, patients are more likely to require nursing home/​residential care, and risk of recurrent stroke within 12 months is increased. Oral anticoagulation for stroke prevention.  Anticoagulant therapy significantly reduces the risk of stroke and death in atrial fibrillation patients. Accordingly, current clinical guidelines (see Table 16.4.9) recommend effective stroke prevention with oral anticoagulation, either as a vitamin K antagonist (VKA, e.g. warfarin) or one of the non-​VKA oral anticoagulants, for all atrial fibrillation patients except those patients at extremely low risk of stroke (see Table 16.4.10). These low-​risk patients are defined as men and women aged under 65 years with no stroke risk factors. It is important to formally assess each patient’s individual risk of stroke to inform appropriate treatment decisions.

Fig. 16.4.25  Virtual geometry of the left atrium using the Carto 3 system (Biosense Webster, Diamond Bar, CA, USA). The view is a posterior view. The pulmonary veins are shown and the veins are labelled (RSPV, right superior pulmonary vein; RIPV, right inferior pulmonary vein; LSPV, left superior pulmonary vein; LIPV, left inferior pulmonary vein). Lesions produced by sequential application of radiofrequency energy are shown by the red spheres, encircling the pulmonary veins to produce electrical isolation, which is confirmed using a circular mapping catheter, seen inside the RSPV.

Stroke risk assessment: CHA2DS2-​VASc.  The National Institute for Health and Care Excellence (NICE), American Heart Association/​ American College of Cardiology/​ Heart Rhythm Society, and European Society of Cardiology (ESC) guidelines advocate the use of CHA2DS2-​VASc to assess stroke risk (see Table 16.4.9). CHA2DS2-​ VASc is an acronym for the stroke risk factors which comprise it (see Table 16.4.10): congestive heart failure, hypertension, age 75 years or more, diabetes mellitus, previous stroke or TIA, vascular disease, age 65–​74 years, and female gender. The presence of each risk factor scores 1 point, except for age 75 years or over and previous stroke/​TIA, which score 2 points each; the maximum score is 9. The ACCP9 guidelines recommend assessing stroke risk using the older CHADS2 score: congestive heart failure, hypertension, age 75 years or more, diabetes mellitus (1 point for each), and previous stroke or

16.4  Cardiac arrhythmias

Table 16.4.9  Current guidelines for the antithrombotic management of atrial fibrillation Guidelines

Assessment of stroke risk

Assessment of bleeding risk

Treatment recommendations

Other recommendations

NICE (2014)

CHA2DS2-​VASc

HAS-​BLED

Offer OACa when CHA2DS2-​VASc ≥2, taking into consideration bleeding risk Consider OACa for men with CHA2DS2-​VASc ≥1, taking into consideration bleeding risk Review need for OAC at least yearly Do not offer aspirin monotherapy for stroke prevention in AF Only consider dual antiplatelet therapy if OAC contraindicated in patients with CHA2DS2-​VASc ≥2

OAC with VKA TTR ≥65% Assess TTR at each visit Correct modifiable reasons for poor INR controlc Consider alternative OAC if TTR cannot be improvedd NOACs In accordance with NICE STAs

ESC (2016)

CHA2DS2-​VASc

No formal bleeding risk tool specified. Stresses attention to modifiable bleeding risk factors

Consider patients’ treatment preferences No antithrombotic therapy if patient 3 ULN.

nonessential antiplatelets or NSAIDs, and minimizing alcohol intake (≤8 units/​week). A high HAS-​BLED score (≥3) does not indicate that OAC should be withheld, but warrants caution and should encourage more regular review and control of modifiable bleeding risks. In addition, OAC should not be withheld exclusively because of the risk of falls. Prediction of  INR control:  SAMe-​TT2R2.  Oral anticoagulation treatment options for stroke prevention in atrial fibrillation include VKAs and NOACs (see Fig. 16.4.27). The SAMe-​TT2R2 score (see Table 16.4.10), made up of routine demographic and clinical risk factors, can be used to identify upfront those newly diagnosed non-​ anticoagulated atrial fibrillation patients who are likely to have poor INR control on a VKA (SAMe-​TT2R2 score >2) and who may require more frequent INR monitoring and other interventions to help them achieve adequate time in therapeutic range (TTR) and for whom a NOAC might be a more effective option. Use of the SAMe-​TT2R2 score is recommended by an ESC Task Force on Anticoagulants in Heart Disease to aid decision-​making, rather than subjecting atrial

fibrillation patients to a ‘trial of warfarin’ which may put such patients at risk of stroke during the initial period of treatment. Patient preferences for treatment.  All of the most recent clinical guidelines advocate the importance of eliciting patients’ preferences regarding antithrombotic therapy and incorporating them into the decision-​making process. Central to informed decision-​making is patient education. The clinician’s role is to provide patients with information about their own risk of stroke, the benefits of OAC in reducing this risk, and their risk of bleeding with such treatment to allow them to make appropriate treatment decisions, and to respect their views and beliefs. Patients with better knowledge about atrial fibrillation, who understand the necessity of OAC for stroke prevention, despite having awareness and/​or concerns about the bleeding risk associated with OAC, are more likely to adhere to treatment. Use of oral anticoagulation in the United Kingdom and globally.  Despite the overwhelming evidence of the benefit of OAC for stroke prevention in atrial fibrillation, two recent sizeable observational

16.4  Cardiac arrhythmias

Patient with atrial fibrillation; eligible for oral anticoagulation

Bleeding risk assessment

Identifies ‘at-risk’ patients for more regular review and follow-up

EHR and ‘electronic alerts’ Low risk = no action High risk = patient ‘flagged up’ for review

A ‘high-risk’ bleeding risk score is not a reason or execuse to withhold oral anticoagulation

Review and address potentially reversible bleeding risk factors - Uncontrolled hypertension - Labile INRs (if receiving a VKA) - Concomitant use of aspirin or NSAIDs in anticoagulated patient - Alcohol excess

For patients with an increased risk of bleeding the benefit of oral anticoagulation usually, but not always, outweighs the bleeding risk; thus, regular review and careful monitoring of bleeding risk is important Do not withhold oral anticoagulation solely because the patient is at risk of falls

Fig. 16.4.26  Bleeding risk assessment in AF—​observations on the use and misuse of bleeding risk scores. EHR, electronic health record; INR, International Normalized Ratio; NSAID, non​steroidal anti-​inflammatory drug; VKA, vitamin K antagonist. From Lip GYH and Lane DA (2016). Bleeding risk assessment in atrial fibrillation: observations on the use and misuse of bleeding risk scores. J Thromb Haemost, 14, 1711–​4, © 2016 International Society on Thrombosis and Haemostasis, with permission from John Wiley and Sons.

Fig. 16.4.27  The approach to decision-​making in the AF patient management pathway using the CHA2DS2-​VASc, HAS-​BLED, and SAMe-​TT2R2 scores.

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studies have demonstrated that large proportions of patients at risk of stroke (CHA2DS2-​VASc score ≥2 or CHADS2 score of ≥2) still do not receive OAC. In the first cohort from the Global Anticoagulant Registry in the FIELD (GARFIELD) study, of 10 614 AF patients in 19 countries, 40.7% of patients with a CHA2DS2-​VASc score of 2 or more did not receive OAC. More than one-​half of the reasons given for withholding OAC therapy for patients at risk of stroke in the GARFIELD registry were linked to physician choice (i.e. bleeding risk, concerns over patient adherence, falls risk). Perhaps a more worrying finding from the GARFIELD registry revealed that approximately one-​quarter of patients with a CHA2DS2-​VASc score of 2 or more were receiving antiplatelet monotherapy. A  similar underuse of OAC in patients at high of stroke and overuse in those at low risk was seen in the Euro Heart Survey which was conducted a decade ago. The recent analysis in 1857 general practices in the United Kingdom, utilizing the GRASP-​AF tool (which assessed stroke risk on the basis of the CHADS2 score and recommends treatment based on the 2006 NICE guidelines), demonstrated that 34.0% of patients with a CHADS2 score of 2 or more, with no documented contraindication to OAC, were receiving OAC and the use of antiplatelet therapy rose as stroke risk increased. Use of OAC declined significantly among patients aged 80  years or over (47.4% vs. 64.5%; p 133 μmol/​l; age ≥80 years; body weight ≤60 kg

≥80 years; concomitant verapamil; HAS-​BLED score ≥3e

≥1 of the following: CrCl ml/​min 15–​50 ml/​min; body weight ≤60 kg; on ciclosporin, dronedarone, erythromycin, or ketoconazole

No dose reduction except for renal function

Drug interactions

Anticoagulants, antiplatelets, NSAIDs; ketoconazole, itraconazole, voriconazole, posaconazole, HIV protease inhibitors (ritonavir), rifampicin, St John’s wort, phenobarbital, phenytoin, carbamazepine

Anticoagulants, antiplatelets, NSAIDs; systemic ketoconazole, ciclosporin, tacrolimus, itraconazole, verapamil; quinidine, dronedarone, amiodarone, clarithromycin, rifampicin, St John’s wort, phenytoin, carbamazepine, SSRIs, SNRIs

Anticoagulants, antiplatelets, NSAIDsb Ciclosporin, dronedarone, erythromycin, or ketoconazoleb Quinidine, verapamil, amiodarone Phenytoin, carbamazepine, phenobarbital, or St John’s Wort

Anticoagulants, antiplatelets, NSAIDs; ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole quinidine, HIV protease inhibitors (ritonavir), clarithromycin, erythromycin, dronedarone, rifampicin, St John’s wort, phenobarbital, phenytoin, carbamazepine

Take with/​after food

No

Yes

No

Yes

Check renal function

Divide CrCl by 10; e.g. CrCl 60 ml/​min monitor every 6 months; if decline in renal function is suspected (e.g. hypovolaemia, dehydration) or concomitant use of certain medicinal products, check renal function

a

if CrCl 15–​50 ml/​min Reduce dose to 30 mg once daily if use of concomitant use of ciclosporin, dronedarone, erythromycin, or ketoconazole. c Dose reduction if serum creatinine >133 μmol/​litre plus age ≥80 years and/​or body weight ≤60 kg. d Dabigatran not to be used if CrCl 2)

VKA with additional education and more regular follow-up, dabigatran†, rivaroxaban 20 mg once daily¶, apixaban 5 mg BID*, or edoxaban 60 mg once daily

Fig. 16.4.28  Stroke prevention in atrial fibrillation: fitting the drug to the patient profile. CrCl, creatinine clearance; TTR, time in therapeutic range; VKA, vitamin K antagonist. *Reduced to 2.5 g BID with two or three criteria from age ≥80 years, bodyweight ≤60 kg, or serum creatinine concentration ≥133 μmol/​litre. †110 mg BID for patients with a CrCl 30–​49 ml/​min (most countries, but not in the United States); in the United States only, 75 mg BID (available in the United States only) for patients with CrCl 15–​29 ml/​min (and only 150 mg BID dose available in the United States for CrCl >30 ml/​min). ‡30 mg with CrCl 15–​49 ml/​min, P-​glycoprotein inhibitors, or weight 2 Regular review/INR checks/ counselling for VKA users ... or try a NOAC

Fig. 16.4.29  The Birmingham ‘3-​step’ to streamline decision-​making for stroke prevention in patients with atrial fibrillation. Reprinted from Lip GYH (2017). Stroke prevention in atrial fibrillation. The Lancet, 38(1), 4–​5, by permission of Oxford University Press.

16.4  Cardiac arrhythmias

RA

Fig. 16.4.32  Atrial tachycardia, with variable AV conduction. Lead V1.

IVC

TVA

Fig. 16.4.30  Mechanism of atrial flutter. Typical atrial flutter results from a counterclockwise re-​entry circuit in the right atrium. The isthmus between the tricuspid valve annulus (TVA) and inferior vena cava (IVC) forms a critical part of this circuit, and linear ablation to create block can prevent recurrent atrial flutter.

a degree of AV block, although 1:1 AV conduction can occur. The ECG usually shows regular P-​waves which do not show the same ‘sawtooth’ appearance as in atrial flutter (Fig. 16.4.32). In contrast to most other forms of supraventricular tachycardia, focal atrial tachycardia usually has a long RP interval (defined as >50% of the RR interval). The rate characteristically accelerates or ‘warms up’ before reaching a rate of 125–​200/​min, and careful analysis of morphology of the P-​wave aids in localization of the source. Multifocal atrial tachycardia, in which rapid, irregular P-​waves of three or four different morphologies are seen, may occur in severely ill elderly patients, or in association with acute exacerbation of pulmonary disease. Acute management includes drug treatment or cardioversion, as for atrial fibrillation. Focal atrial tachycardia may be amenable to treatment with radiofrequency ablation with success rates approaching 80%, although recurrence rate is high.

but does not, however, alter the risk of future development of atrial fibrillation. With regards to thrombo-​prophylaxis, anticoagulation is indicated before and after cardioversion, as for atrial fibrillation. The role of longer-​term anticoagulation is less clear and is currently not mandated. However, given the close link between atrial flutter and atrial fibrillation, the presence of silent atrial fibrillation should be considered, especially in those with high CHA2DS2-​VASc scores. Finally, while it is important to note that although typical flutter accounts for more than 90% of all re-​entrant circuits occurring spontaneously in the atria (others include incisional or scar-​related re-​entry), iatrogenic left atrial flutters are increasing in frequency as a consequence of increased use of ablation to treat AF.

Although all atrial arrhythmias are (by definition) supraventricular in origin, the term supraventricular tachycardia is commonly reserved for those in whom the AV node is an obligate part of a re-​ entry circuit—​AV nodal re-​entrant tachycardia (AVNRT) or AV re-​entry tachycardia (AVRT). Correct recognition of these arrhythmias has achieved additional importance with the development of effective curative measures.

Focal atrial tachycardia

Atrioventricular nodal re-​entry tachycardia

Focal atrial tachycardia is an automatic arrhythmia, usually resulting in an atrial rate between 120 and 250/​min. There may be

Mechanism

Fig. 16.4.31  Atrial flutter with 1:1 AV conduction (top), 2:1 conduction (middle), and following adenosine administration (bottom) (6 mg intravenous injection 10 s previously).

Supraventricular tachycardia

This is the commonest cause of paroxysmal re-​entry tachycardia manifesting regular, normal QRS complexes. The basis of the arrhythmia is the presence of two functionally distinct pathways in the region of the AV node (Fig. 16.4.33). The ‘fast’ pathway conducts more rapidly but has a longer refractory period. The ‘slow’ pathway has slower conduction properties but a shorter refractory period. During sinus rhythm, AV nodal conduction occurs via the fast pathway with a normal PR interval (Fig. 16.4.33a). If a sufficiently premature atrial extrasystole arises, conduction in the fast pathway is blocked, but slow pathway conduction may continue, resulting in an abrupt increase in the AH interval as recorded in the His bundle electrogram. This corresponds to an increased PR interval on the surface ECG (Fig. 16.4.33b). If conduction down the slow pathway is sufficiently delayed to allow the fast pathway to recover excitability before activation reaches the distal end of the pathways, retrograde activation occurs via the fast pathway. The stage is then set for a re-​ entry circuit with anterograde conduction via the slow pathway and retrograde conduction via the fast pathway (‘slow/​fast AV nodal re-​ entry’; Fig. 16.4.33c). Characteristically, anterograde activation of the ventricles and retrograde activation of the atria occur virtually simultaneously, resulting in the P-​wave being ‘buried’ within the QRS complex, or producing a very small distortion of the terminal

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Fig. 16.4.35  Atypical atrioventricular nodal re-​entry tachycardia (‘long RP’). Inverted P-​waves precede the QRS complex during tachycardia (compare with preceding sinus beats).

Clinical features Atrioventricular nodal re-​entry tachycardia commonly presents in young adults, although it may appear at any age. Episodes are characterized by sudden onset and sudden offset of symptoms of regular palpitations, which are normally well tolerated unless the tachycardia is particularly rapid, prolonged, or if the patient has other heart disease. The natural history is of episodic paroxysmal tachycardia, occurring at random intervals, although there may be clustering of attacks interposed with periods of relative freedom from symptoms. Atrioventricular nodal re-​entry tachycardia has no specific association with other organic heart disease. Fig. 16.4.33  Atrioventricular nodal re-​entry tachycardia. Mechanism of initiation by atrial extrasystole. See text for details.

QRS, recognition of which requires careful comparison with the ECG during sinus rhythm (Fig. 16.4.34). A less common variant of AV nodal re-​entry tachycardia may arise where anterograde conduction during tachycardia is via the fast pathway with retrograde conduction via the slow pathway (‘fast/​ slow AV nodal re-​entry’, also termed ‘atypical AVNRT’). Under these circumstances, the atrium is activated well after the QRS complex, characteristically producing an inverted P-​wave, with the RP interval greater than the PR interval during tachycardia, termed ‘long RP tachycardia’ (Fig. 16.4.35).

Management Termination of an attack of AV nodal re-​entry tachycardia is achieved by producing transient AV nodal block. This may be achieved by vagotonic manoeuvres, by intravenous adenosine (3–​18 mg; see Fig. 16.4.34), or by intravenous verapamil (6–​18 mg). Drug prophylaxis of AV nodal re-​entry tachycardia is undertaken with β-​ blockers, a combined β-​ blocker/​ class  III agent such as sotalol, or AV nodal blocking drugs such as verapamil or digoxin, although curative treatment of AV nodal re-​entry tachycardia by radiofrequency ablation is increasingly used as a first-​line therapy. Radiofrequency energy is delivered to the ‘slow’ pathway, which lies between the compact AV node and the tricuspid annulus. Ablation at this site is normally curative in over 95% of cases but carries a small risk (0.5–​1%) of inducing complete heart block.

Atrioventricular re-​entry tachycardia Mechanism

Fig. 16.4.34  Atrioventricular nodal re-​entrant tachycardia. Rapid narrow-​ complex tachycardia with no apparent P-​waves (upper) responding to 6 mg adenosine with restoration of sinus rhythm (lower). Close inspection reveals a positive deflection of the terminal QRS during tachycardia (pseudo R′, arrowed) which is absent during sinus rhythm. This is due to retrograde atrial activity coincident with ventricular activation. Lead V1.

In contrast to AV nodal re-​entry tachycardia, the substrate for AV re-​entry is the presence of a second atrioventricular connection, separate from the AV node. This accessory pathway can lie anywhere along the mitral or tricuspid annuli. Anterograde pathway conduction produces ventricular pre-​excitation and is discussed in the ‘Pre-​excitation syndromes’ section to follow. However, some accessory pathways only conduct in the retrograde (ventriculoatrial) direction and are termed ‘concealed’, since there is no clue to their presence on the resting ECG. The anterograde limb of the re-​entrant circuit is the AV node, with retrograde atrial activation occurring over the accessory pathway (see Fig. 16.4.36). This is termed orthodromic tachycardia and normally produces a narrow-​complex QRS morphology. Retrograde atrial activation can be identified by the presence of a characteristic inverted P′-​wave early in the ST segment, an important diagnostic feature of AV re-​entry tachycardia (Fig. 16.4.37). Rarely, an accessory pathway with slow retrograde

16.4  Cardiac arrhythmias

(a)

(b)

(c)

Fig. 16.4.36  Atrioventricular re-​entry tachycardia. Mechanism of initiation by atrial extrasystole. See text for details: if the accessory pathway were concealed the ECG in sinus rhythm would not show the characteristic δ-wave.

conduction may allow a stable, incessant re-​entrant circuit with a long RP interval, referred to as permanent junctional reciprocating tachycardia. Clinical features Features are similar to AV nodal re-​entry tachycardia, although accessory pathways are the more common tachycardia substrate in children. Patients have a similar relapsing course of symptoms interspersed with periods of relative quiescence. Multiple pathways can be present within the same patient and are more common if there is coexisting structural heart disease such as Ebstein’s anomaly (see Chapter 16.12). Management As with AV nodal re-​entry tachycardia, the AV node is an obligate part of the circuit and attacks may be aborted by vagotonic manoeuvres or with intravenous adenosine. Antiarrhythmic therapy may be effective, but radiofrequency ablation offers high success rates with low incidence of complications and should be considered early in a patient’s treatment.

Pre-​excitation syndromes (Wolff–​Parkinson–​White syndrome) The term ‘pre-​excitation’ refers to the premature activation of the ventricle via one or more accessory pathways that conduct in the antegrade direction (from atrium to ventricle), bypassing the normal

AV node and His–​Purkinje system. Accessory pathways with electrophysiological properties of normal myocardium may lie at any point in the AV ring, the commonest sites being in the left free wall or the posteroseptal region (Fig. 16.4.36). The characteristic electrocardiographic appearance is due to the fusion of wavefronts progressing down the normal His–​Purkinje system and the antegradely conducting accessory pathway. Early ventricular activation through the pathway occurs more quickly than conduction through the AV node, producing a short PR interval, but thereafter intraventricular conduction is slow, resulting in slurred initiation of the QRS complex (the δ-wave; Fig. 16.4.38), before the remainder of the ventricle is excited via the normal His–​Purkinje system. QRS morphology therefore reflects fusion of AV nodal and accessory pathway conduction. As such, the degree of pre-​excitation during sinus rhythm is variable:  it may be intermittent if the refractory period of the accessory pathway is close to the sinus cycle length (Fig. 16.4.38), or inapparent if the δ-wave is obscured due to rapid AV nodal conduction. In such instances, transient slowing of AV nodal conduction (e.g. by adenosine) will enhance the proportion of the ventricle excited by the accessory pathway and reveal pre-​excitation. The ECG appearances of a δ-wave occur in approximately 1.5 per 1000 of the population, but many individuals never experience paroxysmal tachycardias. The Wolff–​Parkinson–​White syndrome describes the combination of the symptoms of palpitation and the presence of pre-​excitation on the ECG.

Fig. 16.4.37  Initiation of atrioventricular re-​entry tachycardia. The third sinus beat is followed by the onset of narrow-​complex tachycardia, initiated by an atrial extrasystole (obscured by T-​wave). Retrograde atrial activation, with inverted P-​waves in the ST segment (arrows), are seen during tachycardia.

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Fig. 16.4.38  Intermittent pre-​excitation in Wolff–​Parkinson–​White syndrome. The first two beats show the characteristic short PR interval and δ-wave. The middle two beats, however, show that the pre-​excitation was intermittent. The pathway has become refractory, with normal PR interval and QRS morphology. Pathway conduction returns to cause pre-​excitation in the final two beats.

Mechanisms of orthodromic and antidromic tachycardia The mechanism for orthodromic AV re-​entry tachycardia is illustrated in Fig. 16.4.35. A premature atrial extrasystole may find the pathway refractory but be conducted through the AV node to the ventricles (Fig. 16.4.36b). If sufficient delay has occurred by the time the ventricular insertion of the accessory pathway is depolarized, the pathway may have recovered excitability and allow retrograde activation from the ventricle to atrium, with the establishment of a re-​entry circuit (Fig. 16.4.36c). Since the circuit involves activation of the ventricles via the His–​Purkinje system, the QRS morphology during re-​entry tachycardia is normal, unless a rate-​related bundle branch block develops. If a bundle branch block is seen at a lower heart rate than a documented narrow-​complex tachycardia, this is diagnostic of an accessory pathway ipsilateral to the bundle branch block (Coumel’s sign). A rare form of AV re-​entry tachycardia has anterograde conduction via the accessory pathway and retrograde conduction via the AV node (antidromic tachycardia). The QRS morphology of this tachycardia is broad and grossly abnormal, with appearances dependent upon the site of insertion of the accessory pathway. Pre-​excited atrial fibrillation The major prognostic concern in Wolff–​Parkinson–​White syndrome is pre-​excited atrial fibrillation. Conduction via an accessory pathway with a short refractory period, bypassing the normal AV nodal slowing, may result in very rapid conduction to the ventricle (Fig. 16.4.39) that can degenerate into ventricular fibrillation. The degree of pre-​excitation during atrial fibrillation varies, giving a characteristic pattern of an irregular ventricular response with QRS morphology ranging from normal to fully pre-​excited. The risk of sudden death is increased if the shortest R-​R interval is less than 250 ms during pre-​excited atrial fibrillation, and is an indication for urgent cardioversion and early radiofrequency ablation.

Management of the symptomatic patient with ventricular pre-​excitation The AV node is a part of the re-​entry circuit in both ortho-​and antidromic tachycardia, and adenosine and other AV nodal-​blocking drugs may be effective. However, adenosine may precipitate pre-​ excited atrial fibrillation and should be used with caution. In patients with known Wolff–​Parkinson–​White syndrome presenting with AV re-​entrant tachycardia, drugs which also act on the accessory pathway such as flecainide or sotalol may be preferred. In pre-​ excited atrial fibrillation, AV nodal blocking drugs such as digoxin or verapamil should be avoided, because of the risk of ventricular fibrillation; treatment should be with antiarrhythmic therapy such as flecainide or by DC cardioversion. Patients with Wolff–​Parkinson–​ White syndrome should be offered radiofrequency ablation as first-​ line therapy. This abolishes the risk of pre-​excited atrial fibrillation as well as preventing further attacks of AV re-​entry tachycardia. Careful mapping of the AV annulus using an electrode catheter is necessary to identify the site of the accessory pathway, at which the interval between the atrial and ventricular electrograms is at a minimum. Passage of the radiofrequency current causes heating of the catheter tip and results in the disappearance of accessory pathway conduction within a few seconds (Fig. 16.4.40). The success rate of I

V1

CS RF Map

0

1s

Fig. 16.4.39  Pre-​excited atrial fibrillation. Conduction via an accessory pathway results in an irregular broad-​complex tachycardia. The third and fourth beats show less pre-​excitation, with activation mainly through the normal conducting system, with more normal QRS-​complex morphology. Lead V1.

1s

2s

Fig. 16.4.40  Radiofrequency ablation of an accessory pathway. The patient had Wolff–​Parkinson–​White syndrome with evidence of ventricular pre-​excitation on the surface electrogram during sinus rhythm (short PR interval, δ-wave). One beat after switching on the radiofrequency (RF) current the QRS becomes normal, indicating successful ablation of the accessory pathway. This was a left-​sided accessory pathway, as shown by the short interval between left atrial and left ventricular activation recorded from the coronary sinus (CS). This interval is prolonged following ablation of the pathway. Surface leads I, V1, and intracardiac electrograms from CS and mapping catheter (Map) are shown.

16.4  Cardiac arrhythmias

ablation varies according to the location of the pathway, but is usually over 90%.

(a)

Approach to the asymptomatic patient with ventricular pre-​excitation Patients with Wolff–​Parkinson–​White syndrome should be evaluated carefully for the risk of pre-​excited atrial fibrillation, even in the absence of symptoms. The risk of sudden death due to rapid pre-​excited atrial fibrillation is very low among adults who have not had any symptomatic tachycardias, but is higher in symptomatic patients. If pre-​excitation is intermittent, this indicates a long refractory period of the pathway and a low risk of life-​threatening tachycardias. Abrupt disappearance of the δ-wave in response to exercise testing, or during Holter monitoring, or with the administration of a class Ia or Ic antiarrhythmic drug, also suggests a low risk. Some centres advocate diagnostic electrophysiological studies to identify a high-​risk group with short pathway refractory periods and inducible tachycardia or pre-​excited atrial fibrillation. The general tendency is for accessory pathway conduction to become slower with increasing age, and spontaneous disappearance of conduction is well documented. Other pre-​excitation syndromes Other forms of pre-​excitation include the Mahaim pathway, a direct AV, or atriofascicular connection with decremental conduction properties similar to AV nodal tissue.

Ventricular tachycardia Definitions Ventricular tachycardia is defined as the presence of three or more consecutive ventricular beats at a rate of 120/​min or greater. It is considered to be sustained if an individual salvo lasts for 30 s or more, and non​sustained if the duration is between 3 beats and 30 s.  Monomorphic ventricular tachycardia has a consistent QRS morphology, whereas polymorphic ventricular tachycardia demonstrates a constantly changing QRS morphology, often without discrete QRS complexes. Polymorphic ventricular tachycardia may degenerate into ventricular fibrillation and the ECG distinction between the two is difficult. Torsades de pointes is a polymorphic VT in association with QT interval prolongation and is discussed in more detail later in the chapter. ECG characteristics The presence of AV dissociation is a particularly important feature to seek in a broad-​complex tachycardia as it makes the diagnosis of ventricular tachycardia virtually certain (Fig. 16.4.41a). A careful search for P-​waves perturbing the QRS complex or T-​waves is necessary, ideally using multilead recordings. Occasionally, a fortuitously timed P-​wave allows the development of a capture beat of normal QRS morphology without interrupting the tachycardia. A fusion beat occurs when activation of the ventricle is partly via the normal His–​Purkinje system and partly from the tachycardia focus (Fig.  16.4.41b). Fusion and capture beats are diagnostic of ventricular tachycardia but are commonly present only if the ventricular rate is relatively slow. Although AV dissociation is diagnostic of ventricular tachycardia, it is not invariable. Retrograde ventriculoatrial conduction may occur, giving either 1:1 conduction or higher degrees of block (Fig. 16.4.41c).

(b)

(c)

Fig. 16.4.41  Sustained monomorphic ventricular tachycardia. (a) Ventricular tachycardia with atrioventricular dissociation. P-​waves (arrowed) are seen to have no relationship to the ventricular activation. Lead V1. (b) Ventricular tachycardia with fusion beat (arrow). Lead V1. (c) Ventricular tachycardia with 2:1 ventriculoatrial conduction. Lead III. P-​waves (arrows) follow every second ventricular complex.

The QRS duration in ventricular tachycardia is commonly greater than 120 ms, and values greater than 140 ms are particularly suggestive of ventricular tachycardia. Although the QRS morphology may superficially resemble left or right bundle branch block, the morphology is commonly atypical (see Fig. 16.4.16). Ventricular tachycardia arising from the right ventricular free wall has a left bundle branch block-​like pattern, whereas left ventricular free wall tachycardias show right bundle branch block morphology. The presence of concordant positive or negative QRS complexes across the chest leads is suggestive of ventricular tachycardia, as is the existence of extreme axis deviation. ECG features consistent with VT are listed in Fig. 16.4.16. Aetiology Sustained monomorphic ventricular tachycardia commonly occurs in the presence of structural heart disease, but also arises in structurally normal hearts. It rarely occurs in the acute phase of myocardial infarction, but may be seen in the subacute phase (>48 h), or may arise many years later, particularly in association with left ventricular scar or aneurysm formation. The arrhythmia also occurs in other forms of structural heart disease associated with ventricular dilatation or fibrosis such as dilated cardiomyopathy, hypertrophic cardiomyopathy, or previous ventricular surgery (e.g. following repair of Fallot’s tetralogy). Ventricular tachycardia may degenerate into ventricular fibrillation. Sustained monomorphic tachycardia can occur as a proarrhythmic response to antiarrhythmic drugs, particularly class I agents. Although ventricular tachycardia normally occurs in individuals with overt heart disease, it is also seen in young and apparently healthy subjects. In these, occult cardiac disease or cardiac genetic syndromes should be considered (see ‘Genetic syndromes’). There

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section 16  Cardiovascular disorders

remain a few patients with documented ventricular tachycardia in whom no structural heart disease is evident on clinical, ECG, or echocardiographic examination. The tachycardia may arise from the outflow tract of the right or left ventricle, or from one of the fascicles of the left bundle branch, and is amenable to radiofrequency ablation. Acute management of ventricular tachycardia Rapid ventricular tachycardia may present with cardiac arrest, syncope, shock, anginal chest pain, or left ventricular failure, but slower tachycardias in patients with preserved cardiac function may be well tolerated. Sustained ventricular tachycardia is a medical emergency. If the patient is pulseless or unconscious, immediate DC cardioversion is necessary. If the patient is conscious but hypotensive, urgent DC cardioversion under general anaesthesia or deep sedation is used. Haemodynamically tolerated tachycardias may be terminated by drug therapy (see Fig. 16.4.17). Adenosine may be administered in the presence of haemodynamic stability to exclude the differential diagnoses of SVT with aberrancy or antidromic AVRT, but is likely to be ineffective in terminating VT (see Table 16.4.6). Amiodarone 300 mg over 20 min (ideally via a central vein) followed by 900 mg/​24 h may be effective in restoring sinus rhythm. Second-​ line drugs for the termination of ventricular tachycardia include intravenous lidocaine (lignocaine) 100 mg, sotalol, procainamide, and disopyramide, although all may be proarrhythmic. Flecainide is contraindicated in view of the risk of developing incessant tachycardia. Verapamil should be avoided as it may cause clinical deterioration. The only exception to this is in the rare instance of patients with structurally normal hearts who have ventricular tachycardia that is known to respond to verapamil (e.g. LV fascicular tachycardia). All antiarrhythmic drugs have significant negative inotropic actions that may further impair the haemodynamic status of the patient if sinus rhythm is not restored. For this reason, no more than one antiarrhythmic drug should normally be given before recourse to alternative therapy, usually DC cardioversion. Overdrive termination of ventricular tachycardia following insertion of a temporary pacing lead may be effective, particularly if the tachycardia is relatively slow. Facilities for cardioversion must be available in view of the risk of acceleration or degeneration into ventricular fibrillation. Secondary prevention Ventricular tachycardia is a potentially life-​threatening condition. Unless the acute episode was clearly precipitated by some transient or reversible factor, there is a high probability of recurrent attacks, which may result in sudden death. Prognosis is worse if the arrhythmia was poorly tolerated, or if there is severe left ventricular dysfunction. Clinical evaluation of the patient after restoration of sinus rhythm should be supported by ECG, echocardiography, cardiac magnetic resonance imaging, and/​or radionuclide ventriculography. Coronary angiography should be considered to identify the presence of significant coronary artery disease, which may act as a trigger to ventricular tachycardia. Unless there is a clear precipitating factor such as drug toxicity, electrolyte abnormality, or acute ischaemia, the risk of sudden death is high and patients should be considered for a secondary prevention ICD (see Fig. 16.4.20). A meta-​analysis of three secondary prevention trials of patients resuscitated from ventricular fibrillation or ventricular tachycardia causing haemodynamic

compromise showed defibrillators to be better than antiarrhythmic drug therapy in preventing death from any cause (Fig. 16.4.42a). Primary prevention Patients with left ventricular dysfunction of any cause are at risk of sudden death from ventricular tachycardia or fibrillation and implantable defibrillators are appropriate for a subgroup of these patients as part of a primary prevention strategy. Those with non-​ sustained ventricular tachycardia, in whom sustained tachycardia can be induced at electrophysiological testing, have a better survival with defibrillator implantation compared with drug therapy. Primary prevention trials such as the Sudden Cardiac Death in Heart Failure Trial (SCD-​HeFT) have expanded the indication to include patients with class II/​III heart failure and an ejection fraction less than 30%, even in the absence of known arrhythmia (Fig. 16.4.42b). Antiarrhythmic therapy Implantable defibrillator therapy is not affordable in all countries, and not appropriate for patients with New York Heart Association (NYHA) class  IV heart failure or other conditions causing a severely limited prognosis. Medical therapy is necessary for many patients, but is limited by a relative lack of evidence from randomized controlled trials. β-​Adrenoceptor blockers are comparable to conventional antiarrhythmic agents in the prevention of recurrent ventricular tachyarrhythmias. Since they have been shown to reduce the risk of sudden death in unselected survivors of myocardial infarction and in patients with chronic heart failure, they should be used routinely in the prophylaxis of ventricular tachycardia if tolerated. Amiodarone did not improve mortality compared to placebo in the SCD-​HeFT trial. The class I antiarrhythmics should not be used for this indication as they were associated with a higher rate of arrhythmic deaths in the Cardiac Arrhythmia Suppression Trial. Other therapies Radiofrequency ablation is used in the management of ventricular tachycardia, particularly in those with no structural heart disease. Right or left ventricular outflow tract tachycardia and fascicular tachycardia are particularly amenable to ablation. Radiofrequency ablation of critical areas of slow conduction in scar-​related ventricular tachycardias is now frequently undertaken but success rates are lower than for other types of ablation and this approach is often reserved for the treatment of recurrent tachycardia in patients with implantable defibrillators. Direct surgical management of recurrent ventricular tachycardia involves aneurysmectomy, endocardial mapping, and resection of the area containing the micro re-​entry circuit. The indications for surgery have been reduced considerably since the advent of the ICD and the emergence of catheter ablation, since the surgical mortality is up to 10–​15%. Where medically intractable ventricular tachyarrhythmias are associated with very poor left ventricular function, cardiac transplantation should be considered if catheter ablation fails. Non​sustained ventricular tachycardia The mechanism and causes of non​ sustained ventricular tachycardia (Fig. 16.4.43) are similar to those of sustained ventricular tachycardia. There is often slight variation in the R-​R interval, particularly if the salvo involves only a few beats. Short salvos of

16.4  Cardiac arrhythmias

(a) Arrhythmic death

Death 50

50

40

40

30

30 Amio ICD

20

20

Amio

10

10

0

1

2

Number at risk ICD: 934 Amio: 932

3 Years

715 664

4

467 427

0

5

273 248

ICD

159 128

104 82

1

934 932

2

715 664

3 Years 467 427

4

273 248

5

159 128

104 82

(b) Amiodarone vs. placebo ICD therapy vs. placebo

Hazard ratio (97.5% CI) 1.06 (0.86–1.30) 0.77 (0.62–0.96)

0.4

Placebo (244 deaths; 5-yr event rate, 0.361) ICD therapy (182 deaths; 5-yr event rate, 0.289)

Amiodarone (240 deaths; 5-yr event rate, 0.340)

0.3 Mortality rate

P value 0.53 0.007

0.2

0.1

0.0 0

12

24

36

48

60

484 505 501

280 304 304

Months of follow-up No. at risk Amiodarone 845 Placebo 847 ICD therapy 829

772 797 778

715 724 733

97 89 103

Fig. 16.4.42  Improved survival with the implantable cardioverter–​defibrillator (ICD). (a) Cumulative risk of fatal events for ICD or amiodarone (amio) from a meta-​analysis of trials of secondary prevention, showing reduced death with ICD (left panel), due to reduced arrhythmic death (right panel). (b) Improved survival with ICD compared to amiodarone or placebo in a study of primary prevention in patients with heart failure. (a) Reproduced from Connolly SJ, et al. (2000). Meta-​analysis of the implantable cardioverter defibrillator secondary prevention trials. Eur Heart J, 21(24), 2071–​8, by permission of Oxford University Press; (b) Bardy GH, et al. (2005), New Engl J Med, 352, 230. Copyright ©2005 Massachusetts Medical Society. All rights reserved.

Fig. 16.4.43  Non​sustained ventricular tachycardia.

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non​sustained ventricular tachycardia are often asymptomatic. Apart from the instances where non​sustained ventricular tachycardia produces troublesome symptoms, the major clinical significance of the arrhythmia is as a risk marker for sustained ventricular tachycardia or sudden cardiac death in patients with left ventricular dysfunction or hypertrophy. Patients with structural heart disease, in particular those with severe left ventricular dysfunction, with QRS duration greater than 120 ms or heart muscle disease, should be considered for an implantable defibrillator as primary prevention of sudden cardiac death. If no structural heart disease or ion channel disease is present, and the patient is asymptomatic, no treatment is indicated as long-​term follow-​up of such patients indicates a good prognosis with no excess risk of sudden death. Polymorphic ventricular tachycardia Polymorphic ventricular tachycardia is an unstable rhythm with varying QRS morphology. It is most commonly seen in the acute phase of myocardial infarction. It either undergoes spontaneous termination or degenerates into ventricular fibrillation. If episodes of polymorphic ventricular tachycardia are frequent in the early hours of myocardial infarction, they can be suppressed by β-​blockade.

Torsades de pointes and the long-​QT syndromes Torsades de pointes is a characteristic type of polymorphic ventricular tachycardia with a typical undulating variation in QRS morphology as a result of variation in axis. It occurs in association with a prolonged QT interval during sinus rhythm. Long-​QT syndromes may be acquired or congenital; the latter are discussed later in the chapter. Aetiology Although class Ia and III antiarrhythmic drugs are the best-​known causes of acquired long-​QT syndrome, a very large number of non-​ cardiac drugs inhibit the outward potassium current IKr, and may cause significant lengthening of the QT interval either singly or in combination (Table 16.4.12). Episodes of torsades de pointes are often multifactorial in origin, with prolongation of the QT interval by an IKr inhibitor in association with predisposing factors such as

Table 16.4.12  Causes or contributory factors in acquired long-​QT syndromes Drug induced

bradycardia or pauses, hypokalaemia, or hypomagnesaemia. All of these predispose to early after-​depolarizations in vitro and this mechanism appears to be the likely cause of torsades de pointes in the acquired syndromes. The prognosis of the acquired long-​QT syndromes is excellent, provided the underlying predisposing factors are identified and corrected. However, it is increasingly recognized that there is a genetic predisposition to the development of acquired long-​QT syndrome in the face of predisposing factors, leading to the concept that patients developing acquired long-​QT syndrome have reduced ‘repolarization reserve’ as a result of a forme fruste of the congenital syndrome. ECG characteristics Torsades de pointes is an atypical ventricular tachycardia characterized by a continuously varying QRS axis (‘twisting of points’; see Fig. 16.4.44). Episodes of torsades are commonly repetitive and normally self-​terminating, although they may degenerate into ventricular fibrillation. Paroxysms of torsades de pointes are associated in the preceding beats with evidence of marked QT prolongation, and frequently with morphological abnormalities of the T-​wave such as T-​U fusion, gross increases in T-​wave amplitude, or T-​wave alternans. In the acquired long-​QT syndromes a slowing of the heart rate, and in particular a postextrasystolic pause, is often associated with initiation of the arrhythmia. This produces a characteristic ‘short–​long–​short’ sequence of initiation (Fig. 16.4.44). Acute management The common clinical presentation is of recurrent dizziness or syncope, and the condition may easily be misdiagnosed as self-​ terminating polymorphic ventricular tachycardia or ventricular fibrillation unless the characteristic morphology of torsades de pointes and the associated QT interval prolongation is recognized. It is essential to discontinue predisposing drugs or other agents and to avoid empirical antiarrhythmic drug therapy, which may worsen the arrhythmia. Individual paroxysms of torsades de pointes are normally self-​limiting, but if they are persistent, cardiac arrest will occur and emergency defibrillation is necessary. Intravenous magnesium sulphate (8 mmol over 10–​15 min, repeated if necessary) is a safe and effective emergency measure for the prevention of recurrent paroxysms of tachycardia. If torsades de pointes is associated with bradycardia and pauses, the heart rate should be increased to between 90

Antiarrhythmic drugs—​classes Ia, III Macrolide antibiotics—​erythromycin Antifungals—​ketoconazole Psychotropics—​tricyclic/​tetracyclic antidepressants, antipsychotics Antihistamines—​terfenadine, astemizole Antiemetics—​domperidone, ondansetron Synthetic opioid—​methadone

Electrolyte disturbances

Hypokalaemia, hypomagnesaemia, hypocalcaemia

Metabolic

Hypothyroidism, starvation, anorexia nervosa, liquid protein diet

Bradycardia

Sinoatrial disease, AV block

Toxins

Organophosphorus insecticides, heavy metal poisoning

Fig. 16.4.44  Torsades de pointes. Note the marked QT interval prolongation in the sinus beats, and the ‘short–​long’ pattern of R-​R intervals immediately prior to initiation of the arrhythmia. Ambulatory monitoring recording is shown (continuous tracing).

16.4  Cardiac arrhythmias

and 100/​min by atrial or ventricular pacing or isoproterenol (isoprenaline) infusion. Hypokalaemia and hypomagnesaemia should be sought and corrected if necessary.

Accelerated idioventricular rhythm The term ‘accelerated idioventricular rhythm’ is used to describe a continuous ventricular rhythm with a rate less than 120/​min. Idioventricular rhythm commonly occurs in the setting of acute myocardial infarction and appears to be a marker of successful reperfusion therapy. No active treatment is necessary.

Ventricular fibrillation Ventricular fibrillation is defined as a chaotic, disorganized arrhythmia with no identifiable QRS complexes (Fig. 16.4.45). The mechanism is of multiple, unstable re-​entry circuits. The electrocardiographic pattern depends on the duration of fibrillation: recent-​ onset fibrillation is described as ‘coarse’, with a peak-​ to-​ peak amplitude of around 1 mV (1 cm). With increasing duration of cardiac arrest, the amplitude of ventricular fibrillation diminishes and such ‘fine’ ventricular fibrillation is less likely to be amenable to successful electrical defibrillation. Ventricular fibrillation may occur during acute myocardial ischaemia often initiated by an R on T extrasystole, and is the principal cause of death in the first 2 h following acute myocardial infarction (Fig. 16.4.45). Ventricular fibrillation during myocardial infarction is subdivided into primary, occurring without warning in an otherwise stable patient, and secondary, where fibrillation occurs in the context of left ventricular failure or cardiogenic shock. Ventricular fibrillation occurring in chronic heart disease is most commonly a result of degeneration of rapid ventricular tachycardia, whose causes have been described earlier. Rarer causes of fibrillation are listed in Box 16.4.4. Ventricular fibrillation is rarely self-​terminating, and normally causes cardiac arrest with the rapid onset of pulselessness, unconsciousness, and apnoea. The management of cardiac arrest due to ventricular fibrillation is discussed in Chapter 17.2. Patients who survive an episode of ventricular fibrillation should be assessed carefully to determine the risk of recurrence. If ventricular fibrillation has occurred in the first few hours of a typical ST-​elevation myocardial infarction, the risk of recurrent cardiac arrest is low, and no specific prophylactic therapy other than assessment and treatment of residual ischaemia and conventional postinfarction β-​blockade is indicated. However, in many instances ventricular fibrillation arises as a result of acute ischaemia in patients with known, extensive heart disease who have not sustained an acute infarction. These patients remain at high risk of recurrent ventricular fibrillation, and should be evaluated fully by exercise testing and coronary arteriography with a view to revascularization,

Fig. 16.4.45  Ventricular fibrillation complicating acute myocardial infarction. The arrhythmia is initiated by an ‘R on T’ ventricular extrasystole.

Box 16.4.4  Causes of ventricular fibrillation • Acute myocardial ischaemia • Acute myocardial infarction—​primary or secondary • Advanced organic heart disease with poor LV or RV function • Severe LV hypertrophy • Ventricular tachycardia/​torsades de pointes • Electrical—​electrocution, lightning, unsynchronized DC shock, competitive ventricular pacing • Pre-​excited atrial fibrillation • Profound bradycardia • Hypoxia, acidosis • Genetic syndromes (e.g. long-​QT syndrome, Brugada syndrome)

and managed with an ICD or antiarrhythmic therapy as discussed in the section on ventricular tachycardia.

Genetic syndromes Ion channel diseases Congenital long-​QT syndromes The congenital long-​QT syndromes (LQTS) are inherited conditions due to mutations in genes encoding ion channel proteins. They are mainly autosomal dominant and are subclassified according to the underlying gene defect (Table 16.4.13). Most cases are either LQT1 or LQT2, due to mutations affecting either the slow (IKs) or rapid (IKr) components of the outward potassium current. In the less common LQT3, the inward sodium current (INa) is affected. Lengthening of ventricular repolarization, and hence of the QT interval, occur as a result either of reduced outward current flow via IKr or IKs or increased duration of current flow via INa. The arrhythmia, torsades de pointes, has characteristics consistent with triggered activity. Attacks of torsades de pointes in the congenital syndromes are commonly associated with sympathetic stimulation such as exercise, waking, or fright, and are associated with increases in sinus rate. Cardiac events are particularly associated with exercise in LQT1, with auditory stimulation in LQT2, and can occur during sleep in LQT3. Paroxysms may produce syncope, which if prolonged may be complicated by convulsion, leading to misdiagnosis as epilepsy. A  family history of recurrent syncope or sudden death may be obtained. Sinus bradycardia is commonly seen in these syndromes. The diagnosis of long-​QT syndrome can be challenging and is not based on the ECG characteristics alone. The finding of a long QT interval on an ECG in patients with a history of syncope or palpitations or a routine ECG in asymptomatic patients can cause considerable anxiety among clinicians. The probability of LQTS can be assessed using the Schwartz score, with a score more than 3.5 supporting the diagnosis (Table 16.4.14). The prognosis of untreated congenital long-​QT syndrome is poor, with a high incidence of sudden death in childhood. Factors associated with high risk include personal history of aborted sudden cardiac death or syncope, and corrected QT interval greater than 500 ms. Males with LQT3 are at increased risk regardless of the degree of QT interval prolongation. LQT1 has a better prognosis than other subtypes. Episodes of torsades de pointes and T-​wave alternans on Holter monitoring also confer a higher risk.

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Table 16.4.13  Genetics of congenital long-​QT syndromes Subtype

Chromosome

Gene

Product

Ion current affected

Frequency

LQT1

11

KCNQ1

KvLQT1

↓IKs

c.50%

LQT2

7

KCNH2

HERG

↓IKr

30–​40%

LQT3

3

SCN5A

Nav 1.5

↑INa

5–​10%

LQT4

4

ANKB

Ankyrin-​B

↓Multiple

Rare

LQT5

21

KCNE1

minK

↓IKs

Rare

LQT6

21

KCNE2

MiRP1

↓IKr

Rare

LQT7

17

KCNJ2

Kir2.1

↓IK1

Rare

LQT8

12

CACNA1C

Cav1.2

↑ICaL

Rare

CAV3

Caveolin 3

↑INa

Rare

Sodium channel β4

SCN4B

↑INa

Rare

AKAP9

Yotiao

↓IKs

Rare

SNTA1

↑INa

Rare

Kir3.4

↓IKr

Rare

Calmodulin 1

N/​A

Rare

Calmodulin 2

N/​A

Rare

Calmodulin 3

N/​A

Rare

LQT9

3

LQT10

11

LQT11

7

LQT12

20

Syntrophin α1

LQT13

11

KCNJ5

LQT14

14

CALM1

LQT15

2

CALM2

LQT16

19

CALM3

Table 16.4.14  Schwartz score for the diagnosis of long-​QT syndrome Clinic features

Points

ECG findingsa A

QTcb

≥480 ms

3

460–​479 ms

2

450–​459 ms (male)

1

B

QTcb 4th minute of recovery from exercise stress test ≥480 ms

1

C

Torsade de pointesc

2

D

T-​wave alternans

1

E

Notched T-​wave in three leads

F

1

d

0.5

Low heart rate for age Clinical history

A B

Syncopec Congenital deafness

With stress

2

Without stress

1 0.5

Family history A

Family members with definite LQTSe

1

B

Unexplained sudden cardiac death 85

—​

7.1 per 1000 (though not 85–​90.1 per 1000

Utrecht, Netherlands

40–​95

53% had echoes 97%-​LVSD

1640 (43)

North Glasgow, UK

25–​74

2.9% LVSD

1.4% ALVSD

15 per 1000

ECHOES

3960 (72)

West Midlands, UK

1.8% LVSD 3.5% Preserved EF

0.9% ALVSD

31 per 1000 (>45 yrs of age)

Kupari et al., 1997

Helsinki Ageing Study

501 (41)

Helsinki, Finland

75–​86

4.1 % HEFPEF 3.9 % LVSD

9% ASLVD

Mosterd et al., 1999

Rotterdam Heart Study

2267 (88)

Rotterdam, Netherlands

55–​94

3.7% LSVD

1.4% ASLVD

Morgan et al., 1999

Poole Heart Study

817 (61)

Poole, Dorset, UK

70–​84

7.5 % LVSD

3.9 % ASLVD

Authors

Name of study

Number of patients (no. of cases of heart failure)

Location

Age range

Percentage of symptomatic left ventricular systolic dysfunction (LVSD)

Parameshwar et al., 1992

Prevalence of heart failure in 3 GP practices

30 204 (117)

Northwest London, UK

5–​99

Murphy et al., 2004

National survey of heart failure

307 741 (2186)

Scotland, UK

Rutten et al., 2003

A questionnaire-​ based survey of heart failure

(202)

McDonagh et al., 1997

MONICA

Davies et al., 2001

Percentage of asymptomatic left ventricular systolic dysfunction (ASLVD)

(75–​86) –​82 per 1000 Men 7 per 1000 (55–​64) Women 6 per 1000 (55–​64)

Men 37 per 1000 (65–​74) 144 per 1000 (75–​84) 59 per 1000 (85–​94) Women 16 per 1000 (65–​74) 121 per 1000 (75–​84) 140 per 1000 (85–​94)

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Table 16.5.1.2  Studies demonstrating incident rates of heart failure within different populations Study

Name of study

McKee et al., 1971

Framingham

Erikkson et al., 1989

The men born in 1913

Cowie et al., 1999

Number of patients

Incidence of heart failure >65 yrs of age

2 per 1000 (45–​54 years)

40 per 1000 (85–​94 years)

Age range

Framingham, US

45–​94

973

Gothenburg, Sweden

67

Hillingdon Heart Study

151 000

Hillingdon, northwest London, UK

29–​95

76 years

0.02 per 1000 (25–​34 years) 0.2 per 1000 (35–​44 years) 0.2 per 1000 (45–​54 years) 1.2 per 1000 (55–​64 years)

3 per 1000 (65–​74 years) 7.4 per 1000 (75–​84 years) 11.6 per 1000 (85–​94 years)

Murphy et al., 2004

GP database, Continuous morbidity recording scheme

307 741 (2186 cases)

Scotland, UK

45–​85

—​

1.3 per 1000 (45–​64 years)

6.1 per 1000 (65–​74) 16 per 1000 (75–​84 years)

De Giuli et al., 2005

GP research database

696 884 (6478 cases)

United Kingdom

45–​101

77 years

3.4 per 1000 (55–​64 years)

25.5 per 1000 (75–​84 years)

Kalogeropoulos et al., 2009

ABC study

2934 (258)

Pittsburgh, and Memphis, Tennessee US

70–​79

73.6 years

Bibbins-​ Domingo et al.

CARDIA study

5115 (27)

Birmingham, Alabama, Chicago, Illinois, Minneapolis, Oakland, California, US

18–​30

39.1 years

Many epidemiology studies therefore focused on characterizing the incidence and prevalence of LVSD, using varying cut points of the normally distributed variable, LVEF, ranging from less than 30% to 50%. This difference in the cut points chosen affects the incidence and prevalence rates which are quoted (see Tables 16.5.1.1 and 16.5.1.2). Often studies have classified those with heart failure symptoms and signs with a normal or only mildly reduced left ventricular function to have heart failure with preserved ejection fraction (HF-​PEF). In the absence of any convincingly positive drugs trials for this end of the spectrum of heart failure, no unifying definition of HF-​PEF has emerged and been applied to community-​based studies. The latest definitions of HF-​PEF, in addition to symptoms and or signs of heart failure and a relatively preserved ejection fraction, also require evidence of structural heart disease (usually left ventricular hypertrophy, increased left atrial size/​volume and Doppler or tissue Doppler evidence of diastolic dysfunction). Rigorous population-​based studies with these more modern definitions have yet to appear.

Prevalence studies

Mean/​ Median age of diagnosis

Incidence of heart failure 5 litres) is the dominant feature. Management is principally with bed rest, loop diuretics (usually by intravenous infusion), and, where appropriate, mineralocorticoid receptor antagonists. Thiazide diuretics can be added in resistant cases. Prophylactic low molecular weight heparin should be prescribed. Careful monitoring of fluid balance with daily weights and

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daily electrolytes is essential. Angiotensin-​converting enzyme inhibitors and subsequently β-​blockade can be introduced once a satisfactory diuresis has been achieved. Management of cardiogenic shock is usually determined by the cause. Fluid status should be assessed, and an adequate left ventricular filling pressure ensured by the administration of intravenous fluids where required (particularly in the case of right ventricular infarction). Revascularization is the mainstay of therapy in acute myocardial infarction. Circulatory support with intra-​ aortic balloon counterpulsation, inotropic agents, ventricular assist devices, and extracorporeal membrane oxygenation should be considered for reversible causes (e.g. ventricular septal rupture, papillary muscle rupture, acute myocarditis, and peripartum cardiomyopathy).

Prognosis Hospital admission with acute heart failure caries a poor prognosis with an average in-​hospital mortality of 10–​15% rising to up to 60% at 30 days in cases of cardiogenic shock.

Introduction Although the term ‘acute heart failure’ often conjures up an image of a patient with acute pulmonary oedema, in extremis, struggling to breathe and producing pink, frothy sputum, such a dramatic presentation is not common. Admissions to hospital for heart failure, on the other hand, are extremely common, and most patients admitted are not breathless at rest, only becoming breathless on mild exertion. It is better to think of acute heart failure as being a worsening of symptoms and/​or signs leading the patient, carer, or primary care physician to seek urgent expert advice—​leading, in turn, to an urgent admission to hospital for investigation and/​or treatment. Many patients will be able to walk, albeit slowly, from their wheelchair to their hospital bed. Patients admitted with heart failure usually have a problem with oedema (i.e. fluid in the wrong place). The old-​fashioned term ‘anasarca’ describes a state of severe generalized oedema. It can be helpful to think of patients as being on a spectrum between pulmonary oedema at one end, in which the fluid is predominantly in the lung, and anasarca on the other, in which patients have an absolute excess of fluid, usually manifesting as peripheral oedema. This notion is similar to the classification system used for patients with chronic airways disease and emphysema: patients with pulmonary oedema can be termed ‘puffers’, and those with anasarca as ‘bloaters’ or having dropsy (Table 16.5.2.1). Patients with pulmonary oedema usually present with a short history of deterioration. There is often an obvious acute precipitating factor such as acute coronary syndrome or atrial fibrillation, particularly with a rapid ventricular response. They often have hypertension and a high peripheral vascular resistance. The patient has had no time to retain a substantial excess of body fluid. In contrast, patients with dropsy (‘bloaters’) usually have a history of deterioration over a period of weeks and no acute precipitating factors (although the development of atrial fibrillation with a slow ventricular response, anaemia, and chronic kidney disease (CKD) could be

Table 16.5.2.1  The spectrum of acute heart failure ranges from patients with acute pulmonary oedema, perhaps 15% of patients presenting to hospital with acute pulmonary oedema, to those with fluid retention. Differences between the two groups are highlighted Pulmonary oedema

Anasarca

Syndrome

Puffers

Bloaters

Acute precipitant

Yes

Usually no

Oedema

In lungs

Predominantly peripheral

Absolute fluid excess

No

Yes

Time course

Minutes to hours

Days to weeks

considered chronic precipitants). They have a low blood pressure and have had time to retain many litres (sometimes ≥20 litres) of excess fluid. The distinction is important in interpreting the results of clinical trials: an agent that is designed to improve acute breathlessness, but given to someone who is already comfortable at rest (perhaps rendered so by standard background therapy) is likely to appear ineffective, even if it is highly effective in the appropriate patient at the appropriate time. There is little evidence from randomized controlled trials in acute heart failure syndromes to guide management. Much of what follows in terms of management advice thus reflects the balance of expert opinion rather than definitive recommendations. The lack of evidence reflects a constellation of difficulties. The reasons for hospital admission may be misunderstood and patients often present at inconvenient hours of the night when it is least likely they will encounter people with the time or inclination to do research (funding nocturnal research can be expensive). Protocol procedures often cause delays which allow standard therapies to be effective before a new intervention can be started. Indeed, the effectiveness of oxygen, nitrovasodilators, and diuretics for the short-​term management of symptoms suggests that the needs for managing acute pulmonary oedema are largely satisfied. The big problems for ‘acute’ heart failure really appear 2–​3 days after admission when it is clear that diuretics alone have not solved the immediate problem. For most patients, the problem then is peripheral oedema and exertional breathlessness rather than breathlessness at rest. In the longer term, the big problems are recurrent exacerbations and death. Thankfully, the vast majority of patients who survive to discharge attain a reasonable quality of life in the intervening period. There are guidelines to help guide practice, but those relating to acute heart failure tend to focus most on the patients with acute pulmonary oedema. The European Society of Cardiology’s (ESC) guidelines of 2016 are helpful, but it is noteworthy that the only treatment to receive a class I, level A recommendation was the use of prophylaxis against thromboembolism. The National Institute for Health and Clinical Excellence clinical guideline of 2014 covered both patients with pulmonary oedema and the more common presentation with fluid retention. This placed a great deal of emphasis on the importance of organization of care and the need for patients with acute heart failure to be managed in the appropriate environment, but was notably frank regarding the absence of good trial evidence and gave a series of helpful recommendations for future research.

16.5.2  Acute cardiac failure

Cardiogenic pulmonary oedema Pathophysiology In patients with pulmonary oedema, fluid from the lung capillaries collects in the extravascular spaces of the lung. The Starling equation describes the forces acting on fluid in the pulmonary capillaries (Fig. 16.5.2.1). Hydrostatic pressure tends to force fluid out of the capillaries while the colloid osmotic pressure (largely provided by proteins) tends to maintain the fluid within the capillary. The balance between the forces varies between arteriole and venule; however, there is net filtration along the length of the capillary. Some resistance to fluid movement is provided by the alveolar–​capillary membrane and any fluid entering the interstitium is removed by the lymphatics. Problems with any of these components can lead to (or worsen) pulmonary oedema. Pulmonary lymphatic flow may increase substantially in heart failure, reducing the risk of pulmonary oedema. However, the lymphatics drain into the venous circulation and so a rise in venous pressure may inhibit lymphatic clearance. Lymphatic occlusion, as occurs in lymphangitis carcinomatosa, and disruption to the alveolar capillary membrane, as happens in adult respiratory distress syndrome, can cause pulmonary oedema. Hypoalbuminaemia causes peripheral oedema and reduces the hydrostatic pressure at which pulmonary oedema occurs. In the normal circulation, the Frank–​Starling relation describes the relation between the load on the left ventricle at the end of diastole, usually expressed as the end-​diastolic pressure, and the work subsequently performed by the ventricle during systole. The end-​ diastolic pressure is the same as the left atrial and hence pulmonary venous pressure. In patients with heart failure, the curve relating the two is shifted to the right: for any given cardiac output, the filling pressure required is greater in the failing ventricle (see Fig. 16.5.2.2). An acutely failing ventricle needs a higher and higher filling pressure to maintain cardiac output. The rising end-​diastolic pressure is reflected in a rise in left atrial, pulmonary venous, and pulmonary capillary pressure, resulting in faster rates of fluid filtration. Ultimately, fluid is filtered faster than the rate at which the lymphatics can remove it, and pulmonary oedema results. This sequence cannot be quite the full explanation: a rise in pressure (including left ventricular filling pressure) can only arise from

Fig. 16.5.2.2  The Frank–​Starling relation. As preload increases, so does cardiac output. In the failing ventricle, the relation is shifted to the right so that to deliver any given cardiac output, the ventricle requires a higher filling pressure.

an input of energy. In acute pulmonary oedema, the energy for the rise in left ventricular pressure can only come from the right heart. When the left ventricle fails, there is a fall in left ventricular stroke volume and consequent mismatch between left and right ventricular stroke volumes. The higher right ventricular stroke volume causes the increase in left ventricular filling pressure and restoration of cardiac output, but an inevitable consequence is some accumulation of fluid in the pulmonary circulation. The greater the fall in stroke volume of the left in relation to the right ventricle, the higher the left ventricular filling pressure will be and the greater the pulmonary fluid volume. Note that the total amount of fluid in the body does not increase and the effect is brought about by fluid moving to the ‘wrong’ body compartment. The fluid extravasation into the alveoli results in a reduction in blood volume during acute pulmonary oedema, which then increases back to normal levels during successful treatment. The fluid accumulation in the lungs starts with peribronchial swelling/​oedema, followed by distension of the alveolar walls; only then does fluid enter the alveoli, initially at the alveolar angles, and eventually flooding the alveoli. The accumulation starts at the lung bases as the hydrostatic pressure is greatest here.

Clinical presentation

Fig. 16.5.2.1  The forces acting on fluid in a pulmonary capillary.

Acute pulmonary oedema is a dramatic medical emergency. The typical patient presents with very severe shortness of breath that has developed abruptly over minutes or hours. He or she has to sit upright (and might indeed die if forced to lie flat) and may be unable to speak or gasp only a few words. Patients are usually very frightened and often certain that they are dying. Coughing may be prominent and will often produce blood-​tinged oedema fluid. There may be some clues in the history as to the precipitant of pulmonary oedema. Sympathetic nervous system activation usually results in a tachycardia and a rise in blood pressure; the skin is white, cold, and clammy. The patient usually exhibits central cyanosis. Heart sounds may be inaudible but a gallop rhythm is common. The lung fields

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Patient with suspected AHF

Urgent phase after first medical contact

1. Cardiogenic shock? Yes

Circulatory support • pharmacological • mechanical

No 2. Respiratory failure?

Yes

No

Ventilatory support • oxygen • noninvasive positive pressure ventilation (CPAP, BiPAP) • mechanical ventilation

Immediate stabilization and transfer to ICU/CCU

Immediate phase (initial 60–120 minutes) Identification of acute aetiology: C acute Coronary syndrome H Hypertension emergency A Arrhythmia M acute Mechanical cause’ P Pulmonary embolism No

Yes

Immediate initiation of specific treatment

Follow detailed recommendations in the specific ESC Guidelines

Diagnostic work-up to confirm AHF Clinical evaluation to select optimal management

Fig. 16.5.2.3  The treatment algorithm recommended by the European Society of Cardiology. Note that investigations and active management have to be undertaken simultaneously. From Ponikowski P, et al. (2016). 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur Heart J, 37(27), 2129–​200.

are usually filled with crackles and sometimes wheezes (so-​called ‘cardiac asthma’). Given how sick the patient with pulmonary oedema is, the initial investigations and management have to be carried out at speed. The ESC guidelines for the management of acute heart failure emphasize the need to investigate and treat simultaneously (Fig. 16.5.2.3). There are three strands: making the diagnosis, identifying the immediate precipitant, and initiating treatment. Identifying precipitating factors is particularly important as it will influence subsequent management (see Table 16.5.2.2).

Initial investigation A 12-​lead electrocardiogram (ECG) will often show grossly abnormal QRS complexes, including evidence of acute myocardial

infarction, or abnormal heart rhythm, including atrial fibrillation with a rapid ventricular response and ventricular tachycardia (see Fig. 16.5.2.4). A chest radiograph gives vital information. At early stages in the development of pulmonary oedema, the patient may have septal (or Kerley B) lines (Fig. 16.5.2.5), fluid in the lung fissures, and pleural effusions. There is peribronchial cuffing and upper lobe blood diversion. As oedema worsens, confluent shadows spreading out from the hila develop (Fig. 16.5.2.6). Near-​ patient testing for cardiac markers is becoming more widely available. Natriuretic peptide measurement can be helpful in making the diagnosis where there is clinical uncertainty: a patient with a normal natriuretic peptide level is extremely unlikely to have heart failure. A raised troponin suggests that there might be an acute

16.5.2  Acute cardiac failure

Table 16.5.2.2  Common precipitants of acute pulmonary oedema, helpful investigations, and possible immediate treatment options. ECG is electrocardiogram; CXR is chest X-​ray; (N)STEMI is (non) ST elevation myocardial infarction Precipitant

Examples

Investigation

Immediate management

Acute ischaemia

STEMI NSTEMI

ECG, troponina

Immediate cardiology review

Arrhythmia

Atrial fibrillation Ventricular tachycardia

ECG

DC cardioversion

Mechanical disaster

Rupture of: interventricular septum Mitral papillary muscle Sinus of Valsalva

Echocardiogram

Cardiac surgery

Hypertensive crisis

Renal artery stenosis Salt load

During recovery

Vasodilators

Intercurrent illness

Pneumonia Urinary infection Sepsis

CXR, septic screen

As appropriate

CT pulmonary angiogram

Thrombolysis, anticoagulation

History

Education

Pulmonary embolus Environment a

Lack of compliance with medication/​diet High salt intake

often elevated in acute or chronic heart failure in the absence of any other evidence of ACS. An elevated troponin in patients with heart failure is a bad prognostic sign.

coronary syndrome (ACS) in progress, but troponin is commonly raised in acute heart failure even in the absence of ACS. A full blood count, biochemical screen, and thyroid function are important investigations. Anaemia is common, often due to iron deficiency but exacerbated by plasma volume expansion. Glucose is very commonly raised due to the high sympathetic drive, and does not necessarily mean that diabetes is present. Other appropriate investigations may include CT pulmonary angiography and a septic screen. Echocardiographic assessment early in the course of admission is very useful in confirming the cause of presentation and guiding subsequent therapy.

The lowest dose of oxygen needed to restore normal oxygenation should be used. Care should be taken in patients with chronic airways disease who are at risk of developing CO2 retention (which may be exacerbated by the use of opiates). In a patient who is tiring or whose gas exchange is worsening despite treatment, positive pressure ventilation provides immediate relief. Non​invasive ventilation should be tried first: there is good evidence that both continuous positive airway pressure ventilation and bilevel positive airway pressure ventilation are safe.

Management

Medical treatment

Patients with acute pulmonary oedema should be managed in a high-​dependency unit. Whether this should be cardiac care or a unit where intubation and ventilation is available will depend upon the degree of respiratory distress.

Opiates are commonly prescribed to relieve the distress of acute pulmonary oedema, but there is no evidence that they are safe and some data suggest that their use is associated with adverse outcomes. They should be used cautiously, if at all.

Ventilatory support

Fig. 16.5.2.4  A 12-​lead electrocardiogram from a 76-​year-​old man presenting with acute pulmonary oedema. His ventricular tachycardia had been precipitated by an acute coronary syndrome.

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Vasodilators

Fig. 16.5.2.5  A plain postero-​anterior chest X-​ray in a breathless patient showing Kerley B lines–​multiple short horizontal lines visible towards the lung peripheries. There are also small pleural effusions.

Diuretics Diuretics are almost universally used in patients with acute pulmonary oedema, although trials to prove efficacy are lacking. As patients are usually not fluid overloaded, diuretics may not be the most logical therapy, although by reducing circulating volume, they do reduce filling pressure and relieve oedema. There is a firmly held view that furosemide is a vasodilator, but its haemodynamic effects coincide with the onset of diuresis.

Nitrovasodilators are a more logical approach to the treatment of pulmonary oedema. They reduce both preload and afterload, as well as helping to relieve any myocardial ischaemia. Small studies suggest that nitrates may be more helpful than diuretics, but the evidence is not definitive, and clinical surveys suggest that they are used in few patients. The National Institute for Health and Care Excellence (NICE) guideline does not recommend their routine use. Other vasodilators have been tried. Despite early promise (and, indeed, licensing in some countries), nesiritide (human recombinant B-​type natriuretic peptide) had no effect on outcome in a large trial, and no patient subset obtained a striking benefit. Serelaxin (human recombinant relaxin, a vasoactive peptide produced in pregnancy) was again promising, but a definitive trial, RELAX-​AHF-​2, was again neutral. In TRUE-​AHF, patients with acute heart failure were randomized to receive either ularitide (another natriuretic hormone) or placebo, and the results were again neutral both for longer term cardiovascular mortality and for short-​ term symptom relief. Patient selection is part of the reason for the neutral studies of vasodilators. By the time a patient has been through the processes required for study entry, several hours have typically passed since presentation and the worst may by then be over. Severely ill patients may be excluded as not being able to consent, and most studies exclude patients with many of the precipitants of acute pulmonary oedema, such as acute myocardial infarction. Indeed, it can be difficult to tell who, precisely, the criteria for the trials are targeting for inclusion. They usually appear to be trying to recruit patients with pulmonary oedema, who perhaps may have most to gain from a vasodilator, but in are in practice predominantly recruiting those with fluid retention, and if a patient is not breathless at rest, then a treatment targeting breathlessness is unlikely to be helpful. Inotropes Inotropic support is often used, particularly as a ‘last ditch’ attempt to help very sick patients, more in despair than hope. Such evidence as there is from randomized trials suggests that all positive inotropic drugs working through adrenergic pathways are associated with an adverse outcome. Investigational approaches include cardiac myosin activators and inhibitors of sarcoplasmic calcium re-​uptake. Mechanical support In selected patients, there may be a role for intra-​aortic balloon pumping to buy time, particularly when there is a potentially reversible cause for the pulmonary oedema. Similarly, a left ventricular assist device and extracorporeal membrane oxygenators may have a role when there is a potential either for recovery or for heart transplantation.

Prognosis

Fig. 16.5.2.6  More severe pulmonary oedema on supine antero-​ posterior film showing confluent shadowing spreading out from the hila. Note the relatively small heart shadow suggesting that this is an acute event in a previously normal heart.

The clinical course of acute pulmonary oedema is usually very brisk: the patient usually recovers rapidly after treatment, or deteriorates rapidly and dies. Overall, in-​hospital mortality is around 15%, but strongly age-​related; it is less than 10% in those aged less than 65  years and much higher in those aged more than 85  years, but these figures do not include those dying before reaching hospital.

16.5.2  Acute cardiac failure

The recovery from pulmonary oedema is in part an active process in which cells take up fluid and return it to the capillary or lymphatic circulation. Novel agents designed to enhance this process are being developed.

Cardiogenic anasarca Pathophysiology At the other end of the scale from pulmonary oedema are patients with fluid retention. Two processes result in oedema: the retention of sodium and water, and the transfer of fluid into the tissues. To take the second first: fluid collects in the tissues as a consequence of a rise in intravascular hydrostatic pressure or fall in osmotic pressure. As with the lungs, there is continuous filtration of fluid from the capillaries to the tissues: if extravasation exceeds lymphatic drainage, oedema develops. The effect of gravity means that the hydrostatic pressure is highest in the feet, so ankle swelling is usually the first sign of fluid retention. In a patient confined to bed, though, the fluid will collect around the sacrum. The reasons why the body retains water are less certain. Sodium and water are retained by the kidneys, presumably in response to decreased renal perfusion or deviation from the kidney’s set-​point for renal perfusion pressure (i.e. the blood pressure the kidney ‘wants’). The consequence is renin production by the juxtaglomerular apparatus leading to conversion of angiotensinogen to angiotensin I and ultimately to aldosterone production, which in turn causes salt and water retention by the kidney. In addition, antidiuretic hormone (or arginine vasopressin) is released in increased quantities, stimulating fluid retention and, importantly, thirst, and thus greater fluid intake. However, antagonists of each of these systems, even when used in combination, do not seem sufficient to prevent salt and water retention and do not obviate the need for diuretics, although they might reduce the dose required. The stimulus leading to neuroendocrine activation is not clear. A common assumption is that it is a fall in blood pressure due to the failing heart. The body responds in the same way as it would to any other cause of a fall in blood pressure, such as dehydration or haemorrhage, with avid salt and water retention to maintain blood pressure. Although some patients have a normal or high blood pressure compared to healthy people, this blood pressure may be below their individual set-​point. If the set-​point could be changed, then perhaps salt and water retention would not occur.

have had to loosen my belt’ or ‘I have increased a waist size’ in a patient with increasing breathlessness should alert the clinician to the possibility of oedema. The oedema is usually very obvious on examination. Cardiogenic oedema is pitting. The highest level of pitting oedema should be sought. The jugular venous pressure will be raised: however, when it is very high, the top of the column of the blood may not be visible in the neck, even with the patient sitting upright. There is usually a tachycardia and often hypotension. The apex beat is displaced and dyskinetic and there is almost always a third sound or gallop rhythm. Mitral regurgitation is very common. There are commonly signs of ascites and pleural effusions, with basal crackles in some patients who have pulmonary congestion.

Differential diagnosis It is important to consider the differential diagnosis of peripheral oedema (Table 16.5.2.3). Once a firm diagnosis of cardiogenic oedema is made, the next step is to consider the possible causes of the ‘right heart’ failure. Although the commonest cause is left heart failure, other cardiac conditions, particularly constrictive pericarditis, can result in severe fluid overload and be difficult to diagnose (see Table 16.5.2.4). Pulmonary hypertension leading to right ventricular dysfunction appears increasingly common in frail elderly patients with right heart failure, many of whom also have lung and left heart disease.

Initial investigations Patients presenting with anasarca should be investigated as patients presenting with chronic heart failure (see Chapter 16.5.3) with the aim of making the diagnosis, unmasking any treatable cause, and identifying any associated comorbidities. • Common ECG abnormalities include previous myocardial infarction, left bundle branch block, atrial fibrillation. • A chest radiograph will show a large heart shadow and evidence of pulmonary venous congestion. It may also exclude other causes of breathlessness. • Urinary dipstick testing will help pick up infection and gross proteinuria. • Anaemia is common in anasarca due to heart failure. Patients may benefit from an iron infusion should they have iron deficiency. • Renal dysfunction and electrolyte abnormalities are common in patients with heart failure and are major determinants of outcome. Regular testing during treatment (see next) is vital.

Clinical presentation The typical picture is of a patient with gradual weight gain, often in the context of previous coronary disease, hypertension, atrial fibrillation, and CKD. Around 5 litres of fluid (weighing 5 kg) are needed before oedema first appears. As the process is often very gradual, patients will often present only once they have retained many litres of fluid and have pitting oedema affecting the abdominal wall, and sometimes even the thoracic wall. Pleural and pericardial effusions and ascites are common in this situation. In some patients, the oedema causes obvious ballooning of the ankles. However, in many patients the oedema does not grossly distort the shape of the leg, and oedema of the trunk may develop and go unobserved by the patient or a careless doctor. Symptoms such as ‘I can’t get my shoes on’ or ‘I

Table 16.5.2.3  Differential diagnosis of peripheral oedema. Note that anasarca is easily overlooked without careful examination Oedema fluid

Cardiogenic Hypoalbuminaemia

Fluid overload

Pregnancy

Lymphatic obstruction

Idiopathic

Medicines

Dihydropyridines/​glitazones

Venous insufficiency

Varicose veins Previous DVT

Chronic stasis Fat

(Obesity)

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Table 16.5.2.4  Differential diagnosis of cardiogenic peripheral oedema Possible cause

Examples

Raised left atrial pressure (left heart failure)

Impaired left ventricular  Contraction  Ischaemic heart disease (IHD)  Dilated cardiomyopathy  Relaxation  Left ventricular hypertrophy (hypertension)  Hypertrophic cardiomyopathy  Amyloid Mitral valve disease

Raised right atrial pressure (right heart failure)

Chronic left atrial hypertension Pulmonary hypertension IHD Tricuspid valve disease (often tricuspid regurgitation due to dilated right ventricle) Right ventricular cardiomyopathy

Congenital heart disease

Left-​to-​right  shunts Right ventricle in systemic position

Pulmonary hypertension

Chronic left atrial hypertension Lung disease (cor pulmonale) Thromboembolic disease

Pericardial disease

Constrictive pericarditis

• Natriuretic peptide levels are usually grossly raised. • An echocardiogram is essential (see Fig. 16.5.2.7). The key elements to look at are: ■ Left atrial size—​mitral valve disease or chronic elevation in left ventricular filling pressure will cause left atrial dilation. It is probably the best guide to the chronic health of the left heart but may not be enlarged with severe acute-​onset disease. ■ Left ventricular size and contractility—​the left ventricle is commonly dilated with reduced systolic function but sometimes small, hypertrophied, and ‘stiff ’. Regional wall motion abnormalities suggest a possible underlying diagnosis of ischaemic heart disease. ■ Valve disease. • More sophisticated investigation may reveal pulmonary hypertension, right ventricular disease, and dilated venae cavae.

Ultrasound can also be used to identify ‘lung comets’ indicating pulmonary congestion.

Management The problem is one of an absolute excess of fluid, and initial management is directed at fluid removal. General care is important: the patient should be managed with bed rest with prophylactic low molecular weight heparin used to reduce the (high) risk of venous thrombosis. The only way to monitor progress accurately is with strict fluid balance monitoring and daily weights. The urea and electrolytes should be measured at least daily, and the patient should be reviewed daily by an experienced member of the team. Oedema is due to retention of water, not salt: in 1 litre of oedema fluid, there are 991 g of water and 9 g of salt. There is no good evidence that sodium restriction is useful, although restricting a very high intake may be useful in the occasional patient. Salt restriction may lead to hyponatraemia. Aquaresis may be greater (and hyponatraemia less likely) when moderate salt intake is allowed. Fluid intake is often restricted to around 1.5 litres per day, but the evidence for this is weak. The aim should be to try and induce a net diuresis of around 2 litres per day. Diuretic management is key. Diuretics work by preventing the reabsorption of some of the filtered sodium from the tubular lumen. • Loop diuretics block the sodium–​potassium–​chloride cotransporter in the thick ascending loop of Henle. As they reach their site of action from the lumen of the nephron, they only work if there is at least some glomerular function. Once their effects are over, the kidney goes into overdrive to restore the lost salt and water. • Thiazide diuretics work at the distal convoluted tubule. They induce a small but persistent diuresis; over a 24-​hour period loop and thiazide diuretics may have the same natriuretic effect. • Mineralocorticoid receptor antagonists block the effects of aldosterone at the sodium–​potassium exchanger in the distal convoluted tubule, resulting in potassium retention. A typical approach is to use intravenous loop diuretic. Oral absorption is very erratic in patients with cardiogenic oedema because of bowel oedema. An infusion of 10 mg per hour of furosemide is

Fig. 16.5.2.7  Echocardiogram of a patient presenting with anasarca. Long axis parasternal view. The left ventricular internal diameter is approximately 8 cm, and there is little difference between systolic and diastolic frames.

16.5.2  Acute cardiac failure

often used. Data from small studies suggests that an infusion causes a greater natriuresis than repeated boluses to the same dose, but the biggest study of infusion versus bolus dosing showed no difference between the two strategies. Particularly after chronic loop diuretic usage, the cells of the distal convoluted tubule hypertrophy and increase their capacity to reabsorb sodium. The addition of a thiazide will block the distal convoluted tubule (so-​ called ‘progressive nephron blockade’) which may lead to a profound diuresis. Metolazone is often used for this purpose although there is no convincing evidence that it is more potent than other thiazides. Combination therapy can be very helpful, but patients having the two diuretics must be monitored very closely. Potentially nephrotoxic drugs, such as non​ steroidal anti-​ inflammatory drugs (including aspirin) should be stopped. It is not certain whether pre-​existing β-​blocker (or angiotensin-​converting enzyme inhibitor or ACE) therapy should be stopped: the evidence available suggests that those patients whose pre-​existing therapy is not stopped are less likely to be discharged without these life-​saving treatments. Towards the end of intravenous therapy, ACE inhibitors and β-​blockers should be started simultaneously at low doses. If not already being used, a mineralocorticoid (aldosterone) receptor antagonist (MRA) should also be started (see Fig. 16.5.2.8). The dose of ACE inhibitor should be titrated rapidly to target with careful monitoring of blood pressure and renal function. β-​Blockers are titrated more slowly and often only after discharge. Intravenous diuretic therapy should be continued until the oedema has resolved unless an oral diuretic regimen is clearly having the desired results. It is not uncommon for renal function to improve following diuresis and diuretic therapy should not be withheld or reduced in patients with impaired renal function at the time of presentation where there is clear evidence of fluid overload. For some patients, however, complete resolution of oedema cannot be achieved due to worsening renal impairment and a balance has to be struck between some peripheral oedema and a raised creatinine. Ideally, a patient finishing intravenous therapy will be monitored for 48 h to make sure that the fluid does not re-​accumulate immediately. Some patients may fail to respond adequately to intravenous diuretics. It is important to reconsider the diagnosis: has constrictive pericarditis been missed? Is there some correctable cause of renal dysfunction, such as renal artery stenosis?

Fig. 16.5.2.8  Time course of diuresis for a patient presenting with approximately 25 litres of anasarca. Note the brisk response once the furosemide infusion was started, and the timing of introduction of long-​ term medication. ACEi is angiotensin-​converting enzyme inhibitor and βB is beta adrenoceptor antagonist.

Other therapeutic options include the use of digoxin, which has a diuretic effect, although the evidence base for its use in acute heart failure is poor. Positive inotropic drugs, particularly in hypotensive patients, are sometimes used. There is no evidence to support the practice, and no evidence that ‘renal dose dopamine’ has anything to offer. Ultrafiltration can be used to remove fluid rapidly from patients with anasarca (see Table 16.5.2.5). Veno-​venous filtration is possible in a cardiac care unit setting with small devices. There is conflicting evidence as to its value: in one study, its use was associated with a reduction in the need for subsequent emergency care, but in patients with worsening renal function, a second study suggested that ultrafiltration was associated with a higher creatinine, although this finding may simply have reflected haemoconcentration. The most recent study was terminated early by the sponsoring company: although the primary endpoint was not met, several of the secondary endpoints suggested a benefit for ultrafiltration. The role of ultrafiltration in routine practice is still uncertain, but there is no doubt that as much as 5 litres can safely be removed from a patient in 24 h, and it is useful in selected patients who are unresponsive to combined diuretic therapy or when diuresis is limited by renal dysfunction (Fig. 16.5.2.9).

Table 16.5.2.5  Diuretics commonly used in the management of anasarca. DCT is distal, and PCT, proximal, convoluted tubule. MRA is mineralocorticoid antagonist Class

Example

Route

Site of action

Comments

Loop

Furosemide, bumetanide

Intravenously

Na+/​K+/​Cl–​cotransporter in thick ascending loop of Henle

High ceiling; short duration of action

Shorter half-​life than thiazides

Thiazide

Bendroflumethiazide

By mouth

DCT

Low ceiling; longer period of action

Combined with loop may cause profound diuresis

‘Thiazide-​like’

Metolazone

By mouth

DCT (and PCT)

Combined with loop may cause profound diuresis

MRA

Spironolactone, eplerenone

By mouth

DCT–​Mineralocorticoid receptor antagonists

Essential component of long-​term management

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pulmonary capillary wedge pressure and hence confirm adequate filling. There is no evidence that using the catheter to guide further management is helpful. An ECG with right-​sided leads will help make the diagnosis of a predominantly right-​sided myocardial infarct. An echocardiogram to confirm the extent of left and right ventricular damage and to exclude a mechanical problem (free wall rupture, papillary muscle rupture, ventricular septal rupture) is a vital early investigation. Bladder catheterization will confirm that the patient is genuinely oliguric rather than confused due to retention of urine. Sepsis should be excluded.

Management

Fig. 16.5.2.9  A patient receiving ultrafiltration. There is a two-​lumen right internal jugular venous line from which blood is continuously removed, pumped through a filter (black arrow) and then returned to the body. Filtrate is seen collecting in the bag (white arrow).

Cardiogenic shock Shock occurs when there is tissue hypoperfusion despite adequate ventricular filling. There is no blood pressure level that can be used to define shock, with the consequence that the incidence and prognosis quoted varies from study to study.

Pathophysiology Cardiogenic shock most commonly arises from an acute myocardial insult which results in sufficient reduction in cardiac output that the perfusion to vital organs is insufficient to maintain organ function. By far the commonest cause is acute myocardial infarction, although patients with acute presentation of cardiomyopathy, including peripartum cardiomyopathy, may develop shock. The result is massive sympathetic nervous system activation as the body tries to restore blood pressure. The consequent increase in afterload cannot be met by the failing left ventricle. Reduced coronary artery perfusion results in worsening myocardial function, perpetuating the problem.

Clinical presentation The patient is hypotensive, usually tachycardic, pale, and sweaty. Reduced cerebral perfusion results in confusion and agitation, and the patient becomes oliguric or anuric. Except for those patients with predominant right ventricular infarction, some degree of pulmonary oedema is invariably present.

Differential diagnosis and investigations Making the correct diagnosis is fundamental: investigations should be directed at finding any reversible cause for the patient’s state. Making certain that the left ventricle is adequately filled is essential to make the diagnosis of shock:  if the left ventricle is underfilled, then fluid replacement should result in rapid resolution of symptoms. If there is doubt, then fluid challenges with rapid infusion of 100–​200 ml fluid can be helpful. In some cases, pulmonary artery catheterization is used to determine the

Dealing with any treatable cause of shock is the most important step. Revascularization in patients presenting with acute myocardial infarction may relieve shock, although if shock develops following or despite a successful procedure, the outlook is particularly poor. Patients with mechanical problems tend to have smaller and more localized infarctions than those without: although it is very high risk, early surgery may be life-​saving. For those patients with right ventricular infarction as the cause, fluid loading may improve the patient’s condition, but at a cost of high central venous pressure. Trying to sustain the circulation in patients with no readily reversible cause is rarely successful. • Positive inotropic drugs, such as catecholamines and phosphodiesterase inhibitors, may improve cardiac output and blood pressure: however, their use has not been shown to improve prognosis. Indeed, dobutamine in randomized trials is associated with a worse outcome. • Intra-​aortic balloon counterpulsation (IABP) can improve the situation, at least temporarily. Trial evidence suggests that the IABP does not improve prognosis in patients with cardiogenic shock due to acute infarction, but it can certainly help patients with acute mechanical causes such as septal rupture and mitral regurgitation. In some patients with potentially reversible causes, such as peripartum cardiomyopathy, IABP has been used successfully to sustain the circulation for many weeks. • Advanced therapies with ventricular assist devices (VADs), extracorporeal membrane oxygenation (ECMO), and even heart transplantation have been successful in selected patients. VADs and ECMO are only available in the United Kingdom in transplant centres, but there is a move to make them more widely available as a temporizing measure before patients are transferred to the centres. The prognosis of cardiogenic shock is bleak. Unless there is a readily correctable cause, the mortality rate approaches 60% at 30 days. Once treatable causes of shock have been excluded, conservative management and an easy death may be preferred rather than transfer to the intensive care unit for valiant, desperate, protracted, but ultimately futile, intervention.

FURTHER READING Chen HH, et  al. for the NHLBI Heart Failure Clinical Research Network (2013). Low-​dose dopamine or low-​dose nesiritide in acute heart failure with renal dysfunction:  the ROSE acute heart failure randomized trial. JAMA, 310, 2533–​43. Clark AL, Cleland JG (2013). Causes and treatment of oedema in patients with heart failure. Nat Rev Cardiol, 10, 156–​70.

16.5.3  Chronic heart failure

Costanzo MR, et  al. (2017). Extracorporeal ultrafiltration for fluid overload in heart failure:  current status and prospects for further research. J Am Coll Cardiol, 69, 2428–​45. Gray A, et al. 3CPO Trialists (2008). Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med, 359, 142–​51. Harris P (1983). Evolution and the cardiac patient. Cardiovasc Res, 17, 313–​19, 373–​8, 437–​45. MacIver DH, Clark AL (2015). The vital role of the right ventricle in the pathogenesis of acute pulmonary edema. Am J Cardiol, 115, 992–​1000. MacIver DH, Dayer MJ, Harrison AJ (2013). A general theory of acute and chronic heart failure. Int J Cardiol, 165,  25–​34. National Institute for Health and Care Excellence (2014). Acute heart failure: diagnosis and management. Clinical guideline. https://​nice. org.uk/​guidance/​cg187 Ponikowski P, et al. (2016). 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J, 37, 2129–​200. Tharmaratnam D, Nolan J, Jain A (2013). Management of cardio­genic shock complicating acute coronary syndromes. Heart, 99, 1614–​23. Thiele H, et al. IABP-​SHOCK II Trial Investigators (2012). Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med, 367, 1287–​96.

16.5.3  Chronic heart failure: Definitions, investigation, and management John G.F. Cleland and Andrew L. Clark ESSENTIALS Heart failure is a common clinical syndrome, predominantly a disease of older people, often presenting with breathlessness, fatigue, and peripheral oedema. Its pathophysiology is complex, with a common feature being salt and water retention, possibly triggered by a relative fall in renal perfusion pressure. Common aetiologies include ischaemic heart disease, hypertension, and valvular heart disease. New treatments have improved prognosis substantially over the past two decades. Early diagnosis relies on a low threshold of suspicion and screening of people at risk. Low plasma concentrations of BNP/​NT-​ proBNP exclude most forms of heart failure, and intermediate or high concentrations should prompt referral for echocardiography to identify possible causes and determine the left ventricular ejection fraction (LVEF), leading to classification as heart failure with reduced LVEF (50%, HFnEF), or borderline LVEF (40–​50%, HFbEF). HFbEF and HFnEF are managed similarly by current guidelines. Treatable causes for heart failure (e.g. valvular disease, tachyar­ rhythmias, thyrotoxicosis, anaemia, or hypertension) should be identified and corrected. Pharmacological therapy is given to improve

symptoms and prognosis. Diuretic therapy is the mainstay for control of congestion and symptoms, but its effect on long-​term prognosis is unknown. For patients with HFrEF, either angiotensin-​converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor–​ neprilysin inhibitors, combined with β-​ blockers and mineralocorticoid receptor antagonists (triple therapy) provide both symptomatic and prognostic benefit. Other treatments that may be appropriate in particular cases include ivabradine, digoxin, cardiac resynchronization therapy, and implantable defibrillators. Heart transplantation or assist devices may be options for highly selected patients with end-​stage heart failure; many others may benefit from palliative care services.

Introduction Heart failure is the most common malignant disease in the United Kingdom. Heart failure in its various manifestations now causes or complicates twice as many hospital admissions (about half a million deaths and discharges each year in the United Kingdom) as do all cancers or acute coronary syndromes combined. This is likely to be a gross underestimate of total activity as the diagnosis of heart failure is often missed or ignored during admission. In the community, heart failure syndromes are almost as common as diabetes mellitus and far more deadly. For some cardiac phenotypes (e.g. left ventricular systolic dysfunction), treatment is often highly effective and may even be curative, but diagnostic awareness is low and care, when given, is often fragmented and disorganized. The reasons for the current clinical neglect of heart failure are not entirely clear but may reflect the lack of a robust definition, the difficulty and uncertainties of its clinical diagnosis, the relative complexity of its treatment, all combined with ageism and fatalism on the part of both the clinician and patient.

Definition No consensus has been reached on a simple, practical universal definition of heart failure. Indeed, it may be better to consider the diagnosis of heart failure across a spectrum of certainty based on clinical acumen supported by blood tests (particularly natriuretic peptides) and cardiac imaging. Until now, most experts and guidelines have required that the patient should have symptoms before a diagnostic label of heart failure is applied. Of course, a sedentary lifestyle and liberal use of diuretics may mask symptoms. Simply asking the patient to take a walk will often reveal how poor their effort tolerance is, and stopping diuretics will often lead to the diagnosis becoming obvious. Other specialties use biochemical definitions to define organ failure (kidney, pancreas, liver). Central to the concept of heart failure is congestion, indicating that the heart is unable to sustain a normal filling (atrial) pressure for the required cardiac output. Cardiac output is usually fairly normal at rest until the late stages of heart failure. How then should congestion be measured? Natriuretic peptides, hormones that are secreted by the stressed heart and designed to counter sodium retention, provide a simple objective method of detecting congestion, even before it becomes clinically overt (Fig. 16.5.3.1). Thus, heart failure could be considered cardiac dysfunction leading to an increase in natriuretic peptides. Natriuretic

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suggesting that the diagnosis is usually missed until the problem is bad enough to provoke severe symptoms. The onset of symptomatic heart failure may well be precipitated by an acute event, but usually on a background of chronic cardiac dysfunction. Earlier diagnosis will increase identification in the community before the onset of severe symptoms and at a time when therapy might be more effective.

Clinical physiology

Fig. 16.5.3.1  Natriuretic peptides are the earliest and most sensitive sign of congestion but do not distinguish between cardiac and renal causes. Cardiac imaging is less sensitive and accurate (i.e. abnormal cardiac function may not cause congestion) for detecting congestion but, along with tests for heart rhythm and renal function, it helps to determine the cause of congestion. Symptoms and signs are late manifestations of congestion and usually only first detected when they have deteriorated sufficiently to precipitate a hospital admission.

peptides are now an essential tool for the early detection and confirmation of a diagnosis of heart failure in any modern health service. Broadening the definition of heart failure has many consequences, the most obvious being a great increase in the number of patients. About 3% of the adult population is taking loop diuretics for no obvious reason other than symptoms or signs suggestive of heart failure. Currently, most cases of heart failure are diagnosed during a hospital admission,

Heart failure can be considered as a sequence of unfortunate events (Fig. 16.5.3.2), starting with cardiac (usually left ventricular) dysfunction leading to haemodynamic changes that are often initially subtle, including a rise in atrial pressures and a fall in blood pressure below the set-​point for renal sodium retention. This triggers activation of neuroendocrine systems such as the renin–​angiotensin–​ aldosterone and sympathetic nervous system in an attempt to restore blood pressure by vasoconstriction and blood volume expansion. This has long-​term deleterious effects on the heart. Fortunately, there is also activation of counter-​regulatory mechanisms, most notably the natriuretic peptides, which attempt to prevent sodium retention and delay the onset of symptomatic congestion. Eventually, counterregulatory systems are overwhelmed, and clinical evidence of congestion appears, manifest either as breathlessness (loosely related to left atrial pressure) or peripheral oedema (loosely related to right atrial pressure). The treatment of heart failure revolves around preventing or reversing congestion and avoiding sudden death due either to arrhythmias or vascular events, which can arise at any time.

Cardiac (imaging) phenotypes Cardiac phenotype is strongly linked to the aetiology of cardiac dysfunction and is a key determinant of management. For some cardiac phenotypes there is little evidence that treatment alters outcome.

Left ventricular dysfunction Mitral regurgitation Rise in left atrial pressure • At rest • During stress • Volume (fluid load, exercise) • Pressure (hypertension, exercise) • Pulmonary congestion • Breathlessness

• Pulmonary arteriolar hypertrophy & vasoconstriction • Pulmonary hypertension

• Right ventricular dysfunction • Tricuspid valve regurgitation • Rise in right atrial pressure • Peripheral congestion • Peripheral oedema

Fig. 16.5.3.2  Development and progression of heart failure.

16.5.3  Chronic heart failure

Table 16.5.3.1  Common cardiac phenotypes in heart failure HFrEF

HFbEF

HFpEF/​HFnEF

LVEF

50%

Ischaemic heart disease

XXX

XX

X

Hypertension

X

XX

XXX

Atrial fibrillation

XX

XX

XXX

Dilated cardiomyopathy

XXX

?

NA

Aortic stenosis

X

XX

XXX

Mitral regurgitation

XX

XX

XX

Number of crosses reflects strength of association (although not necessarily proportion affected or prevalence). HFrEF = heart failure with a reduced left ventricular ejection fraction. HFbEF = heart failure with a borderline left ventricular ejection fraction. HFpEF/​HFnEF = heart failure with a preserved or normal left ventricular ejection fraction.

Few patients have a single pure phenotype; most patients manifest several phenotypes, but usually one is dominant (Table 16.5.3.1). When heart failure is associated with a reduced left ventricular ejection fraction (LVEF) this is often termed HFrEF or left ventricular systolic dysfunction (LVSD). Patients with heart failure and a normal or preserved LVEF are termed HFnEF and HFpEF, respectively. Left ventricular diastolic dysfunction (LVDD) is a subset of HFnEF as it is possible to have HFnEF without LVDD (e.g. patients with isolated right ventricular dysfunction). Various authorities suggest different LVEF thresholds for defining HFnEF, with the cut-​off ranging from less than 40% to over 50%. Since echocardiographers usually refer to a LVEF of under 50% as LVSD the terminology is confusing, and some believe that patients with an LVEF of 40–​50% should be considered a separate group HFbEF (heart failure with a borderline LVEF), which seems a helpful concept. LVEF measured by conventional echocardiography is only accurate to within about 10%, although more advanced imaging techniques such as cardiac MRI (CMRI) may have greater precision. Each of the phenotypes is heterogeneous, particularly HFnEF (Fig. 16.5.3.3). HFrEF is the predominant cardiac phenotype in men

and patients aged less than 75 years and is often due to ischaemic heart disease. HFnEF is the predominant phenotype in older women and is often due to hypertension. In patients with HFrEF, it is important to consider to what extent contractile dysfunction is due to dysfunction of viable myocardium, which may be reversible, or to consolidated scar that is likely to be irreversible using existing technology. The relative contribution of extracellular matrix and fibrosis and impaired cardiac myocyte relaxation to HFnEF is uncertain, and the therapeutic target at the myocardial level is unclear. Heart failure due to valve disease may occur at any age, but degenerative valve disease is an increasingly common cause in older people.

Risk factors and aetiology The most important risk factor for heart failure is age. It is likely that everyone will develop heart failure if they live long enough. Biological rather than chronological age may account for the link between physical frailty and the risk of developing heart failure. Currently, one in five people is expected to develop heart failure before they die, which may be a gross underestimate given the diagnostic gap outlined earlier. The most important medical risk factors for developing heart failure are hypertension and ischaemic heart disease, and their combination may confer more than additive risk (Table 16.5.3.1). Both may go undetected and untreated for years; the onset of symptoms of heart failure may be the first time the patient seeks help. There is a wealth of evidence that hypertension, even when detected, is often poorly managed. Alarmingly, studies suggest that most myocardial infarctions, perhaps especially among older people, do not provoke symptoms sufficient for the person to seek immediate medical assistance. Good treatment of hypertension and other risk factors for coronary artery disease will undoubtedly delay the onset of disease. Poor lifestyle and inferior medical care probably account for the association between social deprivation and the onset of heart failure at an earlier age. Among patients aged under 50 years, cardiomyopathies and congenital heart disease account for a large proportion of heart failure.

Fig. 16.5.3.3  Heterogeneity of heart failure with normal left ventricular ejection fraction. Conceptually, the diagnosis of heart failure requires evidence of congestion: for example, elevated natriuretic peptides, evidence of a cardiac abnormality, and (retrospectively) an increased risk of cardiovascular events.

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Table 16.5.3.2  Some rarer causes of heart failure Causes

Comments

Phenotype and specific therapy

Amyloidosis

Due to plasma cell expansion/​myeloma (AL), transthyretin (ATTR) gene mutation or chronic infection/​inflammation (AA). TTR mutations may cause 10% of HFpEF in older people

Increased LV wall thickness, HFbEF, or HFpEF. Often atrioventricular conduction delay Poor prognosis for AL. Most patient die within a year of diagnosis. ATTR better prognosis. Specific therapies in discovery (e.g. tafamidis)

Haemochromatosis

High serum ferritin and transferrin saturation. Often diabetic. Affects c.0.05% of Northern Europeans

Haemosiderosis

Usually associated with multiple blood transfusions due to haemolytic or aplastic anaemia.

HFrEF or HFbEF. Often a restrictive picture Treat with phlebotomy and iron chelation therapy. Early detection important

Carcinoid syndrome

Caused by hepatic or more rarely pulmonary metastasis of serotonin secreting tumours

Tricuspid regurgitation and pulmonary stenosis leading to low output and peripheral congestion.

Sarcoid heart disease

Often associated with pulmonary disease

HFrEF or HFpEF. Arrhythmias and conduction defects common

Tachy-​cardiomyopathy

Ventricular rate usually persistently >150 bpm. Usually supraventricular but rarely ventricular tachycardia. Lower rates suggest that tachycardia is a consequence of heart failure

Dilated cardiomyopathy. Resolves usually within a few weeks when arrhythmia is corrected

Thyrotoxicosis

May be iodine/​amiodarone induced. Weight loss, tachycardia, and other features of thyroid hormone excess

High output

Phaeochromocytoma

Due to catecholamine secreting tumours—​usually adrenal

HFrEF. Care with the use of adrenergic antagonists. Requires surgical correction

Genetic DCM

More than a dozen genetic mutations, notably of the titin gene

HFrEF

Lamin A/​C gene mutation

Rare

HFbEF. Atrioventricular conduction defects, ventricular arrhythmias, and sudden death

Muscular dystrophy

Duchenne, Becker, and myotonic dystrophy

HFrEF often with conduction defects

Hypertrophic cardiomyopathy

May be genetic or sporadic

HFpEF or HFbEF

Left ventricular non​compaction

May be familial

HFrEF or HFbEF

Endomyocardial fibrosis

Usually a tropical disease possibly due to parasitic disease. Consider if eosinophilia

HFpEF or HFbEF. Restrictive defect

Iatrogenic

Cancer chemotherapy, radiation, calcium channel blockers, hypoglycaemic therapies

Anthracycline and radiation induced damage may be irreversible. May be HFrEF or HFpEF

Nutritional deficiency

Thiamine, iron, selenium

Rare unless severe deficiency

Peripartum Cardiomyopathy

Usually in last trimester or within a few weeks of delivery

May only be recognized when severe. Usually recovers if patient survives. May recur with further pregnancy

Myocarditis

May be viral, including HIV, or due to borrelia (Lyme disease) or trypanosomiasis (Chagas disease). Giant cell myocarditis has a particularly poor prognosis

HFrEF HIV—​often pulmonary hypertension Chagas disease—​arrhythmias Borrelia—​consider doxycycline Giant cell—​steroids?/​immunosuppression?

In patients aged over 50 years, ischaemic heart disease is the dominant cause of HFrEF and hypertension the dominant cause of HFnEF. There are many rare causes of heart failure (Table 16.5.3.2), but collectively these affect a substantial number of patients.

Diagnosis Most heart failure is first diagnosed at a late stage in the disease, subsequent to a hospital admission. This is unlikely to change until screening the population at risk with natriuretic peptides becomes routine. There are six diagnostic steps:

Step 1: Case ascertainment The first and most important step is suspecting that something might be wrong. The patient may complain of breathlessness, but this is a

late manifestation of disease in a sedentary population. By the time orthopnoea, paroxysmal nocturnal dyspnoea, or breathlessness on mild exertion have developed, the disease is far advanced. Walking with the patient at a brisk pace may well provoke symptoms but does not lend itself to the organization of conventional clinics in primary or secondary care. Ankle oedema due to rising systemic venous pressure is also a late manifestation of disease and carries low specificity. Symptoms and signs may be abolished by diuretic therapy, but there is concern that such treatment may accelerate the progression of disease by deleterious activation of neuroendocrine systems. Earlier detection of heart failure requires a provocative test of cardiac reserve (e.g. a corridor walking test) or identification of activated compensatory mechanisms (e.g. natriuretic peptides) in patients deemed at risk of heart failure by virtue of age or medical risk factors. Any patient prescribed a loop diuretic should be presumed to have heart failure until proven otherwise.

16.5.3  Chronic heart failure

Step 2: Proving that cardiac dysfunction and heart failure are present Once heart failure is suspected, objective evidence of cardiac dysfunction is required. Breathlessness and ankle swelling are not specific to heart failure. Signs of heart failure, such as jugular venous distension, are relatively specific but insensitive, often difficult to elicit, and not easily recorded in a way that convinces colleagues. Chest radiography is no longer regarded as essential. A normal chest radiograph is not uncommon in patients with heart failure, and radiographic cardiomegaly is frequently a spurious finding. The electrocardiogram (ECG) is almost universally abnormal in heart failure and if genuinely normal places the diagnosis in doubt. Until recently, echocardiography was considered the practical gold-​standard measure for cardiac dysfunction and focused almost exclusively on identifying valve disease and HFrEF. However, there is growing awareness of the limitations of echocardiography, especially when not interpreted by experts. Reproducibility of LVEF estimation is poor, and measurements of diastolic function are complex and often contradictory. Probably the best echocardiographic guide to cardiac dysfunction, at least when chronic, are atrial volumes. Natriuretic peptides provide a simple approach to diagnosis and are more closely associated with atrial volumes than many other measures of cardiac dysfunction. They are not only more sensitive than cardiac imaging but a better guide to the patient’s prognosis. Natriuretic peptides are also more specific than imaging when the question is ‘Does this patient have serious disease requiring further investigation?’ rather than ‘Does this patient have cardiac dysfunction?’ A normal plasma concentration of a natriuretic peptide in the absence of a diuretic effectively excludes heart failure with one uncommon exception—​constrictive pericarditis. Gross obesity is associated with somewhat lower plasma concentrations of natriuretic peptides and diuretics may reduce them as they improve congestion. The N-​terminal fragment of pro brain natriuretic peptide (NT-​proBNP) is stable for days in blood samples and therefore can be measured easily and inexpensively in primary or secondary care. Interpretation of results requires additional information. Atrial fibrillation and renal dysfunction are other common reasons for an increase in plasma natriuretic peptides concentrations. Clinical acumen supported by a measurement of natriuretic peptide is usually sufficient to make or refute a diagnosis of heart failure.

Step 3: Differential diagnosis If a patient has symptoms, merely excluding or diagnosing heart failure is not enough. Alternative causes of symptoms should be sought. The common differential diagnoses for breathlessness are lung disease, obesity, and being unfit, all of which may coexist with heart failure. Determining how much each is contributing to symptoms will help guide use of diuretics; dehydrating patients with lung disease is unlikely to make them better and may make them worse. Spirometry may help identify lung disease, but low values may reflect general frailty and poor technique rather than lung disease. Natriuretic peptides can help; a slim patient who is very breathless but only has moderately elevated NT-​proBNP is likely to have lung disease as the dominant pathology. Cardiopulmonary exercise

Table 16.5.3.3  Conditions masquerading as diastolic heart failure COPD/​Cor pulmonale (without RV dysfunction) Obesity-​hypoventilation syndrome Obstructive sleep apnoea Severe renal disease Anaemia Thyrotoxicosis Nephrotic syndrome Silent myocardial ischaemia Venous insufficiency Lymphatic obstruction

testing aids differential diagnosis but requires special equipment and expertise. Echocardiographic evidence of mild diastolic dysfunction is very common in elderly people and heart failure can be readily overdiagnosed. A diagnosis of HFnEF made on the isolated echocardiographic finding of diastolic dysfunction should always be regarded with caution, and only following exclusion of alternative pathology. Conditions that may masquerade as ‘diastolic heart failure’, either in isolation or in combination, are listed in Table 16.5.3.3.

Step 4: Cardiac phenotype and cause(s) of cardiac dysfunction Clinical acumen combined with natriuretic peptides may be enough to make a diagnosis of heart failure, but is a poor guide to cardiac phenotype. The workhorse of cardiac phenotyping is the echocardiogram. The echocardiogram provides an approximate guide to LVEF and therefore differentiates HFrEF from HFnEF, identifies abnormal heart valves, and quantifies atrial volumes. Of the many parameters of diastolic function, increased left atrial size is probably the simplest and most reliable, and is an important prognostic indicator regardless of baseline left ventricular function. For patients with HFrEF, the amount of myocardial scar is an important determinant of the response to treatment and is best assessed by CMRI. However, many heart failure services have little access to this investigation. Radionuclear imaging is an alternative. A diagnosis of coronary disease can usually be made based on the clinical history or, failing that, by CMRI, stress echo, or radionuclear imaging. In the absence of symptomatic angina there is no evidence that revascularization improves outcome in patients with chronic heart failure. The presence or absence of coronary disease should have little influence on the choice of pharmacological or device treatment, and there is no evidence that antiplatelet agents are safe or effective in this setting. Angiography should therefore be reserved for patients with limiting angina despite pharmacological therapy, and those presenting with heart failure in the context of an acute coronary syndrome. CT angiography can be used if it is felt necessary to exclude left main-​stem disease or that of another proximal coronary artery. There is little information to be gained from heart catheterization that cannot be obtained more pleasantly, safely and at lower cost by non​invasive methods, which may also supply information that an angiogram cannot.

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Table 16.5.3.4  Common problems (comorbidities) complicating the diagnosis and management of heart failure Problem

Comment

Obesity (and lack of fitness)

Alternative cause for breathlessness creating diagnostic uncertainty and problems with judging diuretic dose. Diuresis will not help breathlessness due to obesity. Obesity is consistently associated with a better prognosis in a broad spectrum of patients with cardiovascular disease, including heart failure.

Cachexia

Ominous sign in heart failure. Exclude cancerous malignant disease. If patient is a candidate for transplant or mechanical assist, consider urgent referral.

COPD

Alternative cause for breathlessness creating diagnostic uncertainty and problems with judging diuretic dose. Diuresis will not help breathlessness due to COPD. Patients with heart failure and COPD have a worse prognosis.

Atrial fibrillation

AF may cause heart failure and vice versa. Optimal ventricular rate control may be about 80 bpm at rest. Need for anticoagulation.

Ischaemic heart disease

Common cause of a reduced LVEF. Little evidence that revascularization improves prognosis. Coronary angiography only indicated if patient has angina. Ongoing research into revascularization of viable myocardium but randomized controlled trials neutral so far.

Hypertension

A sign that the left ventricle still has some reserve. Most treatments for heart failure reduce blood pressure, so in this context hypertension is a good sign!

Hypotension

Often limits amount of pharmacological treatment and is a poor prognostic sign. Cardiac resynchronization will increase systolic blood pressure in appropriately selected patients.

Anaemia

Often associated with iron deficiency although not always corrected by oral or even intravenous iron. Some anaemia is dilutional (plasma volume expansion) and some caused by renal dysfunction and deficient erythropoiesis. Folate and B12 deficiency are rarely important causes of anaemia in heart failure.

Diabetes mellitus

Indicates a worse prognosis, possibly because of associated renal problems. Treatment for diabetes may make heart failure worse. Optimal HbA1c in patients with heart failure being treated for diabetes may be around 7.5% (lower if ‘prediabetic’).

Chronic kidney disease

Often due to pre-​existing renal damage and exacerbated by hypotension and low renal blood flow. Often limits the doses of medication that can be given. Renal function is a powerful prognostic marker (more powerful than LVEF).

Stroke

Related mainly to pre-​existing hypertension, atherosclerosis, and atrial fibrillation.

Dementia

Age often brings deterioration in cognitive as well as cardiac function. Dementia reduces ability for self-​care and adherence to advice and medication. Worsening heart failure may impair cognitive function.

Aortic stenosis

Common in older people. Diuretics may reduce congestion and symptoms, but other medication may be of little help and may cause hypotension. Consider aortic valve surgery or transcutaneous procedure.

Mitral regurgitation

Common in all forms of heart failure. May improve with treatments that reduce ventricular volume, especially cardiac resynchronization. Patient selection for surgery often difficult. Transcutaneous repair may be considered.

Step 5: Comorbidity—​what other problems might exacerbate or complicate heart failure? Patients rarely only have heart failure. Identifying important cardiovascular and non​cardiovascular comorbidity provides additional therapeutic targets (Table 16.5.3.4).

Step 6: Diagnostic tests required to achieve therapeutic aims The therapeutic goals should first be defined. If it is palliative care, then only treatments designed to control symptoms are appropriate (this may include diuretics, ACE inhibitors, mineralocorticoid antagonists (MRA), cardiac resynchronization therapy, and possibly digoxin and intravenous iron). If the goal is to improve prognosis through ‘disease-​modifying’ interventions, then β-​blockers, ivabradine, and implantable cardiac defibrillators should be added to the list. Preventing patients with atrial fibrillation from developing the misery of a stroke might be considered appropriate regardless of other therapeutic aims. The small amount of information (10 items) routinely required to use these agents safely and effectively is shown in Table 16.5.3.5.

Prognosis The prognosis of heart failure depends on the clinical context. Incident heart failure is associated with a 30% mortality at 6 months.

The annual mortality of chronic stable patients is now probably less than 5% per annum, but admission to hospital with worsening heart failure has a mortality of about 10–​15%, with mortality in the 6 months after discharge from an admission being in the range of 15–​25%. Age is an important determinant of mortality, with the influence of treatments shown in Fig. 16.5.3.4. Readmission rates are also high; most patients with heart failure will be admitted at least once in a 3-​year period, and following a readmission, 15–​25% will have a further readmission within 30 days without expert support. Age is not such a good predictor of readmission, perhaps because older people have a higher mortality. A pragmatic prognostic scoring system for chronic heart failure can be found at http://​www.heartfailurerisk.org/​, and may be improved by some simple additional pieces of information, such as whether the patient has had a recent exacerbation of symptoms, the dose of diuretic, and plasma concentration of NT-​proBNP. Knowing prognosis can help with management, both in terms of advice to the patient and choice of therapy.

Management Modern management of patients with heart failure requires the coordinated input of a multidisciplinary team of dedicated cardiologists, specialist heart failure and rehabilitation nurses, primary care physicians, and palliative care specialists. The key to the successful

16.5.3  Chronic heart failure

management of these patients is prompt identification in the community and following admission to hospital, and access to follow-​up and management by a specialist team.

Lifestyle Patients with heart failure should be advised to lead a healthy lifestyle, avoiding smoking and excessive alcohol consumption, eating a balanced diet, and taking regular exercise (http://​www. heartfailurematters.org/​en_​GB). There is little evidence that such advice makes a difference to prognosis, but it probably improves well-​being. Attention to psychological health is important. Keeping socially active, taking holidays (with adequate health insurance; http://​www.bhf.org.uk/​heart-​health/​living-​with-​aheart-​condition/​ living-​with-​heart-​failure.aspx) and investing in hobbies and recreations are more important than pharmacological treatments for anxiety and depression that are, however, mostly safe. There is no evidence that complementary medicine can alter the course of heart failure but, provided the patient is not tempted to stop conventional therapy, it may provide them with psychological support. Patients should know what medication to take and be advised to have a system to ensure that they do so. Excessive dietary salt and fluid consumption should be avoided, but there is scant evidence that severe restriction of dietary salt is helpful and it might do harm. Fluid restriction (to 40%)

Loop diuretics

II-​IV

X

X

X

X

Symptomatic

Symptomatic

Symptomatic/​Prognostic

Symptomatic

Symptomatic/​Prognostic

?

AF

QRS

BNP

ACE/​ARB

II-​IV

X

X

X

ARNI

II-​IV

X

X

X

β-​Blocker

II-​IV

X

Prognostic

?

MRA

II-​IV

X

X

X

Symptomatic/​Prognostic (25% R wave) in at least two leads from II, III, aVF (in absence of left anterior hemiblock), V1–​V4; or I, aVL, V5–​V6

Deep S in V2 (>25 mm)

Clinical There are no clinical major criteria

Unexplained chest pain, dyspnoea, or syncope

LV, left ventricular; SAM, systolic anterior motion of the mitral valve. Reproduced from Heart, McKenna WJ, et al., 77, 130–​2. Copyright 1997 with permission from the BMJ Publishing Group Ltd.

Clinical features History Symptomatic presentation may be at any age with breathlessness on exertion, chest pain, palpitation, syncope, or sudden cardiac death. HCM is occasionally found at autopsy in a stillborn baby or presents during infancy with cardiac failure, which is usually fatal. In children and adolescents, the diagnosis is most often made during screening of siblings and offspring of affected family members. Paroxysmal symptoms or mild impairment of exercise tolerance are often present, but in the absence of a murmur, may not prompt cardiac evaluation. About 50% of adults present with symptoms; in the remainder the diagnosis is made during family screening or following the detection of an unsuspected abnormality on physical, electrocardiographic, or echocardiographic examination. Dyspnoea is common (>50%) as a consequence of elevated left atrial and pulmonary capillary wedge pressures resulting from impaired left ventricular relaxation and filling, and about 50% complain of chest pain, which is exertional, atypical, or both in similar proportions of patients. Atypical pain may have no obvious precipitant; more commonly it follows exercise-​or anxiety-​related tachycardia, when it persists for up to several hours after the stress has been removed without enzymatic evidence of myocardial damage. Syncopal episodes occur in 15 to 25%, but in only a few are there findings suggestive of an arrhythmia or evidence of overt conduction disease: in most patients, the mechanism cannot be determined. Patients rarely present with paroxysmal nocturnal dyspnoea, ascites, or peripheral oedema. Physical examination In most patients with hypertrophic cardiomyopathy the physical examination is unremarkable. There may be a rapid upstroke arterial pulse reflecting dynamic left ventricular emptying. In about one-​third, the jugular venous pulse may demonstrate a prominent ‘a’ wave, reflecting diminished right ventricular compliance secondary

to right ventricular hypertrophy. Many patients have a forceful left ventricular cardiac impulse, best appreciated on full-​held expiration in the left lateral position, when there may be a palpable atrial beat reflecting forceful atrial systolic contraction that may or may not be associated with significant forward flow of blood. The first and second heart sounds are usually normal, and—​unless the patient is in atrial fibrillation—​there is likely to be a loud fourth heart sound, reflecting increased atrial systolic flow into a non-​ compliant ventricle. However, in those patients (20–​30%) who have a resting left ventricular outflow tract gradient, the most obvious physical sign is an ejection systolic murmur. This murmur starts well after the first heart sound and ends before the second. It is best heard at the left sternal border, radiating towards the aortic and mitral areas, but not into the neck or the axilla. The intensity varies with changes in ventricular volume; it can be increased by physiological and pharmacological manoeuvres that decrease afterload or venous return (amyl nitrate, standing, Valsalva, and others), and decreased by manoeuvres that increase afterload and venous return (squatting, phenylephrine, and others). Occasionally there is an ejection sound at the onset of the systolic murmur. Most patients with a left ventricular outflow tract gradient also have mitral regurgitation. Doppler examination reveals that mitral regurgitation usually begins just before (30–​40 ms) the onset of the gradient and continues for the duration of systole. Radiation of the systolic murmur to the axilla is often the best auscultatory clue to the presence of coexistent mitral regurgitation, which may be moderate to severe, either alone or in association with a left ventricular outflow tract gradient. A mid-​diastolic rumble may sometimes result from increased transmitral flow in patients with severe mitral regurgitation. Early diastolic murmurs of aortic incompetence may develop following surgical myectomy or infective endocarditis involving the aortic valve. Although such murmurs are rare in the absence of such complications, they appear to occur more commonly than would be expected by chance and may reflect traction on the non​coronary

16.7.2  The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular

cusp of the aortic valve by the septum. An ejection systolic murmur in the pulmonary area, reflecting right ventricular outflow tract obstruction, is also rare; when present, it is usually associated with severe biventricular hypertrophy in the young or in those with coexistent Noonan’s syndrome and a dysplastic pulmonary valve (see Chapter 16.12).

Prognosis Patients with hypertrophic cardiomyopathy experience slow progression of symptoms and gradual deterioration of left ventricular function, and are at risk of sudden cardiac death throughout life. Annual mortality rates are in the range of 1–​2%, but the risk of death and other disease-​related complications varies between individuals and within individuals during the course of the disease. Severe heart failure symptoms may develop in association with progressive myocardial wall thinning caused by myocardial fibrosis and severe reduction in left ventricular systolic performance and/​ or diastolic filling. The development of systolic failure is associated with a poor prognosis, with rapid progression from onset to death or transplantation, and an overall mortality rate of up to 11% per year. Left atrial size provides important prognostic information on the risk of sudden cardiac death and atrial fibrillation/​flutter. Atrial arrhythmias are important in the clinical course, leading to a risk of acute deterioration and thromboembolic stroke. Onset of atrial fibrillation is part of the evolution of patients with diastolic dysfunction, and with appropriate management need not represent a major cause of morbidity or mortality. A few patients who experience such deterioration present with a clinical picture resembling restrictive cardiomyopathy, with grossly enlarged atria, signs of right heart failure, and relative preservation of left ventricular systolic performance. Left ventricular hypertrophy develops during childhood and adolescence, but is rarely progressive in adults. The trigger and other determinants of disease expression in late-​onset disease are uncertain.

Investigations Cardiological evaluation of patients with hypertrophic cardiomyopathy is performed to confirm the diagnosis, to guide symptomatic therapy, and to assess the risk of complications, particularly that of sudden death. Electrocardiography The 12-​lead ECG is the most sensitive diagnostic test, although occasionally normal (c.5%), particularly in the young. At the time of diagnosis, 5–​10% of patients are in atrial fibrillation. Many have an intraventricular conduction delay and 20% have left-​axis deviation, but complete right bundle or left bundle branch block is uncommon (c.5%). The latter may develop following surgery and is occasionally seen in elderly patients. ST-​segment depression and T-​wave changes are the most common abnormalities and are usually associated with voltage changes of left ventricular hypertrophy and/​or deep S waves in the anterior chest leads V1 to V3. Isolated repolarization changes or giant negative T waves are occasionally seen. Voltage criteria for left ventricular hypertrophy are rare in the absence of repolarization changes. About 20% of patients have abnormal Q waves, either inferiorly (II, III, and aVF), or less commonly in leads V1 to V3. P-​wave abnormalities of left and/​or right atrial overload are common. The distribution of the PR interval is

similar to that in the normal population, but occasionally a short PR interval may be associated with a slurred upstroke to the QRS complex. This is not usually associated with evidence of pre-​excitation, although patients with hypertrophic cardiomyopathy and accessory pathways have been described. Despite the many electrocardiographic abnormalities, there is no ECG that is typical of HCM; a useful rule is to consider the diagnosis whenever the ECG is bizarre, particularly in younger patients. The incidence of arrhythmias during 48-​h ambulatory electrocardiographic monitoring increases with age. Non​ sustained ventricular tachycardia is detected in 20–​25% of adults and, although usually asymptomatic, is associated with an increased risk of sudden cardiac death. Supraventricular arrhythmias are also common in adults and can be poorly tolerated if sustained (>30 s) unless the ventricular response is controlled. Atrial fibrillation or flutter carry an increased risk of thromboembolism. By contrast, most children and adolescents are in sinus rhythm, and arrhythmias during ambulatory electrocardiographic monitoring are uncommon. The increased incidence of supraventricular arrhythmias with age is related to increased left atrial dimensions and increased left ventricular diastolic pressure. The aetiology of ventricular arrhythmias is not known, but may relate to myocyte loss and myocardial fibrosis. Documented sustained ventricular tachycardia is uncommon, but is a recognized complication in patients with an apical aneurysm, which may develop as a consequence of midventricular obstruction. Chest radiography The chest radiograph may be normal or show evidence of left and/​or right atrial or left ventricular enlargement; if left atrial pressure has been chronically elevated, there may be evidence of redistribution of blood flow to upper lung zones. Mitral valve annular calcification is seen, particularly in elderly patients. Echocardiography Left ventricular hypertrophy may be symmetric or asymmetric and localized to the septum or the free wall, but most commonly to both the septum and free wall with relative sparing of the posterior wall (Fig. 16.7.2.2). Isolated apical hypertrophic cardiomyopathy occurs in about 10% of patients. Approximately one-​third of patients also have hypertrophy of the right ventricular free wall, the presence and severity of which is strongly related to the severity of left ventricular hypertrophy. Typically, left ventricular end-​systolic and end-​diastolic dimensions are reduced, and the left atrial dimension is increased. Indices of systolic function such as ejection fraction may be increased, but systolic function is often impaired, which may be best appreciated by measurement of long-​axis rather than short-​ axis function. Colour Doppler provides a sensitive method of detecting left ventricular outflow tract turbulence (Fig. 16.7.2.3), and when combined with continuous wave Doppler the peak velocity (Vmax) of left ventricular blood flow can be measured and left ventricular outflow tract gradients calculated. Doppler gradients (pressure gradient (mm Hg) = 4 Vmax2) are seen in 20–​30% of patients and correlate well with those measured invasively. Systolic anterior motion of the mitral valve is usually present when the calculated outflow tract gradient is more than 30 mm Hg, and early closure or fluttering of the aortic valve leaflets is often seen in association

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Cardiac catheterization

Fig. 16.7.2.2  An echocardiogram (parasternal long-​axis view) of a patient with hypertrophic obstructive cardiomyopathy demonstrating hypertrophy of the interventricular septum (IVS), enlargement of the left atrium (LA), and systolic anterior motion of the mitral valve, bringing it into contact with the septum (arrow).

Two-​dimensional echo/​Doppler evaluation has replaced invasive haemodynamic measurements and angiography as the method of assessing left ventricular structure and function in hypertrophic cardiomyopathy. Cardiac catheterization is not necessary for diagnosis and is rarely indicated unless symptoms are refractory and direct measurement of cardiac pressures is potentially informative, particularly in assessing the severity of mitral regurgitation. Coronary arteriography may be necessary to exclude coexistent coronary artery disease in older patients who have significant angina or ST-​segment changes during exercise. The left coronary arteries are usually large in calibre. The left anterior descending and septal perforator arteries may demonstrate narrowing during systole in the absence of fixed obstructive lesions, but such changes do not appear to relate to symptoms. Left ventricular angiography is rarely indicated, but recognition of the abnormally shaped ventricle, which typically ejects at least 75% of its contents in association with mild mitral regurgitation, may provide a valuable diagnostic clue when hypertrophic cardiomyopathy was not suspected before catheterization. Exercise testing

with such motion. A posteriorly directed mitral regurgitant jet is seen in association with and related to the magnitude of the outflow tract gradient (Fig. 16.7.2.3). An anterior regurgitant jet or mitral regurgitation in the absence of obstruction suggests the coexistence of structural mitral valve abnormalities. Other imaging techniques Good-​quality echocardiography suffices for diagnostic and therapeutic purposes in most patients with hypertrophic cardiomyopathy, but cardiac MRI is useful in selected cases to assess right ventricular, apical, and lateral left ventricular involvement. Gadolinium-​enhanced cardiac MRI permits detection of myocardial fibrosis, the extent of which may predict evolution to the burnt-​out  phase.

Maximal exercise testing in association with respiratory gas analysis provides useful functional and prognostic information, which can be monitored serially. Oxygen consumption at peak exercise (peak Vo2) is usually moderately reduced, even in patients who do not complain of exertional symptoms. Continuous measurement of the blood pressure during upright treadmill or bicycle exercise reveals that about one-​ third of younger patients (70% luminal narrowing) or occlusions. The choice of revascularization procedure is dependent on a range of factors and should be discussed in a multidisciplinary group that includes cardiologists and cardiac surgeons: • Coronary anatomy—​historically, PCI has been preferred for single-​vessel and two-​vessel coronary artery disease and CABG for more extensive disease. This preference, based largely on presumed prognostic benefit for CABG in patients with three-​ vessel or left main stem disease (see next), has now given way to procedure selection based on coronary scoring systems. Most widely used is the SYNTAX score designed to quantify the complexity of left main or three-​vessel disease according to simple lesion criteria readily accessible from the coronary arteriogram. If the SYNTAX score is less than 22, signifying low lesion complexity, 5-​year outcomes favour revascularization by PCI, regardless of the number of diseased vessels. If the SYNTAX score is higher CABG should also be considered, and for scores more than 33 (signifying severe lesion complexity) CABG produces unequivocally better 5-​ year outcomes than PCI. In making revascularization decisions, however, other factors are also important, and there is now clear evidence favouring CABG for patients with diabetes and multivessel disease. • Patient preference—​PCI is often preferred because it avoids surgery, requires no more than 48 h hospitalization (day-​case PCI is now feasible), and permits early return to normal activities within a few days of the procedure. In expressing a preference, however, it is important that the patient is properly informed of the relative risks and benefits of PCI and CABG in his or her particular case. • Procedural risk—​mortality is lower for PCI than CABG (0.9% vs. 2.2%). Stroke risk may also lower, but rates of non​fatal myocardial infarction are comparable. • Symptomatic benefit—​this is comparable for PCI and CABG, but recurrence of symptoms and need for repeat revascularization is higher for PCI because of coronary restenosis in the months following a successful procedure. Indeed, restenosis has been the Achilles heel of PCI, and until the introduction of coronary stents affected 30% or more of all patients. Since then stenting has become widespread, producing more effective coronary patency although reductions in rates of restenosis to less than 10% had to await the introduction of drug-​eluting stents that deliver

antiproliferative drugs (e.g. sirolimus, paclitaxel) locally within the coronary artery. The prospect of providing long-​term relief of symptoms without the need for repeat procedures has considerably enhanced the clinical value of PCI. • Prognostic benefit—​There have been no studies showing survival benefit for PCI in patients with stable angina. For CABG, the small gains in life expectancy that have been reported in patients with left main stem coronary disease and three-​vessel disease are from studies nearly 40 years ago and their contemporary relevance may have changed with advances both in surgical techniques and in medical therapy. Indeed, it is generally accepted that improvements in the prognosis of coronary artery disease in the last 25 years have little to do with revascularization, but much to do with lifestyle changes and advances in secondary prevention therapy.

Refractory angina With current management strategies patients with angina are living longer, but some (perhaps 5 to 10%) remain symptomatic on optimal medical treatment, having exhausted revascularization options. These patients commonly have extensively collateralized coronary circulations and well-​preserved left ventricular function such that prognosis is not worse than other patients with angina, but quality of life is poor because of refractory symptoms. Psychological support is important to treat anxiety and depression and improve confidence. Other options for further antianginal therapy are not evidence-​ based and are not recommended in international guidelines. These include neuromodulatory techniques (stellate ganglion block, transcutaneous electrical nerve stimulation, spinal cord stimulation) and enhanced counterpulsation therapy using pressure cuffs applied to the lower limbs that are inflated sequentially during diastole.

FURTHER READING Boden WE, et  al. (2007). Optimal medical therapy with or without PCI in stable coronary disease. N Engl J Med, 35, 1503–​16. Doris MK, Newby DE (2016). How should CT coronary angiography be integrated into the management of patients with chest pain and how does this affect outcomes? Eur Heart J Qual Care Clin Outcomes, 2,  72–​80. Fihn SD, et  al. (2012). ACCF/​AHA/​ACP/​AATS/​PCNA/​SCAI/​STS Guideline for the diagnosis and management of patients with stable ischemic heart disease:  a report of the American College of Cardiology Foundation/​ American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol, 60, e44–​e164. Head SJ, et al. (2014). The SYNTAX score and its clinical implications. Heart, 100, 169–​77. Jones DA, et  al. (2013). Novel drugs for treating angina. BMJ, 347, f4726. Jordan KP, et al. (2017). Prognosis of undiagnosed chest pain: linked electronic health record cohort study. BMJ, 357, j1194. Montalescot G, et al. (2013). 2013 ESC guidelines on the management of stable coronary artery disease:  the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J, 34, 2949–​3003.

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NICE (2011). Management of stable angina. Clinical guideline. https://​ www.nice.org.uk/​guidance/​cg126 NICE (2016). Chest pain of recent onset:  assessment and diagnosis. Clinical guideline. https://​www.nice.org.uk/​guidance/​cg95 Rapsomaniki E, et al. (2014). Prognostic models for stable coronary artery disease based on electronic health record cohort of 102,023 patients. Eur Heart J, 35, 844–​52. Sekhri N, et  al. (2007). How effective are rapid access chest pain clinics? Prognosis of incident angina and non-​cardiac chest pain in 8762 consecutive patients. Heart, 93, 458–​63. Sekhri N, et al. (2016). A 10-​year prognostic model for patients with suspected angina attending a chest pain clinic. Heart, 102, 869–​75.

16.13.4  Management of acute coronary syndrome Rajesh K. Kharbanda and Keith A.A. Fox ESSENTIALS Acute coronary syndrome (ACS) is precipitated by an abrupt change in an atheromatous plaque and/​or thrombotic occlusion. This results in increased obstruction to perfusion and ischaemia or infarction in the territory supplied by the affected vessel. The clinical consequences of plaque rupture can range from a clinically silent episode, through to unstable symptoms of ischaemia without infarction, to profound ischaemia complicated by progressive infarction, heart failure, arrhythmia, and risk of sudden death. Clinical presentation with an ACS identifies a patient at high risk of further cardiovascular events requiring a defined acute and long-​ term management strategy. The choice and timing of acute management strategy is critically dependent on the extent and severity of myocardial ischaemia, with the spectrum of ACS broken down into three elements:  (1) Unstable angina: typical ischaemic symptoms without ST elevation on ECG and without elevated biomarkers of necrosis. (2) Non-​ST-​ elevation myocardial infarction (NSTEMI): typical ischaemic symptoms without ST elevation on ECG but with biomarkers of necrosis above the diagnostic threshold. (3) ST-​elevation myocardial infarction (STEMI): typical ischaemic symptoms with ST elevation on ECG and with biomarkers of necrosis above the diagnostic threshold. An acute reperfusion strategy (primary percutaneous coronary intervention (PCI) or thrombolysis) is of proven benefit only in ST-​ segment elevation infarction (or MI with new bundle branch block). Prompt relief of pain is important, not only for humanitarian reasons, but also because pain is associated with sympathetic activation, vasoconstriction, and increased myocardial work. Effective analgesia is best achieved by the titration of intravenous opioids, with concurrent administration of an antiemetic. High-​flow oxygen is recommended for symptom relief in those patients with evidence of desaturation, particularly in those who are breathless or who have features of heart failure or shock.

The management of prehospital cardiac arrest requires special attention: at least as many lives can be saved by prompt resuscitation and defibrillation as by reperfusion. Patients may also require management of arrhythmic and haemodynamic complications, including heart failure.

Acute coronary syndromes without ST elevation (unstable angina/​non-​ST elevation MI) Risk stratification and initial management Patients without ST elevation or left bundle branch block can be triaged into low, intermediate, and high-​risk categories. (1) High-​risk—​ patients with typical clinical features of ischaemia and ST-​segment depression or transient ST-​segment elevation, or with troponin elevation and a high-​risk score (risk calculator downloadable from http://​ www.gracescore.org/​or http://​www.timi.org/​). Patients are also at high risk when ischaemia provokes arrhythmias or haemodynamic compromise. (2) Intermediate or low risk—​patients with clinical features of ACS and non​specific ECG changes (e.g. T-​wave inversion, T-​wave flattening, minor conduction abnormalities). (3) Low risk or an alternative diagnosis—​patients with a normal ECG, normal biomarkers, normal cardiac examination, and normal echo. Patients at high risk—​(1) high-​risk patients with acute ischaemia at initial presentation, or those who develop such features after hospital admission, and especially those with haemodynamic compromise, require emergency assessment for revascularization and dual antiplatelet therapy. (2) Those proceeding to emergency revascularization should receive (a) aspirin; (b) P2Y12 receptor inhibitor; (c) unfractionated or low molecular weight heparin (LMWH), or a direct thrombin inhibitor, and (d) if required for bail-​out, glycoprotein IIb/​IIIa inhibition. (3) In addition to anti-​ischaemic therapy, additional therapy may be required:  antiarrhythmic management, or haemodynamic support to reduce ischaemia and stabilize the patient for revascularization. Where the clinical features support a diagnosis of ACS, patients developing ST elevation require emergency assessment with coronary angiography and where appropriate reperfusion by primary PCI, or—​when a primary angioplasty service is not available—​by thrombolysis (see next). Patients at intermediate or low risk—​patients with non-​ST-​elevation ACS and an intermediate risk score require dual antiplatelet therapy (aspirin plus P2Y12 receptor inhibitor, e.g. ticagrelor or prasugrel; if neither available, clopidogrel) plus parenteral anticoagulation. They are candidates for an early elective revascularization strategy (within c.72 h). Clinically stable patients with minor or non​specific ECG abnormalities and a low risk score (including negative repeat troponin) are at very low risk for in-​hospital, major cardiac events. Such patients may, nevertheless, have significant underlying coronary artery disease. They require assessment of the cardiovascular risk and non-​ invasive ischaemia testing to identify the presence and extent of inducible ischaemia, ideally prior to discharge.

Specific pharmacological therapies Anti-​ischaemic therapies—​(1) nitrates—​effective in reducing ischaemia in the in-​hospital management of non-​ST-​elevation ACS, but there is no evidence that they improve mortality; (2) β-​blockers—​patients with suspected acute coronary syndromes should be initiated on β-​blocker therapy unless contraindicated; (3) dihydropyridine calcium entry blockers—​should only be employed with β-​blockers in

16.13.4  Management of acute coronary syndrome

ACS to avoid reflex tachycardia. In patients unable to tolerate β-​ blockers, a heart-​ rate-​ slowing calcium antagonist (e.g. diltiazem or verapamil) may be appropriate. Short-​acting dihydropyridines should not be used in isolation in ACS. Antiplatelet therapies—​(1) aspirin 75–​325 mg daily—​indicated in all patients with ACS unless there is good evidence of aspirin allergy or evidence of active bleeding; (2) P2Y12 receptor inhibitor—​patients with non-​ST-​elevation ACS should be given a loading dose of either ticagrelor 180 mg, prasugrel 60 mg (once anatomy is defined), or clopidogrel 300–​600 mg (if neither ticagrelor nor prasugrel are available), followed by continued treatment, in combination with aspirin. Dual antiplatelet therapy should be maintained for 12 months, unless the risks of bleeding exceed potential benefits. Certain patients may benefit from more prolonged duration of dual antiplatelet therapy. (3)  GPIIb/​IIIa inhibitors (e.g. abciximab, eptifibatide, tirofiban) can be used in patients requiring urgent percutaneous intervention for non-​ST-​segment elevation ACS and in those at intermediate to high risk. Current indications for treatment with GPIIb/​IIIa inhibitors are mainly as a bail-​out at PCI. Anticoagulation—​this is required in addition to antiplatelet therapy. Indirect thrombin inhibitors: low molecular weight heparin is better than unfractionated heparin and is most commonly used. In the absence of an urgent/​early invasive strategy, fondaparinux (a synthetic pentasaccharide that selectively binds antithrombin and causes inhibition of factor Xa) has the most favourable efficacy/​safety profile. Bilvalirudin is the only direct thrombin inhibitor currently used in ACS management.

ST-​segment-​elevation myocardial infarction Patients with clear-​cut evidence of ST-​elevation infarction (STEMI) require immediate triage to reperfusion therapy. ‘Fast-​track’ systems have been developed to minimize in-​hospital delay to reperfusion: these aim to achieve clinical assessment and electrocardiography within 15 min of arrival and rapid transfer for PCI or the institution of thrombolytic therapy within 30 min. Audit programmes and continuous training are necessary for centres to achieve this 30-​min median ‘door-​to-​needle’ time. PCI—​randomized clinical trials of primary PCI vs. thrombolysis have shown consistent findings:  primary PCI is better, providing more effective restoration of vessel patency, achieving better ventricular function, and improving important clinical outcomes with lower rates of death, reinfarction, stroke, major bleeding, and recurrent ischaemia. Particular gains are seen in haemodynamically compromised patients. In consequence, primary PCI is the preferred therapeutic option in national and international guidelines. Thrombolysis—​prehospital thrombolysis is the next best option if a primary PCI programme is not available, or if transfer times are sufficiently prolonged that reperfusion may not be achieved within 120 min of patient call. The current reference standard for the comparison of fibrinolytic agents is the accelerated infusion regimen of alteplase (tPA), or—​for simplicity—​the single-​bolus administration of tenecteplase (TNK), which does not require an infusion pump or refrigeration and hence is particularly suited for prehospital administration. Internationally, streptokinase remains the most widely used fibrinolytic agent, principally because it is relatively inexpensive. If timely primary PCI is not available, a pharmaco-​invasive strategy (thrombolysis and subsequent revascularization) may provide similar benefit to primary PCI, but requires further testing.

Antiplatelet agents and anticoagulants—​ (1) aspirin 75–​ 325 mg daily—​indicated in all patients with ACS unless there is good evidence of aspirin allergy or evidence of active bleeding. (2)  P2Y12 receptor inhibitors should be given to all patients, continuing for at least 1 month in patients managed with fibrinolysis (or as determined by the type of stents implanted). (3) Anticoagulants—​heparin or bivalirudin are indicated in patients managed with primary PCI. Patients treated with fibrinolytic therapy should receive low molecular weight heparin or fondaparinux. (4) GPIIb/​IIIa inhibitors may be used in patients managed with primary PCI (mainly for bail-​out), but not in those managed with fibrinolysis.

Secondary prevention measures in patients with ACS Patients require advice and help regarding cessation of smoking (including the avoidance of passive smoking), dietary modification, exercise, rehabilitation, and management of obesity. The following therapies have been shown to reduce the risk of subsequent cardiovascular events:  (1) antiplatelet therapy—​aspirin in a dose of 75 mg/​day, clopidogrel 75 mg/​day. Certain subgroups may benefit from prolonged dual antiplatelet therapy—​aspirin and ticagrelor 60 mg/​bd or aspirin and clopidogrel; (2)  β-​blockers in those without contraindications; (3) lipid lowering with 3-​hydroxy-​3-​ methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins); (4) angiotensin-​converting-​enzyme inhibitors/​angiotensin receptor blockers, especially in those with left ventricular dysfunction and heart failure, and benefit is also possible in other patients with vascular disease; (5) aldostrone blockade (e.g. eplerenone) in those with left ventricular ejection fraction (LVEF) less than 35% and diabetes or clinical features of heart failure.

Introduction The term ‘acute coronary syndrome’ (ACS) describes the clinical manifestations of a heterogeneous spectrum of conditions that share key pathophysiological features:  disruption or erosion of coronary atheromatous plaque, changes in vascular tone, and a variable extent of thrombotic occlusion. The clinical presentation is determined by the extent of coronary obstruction, the volume of ischaemic myocardium, and timing of the atherothrombotic disease process. ACS occurs in patients with underlying symptomatic or occult coronary artery disease, and flow-​limiting or non-​flow-​limiting atheromatous plaques in the coronary arterial wall (Fig. 16.13.4.1). The ACS is precipitated by an abrupt change in an atheromatous plaque, resulting in increased obstruction to perfusion and ischaemia or infarction in the territory supplied by the affected (culprit) vessel. For discussion of the mechanisms involved, see Chapter 16.13.1. The pattern and severity of clinical manifestations are dependent not only on the degree of obstruction to perfusion, but also on the presence or absence of collateral perfusion, the extent and distribution of fragmented microthrombi, and myocardial oxygen demand in the perfused territory. Thus, the clinical consequences of plaque rupture can range from an entirely silent episode, through to unstable symptoms of ischaemia without infarction, to profound ischaemia complicated by progressive infarction, heart failure, arrythmia, and risk of sudden death.

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Spectrum of acute coronary syndrome myocardial infarction unstable angina Marker: Tn & CK-MB undetectable

Non-ST elevation myocardial infarction

ST elevation myocardial infarction

troponin elevated +/− CK-MB

troponin elevated +/− CK-MB

Fig. 16.13.4.1  The spectrum of acute coronary syndromes.

The goals of early management of ACS are to relieve ischaemia (by reducing myocardial oxygen demand, inhibiting thrombotic occlusion, and reducing coronary obstruction), to prevent further thrombotic occlusion, and to prevent or manage complications. The choice and timing of management strategy, including pharmacological treatment and percutaneous or surgical revascularization, is critically dependent on the extent and severity of myocardial ischaemia. Despite sharing key pathophysiological mechanisms across the spectrum of ACS, ST-​segment-​elevation acute myocardial infarction (STEMI) and non-​ST-​elevation ACS (unstable angina and non-​STEMI) need to be considered separately because an acute reperfusion strategy (primary percutaneous coronary intervention (PCI) or thrombolysis) is of proven benefit in STEMI (or MI with new bundle branch block), but not in the remainder of the syndrome. Thus, although the management of STEMI differs, the remainder of the ACS should be managed as a continuous spectrum, but influenced by risk stratification.

Clinical presentation and definition of ACS The ACS may present de novo (as new-​onset angina), with typical ischaemic discomfort at rest (rest angina) or on minimal exertion. Alternatively, a previously stable pattern of angina may change,

resulting in episodes of typical rest angina or angina provoked by minor exertion (crescendo angina). New-​onset exertional angina has not previously been recognized as part of ‘acute coronary syndrome’, but the outcomes are similar—​c.7% develop non​fatal MI and 4% die, and a further 19% require revascularization within 15  months—​and such patients may fulfil the clinical and ECG/​biomarker characteristics of the syndrome (EuroHeart survey, GRACE, and CRUSADE registries). There are three components to the clinical diagnosis of ACS: the symptom description, the ECG, and biomarker evidence of myocyte necrosis. The symptoms must be distinguished from non​cardiac pain, and from stable angina. To improve the specificity of diagnosis, clinical trials use a more restricted definition, requiring at least 15 to 20 min of typical ischaemic discomfort or two 5-​min episodes at rest. The specificity is further improved when the definition requires objective evidence of ischaemia or evidence of underlying coronary artery disease. ST-​segment depression on the ECG, especially in association with typical pain, is highly predictive, whereas the less specific ECG abnormalities, including T-​wave inversion, are less strong predictors. Markers of myocardial damage (troponins or cardiac enzymes) are powerfully predictive, in the presence of a typical clinical syndrome. ST elevation or depression on the ECG and elevated biomarkers of necrosis are markers of higher risk and adverse outcome (Table 16.13.4.1). In the absence of such markers, documented

Table 16.13.4.1  Prognostic value of admission ECG for early risk stratification in 12 142 patients with an acute coronary syndrome Outcome

ST elevation + ST depression (n = 15)

ST elevation (n = 28)

ST depression (n = 35)

T-​wave inversion (n = 23)

p

Acute infarction on admission (%)

87

81

47

31

0.5  mm in thrombolysis in mycocardial infarction (TIMI) score); isolated T-​wave inversion carries a lower risk. The number of leads demonstrating ST deviation also yields prognostic information:  among those with ST deviation in the anterior leads a rate of death or MI of 12.4% was seen at 1 year—​ higher than seen with similar changes in other locations (TIMI III trial). Patients with a left main and three-​vessel coronary

artery disease may show a combination of ST-​segment elevation and depression. Ambulatory ST-​segment recording can identify patients with unstable angina and either silent or symptomatic myocardial ischaemia with an increased risk for major subsequent cardiac events. However, conventional ambulatory monitoring usually requires offline analysis and is not suitable for the prediction of imminent events. Computer-​ assisted, continuous, multilead, ECG monitoring techniques have become available for real-​time ECG and ST-​segment monitoring. The occurrence and extent of ischaemic territory identified by such continuous recordings can provide additional prognostic information over and above the admission ECG. The information can be combined with biomarkers and, together, they provide additional prognostic information (FRISC study).

Biochemical markers and outcome Markers of myocardial damage Biomarkers of necrosis are gradually released into the systemic circulation following complete or transient occlusion of the coronary artery, or fragmentation of a thrombus and embolization. Following total occlusion of the vessel, troponins and creatine kinase (or more specifically CK-​MB) are released and are detectable at clearly abnormal levels about 6 to 8 h after the event unless there is extensive collateral perfusion. The cardiac isoforms of troponin I and troponin T are exclusively expressed in cardiac myocytes and provide specific evidence of myocardial damage. Following infarction, troponins are released from the cytosolic pool and first appear in the circulation in detectable concentrations between 3 and 4 h after the ischaemic event, reaching diagnostic concentrations at 6 to 8 h. Troponin release is evidence of myocardial injury and carries prognostic significance: the greater the troponin release, the greater the risk of subsequent MI and death. High-​sensitivity or ultrasensitive assays have a 10-​to 100-​fold lower limit of detection than current assays, allowing detection of MI more frequently and earlier (within 1 hour), but it is important to recognize that other causes of myocyte necrosis can give rise to detectable troponin concentrations in the circulation, hence the diagnosis of ACS requires an appropriate clinical context. A clinical assessment of the reasons for troponin detection in the circulation is vital for determination of the correct diagnosis (Fig. 16.13.4.3 and Table 16.13.4.4). When should the cardiac enzymes be measured? The time course of the release of troponins (or enzymes) from myocardium is such that diagnostic concentrations may not be achieved until some time after an ischaemic event, depending on

Table 16.13.4.3  Classification of unstable angina (Braunwald) Class

A: Secondary unstable angina (e.g. anaemia, hypoxia)

B: Primary unstable angina

C: Postinfarction (48 h since last pain)

IIA

IIB

IIC

III

Acute rest angina (99th centile

1

No

Significant change in troponin concentration

No significant change in troponin concentration

CLINICAL ASSESSMENT

CLINICAL ASSESSMENT

Oxygen supply-demand imbalance? eg sustained hypotension, tachycardia, hypoxaemia

Known structural heart disease or clear alternative pathology*

Known CAD

Consider invasive coronary angiography

Consider no further investigation

Yes

Yes

No

No known CAD

Consider invasive or CT coronary angiography

No further cardiac investigation

Consider echocardiography or cardiac MRI scan

INVESTIGATION RESULTS Coronary artery disease with plaque rupture

Obstructive coronary artery disease

1

No coronary artery disease

2

ACUTE

CHRONIC

Injury

Injury

Fig. 16.13.4.3  Algorithm for the investigation of patients with elevated cardiac troponin concentration on serial measurements is used to identify patients with acute and chronic myocardial injury. The definition of significant change in cardiac troponin will be dependent on the particular assay used and should be consistent with the local pathway for the assessment of patients with an isolated presentation with acute coronary syndrome. CAD, coronary artery disease. * alternative pathologies that can lead to troponin elevation are shown in Table 16.13.4.4. Adapted from Chapman AR, Adamson PD, Mills NL (2017). Assessment and classification of patients with myocardial injury and infarction in clinical practice. Heart, 103, 10–​18.

the assays employed. Thus, a normal value for a patient on arrival within a short duration of time after the event does not exclude infarction or unstable angina, but an elevated value is highly predictive of subsequent infarction. Troponins should be measured Table 16.13.4.4  Causes of elevation of serum troponins Cause

Example

Cardiac

Cardiac contusion Cardiac failure Cardiac interventions/​surgery Cardiac toxins, e.g. cocaine, anthracyclines Cardiac tumour Cardiomyopathies Cardioversion Myocardial infarction Myocarditis (Myo)pericarditis

Cardiovascular

Aortic dissection Pulmonary embolism

Neurological

Stroke Subarachnoid haemorrhage

Other

Acute kidney injury Sepsis Chronic kidney disease

on arrival depending upon the clinical presentation, and may require a second sample. The timing of the second sample depends upon the troponin assay. The latest generation of high-​sensitive troponin assays increase diagnostic performance and improve the early diagnosis of MI regardless of the time of chest-​pain onset, and re-test within 3 hours maybe feasible. Implementation of a sensitive troponin assay, and lowering the diagnostic threshold for MI, reduces recurrent MI and death in patients with suspected ACS. Among those with persistently negative troponins and without significant ECG changes, there is a very low risk of subsequent infarction and death (provided that severe underlying coronary artery disease is excluded). Such patients should undergo predischarge risk assessment and stress testing. The best tests are myocardial perfusion scanning or stress echocardiography, but treadmill ECGs on exercise are more widely available. Rule-​in and rule-​out pathways The specific pathway depends upon the biomarker and assay system used. With the use of high-​sensitivity troponins a 0 h/​3 h pathway is suggested, although future refinements may endorse a 0 h/​1 h pathway. Current guidelines advocate a pathway as illustrated in Fig. 16.13.4.4.

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Fig. 16.13.4.4  0 h/​3 h rule-​out algorithm of non-​ST elevation coronary syndromes using high-​sensitivity cardiac troponin assays. From Roffi M, et al. (2016). 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-​segment elevation. Eur Heart J, 37, 267–​315, by permission of Oxford University Press.

Markers of left ventricular wall stress and inflammation Natriuretic peptides such as brain natriuretic peptide (BNP) or its N-​ terminal prohormone fragment (NT-​ proBNP) are associated with left ventricular dysfunction and elevated levels are associated with adverse prognosis; however, current management protocols are not determined by BNP levels. Inflammatory changes in the vessel wall promote plaque fissuring or erosion, and inflammatory changes also follow episodes of minor myocardial damage. In ACS there is evidence that inflammatory markers, such as C-​reactive protein (CRP) and interleukins IL-​6 and IL-​1, are independently associated with adverse outcome. After the acute phase, continuing inflammation (e.g. with elevated CRP) occurs in one-​half of those whose levels are acutely elevated and identifies a category of patients at increased risk. However, although inflammatory mechanisms are implicated in plaque growth and plaque destabilization, specific anti-​ inflammatory therapies have not yet been demonstrated to improve outcome, and measurement of CRP or other inflammatory markers is not part of routine clinical practice.

Non​invasive imaging and outcome Transthoracic echocardiography is useful to identify regional wall motion abnormality and assess LV function, in addition to detecting other important pathology associated with chest pain such as aortic dissection, pericardial effusion, valve disease, or right ventricular strain suggestive of pulmonary embolism for example. Non​invasive assessment of ischaemia can be performed in low risk patients using stress echo, cardiac magnetic resonance, or nuclear perfusion techniques. Multidetector computed tomography (MDCT) allows for visualization of the coronary arteries. It may be applied to assess certain ACS patients but requires a high level of expertise and is not yet routinely available.

Risk characterization in ACS The timing and the nature of key management decisions in ACS are dependent upon risk estimation. For example, the choice of reperfusion therapy in ST elevation may be influenced by the presence of comorbidity, bleeding risk, and time delay from symptom onset. Similarly, in non-​STEMI ACS, ongoing ischaemia with ST depression or the presence of hypotension or a high-​risk score may initiate very early revascularization. Specific pharmacological (e.g. glycoprotein IIb/​IIIa inhibitors) or interventional therapies (PCI) have demonstrated benefit in high-​or moderate-​risk patients but not in low-​risk patients (5-​year outcome: RITA 3, FRISC-​II). In patients with ACS, risk can be separated into two components: ‘prior risk’ and ‘acute ischaemic risk’. Prior risk is determined by patient characteristics (age and gender), prior ischaemic heart disease (MI, heart failure, prior angina), and systemic factors that influence risk (hypertension, diabetes, renal dysfunction, and other life-​threatening systemic disorders). These can be considered as the background level of risk that the patients bring with them to the point of presentation. Although several of the individual risk components may not be modifiable, the combined impact of prior risk influences the balance between benefit and risk for each of the therapeutic strategies in ACS. Thus, prior risk sets the baseline for risk–​ benefit decisions. By contrast, ‘acute ischaemic risk’ is potentially modifiable and determined by the severity of coronary obstruction and the extent of the territory affected. Collateral perfusion, embolization, myocardial oxygen demand, and cytoprotection mechanisms all influence the extent of ischaemia. Patients with similar clinical features may have experienced transient complete occlusion, or severe subtotal occlusion complicated by distal embolization of fragments of a platelet-​rich thrombus, and altered vascular tone in the distal territory. Clinical markers of acute ischaemic risk include ECG changes,

16.13.4  Management of acute coronary syndrome

Box 16.13.4.2  Practical steps to assess risk (in addition to clinical symptoms) • 12-​lead ECG—​obtained directly after first medical contact, repeated after recurrent symptoms • Troponin estimation (cTnT or cTnI)—​ repeated if the initial test is negative • Apply a risk score (such as GRACE, TIMI—​see Table 16.13.4.2 and http://www.outcomes.org/grace) • An echocardiogram may be required to rule in/​out alternative diagnoses and assess left ventricular function • In patients with no recurrence of pain, normal ECG, and no troponin ­elevation, a non​invasive stress test or coronary imaging may be required

release of biomarkers of necrosis into the systemic circulation, and mechanical and arrhythmic complications of the ischaemic episode. Simplistically, prior risk can be regarded as the ‘baggage’ that the patient carries with them, and acute ischaemic risk as an ‘acquired hazard’ arising from the new ischaemic event. The distinction is important because management strategies for prior risk aim to treat heart failure, underlying coronary and systemic disease, and risk factors. The management of acute ischaemic risk aims to reverse the impact of acute coronary obstruction and thrombosis and is the first priority in the management of patients with ACS. Assessment of the extent and impact of underlying coronary artery disease (e.g. with stress testing) and assessment of left ventricular function can take place later in the management of these patients (Box 16.13.4.2), and are important determinants of the longer-​term outcomes. In summary: (1) A diagnosis of ACS is a clinical diagnosis based on the suspicion that coronary ischaemia due to atherothrombosis is responsible for the patient’s presentation; (2) clinical examination and ECG provide early and rapid assessment tools; (3) patients with STEMI require consideration of emergency reperfusion therapy, and those without require further risk assessment to guide the ongoing management (Table 16.13.4.5).

Management of ACS without ST elevation (unstable angina/​non-​STEMI) Anti-​ischaemic therapy Anti-​ischaemic therapy can decrease myocardial oxygen consumption by reducing heart rate, lowering blood pressure, or depressing left ventricular contractility, and may also act by inducing vasodilatation. In consequence, anti-​ischaemic therapy can limit the progression of occlusion and improve perfusion and improve the supply–​demand imbalance. Mechanical revascularization (PCI and coronary bypass surgery) also aims to relieve obstruction and reduce a patient’s susceptibility to ischaemia and its complications—​ these interventions will be considered separately (see later section of this chapter and Chapter 16.13.5). Nitrates Nitrates act by venodilatation and—​ in higher dose—​ by arteriolar dilatation, and hence reduce preload and afterload, thereby decreasing oxygen demand. In addition, nitrates can also induce coronary vasodilatation. They are effective in relieving symptoms of ischaemia. In the acute phase of the syndrome, where dose titration is required, they are most conveniently administered intravenously. Once dose titration is no longer required, oral administration is feasible. However, continuous nitrate administration can induce tolerance, hence oral nitrates should be prescribed with appropriate nitrate-​free intervals when symptoms are controlled. An alternative is to use drugs with nitrate-​like properties but with­ out the same problems of tolerance, such as a potassium channel activator (see ‘Potassium channel activators and other antianginals’). Large outcome trials have been conducted with nitrates in acute STEMI but not in other ACS. However, patients without ST-​segment elevation or bundle branch block were randomized within the ISIS-​ 4 trial: their mortality was 5.3% for nitrate treatment and 5.5% for placebo treatment, a non​significant difference. Nitrates are effective

Table 16.13.4.5  Recommendations for diagnosis and risk stratification in patients with suspected non-​ST-​segment elevation acute coronary syndromes Recommendations

Class of recommendation

Level of evidence

It is recommended to base diagnosis and initial short-​term ischaemic and bleeding risk stratification on a combination of clinical history, symptoms, vital signs, other physical findings, ECG, and laboratory results.

I

A

It is recommended to obtain a 12-​lead ECG within 10 min after first medical contact and to have it immediately interpreted by an experienced physician. It is recommended to obtain an additional 12-​lead ECG in case of recurrent symptoms or diagnostic uncertainty.

I

B

Additional ECG leads (V3R, V4R, V7–​V9) are recommended if ongoing ischaemia is suspected when standard leads are inconclusive.

I

C

It is recommended to measure cardiac troponins with sensitive or high-​sensitivity assays and obtain results within 60 min.

I

A

A rapid rule-​out protocol at 0 h and 3 h is recommended if high-​sensitivity cardiac troponin tests are available.

I

B

A rapid rule-​out and rule-​in protocol at 0 h and 1 h is recommended if a high-​sensitivity cardiac troponin test with a validated 0 h/​1 h algorithm is available. Additional testing after 3–​6 h is indicated if the first two troponin measurements are not conclusive and the clinical condition is still suggestive of ACS.

I

B

It is recommended to use established risk scores for prognosis estimation.

I

B

Diagnosis and risk stratification

Modified from Roffi M, et al. (2016). 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-​segment elevation. Eur Heart J, 37, 267–​315, by permission of Oxford University Press.

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in reducing ischaemia in the in-​hospital management of non-​ST-​ elevation ACS, but there is no evidence that they improve mortality. β-​Blockers

Box 16.13.4.3  Recommendations for anti-​ischaemic therapy • Anti-​ischaemic therapy should be administered in conjunction with antithrombotic and interventional therapy (see next), with the overall strategy guided by risk evaluation of the patient (see risk stratification) • Patients with suspected ACS should be initiated on nitrate and β-​blocker therapy, unless there are contraindications to the use of β-​blockers • In patients with contraindications to β-​blockers, heart-​rate slowing calcium antagonists should be employed • The combination of a calcium antagonist and β-​blocker is superior to either agent alone • Angiography and revascularization should be considered in patients with recurrent or persistent ischaemia, or patients with troponin elevation (including non-​STEMI). The timing of angiography should be guided by the risk status of the patient

β-​Adrenoceptor antagonists reduce heart rate and blood pressure and myocardial contractility and hence decrease myocardial oxygen consumption. They are primarily employed to reduce ischaemia in ACS. Large-​scale trials have not been conducted in patients with non-​ ST-​elevation ACS. However, in the context of acute STEMI treated by thrombolysis, β-​blockers reduce mortality by approximately 10 to 15% (ISIS-​1 study). They may act by reducing ventricular arrhythmias, reinfarction, and myocardial rupture. However, this trial was conducted before the widespread use of reperfusion therapy and the findings may not be relevant to contemporary practice. More recently the large COMMIT/​CCS study demonstrated that immediate intravenous (metoprolol 5–​15 mg) followed by oral metoprolol 200 mg daily had no effect on mortality, with reductions in recurrent MI and cardiac arrest offset by increased cardiogenic shock. A meta-​ analysis of 27 trials showed a 13% relative risk reduction of mortality in the first week after MI. Patients with significantly impaired atrioventricular conduction or asthma or acute left ventricular dysfunction should not receive β-​blockers. Although β-​blockers may exacerbate acute heart failure, extensive trials have produced strong evidence of a benefit for the gradual introduction of β-​blockers in ambulant patients with heart failure (see Chapter 16.5.3). In the absence of bradycardia or hypotension, patients with suspected ACS should be initiated on β-​blocker therapy unless contraindicated.

been shown to be better than placebo in relieving the symptoms of angina. A randomized trial of nicorandil (a combined nitrate-​like and potassium channel activator) suggested benefit on a composite clinical endpoint (IONA study), and this drug may be considered as an alternative to nitrate administration. Ivabradine selectively inhibits the primary pacemaker current in the sinus node and maybe used in selective patients with contraindications to β-​blockers. Ranolazine inhibits the late sodium current, and can reduce recurrent ischaemia in non-​ST-​elevation ACS. The recommendations in Box 16.13.4.3 are based on current clinical and trial evidence.

Calcium entry blockers

Antiplatelet therapy

These agents inhibit the slow inward current induced by the entry of extracellular calcium through the cell membrane, especially in cardiac and arteriolar smooth muscle. They act by lowering myocardial oxygen demand, reducing arterial pressure, and reducing contractility. Calcium channel blockers can provide symptom relief in patients already receiving nitrates and β-​blockers, and may be useful in patients with contraindications to β-​blockade. Some agents induce a reflex tachycardia (e.g. nifedipine, nicardipine, amlodipine) and are best administered in combination with a β-​adrenoceptor antagonist. By contrast, diltiazem and verapamil are suitable for patients who cannot tolerate a β-​blocker because they inhibit conduction through the atrioventricular node and tend to cause bradycardia. All calcium antagonists reduce myocardial contractility and may aggravate heart failure. Calcium entry blockers have been demonstrated to reduce the frequency of angina in patients with variant angina. A meta-​analysis of calcium entry blockers in ACS indicates a non-​ significant trend towards a higher mortality in treated vs. control patients (5.9% vs. 5.2%, in 7551 patients). In individual trials, diltiazem has been compared with propranolol, and both agents produced a similar reduction in anginal episodes. Dihydropyridine calcium entry blockers should be employed with β-​blockers in ACS to avoid reflex tachycardia. In patients unable to tolerate β-​blockers, a heart-​ rate-​slowing calcium antagonist may be appropriate. Short-​acting dihydropyridines should not be used in isolation in ACS. Potassium channel activators and other antianginals These agents (e.g. nicorandil) have arterial and venous dilating properties, but do not exhibit the tolerance seen with nitrates. They have

Aspirin Exposure of the contents of atheromatous plaque to circulating blood triggers platelet activation by several different pathways. Aspirin is a potent and irreversible inhibitor of platelet cyclooxygenase, blocking the formation of thromboxane A2 and inhibiting platelet aggregation. Although the effects of aspirin can be overcome in the presence of potent thrombogenic stimuli, nevertheless the benefits of aspirin treatment in unstable angina are clearly defined and substantial. The Antiplatelet Trialists Collaboration demonstrated a reduction of 36% in death or MI with antiplatelet treatment (predominantly aspirin) vs. placebo in unstable angina trials. Aspirin treatment significantly reduces subsequent MI, stroke, and vascular death, with the largest reductions seen among patients at highest risk. In patients with unstable angina, four key studies have demonstrated that aspirin significantly reduces the risk of cardiac death or non​fatal MI by approximately 50%. The efficacy of lower-​dose aspirin (75 mg/​day) therapy has been demonstrated in several studies, including those of Wallentin and colleagues where long-​term effects were evaluated in men under 70 years of age with unstable coronary artery disease. After 6 and 12 months of aspirin treatment, the risk of MI or death was reduced by 54% and 48%, respectively (risk ratio 0.52 with 95% confidence intervals 0.37–​0.72). The strength of evidence and magnitude of benefit demonstrated with aspirin treatment in non-​ST-​segment elevation ACS is such that aspirin is indicated in all patients with ACS, unless there is a clear contraindication. Nevertheless, patients with ACS remain at significant risk despite aspirin therapy. In prospective registry studies of unstable angina/​non-​STEMI, and

16.13.4  Management of acute coronary syndrome

in spite of aspirin treatment in more than 80% of patients, the risk of death or MI is approximately 10% at 6 months and the risk of death/​MI or refractory angina is approximately 22 to 33% over the same period (OASIS registry, PRAIS registry). Aspirin treatment (75–​325 mg daily) is indicated in all patients with ACS unless there is good evidence of aspirin allergy or evidence of active bleeding. P2Y12 receptor inhibitors Ticlopidine and clopidogrel are ADP receptor antagonists, and they block the ADP-​induced pathway of platelet activation by inhibiting the P2Y12 ADP receptor. Clopidogrel replaced ticlopidine on account of a superior safety profile and has been tested in a large-​scale trial of patients with unstable angina/​non-​STEMI (n = 12 562, CURE trial). The agent was used on top of existing therapy, and in addition to aspirin. It reduced death, non​fatal MI, and stroke from 11.4 to 9.3% (95% confidence interval 0.72–​0.90, p 140 Intermediate-​risk criteria • Diabetes mellitus • Renal insufficiency (eGFR 65 years for aortic valve replacement in European guidelines)

Class IIaC

Guidelines favouring mechanical valves

ECS/EACTS 2017 guidelines

Informed patient preference

Class IC

Accelerated risk of structural valve deterioration (age 10 years) and high risk for future repeat valve replacement

Class IIaC

A mechanical prosthesis is reasonable for those aged 30

1.5

1.5

ABPI, ankle–​brachial pressure index. Most peripheral arterial disease, both stenosing and dilating, is asymptomatic. The data have been derived from several studies and geographical variation may occur.

For aortic aneurysms, strong familial clustering has been observed, and genome wide association studies have identified associations with several genes not associated with coronary artery disease, including those modifying the protease MMP-9. White and northern European populations appear to be at higher risk of aneurysmal disease than black populations. Stenosing and aneurysmal disease are associated with degenerative changes of the artery wall, the prevalence of both diseases increasing sharply with age (Table 16.14.2.1). Epidemiological studies also indicate a difference between stenosing and aneurysmal disease, with death from aneurysmal disease (aortic aneurysm) being more common among those of higher social classes and in affluent geographical areas.

Leg ischaemia Clinical features The terms acute and chronic relate purely to the length of time that symptoms have been present and must not be confused with terms related to severity, such as critical limb ischaemia. Critical leg ischaemia Critical leg ischaemia is defined as gangrenous change, ulceration, tissue loss, or rest pain lasting for 2 weeks, with an absolute ankle pressure of less than 50 mm Hg, although patients with diabetes are difficult to include in this classification because ankle pressures in such patients may be unreliable due to arterial calcification. Acute leg ischaemia The incidence of acute leg ischaemia, which presents as a painful, pale, and pulseless limb, is 1 in 12 000 patients per year. It can be due either to an embolic event or to thrombosis of an atherosclerotic stenosis. The commonest cause of a peripheral embolus used to be rheumatic heart disease in a patient with atrial fibrillation, but this is now uncommon, and other sources of emboli, such as an aortic aneurysm, must be considered. The development of a thrombosis at the site of an atherosclerotic stenosis, in either the superficial femoral artery or the popliteal artery, is undoubtedly now the commonest cause of acute leg ischaemia. However, it should be stressed that, whatever the cause, there is no difference on clinical examination of the acutely ischaemic limb.

Arterial trauma due to road traffic accidents and knife or gunshot wounds is becoming commoner, as is iatrogenic trauma following the insertion of intra-​arterial catheters for diagnosis or therapy. A  rare but dramatic cause of acute leg ischaemia is phlegmasia cerulea dolens, in which massive thrombosis of all the major veins of the limb occurs with gross swelling that obstructs the arterial supply. Patients with a thrombosis of a popliteal aneurysm may present with classic symptoms of pain, paralysis, loss of power, paraesthesia, pallor, lack of pulse, and perishing cold. If the blood supply is not restored, fixed blue staining of the skin is a further sign of irreversible ischaemia, as is a tense calf with plantar flexion. However, most patients presenting with acute ischaemia have symptoms that are less severe. Chronic leg ischaemia Chronic leg ischaemia is much more common than acute ischaemia (Table 16.14.2.1), and its main cause is atherosclerosis. In the young patient, one should also consider cystic adventitial disease, entrapment of the popliteal artery, and occasionally fibromuscular hyperplasia of the iliac arteries, particularly in women. Symptoms are pain on walking, claudication affecting the calf and thigh, rest pain, ulceration, and gangrenous change. Less commonly, patients may present with buttock claudication and impotence (Leriche’s syndrome). Although the differential diagnoses of the acutely ischaemic limb are few, in the chronically ischaemic limb pain may be due to spinal stenosis or nerve-​root compression (spinal claudication) or arthritis of the hip or knee. Classically the patient with claudication will complain of cramp-​like pain in the calf, appearing after walking a particular distance, relieved by a few minute’s rest, and recurring again at the same distance if the patient resumes walking. Failure of the pain to disappear on resting, or its reappearance after a shorter distance after each rest, suggests a possible musculoskeletal cause, particularly if distal pulses are present on examination. However, it should also be remembered that distal pulses may be felt at rest in the limbs of patients with claudication due to peripheral vascular disease, but disappear on exercise to the point of pain.

Investigations The main diagnostic method used to confirm the diagnosis of peripheral arterial disease is Doppler ultrasonography (duplex scanning),

16.14.2  Peripheral arterial disease

Management Critical and acute leg ischaemia

Fig. 16.14.2.1  Occlusion of the superficial femoral artery demonstrated by colour-​coded duplex ultrasonography. On the left, the common femoral artery (CFA) lies outside the colour box. In the colour box antegrade flow through the profunda femoris artery (PFA) is shown in blue. The red flash represents rebound flow against the occluded origin of the superficial femoral artery (SFA).

an example of which is shown in Fig. 16.14.2.1. The ratio of systolic blood pressure at the ankle and in the arm, the ankle–​brachial pressure index (ABPI), provides a physiological measure of blood flow at the level of the ankle. At rest, in a normal leg, the ABPI lies between 1.0 and 1.4. As the blood flow in the leg is compromised, the ABPI falls sharply, and values below 0.9 are considered abnormal and likely to confirm the diagnosis of peripheral vascular disease. To emphasize the important overlap between this condition and coronary artery disease, a reduction in ABPI nearly always signals the presence of coronary artery disease, which is the cause of death in most patients with peripheral arterial disease. Exercise testing provides an objective method of assessing walking distance and helps with the identification of disease processes, such as angina, that may be limiting. It only needs to be used in those people who have a history of claudication but have normal resting ABPI, and can be used as a way of eliminating or suggesting other diagnoses. In addition to establishing the diagnosis of peripheral arterial disease, duplex ultrasonography is able to determine the site of disease and indicate the degree of stenosis or length of an occlusion and hence aid in the planning of interventional treatment. Other imaging modalities such as CT scanning and magnetic resonance angiography can provide three-​dimensional reconstructions of the diseased vessels and may be used for planning surgical treatment. Angiography is only required as an adjuvant to endovascular treatment, for surgical planning in some circumstances, or in the management of the acutely ischaemic limb. Attention to risk factors, in particular smoking, blood pressure, and exercise, are important issues.

Critical limb ischaemia requires administration of analgesia and rapid surgical intervention. The severity of ischaemia will determine the treatment options considered. However, all patients with a severely ischaemic limb should be given adequate analgesia and 5000 units of heparin intravenously. Many will be old and frail, with significant medical comorbidities. These issues must be considered in deciding whether or not surgical intervention is appropriate for any individual case, with action taken to improve those aspects of the patient’s medical condition that can be improved before surgery, or as part of continuing medical management. For a patient with irreversible ischaemia (fixed skin staining and tense muscles), the main decision is whether a primary amputation or palliative care should be offered. If severe but potentially reversible ischaemia is present (white leg), surgery is usually the treatment of choice. Delay while thrombolytic therapy is tried is not advisable in this group. For patients with moderate limb ischaemia, where there is no paralysis and only mild sensory loss, arteriography with consideration of the potential use of thrombolysis should be performed. However, it should be remembered that thrombolysis is associated with numerous potential complications, most notably gastrointestinal haemorrhage and stroke, and is contraindicated in the early postoperative period. If the limb is salvageable, it may be possible to offer the patient an endovascular procedure, such as an angioplasty (with or without stenting). Surgical treatment can involve simple embolectomy, but may require a bypass procedure or endarterectomy, and in the severely ischaemic limb fasciotomies may be needed to treat or prevent a compartment syndrome. For at least 10% of patients, it will not be possible to offer revascularization: a few of these may benefit from the use of a prostacyclin analogue (iloprost), which might diminish amputation rates and alleviate pain. Any benefits of gene therapy on avoidance of amputation, with vascular endothelial growth factor, fibroblast growth factor, or other molecular mediators, are far from established and the only large randomized trial was disappointing. Limb salvage rates for patients presenting with critical limb ischaemia are variable, probably 50–​60% at 2 years, dependent on the severity of disease. In a patient presenting with acute leg ischaemia the outlook is poor, with only about 60% leaving hospital with an intact limb. The 30-​day mortality for this group of patients can be as high as 30%, the main cause of death being cardiac disease. The strategy for management is described in Fig. 16.14.2.2. Controversial areas in the treatment of acute leg ischaemia include the role of arteriography, which technique of thrombolysis is the safest and most cost-​effective, and whether initial treatment with thrombolysis is beneficial or harmful as compared to surgery. A recently updated Cochrane review, which included five randomized trials comparing thrombolysis and surgery for the initial treatment of acute limb ischaemia, found no overall difference in outcomes (limb salvage or death) at 1  year. Initial thrombolysis was associated with higher risk of major haemorrhage, stroke, and distal embolization, but also less severe degree of intervention overall. In the patient who has had an embolic event, long-​ term anticoagulation should not be forgotten, and nor should a search for the source of embolus. If the patient is not in atrial fibrillation, and has normal cardiac enzymes and 12-​lead electrocardiogram (ECG),

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• Pain relief • Intravenous heparin (5000 IU) • Assessment of patient prognosis and limb salvage with vascular surgical consultation

Irreversible Fixed skin staining Tense muscles

Severe White leg

Amputation or palliative care

Surgery

Moderate Dusky leg Mild sensory loss Duplex or arteriogram to evaluate treatment modaility

Fig. 16.14.2.2  Management of the patient with an acutely ischaemic leg.

then they should have an echocardiogram to exclude any valvular lesion, a 24-​h electrocardiogram (ECG) to look for arrhythmia, an ultrasound scan to exclude abdominal aortic aneurysm, and a screen for thrombophilia. In many centres a CT scan of the thoracic and abdominal aorta will be performed. Chronic leg ischaemia In chronic limb ischaemia, management depends upon the severity of the disease. Most patients present with claudication, which is relatively benign: symptoms of intermittent claudication will progress to critical limb ischaemia in less than one in five patients and only about 5% will go on to lose a limb. However, claudication identifies patients with a threefold increased risk of death from either heart disease or cerebrovascular disease compared with age-​and sex-​ matched controls. It is important when planning treatment that all the potential risk factors are covered. In the past surgical intervention was usually considered unnecessary: at least one-​third will have improvement of symptoms with simple medical treatment and exercise. However recent trials have suggested that either angioplasty with adjunct and stents or coated balloons or angioplasty combined with exercise therapy may offer early benefits (to 2 years) and longer-​ term results are awaited eagerly. The current treatment of patients with chronic lower leg pain is shown in Fig. 16.14.2.3. ABPI ≥ 0.9

ABPI Ppv

Zone II Ppa>Palv>Ppv Zone III Ppa>Ppv>Palv Blood flow

Fig. 16.15.1.3  The three-​zone model of pulmonary blood flow distribution.

encompassed in the three-​zone model of pulmonary circulation (Fig. 16.15.1.3). This model relies on the assumption that the site of major flow resistance is in the small vessels whose extravascular pressure is the alveolar pressure (Palv). There is no flow in zone I because Palv is greater than Ppa. Flow increases down zone II because the driving pressure increases by 1 cm of H2O for each 1 cm distance down the lung. Flow increases with distance down zone III, although ΔP (Ppa − Ppv) remains constant, because local PVR decreases due to capillary distension and recruitment. The driving pressure for blood flow is determined by the relationship between Palv, Ppa, and pulmonary venous pressure (Ppv) down the upright lung. A further zone (zone IV) is found at the lung base: in this zone, blood flow is observed to decrease with distance down the lung due to increased perivascular pressure in extra-​alveolar vessels.

Gravity-​independent  flow The branching pattern of pulmonary arteries imposes changes in perfusion that are independent of gravity. Within any given horizontal level of the upright lung, there is a decrease in blood flow in peripheral lung regions compared to central hilar regions. This is thought to be due to the reduction in Ppa in small acinar arteries with increasing distance from the hilum. This pattern is also seen at the level of the secondary lobule (the group of acini supplied by one terminal bronchiole), with a decreasing gradient of blood flow from the centre to the periphery.

Regulation of pulmonary vasomotor tone The pulmonary circulation differs from the systemic in that it is under minimal resting tone and is almost fully dilated under normal conditions. Circulating and local production of vasodilators and vasoconstrictors contribute to the resting tone, with the balance tipped in favour of vasodilators. Nitric oxide, produced locally by endothelial cells, and the arachidonic acid metabolite prostacyclin are important vasodilators that contribute to this low pulmonary vascular tone. The autonomic nervous system interacts with humoral mediators and haemodynamic forces in the control of pulmonary vascular tone, autonomic innervation of the lung being via parasympathetic (cholinergic:  predominantly vasodilator) and

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sympathetic (adrenergic:  predominantly vasoconstrictor) nerves in the periarterial plexus.

Hypoxic pulmonary vasoconstriction The pulmonary circulation responds to a reduction in the partial pressure of alveolar oxygen by vasoconstriction. This is opposite to the response to hypoxia in the systemic circulation, where tissue hypoxia leads to vasodilatation, hence improving tissue oxygen delivery. Hypoxic pulmonary vasoconstriction (HPV) probably plays little role in the normal distribution of pulmonary blood flow or regulation of ventilation–​perfusion relationships in humans. However, in diseases characterized by airway obstruction, such as acute asthma or chronic obstructive lung disease, HPV can divert blood flow away from poorly ventilated lung regions, reducing venous admixture (shunt through poorly ventilated lung regions) and preserving arterial oxygenation. The magnitude of the response varies widely between individuals and is, at best, 50% efficient. It is noteworthy that populations indigenous to high-​altitude regions (e.g. Tibetans), lack HPV with no obviously detrimental effect. At high altitude, with low atmospheric partial pressures of oxygen, HPV would lead to generalized vasoconstriction and pulmonary hypertension, which is presumably more detrimental than the lack of HPV.

Ventilation–​perfusion relationships In the normal lung, it is remarkable that pulmonary blood flow and ventilation are, in general, well matched given the heterogeneity of blood flow described earlier. Of course, regional ventilation is also under similar constraints and forces as the blood flow. In terms of the structure and function of the airways and alveoli in brief, the airways run with the arteries in the bronchovascular bundle and the branching patterns are similar. Regional ventilation is under the influence of gravity: the lung sits in the thorax under its own weight, which leads to a gradient of intrapleural pressure, with more negative pressures at the top of the lung than at the bottom in the upright position. This means that the lung is more expanded at the apex than at the base at the end of a normal breath (functional residual capacity). Thus, the upper and lower parts of the lung are operating on different portions of their pressure–​volume curves. The result is that, during normal breathing, greater ventilation is delivered to the bottom than to the top of the lung. This gradient of regional ventilation down the lung is reminiscent of the gradient of blood flow just described. In fact, with increasing distance up the lung, the rate of change of ventilation per unit of alveolar volume is somewhat less than the rate of change of perfusion (about one-​third). This leads to large regional differences in the ventilation–​perfusion ratio up the lung (Fig. 16.15.1.4):  alveoli at the bottom of the lung are relatively overperfused, leading to a low ventilation–​perfusion ratio (c.0.6); by contrast, alveoli at the apex of the lung are relatively underperfused, leading to ventilation–​perfusion ratios over 3.0. Nevertheless, the overall ventilation–​perfusion ratio for the whole lung is approximately 0.85. The regional ventilation–​perfusion ratio will determine the partial pressures of oxygen and CO2 found in the alveoli at a given level of the lung, and this will be reflected in the gas tensions found in pulmonary venous blood draining those alveoli. The result is that the Po2 is higher, and the Pco2 lower, in blood draining from the top of the lung, compared

Fig. 16.15.1.4  (a) O2–​CO2 diagram showing how the change in ventilation–​perfusion ratio up the lung determines the regional composition of alveolar gas. Dashed lines show the composition of mixed venous (pulmonary arterial) blood and inspired (tracheal) gas. (b) Effects of change in ventilation–​perfusion ratio up the lung on the regional composition of alveolar gas, with volumes of lung slices, ventilations, and blood flows also shown.

with the bottom. The matching of ventilation and perfusion in the normal lung ensures that the overall ventilation–​perfusion ratio remains fairly constant with changes in posture or exercise.

Acknowledgement Much of the chapter written for the third edition of the Oxford Textbook of Medicine by the late J. S. Prichard has been retained here.

16.15.2  Pulmonary hypertension

FURTHER READING De Mello DE, Reid LM (1997). Arteries and veins. In:  Crystal RG, et al. (eds) The lung: scientific foundations, 2nd edition, pp. 1117–​27. Lippincott-​Raven, Philadelphia, PA. Hughes JMB (1997). Distribution of pulmonary blood flow. In: Crystal RG, et  al. (eds) The lung:  scientific foundations, 2nd edition, pp. 1523–​36. Lippincott-​Raven, Philadelphia, PA. Hughes JMB, Morrell NW (2001). Pulmonary circulation: from basic mechanisms to clinical practice. Imperial College Press, London. Singhal S, et  al. (1973). Morphometry of the human pulmonary arterial tree. Circ Res, 33,  190–​7. West JB, Dollery CT, Naimark A (1964). Distribution of blood flow in isolated lung: relation to vascular and alveolar pressures. J Appl Physiol, 19, 713–​24. West JB (1985). Ventilation/​blood flow and gas exchange, 4th edition. Blackwell Scientific Publications, Oxford.

16.15.2  Pulmonary hypertension Nicholas W. Morrell ESSENTIALS Symptoms of unexplained exertional breathlessness or symptoms out of proportion to coexistent heart or lung disease should alert the clinician to the possibility of pulmonary hypertension, and the condition should be actively sought in patients with known associated conditions, such as scleroderma, hypoxic lung disease, liver disease, or congenital heart disease. Heterozygous germ-​line mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR2) are found in over 70% of families with pulmonary arterial hypertension. Pulmonary hypertension is defined as a mean pulmonary arterial pressure greater than 25 mm Hg at rest, and may be due to increased pulmonary vascular resistance (e.g. pulmonary arterial hypertension), increased transpulmonary blood flow (e.g. congenital heart disease), or increased pulmonary venous pressures (e.g. mitral stenosis). Exercise tolerance and survival in pulmonary hypertension is ultimately related to indices of right heart function, such as cardiac output. Investigation—​echocardiography is a good screening tool for the presence of pulmonary hypertension, but right heart catheterization is needed to confirm the diagnosis and guide treatment. CT pulmonary angiography and high-​resolution CT are important to exclude underlying chronic thomboembolic pulmonary hypertension and parenchymal lung disease. In idiopathic pulmonary arterial hypertension a vasodilator study should be undertaken at the time of right heart catheterization to detect the few (5–​10%) patients who will have good long-​term survival on calcium channel blockers. Management—​ treatments for pulmonary arterial hypertension include prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, and direct activators of soluble guanylyl cyclase, which improve symptoms of breathlessness, exercise tolerance, quality of life, and probably survival. Chronic thromboembolic

pulmonary hypertension is an important diagnosis to make because selected patients with predominantly proximal disease can be cured by pulmonary endarterectomy.

Introduction The normal pulmonary circulation, as described in Chapter 16.15.1, is a low-​pressure, high-​flow system that delivers the output of the right ventricle to the alveolar capillary network during each cardiac cycle for the purposes of gas exchange. Pulmonary hypertension is defined as a sustained elevation of mean pulmonary arterial pressure to more than 25 mm Hg at rest. Many diseases can lead to an elevation of pulmonary arterial pressure. Therefore, the term ‘pulmonary hypertension’ is not a final diagnosis, but a starting point for further investigation. In general terms, the main causes of pulmonary hypertension are (1) a narrowing or obstruction of the precapillary pulmonary arteries, (2) an increase in pulmonary venous pressure, (3) a persistent elevation of pulmonary blood flow, (4) chronic thromboembolic disease, or (5) miscellaneous causes. This simplified approach is worth keeping in mind during the assessment of patients found to have pulmonary hypertension, because it has major consequences for prognosis and management.

Classification of pulmonary hypertension Table 16.15.2.1 shows the 5th World Symposium on Pulmonary Hypertension (2013) classification of pulmonary hypertension as determined by an international panel of experts. The grouping of causes in this classification takes into account similarities in aetiology, pathology, and haemodynamic assessment at right heart catheterization. The classification helps to understand the underlying cause of pulmonary hypertension in a given patient and to plan management, hence it is a useful framework to consider the various causes of pulmonary hypertension, described in more detail next.

Pulmonary arterial hypertension The term pulmonary ‘arterial’ hypertension (PAH) refers to conditions characterized predominantly by a precapillary obstruction to blood flow through the pulmonary vascular bed, characterized hemodynamically by a mean pulmonary arterial pressure of greater than 25 mm Hg, an end-​expiratory pulmonary artery wedge pressure (PAWP) 15 mm Hg or less, and a pulmonary vascular resistance more than 3 Wood units. This elevation of pulmonary vascular resistance increases the driving pressure required to maintain blood flow through the lungs: pulmonary arterial pressure rises to maintain adequate left ventricular filling. The normal mean pulmonary arterial pressure (c.17  mm Hg) is about one-​fifth of the systemic mean blood pressure. In PAH, mean pulmonary arterial pressure may approach systemic levels. The normally thin-​walled right ventricle struggles to cope with the increasing pressure. At first it undergoes a degree of hypertrophy, which increases its ability to generate higher pressures, but ultimately it begins to fail and cardiac output

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Table 16.15.2.1  Clinical classification of pulmonary hypertension (NICE 2013) 1 Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1 BMPR2

Increasing PVR Preclinical

Symptomatic / stable

Cardiac output at peak exercise

Progressive / declining Pulmonary pressure

1.2.2 ALK-​1, ENG, SMAD9, KCNK3 1.2.3 Unknown 1.3 Drug and toxin induced 1.4 Associated with:

Cardiac output at rest

1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart diseases 1.4.5 Schistosomiasis 1′ Pulmonary veno-​occlusive disease and/​or pulmonary capillary haemangiomatosis 1″ Persistent pulmonary hypertension of the newborn (PPHN) 2 Pulmonary hypertension due to left heart disease

Fig. 16.15.2.1  Relationship between pulmonary hypertension, right ventricular function, and symptoms in pulmonary hypertension. Pulmonary arterial hypertension (PAH) is characterized by progressively increasing pulmonary vascular resistance. In the early stages, the disease is asymptomatic and only manifests during exercise or during unusually demanding activities, but over time there is a progressive reduction in cardiac output and increasing pulmonary vascular resistance (PVR), eventually progressing to cardiac failure and death.

2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction

Epidemiology and aetiology

2.3 Valvular disease

PAH is broadly divided into idiopathic PAH (previously known as primary pulmonary hypertension), and PAH found with other known associated conditions or triggers. Idiopathic PAH is further divided into familial or sporadic disease, with about 10% of patients with idiopathic PAH having an affected relative. Idiopathic PAH is a rare disorder with an estimated incidence of 1 to 2 per million per year. It is more common in women (female:male sex ratio = 2.3:1), can occur at any age, but most commonly occurs between the ages of 40 and 50 years. PAH that is pathologically indistinguishable from the idiopathic form can occur in a range of associated conditions (Table 16.15.2.1). Of the autoimmune rheumatic diseases, the most common association is with systemic sclerosis, where PAH can complicate the clinical course in 15–​20% of patients in the absence of interstitial lung disease. Other associated conditions include mixed connective tissue disease and systemic lupus erythematosus, and more rarely rheumatoid arthritis, dermatopolymyositis, and primary Sjögren’s syndrome. There is a well-​recognized association of PAH with congenital heart disease leading to left-​to-​right shunts. Overall, the prevalence of PAH is 15–​30%, but varies depending on the nature of the underlying cardiac defect. Portal hypertension, usually associated with cirrhosis, is associated with PAH in less than 5% of patients. There is an unusually high prevalence of PAH (c.0.5%) in patients with HIV infection. Epidemiological studies have confirmed the association of PAH with amphetamine-​like diet pills: in the 1970s, increased numbers of patients with PAH were found to have been exposed to Aminorex, and in the 1990s further studies confirmed an association of PAH with appetite-​ suppressant drugs of the fenfluramine and dexfenfluramine group. An epidemic of PAH also occurred in Spain in the 1980s, following the ingestion of contaminated rapeseed oil. Other more rarely associated conditions are listed in Table 16.15.2.1.

2.4 Congenital/​acquired left heart inflow/​outflow tract obstruction and congenital cardiomyopathies 3 Pulmonary hypertension due to lung diseases and/​or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-​disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4 Chronic thromboembolic pulmonary hypertension (CTEPH) 5 Pulmonary hypertension with unclear multifactorial mechanisms 5.1 Haematologic disorders: chronic haemolytic anaemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH Main modifications to the previous Dana Point classification are in bold. BMPR2, bone morphogenic protein receptor type II; ENG, endoglin; PAH, pulmonary arterial hypertension. Reprinted from J Am Coll Cardiol, vol. 62 (25 Suppl), Simonneau G, et al., Updated Clinical Classification of Pulmonary Hypertension, pp. D34–​41, Copyright 2013, with permission from the American College of Cardiology Foundation.

declines. It is the reduction in cardiac output that generates most of the clinical symptoms in patients, with dyspnoea and fatigue being the most common (Fig. 16.15.2.1). The function of the right heart is the main determinant of prognosis in patients with PAH.

16.15.2  Pulmonary hypertension

The classification of PAH includes another rare pulmonary vascular disease, pulmonary veno-​occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH), which are the same entity. PVOD/​PCH is rarer than idiopathic PAH, but its true prevalence is unknown. Persistent pulmonary hypertension of the newborn is a disorder characterized by a failure of vascular transition from fetal to a neonatal circulation and estimated to affect 0.2% of liveborn term infants.

Genetics Familial or heritable PAH is a rare autosomal dominant condition, with reduced penetrance. It is indistinguishable on clinical or pathological grounds from idiopathic PAH. Linkage studies localized the gene to the long arm of chromosome 2 (2q33). In 2000, heterozygous germ-​line mutations were identified in the BMPR2 gene encoding the bone morphogenetic protein type II receptor, which is a constitutively active serine-​threonine kinase that acts as a receptor for bone morphogenetic proteins (BMPs), these being members of the transforming growth factor β (TGFβ) superfamily. Mutations in BMPR-​II have now been identified in over 70% of cases of familial PAH, and similar mutations are also found in 15–​26% of patients thought to have sporadic or idiopathic disease. Many of these are unexpected examples of familial disease with low penetrance, although de novo mutations have also been reported. BMPR-​II mutations have been identified in most of the 13 exons of the BMPR2 gene, most (c.70%) being nonsense or frameshift mutations predicted to cause haploinsufficiency due to nonsense-​ mediated mRNA decay of the mutant transcript: only the wild-​type allele is expressed in these cases, reducing the amount of BMPR-​ II protein to about 50% of normal. About 30% of the mutations are mis-​sense mutations, which cause retention of mutant protein within the endoplasmic reticulum or affect important functional domains of the receptor, such as the ligand-​binding domain or the kinase domain. Mutations in BMPR-​II have also been found in a small proportion (c.10%) of patients with PAH associated with appetite suppressants, and in children with complicated PAH associated with congenital heart disease. Mutations in another TGFβ receptor, ALK-​1, have also been reported in association with PAH. These are usually found in families with hereditary haemorrhagic telangiectasia, but occasionally some family members develop severe PAH. These findings have highlighted the central role of the TGFβ signalling pathway in the pathogenesis of PAH. The BMPR-​II/​ALK-​1 receptor complex on endothelial cells has been found to be the major signalling complex for BMPs 9 and 10, providing major mechanistic insights into the pathobiology of PAH. Mutations in other TGFβ-​related genes have also been identified in rare cases of heritable PAH, including endoglin, Smad1, Smad9, and BMP9. In addition, mutations in the potassium channel KCNK3 have been reported in rare cases of heritable PAH. Mutations in the eukaryotic translation initiation factor 2-α kinase 4 (EIF2AK4) were recently identified in families with autosomal recessive PVOD/​PCH, accounting for all familial cases and up to 25% of sporadic cases.

Pathology Typical morphological appearances include increased musculari­ zation of small ( vasodilators

Minimal resting tone

Increased tone Vascular remodelling

Fig. 16.15.2.4  An imbalance of pulmonary vascular vasodilators and vasoconstrictors contributes to the vascular constriction and remodelling in pulmonary hypertension. ANP, atrial natriuretic peptide; NO, nitric oxide; PGI2, prostacyclin.

important vasodilator pathways also exert antiproliferative effects on smooth muscle cells and fibroblasts via production of the cyclic nucleotides cAMP and cGMP. Deficiency of these key vasodilator pathways has provided the rationale for many of the new therapies that have emerged over the past two decades (see ‘Newer agents’). Another important pathway involved in the process of pulmonary vascular remodelling includes loss of potassium channel (Kv1.5 and Kv2.1) expression and function, promoting smooth muscle cell contraction and survival. Activation of vascular elastases within the vessel media and disruption of the elastic laminae is also a key step in disease pathogenesis. Inflammatory cells may also contribute, especially in PAH associated with autoimmune conditions, accompanied by increased expression of inflammatory cytokines and chemokines in small pulmonary arteries. Pathological studies have identified the presence of thrombosis in small pulmonary arteries of patients with PAH. It is not clear whether this represents in situ thrombosis as a consequence of the reduced blood flow, or embolic phenomena. Platelet dysfunction has also been recognized in PAH, and an increased frequency of antiphospholipid antibodies associated with an increased thrombotic risk. The identification of mutations in the BMPR-​II receptor has highlighted the important role of the TGFβ superfamily in the pathogenesis of familial PAH. Most mutations lead to a reduction in a critical signalling pathway, the Smad pathway, downstream of BMP receptors. This, in turn, leads to the failure of BMPs to activate transcription of important target genes. In smooth muscle cells, BMPR-​ II mutation leads to a failure of the normal growth suppressive and proapoptotic effects of bone morphogenetic proteins, favouring excessive pulmonary artery smooth muscle cell proliferation and survival (Fig. 16.15.2.5). In endothelial cells, by contrast, BMPR-​ II mutation promotes endothelial dysfunction and endothelial cell apoptosis. The combination of endothelial cell dysfunction and smooth muscle cell proliferation within the pulmonary circulation favours the development of vascular obliterative lesions and pulmonary hypertension. Clonal expansion of apoptosis-​resistant endothelial cells may contribute to the formation of plexiform lesions. However, this simple model does not explain all of the features of heritable PAH. In particular, it does not explain why disease is

confined to the lung circulation, although BMPR-​II is most highly expressed in the lung vasculature. In addition, it does not explain why the presence of the mutation is not sufficient on its own to cause disease, with gene penetrance as low as 20% in some families. These observations indicate that additional environmental and/​or genetic factors are necessary for disease manifestation. This putative ‘second hit’ may further impact on BMP signalling pathways, leading to a critical reduction in bone morphogenetic signalling via Smad proteins and initiation of the process of pulmonary vascular remodelling. Although mutations in BMPR-​II are not generally found in most secondary forms of PAH, it is now becoming clear that dysfunction of the BMPR-​II pathway is involved in their pathogenesis. Further research is likely to reveal further clues to the involvement of this important pathway in vascular disease.

Clinical features Symptoms The three main presenting symptoms are dyspnoea, chest pain, and syncope. The severity of symptoms is related to prognosis. A modified New York Heart Association (NYHA) score is a useful way to assess symptom severity and follow response to treatment (Box 16.15.2.1). Unexplained breathlessness on exertion should always raise the possibility of PAH, particularly in the setting of conditions known to be associated with pulmonary hypertension (Table 16.15.2.1). The condition may have an insidious onset: frequently, there is a delay of years between the onset of first symptoms and diagnosis. Syncope is an ominous sign, usually reflecting severe right ventricular dysfunction. Other symptoms include lassitude, abdominal swelling from ascites, and ankle swelling. Small haemoptyses may occur at later stages. Clinical signs Tachypnoea may be present, even at rest. Peripheral cyanosis is common due to a low cardiac output. Central cyanosis occurs later as pulmonary gas exchange deteriorates or right-​to-​left shunting occurs through a patent foramen ovale. The jugular venous pulse may be elevated with a prominent ‘a’ wave, reflecting the increased force

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MUTANT

cell proliferation clonal expansion

R-smad BMPR-II Co-smad

BMP–2, –4, –7

Primary pulmonary hypertension

GDF–5, –6 Type 1 receptor P

heterodimeric complex WILD TYPE

P DNA binding partner

P

growth inhibition cell differentiation gene transcription

P

Normal pulmonary artery

R - smad cell membrane

Fig. 16.15.2.5  The potential role of mutations in the bone morphogenetic protein type II receptor (BMPR-​II) in familial PAH. The wild-​type receptor signals in response to ligands by activating receptor-​regulated Smad proteins (R-​Smads), which dimerize with common partner Smads (Co-​Smads) to regulate gene expression in the vascular cell. Mutation in BMPR-​II disrupts Smad signalling and leads to abnormal vascular cell proliferation. BMP, bone morphogenetic protein; GDF, growth differentiation factors. By Hughes, J. B. M. From Pulmonary circulation: Basic mechanisms to clinical practice (2001). With permission of Imperial College Press.

of atrial contraction, or—​if tricuspid regurgitation is present—​there may be a large ‘V’ wave. There may be a right ventricular heave and a pulsatile liver. On auscultation, forceful closure of the pulmonary valve leads to an accentuated pulmonary arterial component of the second heart sound. There are often a third and fourth right heart sound. The murmurs of tricuspid regurgitation (systolic) or pulmonary regurgitation (diastolic) may be heard. Jaundice, ascites, and peripheral oedema may be present at advanced stages of the disease.

Differential diagnosis If the symptoms and clinical signs suggest pulmonary hypertension, the differential diagnosis should be considered with reference to the Box 16.15.2.1  Modified New York Heart Association functional classification of pulmonary hypertension • Class I—​pulmonary hypertension without resultant limitation of physical activity. Ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near syncope • Class II—​pulmonary hypertension resulting in slight limitation of physical activity. The patient is comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain, or near syncope • Class  III—​pulmonary hypertension resulting in marked limitation of physical activity. The patient is comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain, or near syncope • Class  IV—​ Pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/​or fatigue may be present at rest. Discomfort is increased by any physical activity

classification in Table 16.15.2.1. Most importantly, the presence of left heart disease, parenchymal lung disease, or congenital heart disease should be excluded. Pulmonary hypertension due to chronic thromboembolic disease is important to detect because specific surgical treatment is available. Idiopathic PAH remains a diagnosis of exclusion.

Clinical investigation The investigation of a patient with suspected pulmonary hypertension involves (1)  the exclusion of other underlying causes and (2) an assessment of severity of pulmonary hypertension and right heart failure for prognosis and treatment. The investigations that are useful in identifying the aetiology of newly diagnosed, unexplained pulmonary hypertension are listed in Box 16.15.2.2. Blood tests A thrombophilia screen, including antithrombin III, proteins C and S, factor V Leiden, anticardiolipin antibodies, and lupus anticoagulant should be performed, and may reveal clotting abnormalities predisposing to chronic thromboembolic pulmonary hypertension (CTEPH). Thyroid function should be checked since both hypo-​and especially hyperthyroidism are commonly reported associations. An autoantibody screen should be performed to exclude underlying autoimmune rheumatic or vasculitic disease:  positive antinuclear antibodies (ANA) can be found in 30–​40% of patients with idiopathic PAH, but a positive test for antineutrophil cytoplasmic antibodies (ANCA) would be uncommon. Since there is an increased incidence of unexplained pulmonary hypertension in HIV-​positive patients, this diagnosis should always be considered.

16.15.2  Pulmonary hypertension

Box 16.15.2.2  Investigation of the patient with suspected idiopathic pulmonary hypertension Blood tests • Full blood count/​film/​differential • Hb electrophoresis • Urea and electrolytes • Liver function including γ-GT • Thyroid function • Thrombophilia screen: − Antithrombin III − Protein C − Protein S − Factor V Leiden − Anticardiolipin antibody − Lupus anticoagulant • CMV DEAFF • Autoantibodies: − RhF − ANA − ENAs − Anti-​dsDNA − Anticardiolipin IgG and IgM − Anti-​sm/​anti-​SCL/​anti-​SS − Complement C3, C4, CH50 − ANCA • Serum angiotensin converting enzyme • Hepatitis screen • HIV test Imaging • Chest radiograph • Ventilation–​perfusion lung scan • High-​resolution and spiral CT • Pulmonary artery angiography

Fig. 16.15.2.6  Chest radiograph demonstrating cardiomegaly with dilated right heart chambers and dilatation of the proximal pulmonary arteries in a patient with PAH secondary to an atrial septal defect. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital.

only sign in predominantly distal disease (Fig. 16.15.2.8). A high-​ resolution CT scan will pick up unsuspected parenchymal abnormalities, such as fibrosis. CT scanning is also useful to indicate more uncommon forms of PAH, such as PVOD, when there may be a degree of mediastinal lymphadenopathy and septal lines in the lung periphery, presumably indicating lymphatic and venous obstruction (Fig. 16.15.2.9). On ventilation–​perfusion lung scanning, the pattern of ventilation is usually normal in idiopathic PAH, and uneven ventilation

Lung function • Pulmonary function tests • Exercise tests with saturation monitoring • Arterial blood gases on air Cardiac function • ECG • Echocardiogram • Diagnostic cardiac catheterization Miscellaneous • Urine microscopy • Abdominal ultrasound—​cirrhosis

Imaging The plain chest radiograph shows enlargement of the proximal pulmonary arteries, which may be dramatic, with peripheral pruning of the pulmonary vascular pattern, giving rise to increased peripheral radiolucency. If heart failure is present the heart may be enlarged, with particular enlargement of the right atrium (Fig. 16.15.2.6). The chest radiograph may also give clues to underlying diagnoses such as interstitial lung disease. Spiral contrast-​enhanced CT will detect proximal pulmonary arterial obstruction suggestive of acute or chronic thromboembolic disease (Fig. 16.15.2.7). A pattern of mosaic perfusion of the lung parenchyma is also a feature of CTEPH, and may be the

Fig. 16.15.2.7  Image from a CT pulmonary angiogram at the level of the right main pulmonary artery demonstrating dilatation of the main pulmonary artery (PA) with laminated thrombus in the distal right pulmonary artery (arrow) in keeping with proximal CTEPH. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital.

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Pulmonary artery angiography is really only required if the diagnosis is likely to be CTEPH, in which situation angiography will provide precise anatomical information regarding the location of vascular obstruction, indicated by abrupt cut-​off of vessels or intravascular webs, that may be of great use if surgical endarterectomy is being contemplated. However, CT pulmonary angiography or MR angiography may be employed in place of conventional angiography. The main contribution of MRI is in the assessment of patients with suspected intracardiac shunts or with anomalous vascular anatomy (e.g. if a shunt is suspected on the basis of right heart catheterization but cannot be demonstrated by echocardiography). MRI can also provide further pulmonary angiographic images. Pulmonary function tests

Fig. 16.15.2.8  Coronal multiplanar reconstruction demonstrating extensive mosaic perfusion in both lungs in a patient with CTEPH. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital.

should suggest underlying lung disease. The pattern of perfusion is also virtually normal, although small patchy perfusion defects may be present. This is in contrast to the appearance in CTEPH when segmental or larger perfusion defects persist, often indistinguishable from the pattern of acute pulmonary embolism (Fig. 16.15.2.10).

The typical pattern for standard pulmonary function test for disease confined to the pulmonary circulation is to find normal lung volumes; normal forced expiratory volume in 1 s (FEV1)/​vital capacity (VC) ratio (>0.75), indicating no airflow obstruction; and low transfer factor (diffusing capacity, TLco), and low transfer coefficient (Kco). The low diffusing capacity probably results from a combination of a reduced cardiac output and disease affecting the small arterioles, thereby reducing local perfusion. If the Kco is less than 50% predicted with normal spirometry, a diagnosis of PVOD/​ PCH should be suspected. Additional findings in the pulmonary function tests—​such as marked airflow obstruction (e.g. severe chronic obstructive pulmonary disease) or a restrictive defect (e.g. pulmonary fibrosis)—​would indicate the presence of an underlying cause for the pulmonary hypertension. However, subtle changes in lung volumes and mild airflow obstruction have been reported in a few patients with PAH. In some groups of patients at high risk of developing PAH (e.g. in scleroderma), the low transfer coefficient can be monitored at intervals, with breathlessness accompanied by a fall in the low transfer coefficient sometimes being the first sign of this complication. Exercise testing

Fig. 16.15.2.9  Transverse CT image through the lower zones demonstrating heterogeneous attenuation of the lung parenchyma, centrilobular ground-​glass opacities, and smooth thickening of the interlobular septa in a patient with pathologically proven veno-​ occlusive disease. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital.

Significant PAH is always associated with a reduced exercise capacity, one of the most useful tests of this being the 6 min walk test, with monitoring of heart rate and oxygen saturation. This can readily be repeated to assess patients over time and as a measure of response to treatment. A normal distance is more than 500 m, with a low 6 min walk predictive of a poor survival. Full cardiopulmonary exercise testing is technically more demanding to perform and is only recommended if the diagnosis is in doubt (e.g. if there was a need to document cardiovascular limitation on exercise). Peak oxygen uptake on exercise is low and the anaerobic threshold is reduced to about 40% of normal. There is excessive ventilation for a given degree of oxygen consumption or CO2 output, even at rest. There is no ventilatory impairment when underlying lung disease is absent. There is often a pronounced tachycardia at submaximal exercise, and usually arterial oxygen desaturation. ECG In symptomatic PAH, the ECG is abnormal in 80 to 90% of cases, but it has inadequate sensitivity (55%) and specificity (70%) as a

16.15.2  Pulmonary hypertension

Perfusion

Ventilation

Fig. 16.15.2.10  Perfusion scintigram demonstrates multiple perfusion defects in a patient with CTEPH. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital.

screening tool for detecting pulmonary hypertension. The typical appearances are right-​axis deviation (more than + 120°) in the limb leads, and a dominant R wave and T wave inversion in the right precordial leads, accompanied by a dominant S wave in the left precordial leads, suggesting right ventricular hypertrophy (Fig. 16.15.2.11). Tall, peaked P waves in the right precordial and inferior leads denote right atrial enlargement. Right bundle branch block is common.

where RAP is right atrial pressure, which can be estimated clinically from the height of the jugular venous pressure. In the absence of pulmonary valve stenosis, the right ventricular systolic pressure is equal to the pulmonary artery systolic pressure (PASP). There is a reasonable correlation between Doppler estimates of PASP and catheter measurements. Newer echocardiographic techniques such as three-​ dimensional echo and tissue Doppler are being evaluated.

Echocardiography

Right heart catheterization

Echocardiography remains the best screening test for significant pulmonary hypertension. It detects the presence, and direction, of intracardiac shunts. Usually this is possible using conventional transthoracic techniques, but if visualization is poor or a small shunt is still suspected, then transoesophageal echocardiography may be necessary. In addition, the left ventricle can be assessed to determine whether there is a contribution from left ventricular systolic or diastolic dysfunction to elevated pulmonary arterial pressure. The function of the right side of the heart can also be assessed qualitatively and quantitatively. Atrial and ventricular dimensions and wall thickness can be measured, and paradoxical bowing of the intraventricular septum into the left ventricular cavity may be seen during systole as a consequence of greatly elevated right-​ sided pressures. Continuous-​wave Doppler echocardiography is used to measure high-​flow velocities across cardiac valves, one of the most commonly derived indices in the right heart being the pulmonary artery systolic pressure estimated by Doppler echocardiography from measurement of the velocity of the tricuspid regurgitant jet (c.80% of patients with PAH and 60% of normal subjects, have measurable tricuspid regurgitation). The maximum flow velocity (v) of the regurgitant jet is measured and inserted into the modified Bernoulli equation for convective acceleration pressure change, giving an estimate of right ventricular systolic pressure (RVSP):

Right heart catheterization remains the best technique for confirming the diagnosis of pulmonary hypertension and for providing important prognostic information. An elevated mean pulmonary arterial pressure of greater than 25 mm Hg at rest is the accepted definition. In patients with idiopathic PAH the mean pulmonary arterial pressure may exceed 60 mm Hg. The pulmonary capillary wedge pressure (PCWP) can also be determined at catheterization, which is an approximation of left atrial pressure. An elevated PCWP (>15 mm Hg) generally indicates left heart disease. Measurement of PCWP is often unreliable in the presence of CTEPH. Sampling of venous blood oxygen saturation as the catheter passes down from the right atrium to right ventricle may detect a sudden ‘step-​up’ in oxygenation, which would indicate the presence of a left-​to-​right shunt. Cardiac output can be determined by thermodilution or the Fick method. Indicators of right heart failure, and hence poorer prognosis, include (1) an elevated right atrial pressure (>10 mm Hg); (2) an elevated right ventricular end-​diastolic pressure (>10 mm Hg); (3) a reduced mixed venous oxygen saturation (Svo2 101.3°F)

7

1

Cardiac examination (any abnormality) Increased P2

21 23

Third heart sound

3

Fourth heart sound

24

Right ventricular lift

4

Jugular venous distension

Wheezes

29 51

18

5

2

Rhonchi

2

Decreased breath sounds Pleural friction rub

4 14

Lung examination (any abnormality) Rales (crackles)

15

17 3

0

11

47a

DVT Calf or thigh Calf only

32

Calf and thigh

14

Thigh only Homans’ sign

2 4

P2, pulmonary component of second sound. a Number of patients with PE who had one or more signs of DVT: oedema, 55; erythema, 5; tenderness, 32; palpable cord, 2. Data from Stein PD, et al. (1991). Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-​existing cardiac or pulmonary disease. Chest, 100, 598–​603 and Stein PD, et al. (2007). Clinical characteristics of patient with acute pulmonary embolism: data from PIOPED II. Am J Med, 120, 871–​9.

of atelectasis or a parenchymal abnormality was present in 98%. The remaining patients usually had either DVT or an unexplained low Pao2. PE was rarely diagnosed in the absence of dyspnoea or tachypnoea or pleuritic pain. Dyspnoea or tachypnoea occurred in 92% of all patients with PE (irrespective of pre-​existing cardiopulmonary disease) in whom the pulmonary emboli were in main or lobar pulmonary arteries, but in only 65% of patients in whom the largest PE was in segmental pulmonary arteries. Dyspnoea or tachypnoea or pleuritic pain occurred in 97% of patients with proximal PE and 77% of patients with pulmonary emboli in only segmental pulmonary arteries. Accuracy of clinical assessment To emphasize the point that the diagnosis of PE is difficult to make, senior staff physicians and postgraduate fellows taking part in the PIOPED study were uncertain of the diagnosis in most patients. Using individual judgement without any specific predetermined

Table 16.16.1.12  A model to determine the clinical probability of pulmonary embolism according to Wells and associates Clinical feature

Score (points)

Clinical signs and symptoms of DVT (objectively measured leg swelling and pain with palpation in the deep vein system)

3.0

Heart rate>100/​min

1.5

Immobilization ≥3 consecutive days (bed rest except to access bathroom) or surgery in previous 4 weeks

1.5

Previous objectively diagnosed PE or DVT

1.5

Haemoptysis

1.0

Malignancy (cancer patients receiving treatment within 6 months or receiving palliative treatment)

1.0

PE as likely or more likely than alternative diagnosis (based on history, physical examination, chest radiograph, ECG, and blood tests)

3.0

Score: 4, likely probability; >6.0, high probability. Data from Wells PS, et al. (2000). Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-​dimer. Thromb Haemost, 83, 416–​20 and from Wells PS, et al. (2001). Excluding PE at the bedside without diagnostic imaging: management of patients with suspected PE presenting to the emergency department by using a simple clinical model and D-​dimer. Ann Intern Med, 135, 98–​107.

criteria, senior staff were correct in the diagnosis in 88% of cases when their clinical assessment indicated a high probability of PE. When their clinical assessment indicated a low probability of PE, senior staff correctly excluded PE in 86%. Postgraduate fellows, on the basis of clinical assessment, were more accurate in excluding PE than they were in making the diagnosis. Objective scoring systems for the probability of acute PE give probability assessments similar to those of experienced physicians and do not require experience or clinical judgement. An example of a scoring system that is mostly objective is shown in Table 16.16.1.12.

Differential diagnosis The commonest presentation of acute PE is with dyspnoea and/​or pleuritic chest pain. There are several other possible causes of these symptoms, the commonest being musculoskeletal pain and pneumonia. Musculoskeletal chest pain can be very similar to that caused by pleurisy, and splinting of the chest can lead to a perception of breathlessness that may be exacerbated by anxiety. If there is an obvious history of local trauma to the chest, then the patient will rarely present to the physician, but it is worthwhile to ask specifically whether there has been any trauma or unaccustomed physical activity, whether the pain can be brought on by particular movements, and to examine carefully for local tenderness of the ribs, muscles, or costal margins. However, tenderness can sometimes be found in cases of pleurisy, and chest pain was reproduced by palpation in 20% of patients with PE. Appropriate history often supports a diagnosis of musculoskeletal pain. Pneumonia complicated by pleurisy can cause dyspnoea and chest pain. Important features to look for in the history include preceding systemic upset (flu-​like symptoms), high fever, and rigors, and on examination, high fever, ‘toxic appearance’, and chest signs of pneumonic consolidation. If a positive diagnosis of another cause of dyspnoea and/​or pleuritic chest pain cannot be made, then the default position should be to assume that the patient has PE until proven otherwise.

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Investigation Detection of evidence of thrombus within the circulation: D-​dimer As when considering the diagnosis of DVT, a ‘negative’ D-​dimer test is useful for excluding PE in patients who are clinically thought to be at low risk, but a ‘positive’ result does not establish the diagnosis. Hence, when used in the appropriate clinical context, D-​dimer testing is useful in defining a group of patients with suspected PE who do not require further investigation. In ranking the D-​dimer assays according to their sensitivity values and likelihood of increasing certainty for ruling out PE, the ELISA and quantitative rapid ELISA assays are significantly superior to the semiquantitative latex and whole-​blood agglutination assays. The quantitative rapid ELISA assay is more convenient than the conventional ELISA and provides a high level of certainty for a negative diagnosis of PE as well as DVT. A  particle-​enhanced immunoturbidometric assay (quantitative latex agglutination) gives results comparable to the rapid ELISA. The 3-​month risk of PE in untreated patients with a negative rapid ELISA D-​dimer measurement and low or intermediate clinical probability Geneva score was 0% (0 of 220). With a negative D-​dimer by rapid ELISA or quantitative latex agglutination assay and an unlikely (≤4) Wells score, PE occurred in 0.4% (4 of 1028), and with an unlikely (≤10) revised Geneva score in 1 of 320 (0.3%). Detection of the physical presence of thrombus in the pulmonary circulation Ventilation–​perfusion lung scans By 2001 in the United States of America the use of CT pulmonary angiography surpassed the use of ventilation–​perfusion lung scans for the diagnosis of acute PE, the use of ventilation–​perfusion lung scans having fallen into disfavour after the PIOPED trial because in most patients they led to an indeterminate result. Now, two decades since PIOPED was published, advances have been made in imaging equipment, improved methods of interpretation, and new radiopharmaceuticals. With such advances, and recognizing the risk of radiation with CT angiography, radionuclear imaging is receiving renewed interest. Based on the results of PIOPED, a high-​ probability lung ventilation–​perfusion scan (Fig. 16.16.1.2) indicates PE in 87%

of patients (Table 16.16.1.13) and a normal scan excludes PE. In the absence of any other information an intermediate probability scan indicates a 30% chance of PE and a low-​probability scan of 14%. A low-​probability ventilation–​perfusion scan by the criteria used in PIOPED does not therefore exclude PE. Intermediate and low-​probability interpretations may be grouped as ‘non​diagnostic’, which was frequently the case in PIOPED. Prior clinical assessment in combination with interpretation of the ventilation–​ perfusion scan improves diagnostic validity (Table 16.16.1.13). If the ventilation–​perfusion scan is interpreted as high probability for PE, and if the clinical impression is concordantly high, then the positive predictive value for PE is 96%. If the ventilation–​perfusion scan is low probability and the clinical suspicion is concordantly low, then PE is excluded in 96% of patients. The probability of PE can be determined based on the number of mismatched defects. Since PIOPED, criteria for the interpretation of very low probability lung scans (positive predictive value 6) n/​N (%)

Intermediate clinical probability (Wells score 2–​6) n/​N (%)

Low clinical probabilitya (Wells score 28 Days

Segmental

Fig. 16.16.1.5  Resolution of pulmonary emboli in main or lobar (▲) pulmonary arteries (PA) or segmental branches (●) according to number of days after initial CT angiogram. Bars = 95% confidence interval. Rate of resolution was slower in segmental branches. Data from Stein PD, et al. (2010). Resolution of pulmonary embolism on CT pulmonary angiography. AJR Am J Roentgenol, 194, 1263–​8.

16.16.1  Deep venous thrombosis and pulmonary embolism

support are indications for intervention. Analysis of data from 72 230 unstable (in shock or requiring ventilatory support) patients with PE throughout the United States of America from 1999 to 2008 showed that in-​hospital mortality with thrombolytic therapy was 15% compared with 47% in those who did not receive thrombolytic therapy. Mortality was further reduced to 7.6% if a vena cava filter was used in addition to thrombolytic therapy compared with 33% mortality in those who received a vena cava filter, but no thrombolytic therapy. All-​cause mortality in unstable patients was lower with thrombolytic therapy in every age group, including older people, irrespective of comorbid conditions. Right ventricular dysfunction on the echocardiogram of normotensive patients with PE may indicate impending haemodynamic instability. For this group meta-​analysis showed mortality was 1.4% with thrombolytics versus 2.9% with anticoagulants, but this benefit was offset by major bleeding in 7.7% with thrombolytics, versus 2.3% with anticoagulants. A more rapid lysis of pulmonary thromboemboli occurs with thrombolytic agents than occurs spontaneously in patients treated only with anticoagulants, but pulmonary reperfusion as demonstrated on perfusion lung scans is similar after 2 weeks in patients treated with thrombolytic agents and patients treated with anticoagulants. In 1973 the Urokinase Pulmonary Embolism Trial showed no improvement of mortality and no difference of the rate of recurrence of PE among stable patients treated with thrombolytic therapy and patients treated with anticoagulants. There have been no subsequent prospective randomized trials to contradict these results, although a trend suggesting a lower rate of recurrent PE has been shown among patients with right ventricular dysfunction who were treated with tissue plasminogen activator. Thrombolysis has risks. Based on pooled data the frequency of major bleeding from tissue plasminogen activator among patients with PE in randomized trials was 14.7%. This occurred despite the fact that all studies excluded patients at a high risk of bleeding, such those with recent surgery, recent biopsy, peptic ulcer disease, blood dyscrasia, or severe hepatic or renal disease. The risk of intracranial haemorrhage with tissue plasminogen activator (2%) was higher among patients with PE than among patients who received tissue plasminogen activator for myocardial infarction. Even though there are risks of thrombolysis, mortality is lower in unstable patients (in shock or requiring ventilatory support) who receive thrombolysis than those who do not receive it. Regimens of thrombolytic therapy When thrombolytic therapy is appropriate, current evidence supports a short (2-hour) infusion through a peripheral vein. The most widely used regimen In the United States is recombinant tissue plasminogen activator (rt-PA)(altelplase) 100 mg IV over 2 hours. In the United States, it is recommended that IV unfractionated heparin should be discontinued during the infusion of rt-PA. • In Europe, rt-​PA is administrated using a 10-​mg bolus, followed by a 90-​mg continuous IV infusion with concomitant unfractionated heparin. Inferior vena cava filters Recommendations for use of inferior vena cava filters are shown in Table 16.16.1.8.

The Prévention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC) study, a randomized controlled trial of permanent filters plus anticoagulants (n  =  200) compared with anticoagulants alone (n = 200) was performed in patients with proximal DVT, with or without symptomatic PE. Fewer patients in the filter group showed symptomatic PE at 1  year (1.1% versus 5.0%) and at 8  years 6.2% versus 15.1%) after recruitment. Recurrent DVT, however, was more frequent in the filter group and there was no difference in mortality. The Prévention du Risque d’Embolie Pulmonaire par Interrup­tion Cave 2 (PREPIC2) trial was a randomized controlled trial of retrievable filters in stable patients with acute pulmonary embolism. This trial showed no reduction of mortality in 200 stable patients with filters compared with 199 who did not receive a filter. Subgroups that might benefit from filters could not be assessed. Such subgroups are 1) haemodynamically unstable patients (in shock or on ventilatory support) 2) require thrombolytic therapy and are stable, 3) undergo pulmonary embolectomy, 4) have solid malignant tumors (except liver gall bladder, bile ducts and ovary) and are >60 years old, 5) have chronic obstructive pulmonary disease and are >50 years old, 6) very elderly (>80 years) even though stable, and 7) patients who suffer recurrent PE during the first 3 months (while on anticoagulants). These subgroups were shown to reduce in–hospital mortality based on administrative data from retrospective cohort studies of huge United States government or commercial databases. These results have not been assessed by randomized controlled trials and are not endorsed by authoritative guidelines. Routine insertion of an inferior vena cava filter is not indicated solely on the basis of a continuing predisposition for DVT, although in special circumstances this may be the best approach (e.g. in high-​ risk patients with DVT, severe pulmonary hypertension, and minimal cardiopulmonary reserve). Several vena cava filters have been designed for percutaneous insertion and many are retrievable. They differ in outer diameter of the delivery system, maximal caval diameter into which they can be inserted, hook design, retrievability, biocompatibility, and filtering efficiency. They may be effective alone in preventing PE, but anticoagulant therapy after insertion of a filter is recommended for the duration of treatment that would be required without a filter. Thereafter, anticoagulant therapy can be discontinued even though the filter remains in place. Complications of permanent vena cava filters include improper anatomical placement, filter deformation, filter fracture, insufficient opening of the filter, and filter migration; also perforation, thrombosis, and stenosis of the cava wall. Symptomatic occlusion of the inferior vena cava is the most frequent complication, occurring in about 9% of patients. Complications at the site of insertion of the catheter do not differ from complications observed locally with other catheter techniques. DVT at the puncture site generally has been reported in 8% to 25%. Retrievable vena cava filters typically are successfully removed after 1 to 3 months, but some have been successfully removed after 1 year. PE after insertion of an inferior vena cava filter is uncommon (1%), and fatal embolism is rare. Possible mechanisms that can explain PE after filter insertion are: (1) ineffective filtration, especially with tilting of the filter; (2) growth of trapped thrombi through the filter; (3) thrombosis on the proximal side of the filter; (4) filter migration; (5)  filter retraction from the caval wall; (6)  embolization through collaterals; (7) embolization from sites other than the inferior vena cava; and (8) incorrect position of the filter. Over the last two decades, the use of inferior vena cava filters in the United States

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of America has increased markedly in patients with PE, patients with DVT alone, and patients at risk who had neither PE nor DVT. The use for primary prevention in patients who do not have DVT or PE has accelerated. Extensive use of permanent and retrievable vena cava filters indicates a liberalization of indications, but despite the benefits of retrievability, retrieval has been attempted in only a minority of patients. For patients with retrievable IVC filters in whom the transient risk of PE has passed, the benefit/risk profile begins to favor filter removal between 29 and 54 days after insertion. Catheter interventions Catheter-​tip devices for the extraction or the fragmentation of PE have the potential of producing immediate relief from massive PE. Such interventions may be particularly useful in patients in whom there is a contraindication to thrombolytic therapy. A  suction-​tip device for extraction of PE has been used in some patients, and thrombus fragmentation with a guide wire, angiographic catheter, balloon catheter, or specially designed devices has been reported in small case series or case reports. The release of fragmented thromboemboli into the distal pulmonary arterial branches is not a problem. A registry of management strategies used by hospitals throughout Germany showed use of catheter fragmentation in 1.3–​ 6.8% of patients with PE, depending on severity. Although originally it was thought that catheter embolectomy or fragmentation could substitute for thrombolytic therapy, it now appears to be an adjunct to thrombolysis, allowing a larger surface area of the fragmented emboli to be exposed to thrombolytic agent. Among patients who undergo fragmentation with standard angiographic catheters, the rate of successful clinical outcome with a local infusion of thrombolytic agents in combination with fragmentation is higher than with a systemic infusion. Pulmonary embolectomy Thrombolytic therapy is likely to give better results than embolectomy, although the latter may have life-​saving potential in some instances. The average operative mortality in the United States of America among 620 unstable patients operated from 2004 to 2008 was 40%, and among 1550 stable patients, mortality was 23%. These data reflect average results. Advanced centres with expertise might show a lower mortality. A candidate for pulmonary embolectomy should meet the following criteria:  (1) massive PE, angiographically documented if possible; (2) haemodynamic instability (shock) despite heparin therapy and resuscitative efforts; and (3) failure of thrombolytic therapy or a contraindication to its use.

Chronic pulmonary thromboembolic hypertension The vast majority of PE resolve because of natural thrombolytic processes. Residual emboli, if any, undergo fibrovascular organization causing chronic obstruction to pulmonary arterial blood flow. It is estimated that 2.8% of patients with PE develop chronic thromboembolic pulmonary hypertension, usually within 3 years after the acute PE. The predominant symptom of chronic thromboembolic pulmonary hypertension is unexplained dyspnoea on exertion, often following an asymptomatic period of several months or years after the acute PE. The reference standard for the diagnosis is combined right heart catheterization to quantify the haemodynamic impairment, and conventional pulmonary angiography to determine the extent and proximal location of the chronic thromboembolic obstruction. CT pulmonary angiography is essential to exclude rare

conditions that may present with similar signs and symptoms such as fibrous mediastinitis, mediastinal carcinoma, and pulmonary artery sarcoma. Pulmonary thromboendarterectomy in an experienced centre is the treatment of choice in symptomatic patients with surgically accessible thromboemboli. Early diagnosis is important because the surgical mortality in patients who have progressed to dyspnoea at rest is substantially greater than among those with less severe symptoms. Neither anticoagulants nor vasodilators are effective, with the haemodynamic and symptomatic benefits of medical therapy being modest in comparison to those resulting from successful pulmonary thromboendarterectomy. See Chapter 16.15.2 for further discussion.

FURTHER READING Agnelli G, Becattini C (2010). Acute pulmonary embolism. N Engl J Med, 363, 266–​74. Agnelli G, et al. (2013). AMPLIFY Investigators: oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med, 369, 799–​808. Chatterjee S, et  al. (2014). Thrombolysis for pulmonary embolism and risk of all-​cause mortality, major bleeding, and intracranial hemorrhage: a meta-​analysis. JAMA, 311, 2414–​21. Collaborative Study by the PIOPED Investigators (1990). Value of the ventilation/​perfusion scan in acute pulmonary embolism—​results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA, 263, 2753–​59. Fedullo P, et al. (2011). Chronic thromboembolic pulmonary hypertension. Am J Resp Crit Care Med, 183, 1605–​13. Goldhaber SZ (2016). Requiem for liberalizing indications for vena caval filters? Circulation, 133, 1992–​4. Guyatt GH, et  al. (2012). Antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-​ Based Clinical Practice Guidelines. Chest, 141(suppl), 7S–​47S. Kearon C, et  al. (2012). Antithrombotic therapy for VTE disease. Antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-​Based Clinical Practice Guidelines. Chest, 141(suppl), e419S–​94S. Kearon C, et al. (2016). Antithrombotic therapy for VTE disease: chest guideline and expert panel report. Chest, 149, 315–​52. Mismetti P, et al. (2015). PREPIC2 Study Group. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA, 313, 1627–​35. Morales JP, et al. (2013). Decision analysis of retrievable inferior vena cava filters in patients without pulmonary embolism. J Vasc Surg Venous Lymphat Disord, 1, 376–84. PREPIC Study Group (2005). Eight-​year follow-​up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation, 112, 416–​22. Schulman S, et al.; RE-​COVER II Trial Investigators (2014). Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation, 18, 129, 764–​72. Sostman, HD et al. (2008). Sensitivity and specificity of perfusion scintigraphy combined with chest radiography for acute pulmonary embolism in PIOPED II. J Nucl Med, 49, 1741–​8. Stein PD, et  al. (1991). Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-​existing cardiac or pulmonary disease. Chest, 100, 598–​603.

16.16.2  Therapeutic anticoagulation

Stein PD, et  al. (2004). D-​dimer for the exclusion of deep venous thrombosis and acute pulmonary embolism:  a systematic review. Ann Intern Med, 140, 589–​602. Stein PD, et al. (2006). Diagnostic pathways in acute pulmonary embolism:  recommendations of the PIOPED II investigators. Am J Med, 119, 1048–​55. Stein PD, et al. (2006). Multidetector computed tomography for acute pulmonary embolism. N Engl J Med, 354, 2317–​27. Stein PD, et al. (2007). Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. Am J Med, 120,  871–​9. Stein PD, et al. (2010). Early discharge of patients with venous thromboembolism: implications regarding therapy. Clin Appl Thromb Hemost, 16,  141–​5. Stein PD, et  al. (2010). Outcome in stable patients with acute pulmonary embolism who had right ventricular enlargement and/​or elevated levels of troponin I. Am J Cardiol, 106, 558–​63. Stein PD, et al. (2010). Silent pulmonary embolism in patients with deep venous thrombosis: a systematic review. Am J Med, 123, 426–​31. Stein PD, et al. (2011). Elevated cardiac biomarkers with normal right ventricular size indicate an unlikely diagnosis of acute pulmonary embolism in stable patients. Clin Appl Thromb Hemost, 17, E153–​7. Stein PD, et  al. (2011). Prognosis based on cardiac biomarkers and right ventricular size in stable patients with acute pulmonary embolism. Am J Cardiol, 107,  774–​7. Stein PD, et  al. (2012). Diagnosis and management of isolated subsegmental pulmonary embolism: review and assessment of the options. Clin Appl Thromb Hemost, 18,  20–​6. Stein PD, et al. (2012). Impact of vena cava filters on in-​hospital case fatality rates from pulmonary embolism. Am J Med, 125, 478–​84. Stein PD, et al. (2012). Trends in case fatality rates in patients with pulmonary embolism according to stability and treatment. Thrombosis Research, 130, 841–​46. Stein PD, Matta F (2012). Pulmonary embolectomy for acute pulmonary embolism. Am J Med, 125,  471–​7. Stein PD, Matta F (2012). Thrombolytic therapy in unstable patients with acute pulmonary embolism:  save lives but underused. Am J Med, 125, 465–​70. Stein PD, Matta F (2013). Treatment of unstable pulmonary embolism in elderly and those with comorbid conditions. Am J Med, 126, 304–​10. Stein PD, et  al. (2014). A critical review of SPECT imaging in pulmonary embolism. Clin Transl Imaging, 2, 379–​90. Stein PD (2016). Pulmonary embolism, 3rd edition. Wiley Blackwell, Oxford. Stein PD, et al. (2019). Optimal therapy for unstable pulmonary embolism. Am J Med, 132, 168–71. Stein PD, et al. (2019). Usefulness of inferior vena cava filters in stable patients with acute pulmonary embolism. Am J Cardiol, 123, 1874–77. Tapson VF (2008). Acute pulmonary embolism. N Engl J Med, 358, 1037–​52. van Belle A, et  al. (2006). Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-​dimer testing, and computed tomography. JAMA, 295,  172–​9. Wells PS, et  al. (1997). Value of assessment of pretest probability of deep-​vein thrombosis in clinical management. Lancet, 350, 1795–​8. Wells PS, et al. (2000). Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-​dimer. Thromb Haemost, 83, 416–​20. Wells PS, et al. (2001). Excluding PE at the bedside without diagnostic imaging: management of patients with suspected PE presenting to the emergency department by using a simple clinical model and D-​dimer. Ann Intern Med, 135, 98–​107.

16.16.2  Therapeutic anticoagulation David Keeling ESSENTIALS Low-​molecular-​weight heparins have largely replaced unfractionated heparin. Their much more predictable anticoagulant response combined with high bioavailability after subcutaneous injection means that the dose can be calculated by body weight and given subcutaneously without any monitoring or dose adjustment. Their widespread use resulted in most patients with deep vein thrombosis being managed as outpatients, and this is also increasingly the case for uncomplicated pulmonary embolism. Oral vitamin K antagonists (most commonly warfarin) have historically been the mainstay of long-term anticoagulant therapy, but direct acting oral anticoagulants (DOACs) that specifically target thrombin or factor Xa are increasingly used to treat acute venous thromboembolism and for stroke prevention in atrial fibrillation. Particular issues—​(1) in patients with cancer and venous thromboembolism, giving low-​molecular-​weight heparins for the first 6 months of long-​term anticoagulant therapy has been shown to be superior to vitamin K antagonist; (2) high-​dose loading regimens of warfarin are unnecessary and may increase the risk of over-​anticoagulation and bleeding; (3) warfarin for venous thromboembolism and atrial fibrillation should be given with a target INR of 2.5 (range 2.0–​3.0); for patients with prosthetic heart valves the target INR is usually greater; (4) indefinite anticoagulation is required for patients with atrial fibrillation or a mechanical heart valve; for venous thromboembolism a careful clinical decision is required regarding duration of treatment; (5)  for patients with atrial fibrillation anticoagulation is much more effective than aspirin in preventing stroke; (6) if warfarin needs to be stopped for surgery, full-​dose heparin does not have to be given perioperatively unless the risk of thromboembolism is high, and warfarin can be continued in patients having dental extractions.

Introduction The main indications for therapeutic anticoagulation are venous thromboembolism (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE) (see Chapter 16.16.1), and the prevention of stroke in patients with atrial fibrillation or mechanical heart valves. Oral vitamin K antagonists (in the United Kingdom, mostly warfarin) have been the mainstay of treatment, but oral direct inhibitors of thrombin or factor Xa (direct acting oral anticoagulants, DOACs) are being increasingly used to treat VTE and to prevent stroke in atrial fibrillation. When warfarin is used in acute venous thromboembolism, initial anticoagulation with heparin is required because warfarin takes time to become effective.

Therapeutic anticoagulation for venous thromboembolism DVT and PE are aspects of the same disease—​VTE. Forty per cent (40%) of patients with DVT without clinical evidence of PE have

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section 16  Cardiovascular disorders

evidence of emboli on lung scanning. The principles of therapeutic anticoagulation are the same for both. In proximal DVT and PE this has historically involved immediate anticoagulation with heparin, followed by a period of anticoagulation with warfarin (or other oral vitamin K antagonists). Distal DVT can be managed in the same way, but an alternative strategy is to use serial non​invasive testing (e.g. ultrasonography), which only reliably detects proximal thrombosis, to ensure that suspected distal thrombosis does not extend above the knee, withholding treatment if it does not. There is clear evidence that an immediately acting anticoagulant is needed in the initial phase and that anticoagulation with oral vitamin K antagonists alone is inadequate. Warfarin can be commenced on the first day and heparin is continued for 5 days or until the international normalized ratio (INR) is greater than 2.0 for two consecutive days, whichever is the longer. Extending the period of heparinization from 5 to 10 days is not more effective and increases the risk of heparin-​induced thrombocytopenia. The DOACs act immediately and rivaroxaban and apixaban have been used to treat acute VTE without initial heparin. Dabigatran and edoxaban have also been used for acute VTE, but with initial heparin.

Heparin Heparin, a glycosaminoglycan, is composed of alternating uronic acid and glucosamine saccharides that are sulphated to a varying degree. Its mode of action is to potentiate the activity of the serine protease inhibitor (serpin) antithrombin, whose main mode of action is to inhibit thrombin, but which also inhibits several other coagulant proteases such as factor Xa. A specific pentasaccharide sequence (see ‘Fondaparinux’) determined by the sulphation pattern along the heparin chain binds to antithrombin and causes a conformational change, giving it full activation against factor Xa but only partial activation against thrombin. Heparins of 18 saccharides (molecular weight (MW) 5400)  or more can extend across the intermolecular gap and also bind to thrombin giving full antithrombin activity, which is lost if the chains are shorter. Unfractionated or standard heparins are a mixture of chains of different lengths (MW 5000–​35 000, mean 13 000) and low-​molecular-​ weight heparins (LMWH, MW 2000–​8000, mean 5000) are derived from them by enzymatic or physicochemical cleavage. LMWH have, with good reason, largely replaced unfractionated heparin for the treatment of venous thromboembolism, but the use of the latter is discussed first. Anticoagulation with unfractionated heparin Unfractionated heparin has most often been given by continuous intravenous infusion, the rate of which has to be adjusted, usually by measuring the activated partial thromboplastin time (APTT). An inadequate APTT response in the first 24 h may increase the risk of recurrence of thromboembolism, although this does not seem to be critical if the starting infusion rate is at least 1250 IU/​h. A validated regimen is to give a bolus dose of 80 IU/​kg and to start the infusion at 18 IU/​kg/​h, performing the first APTT estimate after 6 h. The dose is then usually adjusted to maintain the APTT between 1.5 to 2.5 times the average laboratory control value. With older APTT reagents, this corresponded to a therapeutic heparin level of 0.3–​0.7 IU/​ml by anti-​Xa assay. However, many current APTT reagents show an increased sensitivity to unfractionated

heparin and, with these, higher ratios should be aimed for. The local laboratory should advise on the appropriate therapeutic range with its reagent. When the dose is therapeutic, the APTT should be checked daily. An alternative is to give unfractionated heparin subcutaneously once every 12 h, and a meta-​analysis suggested that this might be more effective and at least as safe as continuous intravenous infusion. A reasonable starting dose is 250 IU/​kg, adjusting the dose according to the mid-​interval APTT. Anticoagulation with LMWH The key clinical property of LMWHs is that they produce a much more predictable anticoagulant response than unfractionated heparin. This, combined with the fact that they have very high bioavailability after subcutaneous injection, means that the dose can be calculated by body weight and be given subcutaneously without any monitoring or dose adjustment. The actual dosage used differs slightly with the different LMWH and the manufacturers’ recommendations should be followed, but a typical dose is 200 IU/​ kg once a day. They are at least as effective and at least as safe as unfractionated heparin. Their widespread use resulted in most patients with DVT being managed as outpatients, and this is increasingly the case for low-​risk PE. LMWH is renally excreted and so the dose needs to be reduced in patients with renal failure, with monitoring and (if necessary) adjustment of the dose based on anti-​Xa levels. In patients with cancer, giving LMWH for the first 6 months of long-​term anticoagulant therapy has been shown to be superior to switching to a vitamin K antagonist. Complications of heparin treatment If a patient on intravenous unfractionated heparin is excessively anticoagulated, it is usually sufficient simply to stop the infusion, the half-​life being 1 to 2 h. If bleeding is severe, the heparin can be neutralized with protamine sulphate, giving 1 mg for every 100 IU that has been infused over the previous hour. The reversal of LMWH is more problematic. Although protamine sulphate may not neutralize the smaller chains, it is often clinically effective, though estimating an appropriate dose is more difficult (the maximum dose is 50 mg, so this is often given if the subcutaneous injection was recent). Heparin-​induced thrombocytopenia is a feared complication, but much less common now that short courses of LMWH are used. It is due to the development of an antibody to the heparin–​platelet factor 4 complex and can be associated with serious venous and arterial thrombosis. Heparin must be stopped if heparin-​induced thrombocytopenia is likely and an alternative immediately acting non​heparin anticoagulant substituted. Fondaparinux The specific pentasaccharide sequence of heparin which binds to antithrombin has been chemically synthesized and is marketed as the drug fondaparinux. Like LMWH it is given by subcutaneous injection with no monitoring. It is equivalent to heparin in the treatment of venous thromboembolism, and is superior to heparin in the treatment of unstable angina and non-​ST elevation myocardial infarction. It carries virtually no risk of heparin-​induced thrombocytopenia.

16.16.2  Therapeutic anticoagulation

Warfarin The oral vitamin K antagonists have historically been the mainstay of long-​term anticoagulant therapy. Warfarin is the commonest vitamin K antagonist given; acenocoumarol (which has a shorter half-​life) and phenindione (which has a higher incidence of skin rashes) are seldom used in the United Kingdom. The procoagulant factors II, VII, IX, and X (and the anticoagulants protein C and protein S) need vitamin K for the γ-​carboxylation of the glutamic acid residues that form their gla domains. Without this post-​translational modification they cannot bind calcium, and as a consequence cannot bind to anionic phospholipid surfaces such that assembly of the key coagulation complexes is disrupted. Warfarin takes several days to become effective, so heparin is given initially if immediate anticoagulation is needed. When warfarin is started, the vitamin K-​dependent factors fall according to their half-​lives. Factor VII and protein C have the shortest half-​lives, so that despite a prolongation of the INR due to factor VII deficiency, warfarin may initially be procoagulant. This is the mechanism for the rare problem of warfarin-​induced skin necrosis, most often described in those with protein C deficiency. Initiation and monitoring of anticoagulation with warfarin Monitoring of warfarin treatment is by the INR. This is a manipulation of the prothrombin time (PT) to allow for the different sensitivities of various laboratory reagents to the warfarin-​induced coagulopathy. The INR equals (PT/​MNPT)ISI where MNPT is the (mean normal) control PT and ISI is the international sensitivity index of the thromboplastin used in the assay. For the treatment of DVT and PE, the target INR should be 2.5 (target range 2.0–​3.0). If the initial coagulation tests are not prolonged, it has been customary to give 10 mg of warfarin on the first evening and check the INR the following morning, adjusting the dose according to the daily INR results until the patient is stable. With such regimens, most patients received 10 mg of warfarin on the first 2 days. There is, however, no evidence to suggest a 10 mg loading dose is superior to 5 mg, and regimens that start with 5 mg doses, or a single 10 mg dose followed by 5 mg doses, may be preferable to regimens that start with repeated 10 mg doses. This is the case in patients with an increased risk of bleeding (e.g. people >60 years old, and those with liver disease or cardiac failure). The dosing algorithm used in Oxford is shown in Table 16.16.2.1. Table 16.16.2.1  A warfarin induction regimen Days 1 and 2

Give 5 mg each evening if baseline INR 3 months ago, bi-​leaflet aortic valve with no other risk factors, AF without recent stroke

Nil or prophylactic LMWH

Prophylactic LMWH

AF, atrial fibrillation; IV, intravenous; LMWH, low-​molecular-​weight heparin; SC, subcutaneous; UFH, unfractionated heparin; VTE, venous thromboembolism. a Stop full-​dose IV UFH 6 h before surgery and check APTT before operation begins, omit full-​dose SC LMWH on day of surgery. b Therapeutic dose heparin must not be given for at least 48 h after high bleeding risk surgery.

Various national and international recommendations are made regarding the target INR in patients with mechanical heart valves, with 3.5 traditionally being advised. This is reasonable for caged-​ball valves, but for tilting-​discs and bileaflet valves the target INR can possibly be lower, for example, 2.5 (range 2.0–​3.0) for aortic valves and 3.0 (range 2.5–​3.5) for mitral valves. When a new valve is inserted, it is recommended that unfractionated heparin or LMWH be given until the INR is stable and at a therapeutic level for two consecutive days.

Perioperative management of therapeutic anticoagulation Warfarin does not need to be stopped for dentistry, nor for some minor surgery. For many operations, however, warfarin will need to be temporarily discontinued. It can generally be stopped 5 days before surgery and the INR be checked on the day of surgery (checking the day before obviates the risk of cancellation as a small dose of oral vitamin K can be given if necessary). The main clinical decision is whether to give bridging therapy with treatment-​dose heparin perioperatively when the INR is less than 2.0. This depends on balancing the risk of bleeding with the risk of thromboembolism. Treatment-​dose heparin is usually given for those at high risk of thromboembolism, such as patients with a mechanical mitral valve, but must not be (re-​)started for at least 48 h after high bleeding risk surgery (Table 16.16.2.4). The DOACs have short half-​lives and so bridging is not required. They can normally be stopped 1 or 2 days preoperatively, although

renal function needs to be taken into consideration, particularly for dabigatran. They must not be given for at least 48 h after surgery with a high bleeding risk.

FURTHER READING Burnett AE, et al. (2016). Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis, 41, 206–​32. Connolly SJ, et al. (2009). Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med, 361, 1139–​51. Dager WE, Roberts AJ, Nishijima DK (2019). Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants. Thromb Res, 173, 71–6. Giugliano RP, et al. (2013). Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med, 369, 2093–​104. Granger CB, et al. (2011). Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med, 365, 981–​92. Kearon C, et  al. (2016). Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest, 149, 315–​52. Keeling D, et  al. (2011). Guidelines on oral anticoagulation with warfarin—​fourth edition. Br J Haematol, 154, 311–​24. Keeling D, et al. (2016). Peri-​operative management of anticoagulation and antiplatelet therapy. Br J Haematol, 175, 602–​13. Patel MR, et  al. (2011). Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med, 365, 883–​91.

16.17

Hypertension

CONTENTS 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

16.17.1  Essential hypertension: Definition, epidemiology, and pathophysiology Bryan Williams and John D. Firth

typically used for both daytime ambulatory blood pressure and home measurements. Isolated diastolic hypertension (systolic blood pressure (SBP) 90  mm Hg) is more common in younger people, and isolated systolic hypertension (SBP >140 mm Hg, DBP 140

and

90 mm Hg) bridging the two extremes of age (Fig. 16.17.1.1). Although traditionally DBP was considered to carry the greatest prognostic significance, it is now clear that this is not the case. Most people with hypertension are over the age of 50 years, and in them SBP is by far the most important contributor to the burden of cardiovascular disease attributable to hypertension. The different patterns of blood pressure and the relative importance of DBP and SBP with regard to prognosis reflect progression of the underlying pathology. The pathogenesis of hypertension in younger people is characterized by an increased peripheral vascular resistance. This results in an increased diastolic pressure, with any associated rise in systolic pressure ‘cushioned’ by a compliant aorta, hence the commonly observed IDH. With ageing there is progressive stiffening of the aorta, a consequent reduction in large-​artery compliance, and a reduced capacity to sustain diastolic pressure and to cushion systolic pressure. The result is an age-​related widening of pulse pressure as diastolic pressure falls alongside a progressive rise in SBP, hence the emergence of ISH (Fig. 16.17.1.2).

80

70

Diastolic blood pressure

0 18–29 30–39 40–49 50–59 60–69 70–79 ≥80 Age, y

Systolic blood pressure

Non-Hispanic black Non-Hispanic white Mexican American

80

70

Diastolic blood pressure

0 18–29 30–39 40–49 50–59 60–69 70–79 ≥80 Age, y

Fig. 16.17.1.2  Data from the United States of America NHANES III population survey (1988–​91) showing the progressive rise in SBP with age and the rise in DBP up until age c.50 years, after which DBP falls and pulse pressure widens. This pattern is typical of Westernized countries and explains the high prevalence of isolated systolic hypertension in older people in these countries. Reproduced from Burt VL, et al. (1995). Prevalence of hypertension in the US adult population. Hypertension, 23, 305–​13.

3737

section 16  Cardiovascular disorders

2000

Men Women

50 37.4 37.2

40

35.3

34.8 22.0 23.7

20.6 20.9

20

Rate of hypertension (%)

40.7

39.1

30

26.9

22.6

19.7

17.0

28.3

14.5

10 0 2025 50

41.6 42.5

40

45.9

44.5

39.1

30

40.2 24.0

22.9 23.6

27.0

27.7

27.0 28.2

27.0 18.8 17.1

20 10

er As i isl a an an d ds Su bSa h Af aran ric a

in a

th

Ch

t e in A Ca m rib er be ica an M id dl e e cr ast es em ce nt

In di a

th

O

La

m

an

d

ar

ke

E t e sta co bli no sh m ed ie Fo s rm er ec so on ci om alis ie t s

0

Fig. 16.17.1.3  Frequency of hypertension in people aged 20 years and older by world region and gender in 2000 (upper panel) and projected to 2025 (lower panel). Reprinted from The Lancet, Vol. 365, Kearney PM, et al., Global burden of hypertension: analysis of world-​wide data, pp. 217–​23. Copyright (2005), with permission from Elsevier.

adult population and affecting 1.6 billion people (Fig. 16.17.1.3). Most of this increase in the worldwide burden of hypertension is expected to result from an increase in the number of people with hypertension in economically developing regions, hence almost 75% of the world’s hypertensive populations will be in economically developing regions by 2025. The prevalence of hypertension in almost all regions of the world increases with age and more steeply in women. By the age of 60, more than one-​half of adults in most regions of the world will be

(a) 100

Risk of hypertension, %

3738

hypertensive. India and Asia have and will most likely continue to have the lowest rates of hypertension, whereas the highest rates are likely to remain in Latin America, the Caribbean, former Soviet republics, and sub-​Saharan Africa. Consequently, hypertension is set to remain the single most important preventable cause of premature death worldwide over the next two decades, with the World Health Organization (WHO) estimating that about 7.1 million deaths per year may be attributable to hypertension, and that suboptimal blood pressure (SBP ≥115 mm Hg by their definition) is responsible for

(b) 100

Women aged 65 years

80

80

60

60

40

40

20

0

1976–1998 1952–1975 0

2

4

6

8 10 12 Years of follow-up

14

16

18

20

Men aged 65 years

20

0

0

2

4

6

8 10 12 Years of follow-up

14

16

18

Fig. 16.17.1.4  Lifetime risk of hypertension in women and men aged 65 years. Reprinted from Vasan RS, et al. (2002). Residual lifetime risk for developing hypertension in middle-​aged women and men, the Framingham Heart Study. JAMA, 287, 1003–​10. Copyright © 2002, American Medical Association.

20

16.17.1  Essential hypertension

62% of cerebrovascular disease and 49% of ischaemic heart disease worldwide, with little variation by sex.

men and women who were not hypertensive at 55 or 65 years old and survived to age 80 to 85 (Fig. 16.17.1.4).

Lifetime risk

Cardiovascular morbidity and mortality associated with hypertension

IHD mortality (floating absolute risk and 95% CI)

(a)

Systolic blood pressure 256

Age at risk: 80–89 years

128

70–79 years

64

60–69 years

32

50–59 years

16

40–49 years

8 4 2

Elevated blood pressure increases the risk of cardiovascular morbidity and mortality. Data from observational studies of over 1 million people has indicated a continuous relationship between blood pressure and cardiovascular risk from blood pressure values as low as 115/​75 mm Hg (Fig. 16.17.1.5). The relationship is steeper

(b)

Diastolic blood pressure 80–89 years

128

70–79 years 60–69 years

64 32

50–59 years

16

40–49 years

8 4 2 1

1 120 140 160 180 Usual systolic blood pressure (mm Hg) (a)

Age at risk:

256 IHD mortality (floating absolute risk and 95% CI)

The prevalence of hypertension increases with age, affecting over one-​half of those aged 60–​69 years and over three-​quarters of those aged over 70 years in the United States of America and most developed countries. As indicated earlier, almost all of the age-​related rise in the prevalence of hypertension is due to a progressive rise in SBP. The lifetime probability of developing hypertension is about 90% for

70

(b)

Systolic blood pressure

Diastolic blood pressure

256

80–89 years

256

128

70–79 years

128

60–69 years

32

50–59 years

16 8 4 2

Stroke mortality (floating absolute risk and 95% CI)

Stroke mortality (floating absolute risk and 95% CI)

Age at risk:

64

80 90 100 110 Usual diastolic blood pressure (mm Hg)

Age at risk: 80–89 years 70–79 years

64

60–69 years

32

50–59 years

16 8 4 2 1

1

120 140 160 180 Usual systolic blood pressure (mm Hg)

70

80 90 100 110 Usual diastolic blood pressure (mm Hg)

Fig. 16.17.1.5  Relationship between usual blood pressure at the start of a decade and the risk of ischaemic heart disease (IHD, top panel) and stroke (bottom panel) mortality rates in that decade, for each decade for each decade of life. Reprinted from The Lancet, Vol. 360, Lewington S, et al., Age-​specific relevance of usual blood pressure to vascular mortality: a meta-​analysis of individual data for one million adults in 61 prospective studies, pp. 1903–​13. Copyright (2002), with permission from Elsevier.

3739

section 16  Cardiovascular disorders

Women

(a)

(b)

Men

14 High normal

8 6 4

Normal

2 0

Optimal

Cumulative incidence (%)

10 Cumulative incidence (%)

No. at risk Optimal 1875 Normal 1126 High normal 891

2

4 1867 1115 874

6 8 Time (yr) 1851 1097 859

1839 1084 840

10 1821 1061 812

12 1734 974 722

10

Normal

8 6

Optimal

4 2

14 887 649 520

High normal

12

0 0

0

No. at risk Optimal 1005 Normal 1059 High normal 903

2

4 995 1039 879

6 8 Time (yr) 973 1012 857

962 982 795

10 934 952 795

12 892 892 726

14 454 520 441

Fig. 16.17.1.6  High normal blood pressure and the risk of cardiovascular disease. Cumulative incidence of cardiovascular events in women (a) and men (b) without hypertension, according to blood pressure category at the baseline examination. For this analysis, optimal blood pressure was defined as SBP less than 120 mm Hg and DBP less than 80 mm Hg, normal blood pressure as SBP 120–​129 mm Hg and/​or DBP 80–​84 mm Hg, and high normal blood pressure as SBP 130–​139 mm Hg and/​or DBP 85–​89 mm Hg (95% confidence intervals are shown). Reprinted from Vasan RS, et al. (2001). Impact of high-​normal blood pressure on the risk of cardiovascular disease. N Engl J Med, 345, 1291–​7. Copyright © 2001, Massachusetts Medical Society.

for stroke than it is for coronary heart disease and is magnified by age. For every 20/​10 mm Hg increase in blood pressure, there is a doubling in risk of stroke and ischaemic heart disease mortality. Hypertension also increases the risk of congestive cardiac failure, end-​stage renal disease, and dementia. Moreover, data from the Framingham Heart Study also indicates that there is a doubling of risk of cardiovascular complications in patients with blood pressure levels above normal but not yet classified as having overt hypertension (Fig. 16.17.1.6). This was the basis for the American guidelines introducing the term ‘prehypertension’ (SBP 120–​139 mm Hg and/​or DBP 80–​89 mm Hg) to emphasize that this level of blood pressure (1) is not benign, (2) is associated with an elevated cardiovascular disease risk, and (3)  predicts with a high degree of certainty that blood pressure is on an upward trajectory and that affected people are almost certain to develop more severe hypertension, unless there is intervention with effective lifestyle changes and/​or drug therapy.

What method of blood pressure measurement best predicts cardiovascular outcome? It has been known for many years that ambulatory blood pressure measurement (ABPM) provides better prediction of mortality than clinic measurements (Fig. 16.17.1.8). The US Preventive Services Task Force (2015) conducted a thorough review of the literature looking at studies comparing ABPM vs. office blood pressure measurement (OBPM), and home blood pressure measurement (HBPM) vs. OBPM. Eleven studies reported that daytime, night-​time, and 24-​hour ABPM predicted stroke and other fatal and non​fatal CV events independently of OBPM (Fig. 16.17.1.9). Five studies suggested similar results for HBPM, but there was insufficient data to allow firm conclusions. Only a single study compared HBPM with ABPM, which was insufficient to allow conclusions to be drawn. OBPM added no significant predictive capacity independently of ABPM (Fig. 16.17.1.10). In healthcare systems where they are readily available, ABPM or HBPM should be used as the basis for diagnosing (and therefore treating) hypertension.

Systolic blood pressure as the main risk factor For many years DBP was considered the main denominator for defining the threshold and treatment targets for hypertension. This is no longer the case. As indicated earlier, there is a progressive rise in DBP up to about the age of 50 years and thereafter it usually falls. By contrast, SBP begins to rise relentlessly from the age of around 40 years (Figs. 16.17.1.1 and 16.17.1.2). Thus, at the age of peak prevalence of hypertension (i.e. older than 60 years), SBP is the major contributor to the diagnosis of the condition and its associated risk. Below the age of 50 years, DBP is also important. Fig. 16.17.1.7 illustrates the shift in the major risk burden attributable to hypertension, from DBP to SBP, at about the age of 50 years. However, because most hypertension (>75%) occurs over the age of 50 years, SBP rather than DBP is by far the most important contributor to the huge global cardiovascular risk burden attributable to hypertension. SBP is also the most difficult to treat, which has led some to argue that for patients over the age of 50 years the attention of doctors should be focused solely on the SBP.

1.0 0.5 β(SBP) - β(DBP)

3740

0.0 −0.5 P = 0.008

−1.0 −1.5 25

35

45

55

65

75

Age (years)

Fig. 16.17.1.7  The impact of DBP and SBP on the risk of coronary heart disease as a function of age. A β-​coefficient level less than 0.0 indicates a stronger effect of DBP on coronary heart disease (CHD) risk, a β-​coefficient level greater than 0.0 indicates a greater importance of SBP. The ‘switch’ from DBP to SBP occurs at around age 50 years. Reprinted from Franklin SS, et al. (2001). Does the relation of blood pressure to coronary heart disease risk change with aging? Circulation, 103, 1245. (http://​circ. ahajournals.org/​cgi/​content/​abstract/​103/​9/​1245).

16.17.1  Essential hypertension

5-Year risk of cardiovascular death (%)

3.5

Nighttime

3.0 24-hour 2.5 Daytime

2.0 1.5

2.2

Nighttime

1.9

24-hour

1.6

Daytime

1.3

Clinic

Clinic 1.0

1.0

0.7

0.5 90

110 130 150 170 190 210 230

50

60

Systolic BP (mm Hg)

70

90 100 110 120 130

80

Diastolic BP (mm Hg)

Fig. 16.17.1.8  Adjusted five-​year risk of cardiovascular death in 5292 patients. Curves are for average night-​time, 24-​hour, and daytime ambulatory readings, and for clinic readings. Reprinted from Dolan E, et al. (2005). Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension, 46, 156–​61.

Study

Outcome

HR (95% Cl)

Cardiac events or mortality Staessen, 1999 Dolan, 2005

Systolic: Cardiac end points, fatal and nonfatal Systolic: Cardiac mortality (fatal HF, MI, sudden death)

1.11 (0.91, 1.35) 1.06 (1.01, 1.10)

CV events or mortality Systolic: CV mortality Dolan, 2005

1.06 (1.02, 1.10)

Systolic: CV mortality Systolic: CV mortality Systolic: CV mortality

1.10 (0.94, 1.29) 1.25 (1.10, 1.42) 1.32 (1.03, 1.68)

Systolic: MI or stroke, fatal and monfatal Systolic: Major CV events (CV death, MI or stroke)

1.10 (0.98, 1.25) 1.30 (1.19, 1.42)

Dolan, 2005 Clement, 2003

Systolic: Stroke, fatal

1.07 (1.00, 1.15)

Systolic: Stroke, fatal or nonfatal

1.21 (1.04, 1.42)

Staessen, 1999

Systolic: Stroke, fatal or nonfatal

1.29 (0.98, 1.71)

Gasowski, 2008 Hansen, 2005 Staessen, 1999 Clement, 2003 Hemida, 2011 Stroke

All cuase mortality Systolic: All-cause mortality Clement, 2003 Systolic: All-cause mortality Dolan, 2005 Systolic: All-cause mortality Hansen, 2005 Systolic: All-cause mortality Staessen, 1999

1.17 (1.05, 1.32) 1.02 (0.99, 1.05) 1.05 (0.96, 1.14) 1.24 (1.03, 1.49)

Note: Weights are from random effects analysis

.5

1

2

Abbreviations: CI = confidence interval; CV = cardiovascular; HF = heart failure; HR = hazard ratio; MI = myocardial infarction.

Fig. 16.17.1.9  Risk for cardiovascular and mortality outcomes: systolic 24 hr ABPM, adjusted for OBPM. Each 10 mm Hg increase in systolic 24 hr ABPM, adjusted for OBPM, was consistently associated with an increased risk for fatal or non​fatal stroke or cardiovascular events. From Piper MA, et al. (2014). Screening for high blood pressure in adults: A systematic evidence review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 121. AHRQ Publication No. 13-​05194-​EF-​1. Rockville, MD: Agency for Healthcare Research and Quality.

3741

3742

section 16  Cardiovascular disorders

Study

HR (95% Cl)

Outcome

Any stroke Ohkubo, 2005

Systolic: Stroke, fatal or nonfatal

1.04 (0.94, 1.15)

CV mortality Gasowski, 2008

Systolic: CV mortality

0.96 (0.79, 1.16)

Ohkubo, 2005

Systolic: CV mortality

1.04 (0.91, 1.19)

Note: Weights are from random effects analysis .5

1

2

Abbreviations: CI = confidence interval; CV = cardiovascular; HF = heart failure; HR = hazard ratio; MI = myocardial infarction.

Fig. 16.17.1.10  Risk for cardiovascular and mortality outcomes: systolic OBPM, adjusted for systolic 24 hr ABPM. Systolic OBPM adds no significant predictive capacity for cardiovascular and mortality outcomes when systolic 24 hr ABPM data is available. From Piper MA, et al. (2014). Screening for high blood pressure in adults: A systematic evidence review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 121. AHRQ Publication No. 13-​05194-​EF-​1. Rockville, MD: Agency for Healthcare Research and Quality.

Pathogenesis and pathophysiology of hypertension The pathogenesis of essential hypertension has remained something of an enigma, in part reflecting the fact that the basis for the diagnosis (i.e. an elevated blood pressure), has so many potential causes. From a physiological perspective, the pressure in the circulation is the product of the cardiac output (CO) and impedance to flow, that is, peripheral resistance (PR): blood pressure = CO × PR. Both cardiac output and peripheral resistance can be influenced by several control mechanisms, including activity of the renin–​ angiotensin–​ aldosterone system, activity of the sympathetic nervous system, and other factors influencing salt and water homeostasis. In addition, vascular structural changes associated with hypertension play a role in accentuating its severity and conferring resistance to treatment. These structural changes include small-​artery remodelling that results in a reduced media/​lumen ratio (which increases peripheral resistance) and large-​artery stiffening (which changes pulse wave characteristics and reduces the compliance of the circulation). Recent reports suggest that a reduced diameter of the proximal aorta may also be a factor contributing to the development of hypertension. Whether structural changes precede and predispose to the onset of hypertension, or follow it, or both, remains a subject of considerable debate. In some cases (probably 10%

If younger than 40 years

Offer antihypertensive drug treatment

Consider specialist referral

Offer lifestyle interventions Offer to check blood pressure at least every 5 years, more often if blood pressure is close to 140/90 mm Hg

1 Signs of papilloedema or retinal haemorrhage 2 Labile or postural hypotension, headache,

palpitations, pallor and diaphoresis

3 Ambulatory blood pressure monitoring 4 Home blood pressure monitoring

Offer patient education and interventions to support adherence to treatment

Offer annual review of care to monitor blood pressure, provide support and discuss lifestyle, symptoms and medication

Fig. 16.17.2.6  Thresholds and appropriate inventions depending on blood pressure. Note: if ABPM or HBPM are not available, then proceed as advised in Table 16.17.2.3. From National Clinical Guideline Centre (2011). Hypertension—​the clinical management of primary hypertension in adults. Clinical Guideline 127, with modification from National Clinical Guideline Centre (2019) Hypertension in adults: diagnosis and management. Clinical Guideline 136.

American guidelines suggest treating to a goal of less than 150/​ 90 mm Hg for patients over 60 years of age; the British guideline recommends the same higher target for those over 80  years of age; and the 2018 European guideline suggests a systolic target of 130–​139 mm Hg in patients over 80 years of age ‘if tolerated’.

The reason that the 2018 European guidelines recommend a lower treatment threshold than most other guidelines is worthy of some comment. The SPRINT trial, published in 2015, found that patients at high risk of cardiovascular events but without diabetes (excluded because of the findings of the ACCORD trial) had lower rates of fatal

16.17.2  Essential hypertension: Diagnosis, assessment, and treatment

Table 16.17.2.3  Typical observation periods for different grades of hypertension and associated cardiovascular disease, diabetes, and/​or target organ damage Grade of hypertension

Typical observation period

Accelerated (malignant) hypertension (papilloedema and/​or fundal haemorrhages and exudates, or with acute cardiovascular complications e.g. aortic dissection)

Immediate treatment—​usually requiring acute hospital admission (see Chapter 16.17.5)

BP ≥220/​120 mm Hg

Treat immediately—​hospital admission not usually required

Grade III hypertension BP >180–​219/​110–​119 mm Hg

Confirm by repeated measurements over 1–​2 weeks, then treat

Grade II hypertension BP 160–​179/​100–​109 mm Hg

In the presence of cardiovascular disease, diabetes, or target organ damage: confirm over 3–​4 weeks, then treat No cardiovascular disease, diabetes, or target organ damage: lifestyle measures, re-​measure weekly initially, and treat if BP persists at these levels over 4–​12 weeks

Grade I hypertension: BP 140–​159/​90–​99 mm Hg

Cardiovascular disease, diabetes, or target organ damage: either confirm or refute diagnosis by (a) ABPM) or HBPM, or (b) repeat clinic measurement within weeks, then treat if diagnosis confirmed No clinical cardiovascular disease, diabetes or target organ damage: lifestyle advice and either confirm or refute diagnosis by (a) ABPM or HBPM, or (b) re-​measure clinic BP at monthly intervals for 3–​6 months. If mild hypertension persists, estimate 10-​year cardiovascular diseases risk and treat if this is ≥20% (if 100 mg/​24 h or protein:creatinine ratio >100 mg/​ mmol) • Haematuria (>10 dysmorphic red blood cells per high power field) • Casts of red and white blood cells

Histopathology Various glomerular patterns of immune complex-​mediated injury are seen on biopsy and classification of lupus nephritis is based primarily on the location (mesangial, endothelial, and epithelial) and nature of lesions seen (active, chronic, focal, or diffuse) (Figs. 21.10.3.1–​21.10.3.3 and Table 21.10.3.1). Immunofluorescence microscopy of biopsies with lupus nephritis can show florid deposition (the classical ‘full-​ house’ picture) of immunoglobulins, IgG, IgA, and IgM, as well as complement proteins, C3, C4, and C1q (Fig. 21.10.3.4). The 2003 International Society of Nephrology/​Renal Pathology Society (ISN/RPS) classification of

Fig. 21.10.3.3  Lupus nephritis. The glomerulus has marked swelling of the glomerular basement membrane (membranous lesions; ISN/RPS class V). Reproduced with permission from Condon M, Dodd P, Lightstone L. The patient with systemic lupus erythematosus: clinical features, investigations, and diagnosis. In: Turner N, Lameire N, Goldsmith DJ, Winearls CG, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

21.10.3  The kidney in rheumatological disorders

Table 21.10.3.1  Active and chronic glomerular lesions Active

Chronic

Endocapillary hypercellularity

Glomerular sclerosis (segmental or global)

Crescents—​cellular or fibrocellular

Fibrous crescents

Karyorrhexis

Fibrous adhesions

Fibrinoid necrosis Rupture of glomerular basement membrane Wire loops Hyaline thrombi

lupus nephritis (Table 21.10.3.2 and Fig. 21.10.3.5) was developed to enable a more uniform description of histopathological lesions, promoting standardization of patient care and enabling improved comparison of outcomes between multinational centres. Inclusion of renal vascular lesions in the 2003 ISN/RPS classification system improves the prediction of renal outcomes.

Treatment of lupus nephritis Decisions regarding treatment of patients with lupus nephritis are primarily dependent on histological lesions seen, but also reflect

Fig. 21.10.3.4  Lupus nephritis. IgG deposition within the glomerulus. Reproduced with permission from Condon M, Dodd P, Lightstone L. The patient with systemic lupus erythematosus: clinical features, investigations, and diagnosis. In: Turner N, Lameire N, Goldsmith DJ, Winearls CG, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

Table 21.10.3.2  The 2003 International Society of Nephrology/​Renal Pathology Society classification of lupus nephritis (which is a modification of the 1995 WHO classification) Class I

Minimal mesangial lupus nephritis Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence

Class II

Mesangial proliferative lupus nephritis Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy with mesangial immune deposits May be a few isolated subepithelial or subendothelial deposits visible by immunofluorescence or electron microscopy, but not by light microscopy (Fig. 21.10.3.1)

Class III

Focal lupus nephritis Active or inactive focal, segmental or global endo-​or extracapillary glomerulonephritis involving 90% global sclerosis without activity

YES

NO

YES

Class I

50% or more of involved glomeruli have segmental lesions?

Class II

Class V

Class III (A or A/C or C)

Class IV-G

Class IV-S

Fig. 21.10.3.5  Algorithm showing how the class of lupus nephritis is determined. In Class III or IV, A = active lesions only, A/C = active and chronic lesions, C = chronic lesions only, and if >50% glomeruli have >50% capillary walls with membranous change = Class III + V, or Class IV + V. See Table 21.10.3.1 for further explanation.

the severity of clinical presentation (the degree of associated proteinuria, hypertension, and/​or extrarenal manifestations of SLE). Proliferative disease (class III and class IV lupus nephritis) is more aggressive than nonproliferative lupus nephritis and requires intensive immunosuppressive treatment to induce remission and prevent lasting kidney damage. Management of nonproliferative lupus nephritis Class I and class II ISN/RPS class  I  and class  II lesions are associated with a better prognosis and consequently renal-​specific therapy is not indicated. Patients with class I lupus nephritis and class II with proteinuria less than 1 g/​day should have treatment dictated by the extrarenal manifestations of SLE. For those patients with class II lupus nephritis and proteinuria greater than 3 g/​day, treatment with corticosteroids or calcineurin inhibitors can be useful if proteinuria cannot be controlled by renin–​angiotensin system blockade alone. Class VI From a renal perspective, immunosuppression is not indicated in class  VI lupus nephritis, which reflects chronic insult without active immune-​mediated injury. However, many patients with class VI lupus nephritis exhibit extrarenal manifestations of SLE necessitating immunosuppressive treatment. Class V (membranous nephropathy) Class V lupus nephritis, while generally regarded as a less aggressive form of lupus nephritis compared to types III and IV, is still

associated with the development of chronic kidney disease and ESRD, particularly if there is marked proteinuria (even with normal baseline renal function). Given the adverse effects of subnephrotic proteinuria on kidneys, most nephrologists would treat these patients with antiproteinuric and antihypertensive medications. Sustained heavy proteinuria (and associated hypercoagulable state) is associated with adverse cardiovascular effects, but there is only a limited evidence base looking at treatment of class V lupus nephritis. Steroids, ciclosporin, and cyclophosphamide treatment have been used, along with other immunosuppressive agents including mycophenolate mofetil (MMF), azathioprine, and tacrolimus. Appropriately sized randomized controlled trials would need to be undertaken before these immunosuppressive therapies can be unequivocally recommended, and such trials are unlikely to be done. In a post hoc review of the outcomes of patients with ‘pure’ class V lupus nephritis in two trials, the combination of MMF and steroids was as effective as high-​dose cyclophosphamide and steroids. Management of proliferative lupus nephritis (class III and class IV) Proliferative lupus nephritis is the most common renal manifestation of SLE. Prior to the advent of immunotherapy regimens, kidney survival and overall patient survival in diffuse proliferative lupus nephritis was only 20 to 25%. While patient and kidney survival in class III and class IV lupus nephritis has markedly improved through intensive immunosuppression (current reviews suggest c.90% survival over 10 years, in those who achieve remission), the response to treatment is often slow, and the risk of relapse remains high.

21.10.3  The kidney in rheumatological disorders

The goal of treatment for active proliferative lupus nephritis is to induce a remission with intensive immunotherapy aimed at switching off the renal inflammation. Once this has been attained, maintenance therapy is commenced with the aim of continuing disease remission, with minimal treatment side effects and ideally prevention of relapse. Induction regimens Traditionally, the mainstay of induction therapy in lupus nephritis has been corticosteroids plus cytotoxic agents. If disease is more severe, pulses of intravenous methylprednisolone are used prior to commencing oral corticosteroids. Since the early 1980s, cyclophosphamide has dominated as the cytotoxic of choice, but concerns about the side effect profile, specifically risks of bladder toxicity, ovarian failure, leucopenia, and alopecia, have led to trials examining reduced doses of cyclophosphamide and the introduction of MMF as an alternative immunosuppressant. The ‘Euro-​Lupus’ regimen compared a lower-​dose of cyclophosphamide (500 mg intravenously every 2 weeks for 3 months) to the original ‘National Institutes of Health (NIH) regimen’ (0.5–​1 g/​m2 given monthly for 6 months). The trial demonstrated that the lower-​ dose regimen was as effective at inducing remission as the higher dose, but patients suffered fewer severe infections. The original study was in an exclusively northern European Caucasian population, but a more recent trial (the Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis (ACCESS) study) used Euro-​Lupus as the standard of care to which abatacept or placebo was added. There was no significant improvement gained by the addition of abatacept, but the trial demonstrated well that the Euro-​ Lupus regimen was effective in African American and Hispanic patients. The Aspreva Lupus Management Study (ALMS) was an international trial designed to compare MMF to intravenous cyclophosphamide (NIH regimen, plus standard glucocorticoid tapering) as induction therapy. The study was designed as a superiority study, with the aim of demonstrating that MMF would be superior at inducing complete remission at 6 months. It was not, but the rates were very similar for cyclophosphamide and MMF, with a similar incidence of adverse effects, serious infections, and deaths in both the MMF and cyclophosphamide arms. Post hoc analysis of the study suggested MMF was as efficacious as cyclophosphamide in the small group of patients with an estimated glomerular filtration rate of less than 30 ml/​min per 1.73 m2 at the outset and in those with class V lupus nephritis. All the recent guidelines on therapy suggest that induction for class  III or IV lupus nephritis can be with cyclophosphamide-​or MMF-​based regimens. They have suggested that in severe class III/​ IV lupus nephritis ‘a cyclophosphamide-​containing protocol for initial therapy may be preferred’, but it is worth noting that MMF may be more effective than cyclophosphamide in patients of African descent and Hispanic patients. A Cochrane review in 2012 systematically analysed nine studies, concluding that MMF is as effective as cyclophosphamide, but with reduced side effects. A  key factor in deciding which induction regimen to use is the importance of preserving fertility. Cyclophosphamide causes infertility in a dose-​ and age-​related manner that may be offset to a degree by the concomitant use of ovarian protection regimens. By contrast, MMF does not cause infertility so may be preferable as a first-​line agent,

although patients must be warned to avoid pregnancy while taking it as it is teratogenic. Regardless of initial therapy used, response needs to be assessed at 6 months to guide further management. There have been several analyses of very long-​term outcomes of the Euro-​Lupus trial and ALMS trial patients. These have clearly demonstrated that early reduction in proteinuria predicts long-​term renal survival and that proteinuria of less than between 500 and 800 mg/​day at 1  year is associated with good long-​term outcomes. Maintenance therapy Following initial therapy to induce remission, the goal of treatment of lupus nephritis is to prevent systemic and lupus nephritis flares, and to preserve renal function while minimizing potential side effects of long-​term therapy. Prolonged maintenance therapy after initial treatment is usually required as patients who receive only a short-​term (6 month) course of therapy have been shown to have an increased frequency of lupus nephritis relapse. Current options for maintenance therapy include azathioprine, MMF, cyclophosphamide, and ciclosporin. When determining long-​term maintenance therapy options, patient-​specific factors, for example, tolerability of side effects, and desire for pregnancy should be considered. Initial studies in maintenance therapy for lupus nephritis compared cyclophosphamide pulses with maintenance azathioprine or MMF and demonstrated that patients treated with MMF or azathioprine were significantly less likely to develop chronic kidney disease. Mortality was similarly reduced compared to the cyclophosphamide group at 72 months. This has led to preferential use of MMF and azathioprine over cyclophosphamide. Trials to determine MMF or azathioprine superiority have yielded mixed results. Two key studies to date have been the ALMS trial extension phase and the Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy of Lupus Nephritis Trial (MAINTAIN Nephritis Trial). In a Caucasian population, azathioprine appears to be equivalent to MMF, whereas MMF is the treatment of choice in a multiethnic population. Differences between the two drugs as maintenance therapy are small, and so if one drug is not tolerated, then the other should be tried. Similarly, patient circumstances may dictate the use of one drug over another: MMF is contraindicated in pregnancy, and azathioprine will be the preferred option in regions where cost or drug availability is an issue. The optimal time to remain on maintenance therapy has not been determined but in general is at least 2 to 3 years after remission induction. Novel therapies Some patients fail to respond to available treatment, and for others treatment-​associated side effects, particularly from corticosteroid therapy, limit patient adherence and subsequent treatment efficacy. Consequently, there is an urgent need to identify and develop new immunotherapies, enabling steroid-​sparing treatment regimens and to better manage refractory cases. Current lupus nephritis immunosuppressive therapies are anti-​ inflammatory, anti-complement and anti-cytokine in a relatively nonspecific manner. In recent years there has been an increased focus on targeting critical pathways in SLE pathogenesis with the aim of disrupting autoimmune mechanisms leading to kidney inflammation and acute and chronic kidney injury (B-​and T-​cell activity, costimulatory molecules, and antibody production). Sadly, all

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trials of new agents to date, all of which have been evaluated as ‘add-​ on’ therapies to standard of care, have not shown significant superiority. The list of negative studies in lupus nephritis includes the use of rituximab, CTLA4-​Ig, and ocrelizumab. In each case, the trial has failed not necessarily due to lack of efficacy of the drug, but because the study was too small, or because of a finding of increased rates of infection (often attributable to higher doses of steroids). However, there remains optimism that better designed trials may translate into improvements in outcomes. Anti CD20 (rituximab) therapy Rituximab is a chimeric anti-​ CD20 human/​ mouse monoclonal antibody that has been used extensively in the treatment of non-​ Hodgkin’s lymphoma and has an excellent safety profile. Binding of rituximab to CD20+ cells results in both complement and FcγR-​ mediated cell killing, and clinically rituximab is an effective B-​cell depleter. B-​cell depletion ultimately might not only lead to reduction in autoantibodies (though note rituximab does not deplete plasma cells) but may also disrupt antigen presentation to T cells, critical for maintaining the autoimmune response, and markedly reduce cytokine production. A small subgroup of patients appear not to respond to rituximab, failing to deplete their B cells. The degree and duration of B-​cell depletion usually correlates with improvements in disease activity and scores. Prospective open-​label studies have reported widely on the efficacy of rituximab in both renal and non renal lupus, and rituximab has been found to be generally safe and well tolerated. However, the LUNAR study (Lupus Nephritis Assessment with Rituximab) and EXPLORER trial (Exploratory Phase II/​III SLE Evaluation of Rituximab)—​ two large, prospective, placebo-​ controlled trials—​both failed to find a benefit of rituximab in renal or non renal lupus when added to standard-​of-​care treatment. Trial design has been implicated in the failure of these studies to meet their primary endpoints. In both studies participants were given high-​ dose corticosteroids in addition to immunosuppressives such as MMF, which may have obscured the ability to discriminate between the rituximab and placebo arms. Efforts continue to try to find regimens using rituximab and MMF (and other agents) that would allow omission of oral steroids without compromising efficacy.

monoclonal), a novel calcineurin inhibitor (voclosporin), as well as studies of small-​molecule inhibitors. It is a crowded area and the trials need to be smart to overcome the limitations of previous negative studies. Refractory lupus nephritis Up to 22% of patients with proliferative lupus nephritis are refractory to therapy with cyclophosphamide or MMF. If induction therapy fails, the general consensus is to switch and use the alternative (MMF or intravenous cyclophosphamide). Rituximab is often added at this stage: although trial evidence is generally lacking, there have been reports of some promising results, for example, Jonsdottir and colleagues demonstrated that the addition of rituximab results in clinical and histological improvements in patients with refractory lupus nephritis. The RING trial (ClinicalTrials.gov identifier: NCT01673295) was formally assessing whether the addition of rituximab in refractory lupus nephritis improved responses. Relapse of lupus nephritis Some patients have persistent relapses of lupus nephritis despite repeated treatment. It is important to recognize and treat relapses quickly, as with each relapse further renal damage is sustained. This is associated with both the development of chronic kidney disease and ESRD. Relapse is diagnosed clinically:  increasing proteinuria, rising serum creatinine level, and changes in urinary sediment should all alert clinicians. A  reduction in serum complement levels and increase in anti-​double stranded DNA antibody titres may be seen prior to clinical relapse, and while these do not justify treatment per se, it is wise to see the patient more frequently in order to detect relapse early. If a renal relapse is suspected, then a renal biopsy may well be indicated to confirm the diagnosis and identify the class of lupus nephritis, which may transform spontaneously from one histological class to another and such changes cannot be predicted clinically with certainty. The most common transformations seen are from class III to class IV, or from a proliferative to nonproliferative class. Importantly, the development of increased proteinuria may represent chronic damage rather than acute inflammation, or a podocytopathy rather than proliferative or class V lupus nephritis. A definitive diagnosis requires a renal biopsy.

Other targets in lupus nephritis

Prognosis

As B cells are depleted in response to rituximab, levels of the B-​ lymphocyte-​stimulating factor (BlyS, also known as BAFF) increase, which may increase the generation of new autoreactive B cells. To counteract this potentially detrimental rise in BAFF, an anti-​BlyS monoclonal antibody, belimumab, has been trialled. A post hoc analysis of phase III belimumab studies in non renal SLE patients examined renal outcomes and demonstrated a reduction in the number of renal flares in belimumab-​treated patients. This is now being evaluated in an ongoing trial in lupus nephritis comparing belimumab and placebo in addition to the standard of care (ClinicalTrials.gov identifier: NCT01639339). Tacrolimus (FK506), a calcineurin inhibitor, has demonstrated similar efficacy to mycophenolate mofetil as induction therapy, and other studies include trials of an interferon-​α receptor blocker, an anti-​CD40, another anti-CD20 (obinutuzumab, a humanised

While the overall prognosis of patients with SLE and a proliferative glomerulonephritis has improved significantly with the judicious use of immunosuppressants, 5 to 10% of patients will have died after 10 years of treatment, and a further 5 to 15% will have developed ESRD. The prognosis is poorer in African and Hispanic people (the reasons are unclear), and this needs to be remembered when interpreting results of randomized control trials. Proliferative glomerulonephritis (class  III and IV) is associated with a worse outcome, along with the presence of chronic histological changes on renal biopsy. Many patients with lupus nephritis (30–​50%) do not achieve complete remission and this is associated with a significantly increased risk of having further renal relapses, of developing ESRD and of dying. In patients who do achieve complete remission, relapses develop in 20–​40% over a follow-​up of about 10 years, and these are also associated with an increased risk

21.10.3  The kidney in rheumatological disorders

of developing ESRD. Significant reduction in proteinuria at 3 and 6 months, and persistent reduction in proteinuria at 1 year, predicts better long-​term renal outcomes.

Antiphospholipid antibody nephropathy in SLE Antiphospholipid antibodies are associated with a syndrome (antiphospholipid syndrome) characterized by arterial and venous thromboses and repeated miscarriages. These antibodies have reactivity against cardiolipin and the lupus anticoagulant and are found in 15 to 30% of patients with SLE. Antiphospholipid syndrome can be primary or associated with SLE. Renal manifestations of antiphospholipid syndrome include thrombotic microangiopathy and chronic vascular lesions, superimposed on those of lupus nephritis. If there is evidence of extrarenal thrombosis, oral anticoagulants should be commenced. Patients with lupus nephritis and antiphospholipid antibodies have a worse renal prognosis, presumably because of the superimposed renal vasculopathy. See Chapter 14.14 for further discussion.

Long-​term outcome The main causes of death in lupus nephritis are treatment-​related sepsis (early) and cardiovascular causes (late). Renal failure can be treated with transplantation and dialysis; generally the activity of lupus nephritis reduces once dialysis is initiated. Overall survival on dialysis is approximately 75% at 10 years. Graft survival in patients with SLE after kidney transplantation is similar to patients with other diseases, and recurrence of lupus nephritis is rare.

Systemic sclerosis/​scleroderma Systemic sclerosis (SSc) is a multiorgan connective tissue disease of uncertain aetiology that is characterized by progressive interstitial and vascular fibrosis in the skin and other organs. There are three subtypes of SSc:  limited cutaneous SSc (lcSSc) where cutaneous involvement is limited to the hands, forearms, face, and feet; diffuse cutaneous SSc (dcSSc) with proximal extension above the elbows or knees; and scleroderma sine scleroderma where skin involvement is absent and patients present only when end-​organ damage has occurred (see Chapter  19.11.3). Renal involvement in SSc can be acute or chronic and most renal manifestations are clinically silent, with autopsy studies detecting occult renal pathology in 60 to 80% of patients. By contrast, scleroderma renal crisis demonstrates the acute effects of microvasculopathy in SSc.

Pathogenesis The pathogenesis of renal involvement in SSc is not fully understood. Acute vascular injury activates the coagulation and other inflammatory pathways, culminating in proliferative fibrovasculo­ pathy and thrombotic microangiopathy. Decreased renal perfusion from arterial constriction leads to hyperplasia of the juxtaglomerular apparatus and hyperreninaemia, resulting in a hypertensive crisis and rapidly progressive renal injury.

Pathology The smaller arcuate and interlobular arteries are predominantly involved in scleroderma renal crisis, showing intimal hyperplasia with concentric mucoid intimal degeneration, but the internal and external elastic laminae remain intact. The adventitia of interlobular arteries shows an abnormal degree of fibrosis. There is fibrinoid necrosis of afferent arterioles and glomeruli, and also glomerular thrombosis. Ischaemia of the glomerular tuft leads to wrinkling and thickening of the glomerular basement membrane and glomerular sclerosis (Fig. 21.10.3.6). These lesions resemble those seen in accelerated hypertension or the haemolytic uraemic syndrome, although the vessels involved tend to be larger and adventitial fibrosis is not seen in accelerated hypertension.

Clinical presentation Mild proteinuria without loss of renal function is the most common presentation of SSc renal disease. An isolated reduction in glomerular filtration rate is also in seen in patients with SSc and often follows a benign, non progressive course. By contrast, scleroderma renal crisis is characterized by new-​onset accelerated-​phase hypertension and a decrease in renal function of at least 30%. It is often associated with systemic symptoms including headache, visual disturbances, seizures, or encephalopathy. Flash pulmonary oedema can occur, and arrhythmias, myocarditis, and pericarditis are all associated with poorer prognosis.

Scleroderma renal crisis Scleroderma renal crisis predominantly affects patients with dcSSC, occurring in 10 to 15% of patients with this disease. Mortality in scleroderma renal crisis remains high, particularly in patients who develop ESRD. Patients with early dcSSc are at greatest risk, and rapidly progressive skin disease or tendon friction rubs are independent risk factors. Other studies have suggested that recent high-​dose corticosteroid use, the presence of anti-​RNA polymerase III antibodies, anaemia, and new-​onset cardiac failure are also risk factors for the development of scleroderma renal crisis.

Fig. 21.10.3.6  Scleroderma kidney. A small artery has concentric mucoid intimal thickening, an arteriole has thrombosis and fibrinoid necrosis, and tubules and a glomerulus have ischaemic damage (periodic acid–​methenamine silver staining, magnification ×25). By courtesy of Professor A.J. Howie.

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Scleroderma renal crisis can (rarely) develop in individuals with a normal blood pressure. They are more likely to have a micro­ angiopathic haemolytic anaemia (90 vs 30%), thrombocytopenia (83 vs 21%), and pulmonary haemorrhage than patients with a hypertensive scleroderma renal crisis.

Investigations/​assessment Autoantibodies (antinuclear antibodies (ANA)) are detectable in virtually all patients with SSc. A speckled ANA pattern is also seen in approximately 60% of patients with scleroderma renal crisis. Other autoantibodies associated with renal disease in SSc include anti-RNA polymerase III antibodies (ARA) and anti-fibrillarin antibodies (AFA, also known as anti-U3 RNP antibodies). In contrast, SSc patients with anti-centromere or anti-topoisomerase 1 antibodies are less likely to develop renal disease. Renal function should be monitored and blood pressure checked at least monthly, with daily self-​monitoring introduced if hypertension develops. Urinalysis may reveal the presence of proteinuria (non-​nephrotic range) and nonvisible haematuria, with casts visible on direct microscopy. Anaemia can be an early feature of scleroderma renal crisis. Thrombocytopenia and anaemia occur in up to 50 and 60% of cases respectively. Elevated levels of lactate dehydrogenase, low haptoglobin, and schistocytes in the peripheral blood smear may also be seen. Occasionally, disseminated intravascular coagulation can develop. Many clinical features of a scleroderma renal crisis are similar to those seen in thrombotic thrombocytopenic purpura. It is important to differentiate the two because management varies markedly. Assays for plasma ADAMTS13 enzyme can be useful to exclude thrombotic thrombocytopenic purpura.

Treatment Control of hypertension is fundamental in preventing irreversible vascular injury. A  gradual decrease in blood pressure should be targeted because a rapid reduction can reduce renal perfusion and increase the risk of acute tubular necrosis. Angiotensin-​converting enzyme inhibitors are first-​line therapy and lead to regression of skin manifestations in some patients:  they should be titrated up to maximum doses. In an acute crisis, continuous intravenous iloprost infusion can help reverse microvascular changes and control blood pressure; if substantial thrombotic microangiopathy is present, plasma exchange can be used.

Prognosis Approximately 25% of patients with scleroderma renal crisis require dialysis at presentation, and 40 to 66% of these may not recover. Assessment of prognosis may be guided by renal biopsy, but clinical predictors of poor outcome include dcSSc, high skin scores (>20), older age, and evidence of cardiac involvement. Long-​term survival following scleroderma renal crisis is poor, especially for patients who do not recover renal function. Increased mortality is seen in males, those with normal blood pressure at presentation, and older patients. Scleroderma renal crisis is one of the few conditions where late recovery of renal function is sometimes seen as the inflammatory process resolves and blood pressure is tightly controlled.

Box 21.10.3.1  Renal disease in rheumatoid arthritis Consequences of rheumatoid arthritis • Amyloid A amyloidosis • Vasculitic glomerulonephritis • Mesangiocapillary glomerulonephritis • Mesangial IgA proliferative glomerulonephritis Drug nephrotoxicity Nonsteroidal anti-​inflammatory drugs • Reversible haemodynamically mediated renal impairment • Acute tubular necrosis • Acute interstitial nephritis with or without a nephrotic syndrome Gold and penicillamine • Proteinuria • Nephrotic syndrome • Membranous nephropathy • Rare reports of a crescentic glomerulonephritis

Rheumatoid arthritis Historically, the main causes of renal disease in rheumatoid arthritis have been secondary (amyloid A) amyloidosis and nephrotoxicity from drugs used in treatment (Box 21.10.3.1) (see Chapter  19.5). Renal vasculitis and glomerulonephritis are also described. However, the pattern of renal disease in rheumatoid arthritis is changing. Gold and penicillamine are now infrequently used, hence nephrotoxicity from these causes has become rare, and the incidences of amyloid A amyloidosis and rheumatoid vasculitis have declined, probably as a result of early use of disease-​ modifying agents.

Secondary amyloidosis Secondary amyloidosis results from deposition of fibrils containing amyloid A  protein that is antigenically related to the acute-​phase reactant serum amyloid A (see Chapter 12.12.3). Rheumatoid arthritis is the commonest disease producing secondary amyloidosis in developed countries. Prevalence rates of 8 to 17% are reported in autopsy series and 5 to 10% in biopsy series, but the incidence has dropped dramatically due to much more aggressive therapy of rheumatoid disease, with fewer patients being left with a persistently active acute-​phase response. Cases of crescentic glomerulonephritis superimposed on renal amyloidosis in patients with rheumatoid arthritis have been described. Clinical features and diagnosis The presentation of renal amyloid is with proteinuria that is often severe enough to cause a nephrotic syndrome. Renal vein thrombosis is particularly common. Diagnosis is established by renal biopsy (Fig. 21.10.3.7), where histological Congo red staining, which is birefringent in polarized light, is characteristic of amyloid. This staining is abolished by potassium permanganate in reactive amyloidosis but not in primary amyloidosis. Monoclonal and polyclonal antibodies that specifically bind amyloid A are available and of use for histological diagnosis. The diagnosis of amyloid is also aided by the availability of scans using radiolabelled serum amyloid P (SAP)

21.10.3  The kidney in rheumatological disorders

tubulointerstitial inflammation. Penicillamine may lead to the development of a rapidly progressive glomerulonephritis with crescents and pulmonary haemorrhage, resembling Goodpasture’s syndrome but without anti-glomerular basement membrane antibodies. Treatment and prognosis In general, gold and penicillamine should be discontinued when significant proteinuria develops (>0.5 g/​24 h). After cessation of the drug, proteinuria peaks at around 1  month then gradually disappears, and most patients will have clear urine by 1 year and almost all will achieve this by 2 years. Renal function does not deteriorate in uncomplicated cases.

Glomerulonephritis Fig. 21.10.3.7  Amyloidosis in rheumatoid arthritis. Arterioles and glomeruli contain acellular masses of amyloid (periodic acid–​ methenamine silver staining, magnification ×40). By courtesy of Professor A.J. Howie.

The most commonly described glomerulonephritis in rheumatoid arthritis that is not related to drug use is a mesangiocapillary glomerulonephritis, which in many cases is accompanied by IgA deposits (IgA nephropathy). Membranous nephropathy is also described.

Renal vasculitis protein, utilizing the strong calcium-​dependent affinity of SAP for amyloid fibrils of any protein type. Treatment and prognosis There is no specific therapy for amyloid A amyloidosis, the general principle being suppression of the underlying chronic inflammation. Uncontrolled evidence suggests that aggressive treatment of rheumatoid arthritis may be effective in delaying the deterioration of renal function in patients with renal amyloid, and treatment with prednisolone and cyclophosphamide or methotrexate can induce remission of the nephrotic syndrome due to amyloid in patients with this condition. Treatment with antitumour necrosis factor-​α antibodies is also reported to lead to remission of renal disease due to amyloidosis. Renal amyloid leads to progressive renal failure; 50% of patients develop ESRD after 5 years, rising to 90% at 10 years, treatment of which is by dialysis and renal transplantation.

The clinical spectrum of rheumatoid arthritis includes a systemic necrotizing vasculitis with involvement of blood vessels ranging in size from capillaries to small and medium-​sized arteries. With more aggressive treatment of rheumatoid arthritis, vasculitis from this cause is now uncommon. The clinical presentation includes nail-​fold infarcts, a leucocytoclastic vasculitis, a peripheral neuropathy, pericarditis, gastrointestinal infarcts, and renal vasculitis. Renal abnormalities are found in about 25% of patients with rheumatoid vasculitis, usually nonvisible haematuria, proteinuria, and renal impairment. Renal histology shows a large-​vessel renal arteritis and a segmental necrotizing glomerulonephritis with crescent formation (vasculitic glomerulonephritis) (Fig. 21.10.3.8).

Gold and penicillamine nephropathy Clinical features and diagnosis The most frequent presenting feature is proteinuria, which occurs in approximately 10% of patients receiving gold and up to 30% of those taking penicillamine. This progresses to the nephrotic syndrome in 30 and 16%, respectively. Haematuria is uncommon, although it is seen more frequently with penicillamine, and still requires the exclusion of other causes when occurring in the context of therapy with these drugs. Renal function is usually normal. Gold and penicillamine are no longer widely used to treat patients with rheumatoid arthritis and nephrotoxicity from these agents is correspondingly uncommon. About 55 to 80% of patients who present with penicillamine-​ or gold-​induced proteinuria will have a membranous glomerulonephritis. Minimal-​ change nephropathy is the next most frequently encountered histological lesion. Other less common renal lesions include mesangiocapillary glomerulonephritis and

Fig. 21.10.3.8  Vasculitic glomerulonephritis in rheumatoid arthritis. Two glomeruli have sharply defined segmental lesions where there has been disruption of the tuft and partial obliteration of Bowman’s space (periodic acid–​methenamine silver staining, magnification ×32). By courtesy of Professor A.J. Howie.

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Treatment is with prednisolone and cyclophosphamide, usually leading to improvement of renal function.

with steroid-​sparing agents. Glomerular involvement will generally be treated in a similar manner to lupus nephritis, depending on the histology.

Renal disease in juvenile chronic arthritis Renal involvement in juvenile chronic arthritis is infrequent, but its presence is associated with a poor outcome. Proteinuria is found in 3 to 12% of patients and nonvisible haematuria in 3 to 8%. The renal lesions reported are usually complications of the underlying rheumatic disease, such as amyloidosis, or those arising as side effects of the drugs used. Cases of necrotizing crescentic glomerulonephritis, focal segmental glomerulosclerosis, and mesangial glomerulonephritis have all been described in children with the condition. Renal amyloid is found in 1.2 to 6.7% of patients with juvenile chronic arthritis, and affects patients with chronic and active disease, with a predilection for systemic-​onset disease. It typically presents with nephrotic-​range proteinuria. Aggressive treatment with chlorambucil has been shown to improve survival in patients with juvenile chronic arthritis and amyloid A amyloidosis.

Sjögren’s syndrome Sjögren’s syndrome is an autoimmune condition in which there is inflammatory cellular infiltration of the exocrine glands (particularly the salivary and lacrimal glands) (see Chapter 19.11.4). The condition can occur in isolation (primary Sjögren’s syndrome) or in conjunction with other autoimmune diseases, usually lupus or mixed connective tissue disease (secondary Sjögren’s syndrome).

Clinical features Dry mouth (xerostomia) and dry eyes (keratoconjunctivitis) are characteristic of Sjögren’s syndrome. Renal involvement is usually mild and often subclinical. Some patients present with distal tubular acidosis, impairment of urinary concentration, hypokalaemia, or rarely with Fanconi’s syndrome. Clinical manifestations of these renal tubular disorders include sterile pyuria, the development of renal calculi, polyuria, and (very rarely) the development of hypokalaemic periodic paralysis. Up to a quarter of patients can develop acute or chronic kidney disease.

Investigation/​assessment Urine dip might reveal occasional leucocytes and moderate proteinuria. The most common histological abnormality is tubulointerstitial nephritis with predominantly T-​lymphocyte infiltrate, but various types of glomerulonephritis are also described. Glomerular abnormalities are rare.

Drug nephrotoxicity following treatment for rheumatic disorders Nonsteroidal anti-​inflammatory drugs The widespread use of nonsteroidal anti-​ inflammatory drugs (NSAIDs) for the relief of pain and inflammation has meant that, although in any individual patient the risk of renal adverse events is small, renal complications are frequently seen. Non selective NSAIDs inhibit both constitutive cyclooxygenase (COX)-​1 and inducible COX-​2 enzymes involved in the prostaglandin and thromboxane A2 pathways responsible for the regulation of pain, renin release, and vascular tone. Since both COX-​1 and COX-​2 are expressed in the kidney, adverse effects are associated with both non selective and COX-​2 selective NSAIDs. Clinical syndromes associated with NSAID use reflect either predictable abnormalities arising from their mode of action, especially in volume-​depleted individuals, or those with vascular impairment or idiosyncratic allergic responses. The clinical syndromes seen include a​ cute tubular necrosis, acute tubulointerstitial nephritis, nephrotic syndrome (minimal-​change disease or membranous nephropathy), and renal papillary necrosis. In addition, NSAID therapy may induce salt and water retention, hypertension, hyperkalaemia, and chronic kidney disease. In patients with chronic kidney disease or a functioning renal transplant, NSAIDs should not be used without careful consideration of the balance of benefit versus risk. Great care must be taken when prescribing NSAIDs to patients with volume depletion, and when using concomitant nephrotoxins.

Chronic analgesic nephropathy Chronic analgesic nephropathy is characterized by renal papillary necrosis and chronic interstitial nephritis caused by prolonged and excessive consumption of analgesic mixtures. Compound analgesic mixtures are associated with the development of analgesic nephropathy, and classic radiographic findings (bilateral small kidneys, irregular contour, and renal papillar calcifications) are easily seen on CT. The course of the disease is dependent on severity of chronic damage at presentation, and unless analgesic consumption ceases, renal dysfunction will progress. If analgesics are discontinued, renal function stabilizes or improves slightly in most patients, but there is an association with the later development of urinary tract malignancies in these patients.

Renal toxicity of anti-rheumatic drugs

Mixed connective tissue disease Mixed connective tissue disease is a rheumatological overlap syndrome associated with anti-​U1-​RNP antibodies and clinical signs including synovitis, myositis, Raynaud’s phenomenon, acrocyanosis, and hand oedema. Renal involvement occurs in up to one-​third of cases. Treatment has generally been with steroid therapy along

Many conventional antirheumatic drugs are nephrotoxic, even in the absence of chronic kidney disease. Calcineurin inhibitors (ciclosporin and tacrolimus) are associated with significant renal toxicity. Acute renal impairment and hypertension are usually dose dependent and improve with dose reduction. Chronic renal dysfunction is associated with characteristic histological changes (vascular hyalinosis, interstitial fibrosis, tubular atrophy, and glomerular

21.10.3  The kidney in rheumatological disorders

sclerosis), is often progressive, and irreversible unless calcineurin inhibitors are stopped. The commonest manifestation of drug toxicity in the kidney is tubulointerstitial nephritis, often with an eosinophilic infiltrate. The presentation may be acute with systemic symptoms such as a drug rash and fever, and may be associated with systemic eosinophilia and hypocomplementaemia as well as acute kidney injury that can be severe. Patients usually have sterile pyuria, may have haematuria and can have nephrotic range proteinuria, though more commonly much lower levels of urinary protein loss. Some patients have a slower more insidious renal limited progression and the major finding will be unexplained chronic kidney disease and sterile pyuria. Unless biopsied, the inflammation will be missed and these patients will present with irreversible advanced tubulointerstitial scarring. Nowadays the commonest drugs associated with tubulointerstitial nephritis are penicillins, NSAIDs, proton pump inhibitors, furosemide, and sulphasalazine (which can also cause crystalluria and urinary stone formation)—​all used frequently in patients with rheumatic diseases. Treatment involves stopping the causative drug, if known, plus a course of oral steroids. Although there are no trials, a large retrospective study strongly suggested that those treated with steroids had better preservation of renal function than those who were not. In patients with pre-​existing chronic kidney disease, leflunomide is contraindicated (the active ingredient is renally excreted) and other medications including methotrexate, azathioprine, chlorambucil, and cyclophosphamide require reduced doses. Hydroxychloroquine is not reported to cause renal toxicity, but increased retinal monitoring should be undertaken in the presence of renal impairment. At present, there has been no reported incidence of renal toxicity in clinical trials of new biological therapies, but their use in patients with severe renal impairment has not been fully evaluated. Also of interest is the pharmacokinetics of these drugs in the face of severe nephrotic syndrome: are larger and/​or more frequent doses needed?

FURTHER READING Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group (2012). KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int Suppl, 2, 139–​274. Rovin BH, et  al. (2019). Management and treatment of glomerular diseases (part 2): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int, 95, 281–95.

Lupus nephritis Almaani S, Meara A, Rovin BH (2017). Update on lupus nephritis. CJASN, 12, 825–35. Appel GB, et al. (2009). Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol, 20, 1103–​12. Austin HA, et al. (1986). Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Eng J Med, 314, 614–​19. Austin HA, et al. (2009). Randomised controlled trial of prednisone, cyclophosphamide and cyclosporine in lupus membranous nephropathy. J Am Soc Nephrol, 20, 901–​11.

Boumpas DT, et al. (1992). Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet, 340,  741–​5. Condon M, et al. (2013). Prospective observational single-​centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis, 72, 1280–​6. Dooley MA, et al. (2011). Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med, 365, 1886–​95. Dooley M, et al. (2013). Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus, 22,  63–​72. Gordon C, et al. (2018). The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults. Rheumatology, 57, e1–e45. Henderson L, et  al. (2012). Treatment for lupus nephritis. Cochrane Database Syst Rev, 12, CD002922. Houssiau FA, et al. (2002). Immunosuppressive therapy in lupus nephritis:  the Euro-​Lupus Trial, a randomised trial of low-​dose versus high dose intravenous cyclophosphamide. Arthritis Rheum, 46, 2121–​31. Houssiau FA, et al. (2010). Azathioprine versus mycophenolate mofetil for long term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis, 69, 2083–​9. Houssiau FA, et  al. (2010). The 10-​year follow-​up data of the Euro-​ Lupus Nephritis Trial comparing low-​dose and high-​dose intravenous cyclophosphamide. Ann Rheum Dis, 69,  61–​4. Jónsdóttir T, et  al. (2013). Long-​term follow-​up in lupus nephritis patients treated with rituximab—​clinical and histopathological response. Rheumatology (Oxford), 52, 847–​55. Korbet S, et al. (2000). Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaboration Study Group. Am J Kidney Dis, 35, 904–​14. Merrill J, et  al. (2010). Efficacy and safety of rituximab in subjects with moderately to severely active systemic lupus erythematosus (SLE): results from the randomised, double blind phase II/​III study EXPLORER. Arthritis Rheum, 58, 4029–​30. Mok C, et al. (2016). Tacrolimus versus mycophenolate mofetil for induction therapy of LN: a randomised controlled trial and long-​term follow-​up. Ann Rheum Dis, 75,  30–​6. Rovin B, et al. (2012). Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum, 64, 2515–​26. Rovin BH, et al. (2019). A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis. Kidney Int, 95, 219–31. Ruiz-​Irastorza G, Hunt B, Kahmashta M (2007). A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum, 57, 1487–​95. Sloan RP, et  al. (1996). Long-​ term outcome in systemic lupus erythematosus membranous glomerulonephritis. Lupus Nephritis Collaborative Study Group. J Am Soc Nephrol, 7, 299–​305. Weening JJ, et al. (2004). The classification of glomerulonephritis in systemic lupus erythematosus revisited J Am Soc Nephrol, 15, 241–​50. Wu L-H, et al. (2013). Inclusion of renal vascular lesions in the 2003 ISN/RPS system for classifying lupus nephritis improves renal outcome predictions. Kidney Int, 83, 715–23. Yo JH, Barbour TD, Nicholls K (2019). Management of refractory lupus nephritis: challenges and solutions. Open Access Rheumatol, 11, 179–88.

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Systemic sclerosis DeMarco PJ, et  al. (2002). Predictors and outcome of scleroderma renal crisis: the high-​dose versus low-​dose D-​penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum, 46, 2983–​9. Denton C, et al. (2009). Renal complications and scleroderma renal crisis. Rheumatology (Oxford), 48, iii32–​5. Kowal-​Bielecka O, et al. (2009). EULAR recommendations for the treatment of systemic sclerosis:  a report from the EULAR Scleroderma trials and research group (EUSTAR). Ann Rheum Dis, 68,  620–​8. Nagaraja V (2019). Management of scleroderma renal crisis. Curr Opin Rheumatol, 31, 223–30. Penn H, et al. (2007). Scleroderma renal crisis: patient characteristics and long-​term outcomes. Q J Med, 100, 485–​94. Steen VD (1994). Renal involvement in systemic sclerosis. Clin Dermatol, 12,  253–​8. Steen VD (2001). Treatment of systemic sclerosis. Am J Clin Dermatol, 2, 315–​25. Teixeira L, et al. (2008). Mortality and risk factors of scleroderma renal crisis: a French retrospective study in 50 patients. Ann Rheum Dis, 67, 110–​16.

Rheumatoid arthritis Adu D, et al. (1993). Glomerulonephritis in rheumatoid arthritis. Br J Rheumatol, 32, 1008–​11. Boers M (1990). Renal disorders in rheumatoid arthritis. Semin Arthritis Rheum, 20,  57–​68. Esteve V, et al. (2006). Renal involvement in amyloidosis. Clinical outcomes, evolution and survival. Nefrologia, 26, 212–​17. Hall CL, et al. (1987). The natural course of gold nephropathy: long term study of 21 patients. BMJ, 295, 745–​84. Hall CL, et al. (1988). Natural course of penicillamine nephropathy: a long term study of 33 patients. BMJ, 296, 1085–​6. Harper L, et al. (1997). Focal segmental necrotizing glomerulonephritis in rheumatoid arthritis. QJM, 90, 125–​32. Honkanen E, et al. (1987). Membranous glomerulonephritis in rheumatoid arthritis not related to gold or D-​penicillamine therapy: a report of four cases and review of the literature. Clin Nephrol, 27,  87–​93. Kuznetsky KA, et  al. (1986). Necrotizing glomerulonephritis in rheumatoid arthritis. Clin Nephrol, 26, 257–​64. Stokes MB, et al. (2005). Development of glomerulonephritis during anti-​ TNF-​ alpha therapy for rheumatoid arthritis. Nephrol Dial Transplant, 20, 1400–​6. Uda H, et al. (2006). Two distinct clinical courses of renal involvement in rheumatoid patients with AA amyloidosis. J Rheumatol, 33, 1482–​7.

Sjögren’s syndrome Goules A, et al. (2019). Renal involvement in primary Sjogren’s syndrome: natural history and treatment outcome. Clin Exp Rheumatol, 37 Suppl 118(3), 123–32. Shioji R, et al. (1970). Sjogrens syndrome and renal tubular acidosis. Am J Med, 48, 456–​63. Tu W, et al. (1968). Interstitial nephritis in Sjogren’s syndrome. Ann Intern Med, 69, 1163–​70.

Mixed connective tissue disease Kitridou R, et al. (1986). Renal involvement in mixed connective tissue disease:  a longitudinal clinicopathologic study. Semin Arthritis Rheum, 16, 135–​45. Sharp G, et al. (1972). Mixed connective tissue disease-​an apparently distinct rheumatic disease syndrome associated with a

specific antibody to an extractable nuclear antigen (ENA). Am J Med, 52, 148–​59.

Drug nephrotoxicity Clive D, Stoff J (1984). Renal syndromes associated with anti-​ inflammatory drugs. N Engl J Med, 310, 563–​72. De Broe M, Elseviers M. (2009). Over the counter analgesic use. J Am Soc Nephrol, 20, 2098–​103. Elseviers M, et  al. (1995). High diagnostic performance of CT scan for analgesic nephropathy in patients with incipient to severe renal failure. Kidney Int, 48, 1316–​23. Joint Formulary Committee. British national formulary (online). BMJ Group and Pharmaceutical Press, London. https://​ www. medicinescomplete.com/​mc/​bnf/​current/​ Pusey C, Saltissi D, Bloodworm L (1983). Drug associated acute interstitial nephritis: clinical and pathological features and the response to high dose steroid therapy. Q J Med, 52, 194–​211. Sandler D, Burr F, Weinberg C (1991). Nonsteroidal anti-​ inflammatory drugs and risks for chronic renal disease. Ann Int Med, 115, 165–​72. Savill J, Chia Y, Pusey C (1988). Minimal change nephropathy and pemphigus vulgaris associated with penicillamine treatment of rheumatoid arthritis. Clin Nephrol, 29, 267–​70.

21.10.4  The kidney in sarcoidosis Ingeborg Hilderson and Jan Donck ESSENTIALS Sarcoidosis is associated with a broad spectrum of renal manifestations, but clinically important disease occurs in few patients. The most common cause of renal dysfunction is abnormal calcium metabolism:  untreated chronic hypercalcaemia and hypercalciuria causes progressive tubulointerstitial inflammation with associated calcium deposits, leading to nephrocalcinosis, which is the leading cause of chronic kidney disease. Interstitial granulomatous nephritis is the most typical histological finding, but development of renal insufficiency is unusual. A range of glomerulopathies can be associated with sarcoidosis. When treatment is required, steroids are the first line, with various steroid-​sparing agents used in cases that are refractory.

Introduction Sarcoidosis is a multisystem inflammatory disease characterized by the presence of noncaseating epithelioid granulomas. These granulomas can resolve without sequelae or result in the development of fibrosis. The disease has a benign course with spontaneous resolution in up to two-​third of cases. However, in one-​third a chronic disorder develops, leading to significant organ impairment. Sarcoidosis most frequently involves the lungs, but may affect any organ system. The most common sites of extrapulmonary disease include skin, eyes, liver, spleen, peripheral lymph nodes,

21.10.4  The kidney in sarcoidosis

central nervous system, and heart. The incidence of renal involvement remains unclear. There is a great difference in reported prevalence due to the heterogeneity of renal manifestations and the often insidious nature of the disease.

Clinical presentations Sarcoidosis is associated with a broad spectrum of renal manifestations, but clinically important disease occurs in only a few patients. The most prevalent cause of renal dysfunction is a disordered calcium metabolism. Interstitial granulomatous nephritis is the most typical histological finding, but development of renal insufficiency is unusual. Finally, there is a wide range of glomerulopathies associated with sarcoidosis. Different types of renal sarcoidosis can coexist.

Calcium metabolism Epidemiology Hypercalcaemia occurs in approximately 10 to 20% of patients with sarcoidosis and hypercalciuria is found in up to 50% of patients. Pathogenesis In sarcoidosis and other granulomatous diseases there is an increased activity of 1-​ α-​ hydroxylase, which is synthetized by granulomas and activated macrophages. This enzyme activity is responsible for the increase in 1,25-​dihydroxy vitamin D (calcitriol) and is resistant to negative feedback mechanisms. Calcitriol augments the gastrointestinal calcium absorption, stimulates the osteoclast activity and bony reabsorption, and increases renal tubular calcium reabsorption. The net result is hypercalcaemia, which is known to cause renal dysfunction by several different mechanisms (Box 21.10.4.1). The rise in calcitriol suppresses the production of the parathyroid hormone. Along with an increased renal calcium load, this results in hypercalciuria. Untreated, chronic hypercalcaemia and hypercalciuria causes a progressive tubulointerstitial inflammation with associated calcium deposits, leading to nephrocalcinosis, which is the leading cause of chronic kidney disease in sarcoidosis. Furthermore, hypercalciuria predisposes to nephrolithiasis and obstructive uropathy.

Interstitial nephritis with granuloma formation

autopsy studies of patients with sarcoidosis, a granulomatous infiltrate is found in the kidneys in 7 to 23%. Clinical course Granulomatous interstitial nephritis is usually present when the initial diagnosis of systemic sarcoidosis is made and rarely develops in patients who have longstanding sarcoidosis. Most often there is diffuse active sarcoidosis, although isolated renal disease is an accepted entity. Interstitial nephritis has an insidious nature and is asymptomatic until late in the course of the disease when severe kidney dysfunction develops as a result of progressive fibrosis. It has a highly variable course with a tendency to wax and wane, either spontaneously or under treatment. Relapses are frequent. Diagnosis Screening for renal disease is important. Renal function tests, measurement of serum calcium, and urine analysis should be performed systematically both during initial evaluation and the follow-​ up of patients with sarcoidosis. Whenever granulomatous interstitial nephritis is suspected, a histopathological confirmation should be attempted. Noncaseating granulomas are the hallmark of the disease, but they are nonspecific (Fig. 21.10.4.1).

(a)

(b)

(c)

Epidemiology Granulomatous interstitial nephritis is the most common renal lesion seen on biopsy, but in only a few patients does this cause clinically significant disease. The true incidence is unknown, but in

Box 21.10.4.1  Mechanisms of renal dysfunction caused by hypercalcaemia • Vasoconstriction of the afferent arteriole, causing a decrease in glomerular filtration • Inhibition of Na+/​K+-​ATPase leading to urinary sodium wasting with polyuria and dehydration • Decreased sensitivity to antidiuretic hormone • Acute tubular necrosis

Fig. 21.10.4.1  Granulomatous interstitial nephritis. (a) On the left there is a localized inflammation of the renal parenchyma, which is not present on the right (haematoxylin and eosin stain, original magnification ×100). (b) Further magnification of the inflammation. There is a granulomatous infiltration with central collections of histiocytes surrounded by lymphocytes (haematoxylin and eosin stain, original magnification ×200). (c) Confirmation of the histiocytic character of the inflammation by an immunohistochemical staining with antibodies directed against CD68 (anti-​CD68 stain, original magnification ×200). Courtesy of Prof. Dr. E. Lerut, University of Leuven, Belgium.

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Table 21.10.4.1  Differential diagnosis of granulomatous nephritis Diagnosis

Example

Drug reaction

β-​lactam antibiotics, nonsteroidal anti-​inflammatory drugs

Infections

Tuberculosis, chronic fungal infection

Autoimmune disorders

Sarcoidosis, granulomatosis with polyangiitis

Neoplasia

Lymphoma

Foreign body reaction

Heroin

Table 21.10.4.2  Treatment of hypercalcaemia and hypercalciuria in sarcoidosis Standard of care: glucocorticoids Starting dose: 0.3–​0.5 mg/​kg per day Maintenance dose: 5–​10  mg/​day Total duration of treatment: at least 12 months Alternatives Hydroxychloroquine Chloroquine Dose: 250–​500 mg/​day Dose: 200–​400 mg/​day

Ketoconazole Dose: 600–​800 mg/​day

Preventive measures

Especially in case of isolated renal disease, other reasons of granulomatous infiltration should be excluded (Table 21.10.4.1). The absence of kidney biopsy findings does not exclude the diagnosis as renal sarcoidosis can be focal in nature and the typical lesions can easily be missed in biopsy. The urinary manifestations are also nonspecific: there is often mild proteinuria, or less frequently aseptic pyuria or nonvisible haematuria. In some cases, the urine sediment is bland.

Glomerular disease Membranous nephropathy is the most common glomerular manifestation of sarcoidosis, although its incidence is very low. Some case reports suggest an association between sarcoidosis and focal segmental sclerosis, mesangioproliferative glomerulonephritis, IgA nephropathy, and crescentic glomerulonephritis, but a definitive causal relationship to these conditions has not been proven.

Tubular dysfunction Tubular dysfunction is frequently associated with hypercalcaemia and granulomatous interstitial nephritis. It may present as isolated proximal or distal tubular acidosis, Fanconi’s syndrome, urinary concentration deficits, or metabolic alkalosis.

Obstructive and vascular uropathy Obstructive uropathy usually results from nephrolithiasis, but in patients with sarcoidosis, obstruction may also be due to retroperitoneal fibrosis or lymphadenopathy. Renal artery stenosis caused by granulomatous angiitis is an extremely rare complication of sarcoidosis, often accompanied by arterial hypertension.

Treatment Treatment is always required for renal disease, as it is for cardiac, ocular, and neurological manifestations of sarcoidosis, given the substantial risk of end-​organ damage. However, there is no standard of care and little is known about the optimal dose and duration of treatment.

Hypercalcaemia and hypercalciuria Glucocorticoids are the mainstay of treatment (Table 21.10.4.2) as they block the 1-​α-​hydroxylase activity and diminish the intestinal calcium absorption and bony resorption. Most often, a

Limit sunlight exposure Low dietary intake of calcium, vitamin D, and oxalate Adequate oral hydration Avoid thiazide use

starting dose of prednisolone of 0.3 to 0.5 mg/​kg once daily is recommended, followed by a taper to a maintenance dose of 5–​10 mg once daily. The total duration of treatment should be at least 12 months. Chloroquine is an alternative treatment. The optimal dose is unknown, but a daily dosage of 250 to 500 mg is most often used. Retinal toxicity is the major concern. Hydroxychloroquine (recommended daily dosing is 200–​4 00 mg) is slightly less effective, but carries a lesser risk of retinopathy. Ketoconazole in a daily dose of 600–​800 mg can also be used. Hepatic toxicity is the major limiting side effect. The effect of these alternative forms of treatment is less predictable and slower than treatment with corticoids. Preventive measures such as ensuring adequate oral hydration, a low dietary intake of calcium, vitamin D, and oxalate, as well as the limitation of sunlight exposure play additional supportive roles. Thiazide use should be avoided given the substantial risk of aggravating hypercalcaemia.

Interstitial nephritis with granuloma formation Glucocorticoids Glucocorticoids are the cornerstone of treatment (Table 21.10.4.3). Most authors recommend a starting dose of 0.5 to 1 mg per kg prednisone once daily, depending on the severity of the disease. The initial dose should be maintained for 4 weeks to allow improvement and/​or stabilization of renal function. Most patients respond rapidly to treatment but a full recovery of renal function is rare. Patients with a poor response after 1 month tend to have a worse renal outcome and are more susceptible to relapse. After 4 weeks of treatment, the dose can be tapered by 5 mg each week until a daily dose of 5 to 10 mg is reached. There is an increased risk of relapse if corticosteroids are tapered too quickly. In this eventuality, the dose should be augmented to the last dose that was effective, with an increase to the initial dose if there is no improvement after 4 weeks. Subsequent tapering should be more gradual. However, in some patients it is impossible to taper the glucocorticoids adequately. Given the many side effects of a prolonged treatment with high-​dose glucocorticoids,

21.10.4  The kidney in sarcoidosis

Table 21.10.4.3  Treatment of granulomatous interstitial nephritis in sarcoidosis

it should be pointed out that the evidence in support of these second-​ line agents is very limited.

Step 1: glucocorticoids

Tumour necrosis factor-​α inhibitors

Starting dose: • Major organ impairment: —  Oral prednisone 1 mg/​kg per day Or — Intravenous pulse methylprednisolone (3 days), followed by oral prednisone 1 mg/​kg per day • Milder disease: oral prednisone 0.5 mg/​kg per day

Tumour necrosis factor (TNF) is thought to be a major player in sarcoidosis through its role in the maintenance of granuloma formation. TNFα inhibitors have therefore been suggested as appropriate treatment in cases of steroid-​resistant sarcoidosis. They should only be used when at least one other immunosuppressive agent has been tried, or in patients who have developed severe steroid toxicity. Evidence is scarce. Infliximab is usually given in a dosage of 3 to 5 mg per kg at weeks 0, 2, and 6, followed by 3 to 5 mg per kg every 6 to 8 weeks thereafter. Adalimumab could be an interesting option for patients intolerant of infliximab, but more research is needed before its use can be advocated. Etanercept seems to have no beneficial effect in patients with sarcoidosis, as in other granulomatous diseases.

Keep initial dose for 4 weeks, if renal function does not stabilize/​improve continue to step 2 After 4 weeks of treatment, reduce dose by 5 mg a week Maintenance dose: 5–​10 mg daily Relapse: • Augment prednisone to the last dose that was effective and continue for 4 weeks • No improvement after 4 weeks: augment corticoids to the starting dose and continue for 4 weeks • Subsequent tapering: more gradual Total duration of treatment: 18–​24 months Step 2: add another immunosuppressive agent Failure of corticosteroids Relative contraindication to corticosteroids Impossibility to taper the corticosteroids Azathioprine Dose: 2 mg/​kg per day

Mycophenolate mofetil Dose: 1 g, twice a day

Subsequently reduce the corticosteroids by 5 mg a week until a daily dose of 5–​10 mg is reached Step 3: add a TNFα inhibitor—​infliximab Steroid-​resistant sarcoidosis when at least one other immunosuppressive agent has been tried Severe steroid toxicity Dose: 2–​5 mg/​kg at weeks 0, 2, and 6 and every 6 to 8 weeks thereafter Experimental therapy Thalidomide, pentoxifylline, rituximab, etc.

a steroid-​sparing agent (azathioprine or mycophenolate mofetil) can be added, with the intention of subsequently reducing the glucocorticoid dose. The ideal duration of maintenance therapy is unknown. A total duration of treatment of 18 to 24 months seems necessary to be effective and to prevent relapse. For the few patients who suffer frequent relapses, lifelong treatment with low-​dose glucocorticoids may be required. There are, however, important side effects from long-​term steroid use which need to be balanced against the risk of progression to endstage renal disease. Azathioprine and mycophenolate mofetil Azathioprine and mycophenolate mofetil can be used as steroid-​ sparing agents or in patients with failure of or a strong contraindication to continued corticosteroids. Treatment with these drugs should only be started after at least 1 month of treatment with corticosteroids, since this duration is needed to allow improvement or stabilization of renal function. The daily dose of azathioprine is 2 mg per kg, mycophenolate mofetil is dosed at 1 g, twice a day. However,

Kidney transplantation Endstage renal disease secondary to sarcoidosis is very uncommon. One concluded that renal transplantation can be carried out safely with excellent graft and patient survival, although there was a relatively high rate of renal recurrence (17%). A short delay between the last episode of sarcoidosis and renal transplantation was a risk factor for recurrence. Experimental therapy With recognition of the role of cytokines in the pathogenesis of sarcoidosis, other immunosuppressive drugs including thalidomide, pentoxifylline, and rituximab have been proposed as steroid-​sparing agents, but more data are needed before their use can be advocated.

Conclusion Sarcoidosis may affect any organ, including the kidney. Disordered calcium metabolism is the most common cause of renal failure. Granulomatous interstitial nephritis is the most typical histological finding, but development of renal insufficiency is rare. The lack of large, randomized controlled treatment trials limits therapeutic options. Corticosteroids remain the cornerstone of treatment. The role of corticosteroid-​sparing medications continues to evolve.

FURTHER READING Berliner AR, Haas M, Choi MJ (2006). Sarcoidosis: the nephrologist’s perspective. Am J Kidney Dis, 48, 856–​70. Hilderson I, et  al. (2014). Treatment of renal sarcoidosis:  is there a guideline? Overview of the different treatment options. Nephrol Dial Transplant, 29, 1841–​7. Mahévas M, et  al. (2009). Renal sarcoidosis:  clinical, laboratory, and histologic presentation and outcome in 47 patients. Medicine (Baltimore), 88, 98–​106. Rajakariar R, et al. (2006). Sarcoid tubulo-​interstitial nephritis: long-​ term outcome and response to corticosteroid therapy. Kidney Int, 70,  165–​9.

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21.10.5  Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Pierre Ronco, Frank Bridoux, and Arnaud Jaccard ESSENTIALS Plasma cell disorders are characterized by uncontrolled proliferation of a single clone of B cells which is responsible for the secretion of a monoclonal immunoglobulin (Ig) or Ig subunit that can deposit in tissues. They can cause a wide range of renal diseases. Light-​chain amyloidosis—​renal presentation is usually with proteinuria, often progressing to nephrotic syndrome. A progressive decline in renal function may occur, leading finally to endstage renal failure. Diagnosis is made by the detection of monoclonal gammopathy and free light-​chain excess in the serum (90% of cases), in combination with biopsy evidence of amyloid-​forming light-​chain deposits. Treatment is based on chemotherapy with oral melphalan plus dexamethasone, or bortezomib-​based regimens in patients with heart involvement. High dose melphalan followed by autologous stem cell transplantation can be considered in highly selected patients. Treatment efficacy should be evaluated by estimation of light-​chain response. Myeloma—​renal failure is found at presentation in 20% of patients, occurs in 50% at some time, and is most commonly caused by cast nephropathy, diagnosis of which relies on the detection of proteinuria mostly composed of monoclonal light chains, with renal biopsy typically showing ‘fractured’ casts. Chemotherapy should be introduced promptly (e.g. high-​dose dexamethasone, combined with bortezomib, and/​or alkylating agents, and/​or thalidomide or another immunomodulatory agent). Light-​ chain, light-​and heavy-​ chain, and heavy-​ chain deposition disease—​collectively known as monoclonal Ig deposition diseases, present with proteinuria and renal failure. Diagnosis is by renal biopsy which reveals nodular glomerulosclerosis, monotypic light-​and/​or heavy-​chain deposits along glomerular and tubular basement membranes (by immunofluorescence), and nonfibrillar linear electron-​dense deposits (by electron microscopy). Treatment strategy is based on chemotherapy (bortezomib-​based regimens) followed by autologous stem cell transplantation in selected cases. Fibrillary glomerulonephritis and immunotactoid glomerulopathy— ​usual presentation is with nephrotic syndrome, microscopic haematuria, and hypertension. Diagnosis is by renal biopsy when electron microscopy reveals (respectively) fibrils (solid, diameter 12–​22 nm, randomly arranged) or microtubules (hollow, diameter 10–​60 nm, in parallel arrays). Immunotactoid glomerulopathy, often associated with chronic lymphocytic leukaemia or lymphoma, usually responds to chemotherapy. Cryoglobulinaemia—​type II (‘essential mixed’), which involves a monoclonal IgM with rheumatoid factor activity and a polyclonal IgG, may present with proteinuria, haematuria, hypertension, and

gradually declining renal function, or with an acute nephritic picture. It should be suspected in the presence of an IgM rheumatoid factor and low complement C4, and confirmed by the finding of a cryoglobulin. It is often associated with hepatitis C. Renal biopsy typically reveals membranoproliferative glomerulonephritis with massive subendothelial deposits. Treatment involves antiviral agents and/​or immunosuppression. Tumour lysis syndrome—​a life-​threatening metabolic emergency that occurs in patients with haemopathies with high cell turnover (e.g. Burkitt’s lymphoma and acute leukaemia), mostly at the onset of chemotherapy. Prevention is by vigorous hydration with 0.9% saline before treatment with the addition of allopurinol (in low-​risk cases) or the recombinant modified urate oxidase rasburicase (in high-​risk cases). Treatment is based on saline diuresis (if possible), rasburicase, and haemodialysis (if required).

Introduction Plasma cell disorders are characterized by uncontrolled proliferation of a single clone of B cells, usually with plasma cell differentiation, which is responsible for the secretion of a monoclonal immunoglobulin (Ig) or Ig subunit that can deposit in tissues. The range of renal diseases secondary to deposition or precipitation of Ig-​related material has expanded dramatically in recent years. These conditions can be classified into two categories on the basis of their ultrastructural appearances (Table 21.10.5.1). Those with organized deposits include diseases with crystal formation, mainly Fanconi’s syndrome and myeloma cast nephropathy; diseases with fibril formation, mainly light-​chain amyloidosis; and diseases with microtubule formation, including cryoglobulinaemia kidney and immunotactoid/​ microtubular glomerulonephritis (also called glomerulonephritis with organized microtubular monoclonal Ig deposits (GOMMID)). A second category of diseases is characterized by the presence of nonorganized granular electron-​dense deposits made of light and/​or heavy chains along the basement membranes of many tissues, most importantly the kidney. First described by Randall and associates, these are referred to as monoclonal Ig deposition diseases (MIDD). More recently, glomerular diseases with amorphous monoclonal Ig deposits distinct from Randall-​ type MIDD and referred to as proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) have been described. It is now established that the spectrum of plasma cell dyscrasia-​related renal complications is due to intrinsic properties of the monoclonal component. Except for myeloma cast nephropathy, diagnosis relies on careful analysis of a biopsy specimen taken from the kidney, which should systematically include immunohistochemical studies with specific antibodies and also electron microscopy in all ambiguous cases. Since most of these patients will develop renal failure, it is essential to identify the underlying plasma cell clone because appropriate treatment may halt the extension of visceral deposits, and even induce their regression. Except in patients with myeloma cast nephropathy, who usually present with a high-​mass myeloma, most renal disorders related to monoclonal Ig deposition occur in the context of an indolent B-​cell disorder that manifests as isolated monoclonal

21.10.5  Renal involvement in plasma cell dyscrasias

Table 21.10.5.1  Pathological classification of diseases with tissue deposition or precipitation of monoclonal Ig-​related material Organized

Nonorganized (granular)

Crystals

Fibrillar

Microtubular

MIDD (Randall-​type)

Other

Myeloma cast nephropathy

Light-​chain amyloidosis

Cryoglobulinaemia kidney

LCDD

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID)

Fanconi’s syndrome

Nonamyloid fibrillary GN

Immunotactoid GN/​GOMMID

LHCDD

Waldenström’s macroglobulinaemia

Other

HCDD

GN, glomerulonephritis; GOMMID, glomerulonephritis with organized microtubular monoclonal Ig deposits; LCDD, LHCDD, HCDD, light-​chain, light-​and heavy-​chain, heavy-​chain deposition disease; MIDD, monoclonal immunoglobulin deposition disease.

gammopathy. To individualize this condition, the term monoclonal gammopathy of renal significance (MGRS) was recently introduced to highlight the association of a small B-​cell clone and renal disease related to the nephrotoxic property of the secreted monoclonal Ig, and the importance of chemotherapy to prevent consequences of renal and sometimes widespread organ deposition.

Renal involvement in Ig light-​chain amyloidosis

tubular dysfunction may be the presenting problem. Hypertension is uncommon but may develop concomitantly with renal failure. The kidneys may be of normal size or large, even when renal function is impaired. Systemic organ involvement is common, particularly cardiac disease, diagnosed in 60% of patients and strongly impacting survival. Deposits commonly also affect the liver, peripheral nervous system, carpal tunnel, gastrointestinal tract, skin, and tongue. Purpuric macules in the periorbital region are very typical of AL amyloidosis.

Definition and epidemiology

Diagnosis

Amyloidosis is a general term for a family of diseases defined by morphological criteria and characterized by deposition in extracellular spaces of a proteinaceous material that stains with Congo red and is metachromatic. Amyloid deposits are composed of a felt-​like array of 10-​nm-​wide, rigid, linear aggregated fibrils of indefinite length with a β-​pleated sheet configuration. They occur in a variety of conditions including Alzheimer’s disease and other neurodegenerative disorders, tumoural and inflammatory diseases, and plasma cell disorders. The various types of amyloidosis differ essentially by the nature of the precursor protein that yields the main component of fibrils, and are classified accordingly (see Chapter 12.12.3 for further discussion). Light-​chain (AL) amyloidosis is the most frequent form of systemic amyloidosis with renal involvement in Western countries. AL amyloidosis most commonly occurs in patients with isolated monoclonal gammopathy or smouldering myeloma, with only 20% of patients having evidence of a symptomatic plasma cell or B-​cell disorder at diagnosis.

AL amyloidosis should be suspected when the clinical manifestations previously described are associated with a monoclonal component in the serum or urine. AL amyloidosis is always the result of the proliferation of a small plasma cell clone: most patients have an increased number of plasma cells in the bone marrow, but only 15% have true myeloma. By immunofixation, a monoclonal Ig is found in the serum and/​or the urine in nearly 80% of patients. The recent development of a sensitive nephelometric immunoassay for circulating free Ig light chains has been an important advance in the management of AL amyloidosis, allowing detection of abnormal serum free light-​chain levels in 98% of patients, the λ isotype being involved twice as frequent as the κ isotype, with an over-​representation of the Vλ6 subgroup found in AL amyloidosis with renal involvement. Monitoring of serum free light chains at diagnosis and throughout follow-​up is mandatory to evaluate the response to chemotherapy. It is important to recognize that detection of monoclonal gammopathy is insufficient for the diagnosis of AL amyloidosis, which should be established in all cases by taking a biopsy specimen from a superficial organ (salivary glands), or by aspiration biopsy of abdominal fat. These biopsies should be performed before biopsies of rectal mucosa and/​or of kidney, because of the risk of bleeding complications due to factor X deficiency, fibrinolysis, or amyloid infiltration of vascular walls. After Congo red staining, amyloid deposits appear faintly red and show characteristic apple-​green birefringence under polarized light. Congo red staining may be falsely negative if tissue sections are less than 5 µm in thickness. In the kidney, the earliest lesions are located in the mesangium, along the glomerular basement membrane, and in the blood vessels (Fig. 21.10.5.1). Because there are specific diagnostic and therapeutic strategies depending on the type of protein deposited within tissues, immunofluorescence with specific antisera including anti-​κ and anti-​λ light chains should be performed routinely. When pathological confirmation of AL type cannot be obtained, genetic studies should be performed to exclude systemic hereditary amyloidosis caused by mutations in the genes encoding leucocyte chemotactic factor 2, fibrinogen A  α-​chain,

Clinical presentation Systemic AL amyloidosis can infiltrate almost any organ and thus be responsible for a wide variety of clinical manifestations. The main presenting symptoms are fatigue and dyspnoea. Renal disease is the most common manifestation of systemic AL amyloidosis. Proteinuria, composed mainly of albumin, is the usual symptom, detected in approximately 70% of patients at presentation and often progressing to a severe nephrotic syndrome, which can be complicated by renal vein thrombosis. Haematuria is uncommon, and when present should prompt examination for a bleeding lesion of the urinary tract. Progressive decline in renal function leading finally to endstage renal failure may occur, particularly in patients with baseline proteinuria greater than 5 g/​24 h and an estimated glomerular filtration rate less than 50 ml/​min per 1.73 m2. In those rare patients in whom renal tubulointerstitial deposits predominate, renal failure may progress without a nephrotic stage, and renal

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Table 21.10.5.2  Diagnostic and response criteria in AL amyloidosis Definition of renal involvement

24-​h urine protein ≥0.5 g/​day, predominantly albumin

Mayo Clinic staging for heart involvement

Stage 1: hs-​cTnTa ≤77 ng/​litre and NT-​proBNP ≤332 ng/​ litre Stage 2: hs-​cTnT >77 ng/​litre or NT-​proBNP >332 ng/​litre Stage 3: hs-​cTnT >77 ng/​litre and NT-​proBNP >332 ng/​ litre

Definition of renal response

2005 criteria: 50% decrease (at least 0.5 g/​day) of 24-​h urine protein (urine protein must be >0.5 g/​day pretreatment) in the absence of a reduction in eGFR ≥25% or an increase in serum creatinine ≥0.5  mg/​dl 2014 revised criteria: ≥30% decrease in proteinuria or drop of proteinuria below 0.5 g/​24 h in the absence of renal progression (as defined by ≥25% decrease in eGFR)

Definition of haematological response

CR: negative serum and urine IFE, normal kappa/​ lambda ratio VGPR: dFLC 30 nm), at times arranged in parallel arrays (Fig. 21.10.5.3). When immunotactoid/​microtubular glomerulopathy occurs in the setting of chronic lymphocytic leukaemia or related B-​cell lymphoma, inclusions showing the same microtubular organization and containing the same IgG subclass and light-​chain type as the renal deposits are often detected in the cytoplasm of leukaemic lymphocytes in the blood. Mesangial proliferation and membranoproliferative glomerulonephritis are the commonest lesions observed in nonamyloid fibrillary glomerulonephritis. Immunofluorescence studies show predominant polyclonal IgG4, usually associated with IgG1 deposits. DNAJB9 was recently found as sensitive and specific biomarker for fibrillary glomerulonephritis. Positive glomerular staining for DNAJB9 by immunohistochemistry is a strong indicator of the diagnosis. Electron microscopy shows the fibrils, devoid of a central lumen, to be randomly arranged with a diameter varying between 12 and 22 nm. In almost all cases there is no evidence of associated lymphoproliferative disorder or monoclonal gammopathy.

(c)

Fig. 21.10.5.3  Immunotactoid/​microtubular glomerulopathy in a patient with chronic lymphocytic leukaemia. Atypical membranous glomerulonephritis showing exclusive staining of the deposits with (a) anti-​ γ (b) and anti-​κ antibodies (immunohistochemistry, alkaline phosphatase, magnification × 312). (c) Electron micrograph of glomerular basement membrane, showing the microtubular structure of the subepithelial deposits (uranyl acetate and lead citrate, magnification × 12 000). From Béatrice Mougenot’s personal collection.

Infection with hepatitis C virus has sometimes been reported in patients with nonamyloid fibrillary glomerulonephritis and immunotactoid glomerulopathy.

21.10.5  Renal involvement in plasma cell dyscrasias

Treatment In patients with GOMMID, especially in those with chronic lymphocytic leukaemia, chemotherapy is associated with partial or complete remission of the nephrotic syndrome, parallel with improvement of the haematological condition. More variable results are obtained with cytotoxic treatments in patients with fibrillary glomerulonephritis, although rituximab produced improvement in renal parameters in few patients. Recurrence of these diseases has been reported in patients receiving a renal allograft.

Renal involvement in cryoglobulinaemia Definition and epidemiology Cryoglobulinaemia is a pathological condition in which the blood contains Igs that precipitate on cooling (4°C) and resolubilize on warming (37°C). According to Brouet’s classification, there are three types of cryoglobulinaemia defined by their composition. Renal involvement is observed mainly in patients with mixed type II cryoglobulinaemia involving a monoclonal IgM (most often including a κ light chain) with rheumatoid factor activity and a polyclonal IgG. Type II cryoglobulinaemia can be associated with overt lymphoproliferative disorders of the B-​cell lineage, although in many cases no underlying haematological disorder is found such that this type of cryoglobulinaemia has long been referred to as essential mixed cryoglobulinaemia. Glomerular disease may also occur in type I  cryoglobulinaemia, composed of a single monoclonal Ig (mostly IgM or IgG), usually in the context of underlying lymphoproliferative or plasma cell disorder (see later). Viral infections may trigger the formation of cryoglobulin. Whereas hepatitis B and Epstein–​Barr virus infections have been implicated in the past, the role of hepatitis C virus infection is now recognized to be an important factor in the pathogenesis of type II cryoglobulinaemia. Antibodies to hepatitis C virus and hepatitis C virus RNA are found in the sera of most patients with type II cryoglobulinaemia, probably explaining the uneven geographical distribution of mixed cryoglobulinaemias, which predominate in southern Europe where hepatitis C infection is more prevalent. The condition is commonest in adults in the fifth and the sixth decades of life, with a slight female predominance.

Clinical presentation Renal disease most often occurs in patients with a long history of cryoglobulinaemia-​related vasculitic symptoms, including palpable purpura (70%), arthralgias (50%), fatigue, Raynaud’s phenomenon, peripheral neuropathy (22%), and hepatic involvement. The renal disease may present as an acute nephritic syndrome (in 20 to 30% of patients) with gross haematuria, heavy proteinuria, hypertension, and renal failure of sudden onset, sometimes with oliguria (5% of patients). The pathological finding in these patients is membranoproliferative glomerulonephritis with the presence of numerous intraluminal thrombi and/​or necrotic vasculitic lesions. Remission may occur spontaneously or during therapy, with relapses following in up to 20% of cases. Most patients with mixed cryoglobulinaemia (55%) have an indolent and protracted renal course, presenting with proteinuria, haematuria, and hypertension. The usual renal lesion in this context

is membranoproliferative glomerulonephritis, with some of the peculiarities described earlier. Nephrotic syndrome affects another 20% of patients. Arterial hypertension is observed in more than 80% of patients at the time of onset of renal disease. Endstage renal disease develops in fewer than 10% of patients. It should be stressed that the overall risk of non-​Hodgkin B-​cell lymphomas is 35 times higher in patients with hepatitis C virus-​related cryoglobulinaemia compared to the general population.

Diagnosis Mixed type II cryoglobulinaemia should be suspected in patients with the clinical picture described previously, an IgM rheumatoid factor, and a very low serum C4 fraction and total haemolytic activity of complement. In this context, a careful search for the presence of cryoglobulin must be made, requiring that a blood sample from a fasting patient should be placed in warm water and taken promptly to the laboratory, which needs to be forewarned that such a sample will arrive. Cryoglobulinaemia-​related membranoproliferative glomerulonephritis usually shows several distinctive histological features, including massive subendothelial deposits filling the capillary lumen and forming so-​called thrombi, and dramatic infiltration by leucocytes, mainly monocytes (Fig. 21.10.5.4). The thrombi are brightly stained with anti-​ μ and anti-​κ antibodies and present a microtubular crystalline structure similar to that of the cryoprecipitate. These glomerular changes may be associated with acute vasculitis of the small and medium-​sized arteries (33%) and lymphocytic infiltrates in the interstitium. Crescentic extracapillary proliferation is rare and always limited.

Treatment The best treatment of mixed cryoglobulinaemia is not firmly established because the course of the disease is unpredictable and acute exacerbations may remit spontaneously. In patients with moderate renal and extrarenal manifestations, immunosuppressive agents are not indicated. In those with hepatitis C virus infection, sustained viral response is generally associated with improvement in clinical manifestations of cryoglobulinaemia. Combined pegylated interferon and ribavirin for at least 1 year was until recently the treatment of choice. The use of novel direct-acting antihepatitis C agents is more efficient in eradicating hepatitis C virus, and with less side effects, will likely result in improved outcomes in type II cryoglobulinaemia. In more severe cases, particularly those with signs of systemic vasculitis, high-​dose steroids, plasma exchange, and cytotoxic drugs are indicated. Among these, the monoclonal anti-​CD20 antibody (rituximab), which is usually well tolerated, is recommended, as it also appears to be as efficient as cyclophosphamide. Hypertension needs to be carefully controlled because cardiovascular complications are the major causes of death. In patients with severe symptomatic type I  or type II cryoglobulinaemia secondary to B-​cell proliferative disorder, treatment relies on chemotherapy adapted to the nature of the underlying clone.

Renal involvement in Waldenström’s macroglobulinaemia A glomerulonephritis with intracapillary thrombi of monoclonal IgM is rare, but is almost specific for Waldenström’s macroglobulinaemia. It is characterized by periodic acid–​Schiff-​positive, noncongophilic

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endomembranous deposits in capillary loops, which sometimes occlude the capillary lumen either partially or completely, thus forming thrombi. These lesions, which occurred in patients with advanced disease and high serum IgM levels, usually with hyperviscosity syndrome and detectable cryoglobulinaemia, have decreased over time. AL amyloidosis currently represents the most frequent glomerular disease, but other types have been described, including membranoproliferative glomerulonephritis with nonorganized monoclonal IgM deposits, type I  and type II cryoglobulinaemic glomerulonephritis, and Randall-​type MIDD. Neoplastic infiltration of the renal interstitium by malignant B cells is common and may be observed alone or associated with glomerular or tubular disorders. Tubular lesions, secondary to monoclonal light chain precipitation, are less frequent, but cases of Fanconi’s syndrome and cast nephropathy have been reported. Management relies on chemotherapy (see Chapter 22.4.6) with rituximab-​based regimens. Plasmapheresis should be considered in patients with acute kidney injury and symptoms of hyperviscosity.

C3 glomerulopathy and monoclonal gammopathy

(c)

Isolated glomerular deposition of C3 is a rare condition in adults that results from dysregulation of the complement alternative pathway. It manifests histologically with mesangial proliferative or membranoproliferative glomerulonephritis, with diffuse, bright deposition of C3 in the mesangium and capillary walls by immunofluorescence, and no significant immunoglobulin deposit. Ultrastructurally, two different patterns may be observed: dense deposit disease characterized by diffuse intramembranous electron-​dense deposits with a typical ‘sausage-​like’ appearance, and C3 glomerulonephritis with less intense granular mesangial, subendothelial, or subepithelial deposits. A high prevalence of monoclonal gammopathy (>60%) was recently identified in patients with C3 glomerulopathy aged over 50  years. Clinical presentation is with hypertension, chronic renal failure, nonvisible haematuria, and proteinuria, with nephrotic syndrome in half of cases. Most patients have an indolent plasma cell proliferation, consistent with MGRS, and one-​third have decreased C3 levels at diagnosis. Control of the underlying plasma cell clone with appropriate chemotherapy may result in significant improvement in renal parameters, before severe renal impairment develops. Although the pathophysiology remains unclear, local or systemic activation of the complement alternative pathway by the monoclonal immunoglobulin is likely to be involved, through autoantibody activity of the monoclonal Ig against a complement alternative pathway regulator protein, or other mechanisms, including direct activation of the complement alternative pathway by the monoclonal immunoglobulin itself. See Chapter 21.8.6 for further discussion.

Renal involvement in lymphomas and leukaemias Fig. 21.10.5.4  Cryoglobulinaemic glomerulonephritis. (a) The glomerulus shows a marked endocapillary hypercellularity with massive infiltration of mononuclear leucocytes (Masson’s trichrome stain, magnification × 500). (b) Frequent double-​contour aspect and intraluminal thrombi (periodic acid–​Schiff stain, magnification × 312). (c) Thrombi and segments of glomerular basement membrane are brightly stained with anti-​IgM antibody (immunofluorescence, magnification × 312). From Béatrice Mougenot’s personal collection.

Renal complications of lymphomas and leukaemias are summarized in Box 21.10.5.1. All patients with unexplained renal failure should undergo ultrasound examination of the kidney, which should be arranged as a matter of urgency, to identify either enlarged kidneys due to tumour infiltration or hydronephrosis. The presence of heavy albuminuria in this setting is suggestive of paraneoplastic glomerulopathy.

21.10.5  Renal involvement in plasma cell dyscrasias

Box 21.10.5.1  Renal complications of lymphomas and leukaemias Mechanical complications: • —​  Infiltration of renal parenchyma —​ Obstructive uropathy (retroperitoneal fibrosis) —​ Compression of renal artery or vein • Electrolyte disturbances and disseminated intravascular coagulation • Glomerulopathies (including amyloidosis) • Treatment-​induced complications: —​ Tumour lysis syndrome —​ Lithiasis and urate nephropathy —​ Radiation nephropathy —​ Drug-​induced toxic nephropathy —​ Thrombotic microangiopathy and mesangiolysis

Hodgkin’s disease and non-​Hodgkin’s lymphoma Glomerulonephritis is a rare complication of lymphoma, most often described in patients with Hodgkin’s disease, of whom 0.4% have minimal-​change disease and 0.1% have amyloid A amyloidosis. This low incidence of amyloidosis in patients with Hodgkin’s disease is most likely attributable to modern treatment protocols that induce rapid remission. Hodgkin’s lymphoma-​related minimal-​change disease shows features of a paraneoplastic glomerulopathy. The nephrotic syndrome usually appears early, revealing the haemopathy in about one-​half of the cases; it rapidly disappears after effective treatment of the underlying condition; and it usually relapses simultaneously with the haemopathy. Cases of crescentic glomerulonephritis with rapidly progressive renal failure due to antiglomerular basement antibodies have also been reported. Glomerulonephritis may also occur in patients with non-​Hodgkin’s lymphoma, including both T-​and B-​cell proliferations. In these conditions, unlike in Hodgkin’s lymphoma, minimal-​change disease is uncommon, and membranoproliferative glomerulonephritis and necrotizing crescentic glomerulonephritis with or without vasculitis are the most frequent lesions. Some cases are associated with type I  cryoglobulinaemia or GOMMID. In other cases, the association between non-​Hodgkin’s lymphoma and renal disease may be coincidental. Presenting renal symptoms are nephrotic syndrome and/​or renal impairment. Full remission of these symptoms can be achieved in some patients by aggressive therapy of the lymphoma.

Chronic lymphocytic leukaemia and low-​grade B-​cell lymphoma These haemopathies, particularly chronic lymphocytic leukaemia, have been reported in association with glomerular disease in about 50 cases. Most commonly, the nephropathy, usually manifesting as nephrotic syndrome with impaired renal function, and the leukaemia are detected simultaneously. The most frequent glomerular disease is membranoproliferative glomerulonephritis with or without cryoglobulinaemia (mostly type I). In type I cryoglobulinaemic glomerulonephritis, glomerular monoclonal Ig deposits often display an ultrastructural organization into microtubules, and less frequently into crystals. In the absence of cryoglobulinaemia, a molecular link can be established between the haemopathy and the glomerulopathy when monotypic Ig deposits are found in the glomerulus, which can occur even in the absence of detectable circulating M component. As discussed previously, some of these patients present with typical immunotactoid/​ microtubular glomerulopathy or MIDD. Improvement of the nephropathy after chemotherapy for the leukaemia is well described.

Acute leukaemias Disseminated intravascular coagulation has been associated with acute progranulocytic leukaemia. Other renal complications are commonly due to treatment, most particularly the tumour lysis syndrome (see ‘Tumour lysis syndrome’).

POEMS syndrome POEMS syndrome is a rare condition defined by the presence of peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder (IgA, IgG, IgM, or LC only the LC being almost always of the lambda isotype), and skin changes. The association of POEMS syndrome with osteosclerotic myeloma or Castleman’s disease is common. Although the pathophysiology of the disease is unknown, POEMS syndrome is characterized by a very high serum level of vascular endothelial growth factor, which seems to be responsible for most symptoms present in this disease. Renal disease may occur, which usually manifests as proteinuria, haematuria, and renal failure that may progress to endstage renal failure. Kidney biopsy reveals lesions resembling thrombotic microangiopathy, with glomerular enlargement, cellular proliferation, and mesangiolysis with marked swelling of endothelial and mesangial cells, associated with endarteritis-​like lesions in the small renal arteries. The monoclonal component is usually not deposited in kidney.

Tumour lysis syndrome Tumour lysis syndrome is a life-​threatening metabolic emergency. It occurs in patients with haemopathies involving a high cell turnover, such as Burkitt’s lymphoma or acute leukaemia, mostly at the onset of chemotherapy and/​or on radiation therapy. The ensuing massive cytolysis generates high levels of uric acid, phosphate, potassium, and xanthine (especially in patients treated with allopurinol), with a concomitant decrease in serum calcium concentration. Oliguric or anuric acute kidney injury may occur, especially in those who are dehydrated or have pre-​existing impairment of kidney function. This acute kidney injury is mostly the consequence of acute precipitation of urate crystals in the tubular lumen, but in those with a moderate increase in uric acid concentration, the role of severe hyperphosphataemia causing precipitation of calcium/​phosphate complexes in renal interstitium and the tubular system has been assumed. Prevention is better than cure, and intensive monitoring is mandatory to prevent the development and the consequences of this syndrome. Patients at risk of the tumour lysis syndrome should be vigorously hydrated with 0.9% saline (assuming normal or near-​ normal baseline renal function, and with care taken to avoid inducing pulmonary oedema) before receiving chemotherapy or radiotherapy. Urinary alkalinization should be used with caution because it may induce phosphate precipitation. Reduction of urate production with allopurinol, which increases the risk of formation of xanthine nephropathy/​stones due to accumulation of xanthine, should be reserved for patients at low risk for developing tumour lysis syndrome. In high-​ risk patients (high tumour burden, aggressive chemotherapy, hypovolaemia) with hyperuricaemia, recombinant modified urate oxidase (rasburicase) should be preferred, which rapidly reduces the uric acid pool, prevents accumulation of xanthine and hypoxanthine, and does

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not require alkalinization for effect. Rasburicase is also indicated in the treatment of established tumour lysis syndrome, associated with vigorous hydration with 0.9% saline to encourage urinary output in patients passing urine, with close clinical monitoring to prevent iatrogenic fluid overload. Patients with severe acute kidney injury should be treated with haemodialysis, which allows recovery of renal function following the reduction of serum phosphate and serum uric acid concentrations.

FURTHER READING Bridoux F, et  al. (2015). Diagnosis of monoclonal gammopathy of renal significance. Kidney Int, 87, 698–​711. Leung N, et  al. (2012). Monoclonal gammopathy of renal significance:  when MGUS is no longer undetermined or insignificant. Blood, 120, 4292–​5. Leung N, et al. (2019). The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol, 15, 45–59.

Renal involvement in Ig light-​chain amyloidosis Dispenzieri A, et al. (2004). Serum cardiac troponins and N-​terminal pro-​brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol, 22, 3751–​7. Gertz MA, Merlini G (2010). Definition of organ involvement and response to treatment in AL amyloidosis:  an updated consensus opinion. Amyloid, 17 Suppl 1, 48–​9. Jaccard A, et al. (2007). High-​dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med, 357, 1083–​93. Kyle RA, Gertz MA (1995). Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol, 32,  45–​59. Palladini G, et al. (2010). The combination of high-​sensitivity cardiac troponin T (hs-​cTnT) at presentation and changes in N-​terminal natriuretic peptide type B (NT-​proBNP) after chemotherapy best predicts survival in AL amyloidosis. Blood, 116, 3426–​30. Palladini G, et al. (2014). A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood, 124, 2325–​32. Ronco PM, Aucouturier P, Moulin B (eds) (2010). Renal amyloidosis and glomerular diseases with monoclonal immunoglobulin deposition. In: Floege J, Johnson RJ, Feehally J (eds) Comprehensive clinical nephrology, 4th edition, pp. 322–​34. Saunders Elsevier, London. Vrana JA, et  al. (2009). Classification of amyloidosis by laser microdissection and mass spectrometry-​based proteomic analysis in clinical biopsy specimens. Blood, 114, 4957–​9. Wechalekar AD, et al. (2015). Guidelines on the management of AL amyloidosis. Br J Haematol, 168, 186–​206.

Renal involvement in myeloma Bridoux F, et al. (2017). Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: a randomized clinical trial. JAMA, 318, 2099–110. Dimopoulos MA, et al. (2010). Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol, 28, 4976–​84. Ecotière L, et al. (2016). Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients. Nephrol Dial Transplant, 31,  64–​72.

Hutchison CA, et al. (2007). Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies. J Am Soc Nephrol, 18, 886–​95. Hutchison CA, et al. (2019). High cutoff versus high-flux haemodialysis for myeloma cast nephropathy in patients receiving bortezomibbased chemotherapy (EuLITE): a phase 2 randomised controlled trial. Lancet Haematol, 6, e217–e228. Leung N, Behrens J (2012). Current approach to diagnosis and management of acute renal failure in myeloma patients. Adv Chronic Kidney Dis, 19, 297–​302.

Light-​chain, light-​and heavy-​chain, and heavy-​chain deposition disease Cohen C, et  al. (2015). Bortezomib produces high haematological response rates with prolonged survival in monoclonal immunoglobulin deposition disease. Kidney Int, 88, 1135–​43. Joly F, et al. (2019). Randall-type monoclonal immunoglobulin deposition disease: novel insights from a nationwide cohort study. Blood, 133, 576–87. Ronco PM, Aucouturier P, Moulin B (2010). Renal amyloidosis and glomerular diseases with monoclonal immunoglobulin deposition. In: Floege J, Johnson RJ, Feehally J (eds) Comprehensive clinical nephrology, 4th edition, pp. 322–​34. Saunders Elsevier, London. Royer B, et al. (2004). High dose chemotherapy in light chain or light and heavy chain deposition disease. Kidney Int, 65,  642–​8.

Non-​Randall-​type  MIDD Gumber R, et al. (2018). A clone-directed approach may improve diagnosis and treatment of proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Kidney Int, 94, 199–205. Nasr SH, et  al. (2009). Proliferative glomerulonephritis with monoclonal IgG deposits. J Am Soc Nephrol, 20, 2055–​64. Touchard G (2003). Ultrastructural pattern and classification of renal monoclonal immunoglobulin deposits. In: Touchard G, et al. (eds) Monoclonal gammopathies and the kidney, pp. 95–​117. Kluwer, Dordrecht.

Nonamyloid fibrillary and immunotactoid glomerulopathies Bridoux F, et al. (2002). Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features. Kidney Int, 62, 1764–​75. Javaugue V, et al. (2013). Long-​term kidney disease outcomes in fibrillary glomerulonephritis: a case series of 27 patients. Am J Kidney Dis, 62, 679–​90. Nasr SH, et al. (2011). Fibrillary glomerulonephritis: a report of 66 cases from a single institution. Clin J Am Soc Nephrol, 6, 775–​84. Nasr SH, et al. (2017). DNAJB9 is a specific immunohistochemical marker for fibrillary glomerulonephritis. Kidney Int Rep, 3, 56–64. Rosenstock JL, et al. (2003). Fibrillary and immunotactoid glomerulonephritis: distinct entities with different clinical and pathologic features. Kidney Int, 63, 1450–​61.

Renal involvement in cryoglobulinaemia Brouet JC, et  al. (1974). Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med, 57, 775–​88. Cacoub P, Terrier B, Saadoun D (2014). Hepatitis C virus-​induced vasculitis: therapeutic options. Ann Rheum Dis, 73,  24–​30.

21.10.6  Haemolytic uraemic syndrome

D’Amico G (1998). Renal involvement in hepatitis C infection: cryoglobulinemic glomerulonephritis. Kidney Int, 54, 650–​71. De Vita S, et  al. (2012). A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum, 64, 843–​53. Saadoun D, et  al. (2006). Antiviral therapy for hepatitis C virus-​ associated mixed cryoglobulinemia vasculitis. Arthritis Rheum, 54, 3696–​706. Saadoun D, et al. (2017). Efficacy and Safety of Sofosbuvir Plus Daclatasvir for Treatment of HCV-Associated Cryoglobulinemia Vasculitis. Gastroenterology, 153, 49–52.e5. Terrier B, et  al. (2012). Management of non infectious mixed cryoglobulinaemia vasculitis: data from 242 cases included in the CryoVas survey. Blood, 119, 5996–​6004.

Renal involvement in Waldenström’s macroglobulinaemia Audard V, et al. (2008). Renal lesions associated with IgM-​secreting monoclonal proliferations:  revisiting the disease spectrum. Clin J Am Soc Nephrol, 3, 1339–​49. Chauvet S, et al. (2015). Kidney disorders associated with monoclonal IgM-​secreting B-​cell lymphoproliferative disorders: a case series of 35 patients. Am J Kidney Dis, 66, 756–​67.

21.10.6  Haemolytic uraemic syndrome Edwin K.S. Wong and David Kavanagh ESSENTIALS Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy characterized by the triad of thrombocytopenia, microangiopathic haemolytic anaemia, and acute kidney injury. It is most often caused by Shiga toxin-​producing Escherichia coli (STEC-​HUS), and any HUS not caused by this is often termed atypical HUS (aHUS). aHUS may be caused by an underlying complement system abnormality (primary aHUS) or by a range of precipitating events, such as infections or drugs (secondary aHUS). Management of STEC-​HUS is supportive. In aHUS, plasma exchange is the initial treatment of choice until ADAMTS13 activity is available to exclude thrombotic thrombocytopenic purpura as a diagnosis. Once this has been done, eculizumab should be instigated as soon as possible.

C3 glomerulopathy and monoclonal gammopathy Bridoux F, et al. (2011). Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association? Clin J Am Soc Nephrol, 6, 2165–​74. Chauvet S, et al. (2017). Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy. Blood, 129, 1437–447. Chauvet S, et al. (2018). Both monoclonal and polyclonal immunoglobulin contingents mediate complement activation in monoclonal gammopathy associated-C3 glomerulopathy. Front Immunol, 9, 2260. Ravindran A, et al. (2018). C3 glomerulopathy associated with monoclonal Ig is a distinct subtype. Kidney Int, 94, 178–86. Zand L, et al. (2013). C3 glomerulonephritis associated with monoclonal gammopathy: a case series. Am J Kidney Dis, 62, 506–​14.

Renal involvement in lymphomas and leukaemias Moulin B, et al. (1992). Glomerulonephritis in chronic lymphocytic leukemia and related B-​cell lymphomas. Kidney Int, 42, 127–​35. Ronco PM (1999). Paraneoplastic glomerulopathies: new insights into an old entity. Kidney Int, 56, 355–​77.

Renal involvement in POEMS syndrome Nakamoto Y, et al. (1999). A spectrum of clinicopathological features of nephropathy associated with POEMS syndrome. Nephrol Dial Transplant, 14, 2370–​8.

Tumour lysis syndrome Coiffier B, et al. (2008). Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-​based review. J Clin Oncol, 26, 2667–​78. Cairo MS, et  al. (2010). Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol, 149, 578–​86. Rampello E, et al. (2006). The management of tumor lysis syndrome. Nat Clin Pract Oncol, 3, 438–​47.

Introduction Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy characterized by the triad of thrombocytopenia, microangiopathic haemolytic anaemia, and acute kidney injury. HUS is broadly classified according to aetiology. The most common form of HUS is secondary to Shiga toxin-​producing Escherichia coli (STEC), STEC-​HUS. The term, atypical HUS (aHUS) has been used to classify any HUS not caused by Shiga toxin. With the discovery of the role of complement gene mutations in aHUS, primary aHUS has been used to refer to those cases with documented complement dysregulation. Many precipitating events, including infections, drugs, autoimmune conditions, transplants, pregnancy, and metabolic conditions have been associated with aHUS. These have frequently been called secondary aHUS. It is increasingly recognized that patients with an underlying complement system abnormality often require a secondary trigger for aHUS to manifest. Classifications describing both the genetic background and aetiological trigger are beginning to be introduced.

Epidemiology The incidence of STEC-​HUS is approximately 20 per million population per year, but it is more common in children. An exception to this was in the 2011 E. coli 0104:H4 outbreak in Northern Europe where more than 800 cases of STEC-​HUS were reported, predominantly adults. The best estimate of aHUS incidence is 0.42 per million population per year in a British population.

Pathology In the acute phase of disease, glomerular capillary wall thickening is seen as a result of endothelial cell swelling and accumulation of

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Atypical HUS Complement-​mediated aHUS A series of groundbreaking studies in the late 1990s established the role of complement overactivation in the pathogenesis of aHUS (Fig. 21.10.6.2). In patients with aHUS, loss-​of-​function mutations in complement regulators, activating mutations in complement components, and autoantibodies to complement regulatory components have been reported (Table 21.10.6.1). Loss-​of-​function mutations

Fig. 21.10.6.1  A glomerulus from a patient with HUS showing severe acute changes of congestion, intraluminal thrombi, red cell fragmentation, and endothelial cell swelling (haematoxylin and eosin, magnification ×400).

flocculent material between the endothelium and the underlying basement membrane (Fig. 21.10.6.1). Double contouring can be seen on silver staining. Collapsed capillary loops containing fragmented red blood cells, fibrin, and platelet thrombi give the classical bloodless glomerular appearance. Fibrinoid necrosis of the afferent arteriole associated with thrombosis is also present. Mesangiolysis and development of aneurysmal dilatation of the capillaries may be seen. Subsequently, there is mucoid intimal hyperplasia with narrowing of the vessel lumen. With time, sclerotic and membranoproliferative changes may develop. Immunofluorescence demonstrates fibrin or fibrinogen in the glomeruli and vessel walls and nonspecific deposition of immunoglobulin and complement may be seen. There are no pathognomonic features to allow discrimination of STEC-​HUS from aHUS on histological grounds.

Pathogenesis STEC-​HUS E.  coli O157:H7 is the most common strain causing STEC-​ HUS. Other serotypes of E. coli can also produce toxin, and the largest recorded outbreak of STEC-​H US occurred in Northern Europe in 2011 due to infection with serotype O104:H4. In developing countries, Shigella dysenteriae type 1 is a common cause of HUS. STEC strains adhere to the gut and Shiga toxin is translocated through the intestinal epithelium. It has been suggested that Shiga toxin is then taken up by circulating leucocytes and transported to the kidney. Globotriaosylceramide (Gb3) is the receptor for Shiga toxin and mediates internalization, following which it is transported to the endoplasmic reticulum. The Shiga toxin complex is then cleaved to release the enzymatically active component that inactivates the ribosome, leading to inhibition of protein synthesis and cell death. It can also activate signalling pathways, inducing an inflammatory response in affected cells

Mutations in the complement factor H gene (CFH) are the most common genetic predisposition to disease, accounting for around 25% of aHUS. The factor H protein (FH) is the major regulator of complement in the fluid phase. It functions by competing with factor B (FB) for C3b binding, decaying the complement component 3 (C3) convertase, and by acting as a cofactor for factor I (FI)-​ mediated C3b proteolysis. There is also a recognition domain at the C-​terminal end of FH that binds to C3b and glycosaminoglycans allowing FH to bind to and regulate complement on the glomerular endothelial surface. In aHUS, many of the mutations alter this region and thus impair cell surface complement regulation. FI is a serum serine protease that cleaves C3b and C4b in the presence of its cofactors (FH and CD46). Mutations in the complement factor I gene (CFI) are found in around 5 to 10% of aHUS, and defective regulation of complement has been demonstrated in functional analyses. CD46 is a cell surface-​bound complement regulator that acts as a cofactor for FI. Mutations in the CD46 gene account for approximately 10% of aHUS cases, with most mutations resulting in a quantitative deficiency. Activating mutations Activating mutations have been described in the genes encoding complement factor B (CFB) and C3 (C3). These are the complement components from which the amplifying C3 convertase is comprised. C3 mutations are found in around 2 to 10% of aHUS cases, whereas CFB mutations are rare. Mutations in both result in increased C3 convertase activity and consequently greater complement-​mediated damage to glomerular endothelium. Inhibitory autoantibodies Autoantibodies against FH have been identified in aHUS. These are usually shown to block the ability of FH to bind to C3b or glycosaminoglycans and, therefore, inhibit complement regulation at the glomerular endothelium. Penetrance of disease Penetrance of disease is age related and has been reported to be as high as 64% by the age of 70 for individuals carrying a single genetic mutation. This suggests that additional disease risk modifiers are important. Around 3% of patients have one or more mutations, with increased penetrance per extra mutation. Together, these still do not explain why some patients develop disease until later in life. This is best explained by the need for an environmental trigger such as infection, drugs, or pregnancy (Box 21.10.6.1).

21.10.6  Haemolytic uraemic syndrome

Activation Classical Pathway

Alternative Pathway

Lectin Pathway

C3b

Amplification Loop

B

C3

Regulation —

FH

Ba

C3b

C3 convertase

FI Bb

C5 convertase

Terminal Pathway

C3b

CD46

C3b Bb C5a

— C5

C5b

MAC

Eculizumab

Fig. 21.10.6.2  Complement cascade. Activation of the complement system occurs via one of three pathways, classical, alternative, or lectin, resulting in the cleavage of C3 into C3b. C3b then forms C3bBb, the C3 convertase of the alternative pathway, which in turn generates more C3b as part of a positive amplification loop. This then leads to the formation of C3bC3bBb, the C5 convertase, and activation of terminal pathway by cleaving C5 into C5a and C5b. C5a is an anaphylatoxin while C5b allows formation of membrane attack complex (MAC) generation and cell lysis. The regulatory proteins (FH, FI, and CD46) protect the host from complement overactivation by preventing persistent amplification of complement. Eculizumab prevents terminal pathway activation by inhibition of the cleavage of C5.

Other forms of aHUS Genetic Autosomal recessive defects in methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type (MMACHC) and diacylglycerol kinase-​ε (DGKE) have been shown to cause aHUS (Table 21.10.6.1). Combined methylmalonic aciduria and homocystinuria (cblC) is a disorder of cobalamin (vitamin B12) metabolism characterized by

neurological, metabolic, and developmental symptoms. It is a heterogeneous disorder and only some patients develop aHUS. The pathophysiological mechanism of HUS in the cblC defect is unclear, but the endothelial abnormalities on kidney biopsies are striking and suggest that endothelial cell dysfunction may be the precipitating event. Long-​term management of cblC disease is with cobalamin, folinic acid, and betaine. Mutations in DGKE have been reported to cause aHUS in the first year of life. DGK-​ε is part of an intracellular signalling cascade and

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Table 21.10.6.1  Genetic causes of atypical HUS

Box 21.10.6.2  Extrarenal manifestations of HUS

Gene name

Gene symbol

OMIM number

Inheritance

Complement factor H

CFH

235400

AD/​AR

Complement factor I

CFI

612923

AD

CD46

CD46

612922

AD/​AR

Complement component 3

C3

612925

AD

Complement factor B

CFB

612924

AD

Diacylglycerol kinase-​ε

DGKE

615008

AR

Methylmalonic aciduria and homocystinuria, cobalamin C type

MMACHC

277400

AR

AD, autosomal dominant; AR, autosomal recessive.

although its role in the pathogenesis of aHUS has yet to be fully elucidated, it is not thought to participate in the complement system. In keeping with this, several individuals with mutations in DGKE have failed to respond to eculizumab. Noninherited Infection with neuraminidase-​producing Streptococcus pneumoniae accounts for approximately 5% of childhood HUS. The incidence is greatest in children younger than 2 years, most commonly in patients with parapneumonic empyema. Neuraminidase cleaves sialic acid residues from the glycoproteins on the cell membrane of erythrocytes, platelets, and endothelium, exposing the normally hidden Thomsen–​Friedenreich antigen (T antigen). This then reacts with anti-​T IgM antibodies that are normally present in plasma. It has been hypothesized that binding of anti-​T IgM to platelets and glomerular endothelium causes thrombotic microangiopathy by platelet aggregation and direct endothelial cell damage. Treatment is supportive with eradication of streptococcal infection. Many drugs have been reported to cause aHUS and this occurs by two main mechanisms:  immune-​mediated damage and direct toxicity. For example, quinine induces the development of autoantibodies reactive with either platelet glycoprotein Ib/​IX or IIb/​IIIa complexes, or both. In contrast, mitomycin C, an alkylating agent used to treat a variety of malignancies, is thought to cause aHUS by a direct toxic effect on endothelium. Box 21.10.6.1  Triggers of atypical HUS Pregnancy • • Respiratory infections: Bordetella pertussis, Streptococcus pneumoniae, Haemophilus influenza • Parasites: Plasmodium falciparum • Non-​STEC diarrhoeal illnesses:  norovirus, Campylobacter upsaliensis, Clostridium difficile • Drugs:  alemtuzumab, cisplatin, gemcitabine, mitomycin, clopidogrel, quinine, interferon-​α, -​β, anti-​VEGF, ciclosporin, tacrolimus, ciprofloxacin, oral contraceptives, illicit drugs • Autoimmune:  anticardiolipin, C3 nephritic factor, systemic lupus erythematosus • Vaccination • Bone marrow transplantation • Malignancy: gastric, breast, prostate, lung, colon, ovarian, pancreatic, lymphoma

Neurological involvement • • Cerebral artery thrombosis/​stenosis • Digital gangrene • Extracerebral artery stenosis • Cardiac involvement/​myocardial infarction • Ocular involvement • Pulmonary involvement • Pancreatic involvement

Pregnancy was historically cited as a cause of aHUS, but recent studies have suggested that over 80% of patients have a complement gene mutation and that pregnancy acts by unmasking complement-​mediated  aHUS.

Clinical features The diagnostic triad of acute kidney injury, microangiopathic haemolytic anaemia, and thrombocytopenia is common to both STEC-​HUS and aHUS. In cases of STEC-​HUS there is usually a prodromal phase. Around 3  days after ingestion of contaminated food, abdominal pain and bloody diarrhoea usually, although not invariably, occur. HUS develops in about 10% of patients after 3 to 4 days. In complement-​mediated aHUS, a triggering event is typically noted prior to presentation. Upper respiratory tract infections, fevers, pregnancy, and drugs have been suggested as potential triggers. Additionally, non-​STEC diarrhoea is a not uncommon trigger and clinicians should not assume diarrhoea equates to STEC-​HUS (Box 21.10.6.1). In pneumococcal-​associated aHUS, pneumonia or meningitis is usually present. Extrarenal manifestations, predominantly neurological, are reported in all types of HUS (Box 21.10.6.2).

Laboratory investigations Once routine biochemical and haematological analyses have demonstrated a thrombotic microangiopathy, investigations are aimed at determining the underlying aetiology and excluding other differential diagnoses (Fig. 21.10.6.3). The most urgent test is an ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) assay, deficiency of which is characteristic of thrombotic thrombocytopenic purpura.

Diagnosis of STEC-​HUS To confirm the diagnosis of STEC-​HUS, stool samples should be sent for STEC culture in tellurite-​enriched sorbitol–​MacConkey agar. Samples may be negative, especially if sampling is late in the course of disease. Even following cessation of diarrhoea, rectal swabs or a faecal culture should be taken. Enzyme-​linked immunosorbent assay identification of Shiga toxins should be attempted from stool and stool cultures, as should polymerase chain reaction testing of stool for Shiga toxin genes. Serology identifying IgM against the commonly occurring STEC strains should also be performed.

21.10.6  Haemolytic uraemic syndrome

In contrast, a nonrandomized assessment from the 2011 E. coli O104:H4 outbreak suggested antibiotics reduced seizures and death. Unlike the O157:H7 strain, treatment of E. coli O104:H4 with antibiotics did not increase quantities of Shiga toxin. Antibiotic treatment of S. dysenteriae does not increase the risk of HUS. There is no conclusive evidence to suggest plasma exchange is beneficial in STEC-​HUS and it is not routinely administered. The complement inhibitor eculizumab did not show any benefit when retrospective analysis of the Northern European STEC-​ HUS O104:H4 outbreak was performed. As STEC-​HUS is a self-​ limiting illness, only a randomized controlled trial will delineate any benefit.

TMA ↓Hb ↓Plts

↑LDH ↓Haptoglobin

TTP HUS

ADAMTS13 activity 80% patients)

Early signs of renal damage (30–​60% of patients)

Markers of progressive disease (10–​20% patients)

Increased glomerular filtration rate

Microalbuminuria

Nonselective proteinuria

Hyposthenuria

Haematuria

Falling glomerular filtration rate (>5 ml/​min per 1.73 m2 per year)

Nocturia/​enuresis

Tendency to hyperkalaemia

Falling steady state haemoglobin concentrationa

Due to falling endogenous erythropoietin production as renal function declines.

sickle haemoglobinopathies. This is highly aggressive, can occur in children as young as 2 years of age, and, so far, has proved to be universally fatal within 2 years of presentation.

Albuminuria and proteinuria The appearance of abnormal levels of albumin in the urine is an early manifestation of SCN. It is present in some teenage children but its prevalence increases with age, reaching approximately 60% in adults over 45  years. For many, the degree of albuminuria appears not to progress, but in others, nonselective proteinuria develops rapidly, and these are the patients most at risk of future renal impairment. Rarely, patients can develop full-​blown nephrotic syndrome, though this should always be investigated to rule out a second pathology. In particular, nephrotic syndrome has been reported in a number of patients following infection with human parvovirus B19, in which case renal biopsy demonstrates the collapsing form of focal segmental glomerulosclerosis and (if taken early in the disease course) occasionally positive staining for the HPV B19 virus. In such cases the nephrotic syndrome is usually self-​limiting, although a gradual decline in renal function often occurs in the months and years following the acute event.

health in those who respond well to this therapy in other respects. Haematopoietic cell transplantation is the only curative treatment currently available for SCD and is usually reserved for children with major complications such as stroke. Although it is probable that recipients of such transplants who have a good outcome are protected from developing SCN in future, most published studies exclude those with established renal disease from receiving this treatment and so its role in treating kidney dysfunction has not yet been studied.

Treatment of endstage kidney disease Despite optimal treatment, some patients with SCD will develop progressive kidney failure that will eventually necessitate the need for renal replacement therapy. The prognosis for patients with SCD on dialysis is poor and the average lifespan after a diagnosis of endstage kidney disease is only 4 years. Kidney transplantation offers a better outcome and can increase life expectancy to 10 to 15 years in those who have a well-​functioning graft. Recurrent SCN can complicate the outcome following transplantation, although this can be mitigated by placing the patient on an exchange transfusion programme.

FURTHER READING Alvarez O, et al. (2012). Effect of hydroxyurea treatment on renal function parameters:  results from the multi-​center placebo-​controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatr Blood Cancer, 59, 668–​74. Derebail VK, et al. (2019). Progressive Decline in Estimated GFR in Patients With Sickle Cell Disease: An Observational Cohort Study. Am J Kidney Dis, pii: S0272-6386(19)30007-1. doi: 10.1053/j. ajkd.2018.12.027. Nath KA, Hebbel RP (2015). Sickle cell disease: renal manifestations and mechanisms. Nat Rev Nephrol, 3, 161–​71. Sharpe CC, Thein SL (2014). How I treat renal complications in sickle cell disease. Blood, 24, 3720–​6. Thompson J, et al. (2007). Albuminuria and renal function in homozygous sickle cell disease:  observations from a cohort study. Arch Intern Med, 167,  701–​8.

Treatment options Therapies to prevent progression of chronic kidney disease Treatment of patients with proteinuria with inhibitors of the renin–​ angiotensin system to reduce glomerular pressure and proteinuria has become accepted as standard practice in those who can tolerate it from a blood pressure and serum potassium perspective. Intermittent or regular blood transfusion is often used to manage the acute complications of SCD or for primary or secondary prevention of stroke, but there is little evidence for its use in the prevention or treatment of SCN. However, using blood transfusion to reduce the percentage of sickle haemoglobin in patients prior to surgery does have proven benefits and this is likely to be particularly important in those undergoing renal transplantation. Hydroxycarbamide (hydroxyurea) therapy has clear clinical benefits for many patients with SCD, including a reduction in hospitalization episodes and painful crises. Although studies have failed to demonstrate any clear benefit of this treatment in the short term, it is likely that it helps maintain kidney

21.10.8  Infection-​associated nephropathies A. Neil Turner ESSENTIALS Infection may be a primary cause of renal disease (e.g. postinfectious glomerulonephritis) or affect the kidneys on a background of debilitating illnesses and previous medical interventions. Renal disease may arise as a consequence of immune responses to a pathogen, direct invasion by the microorganism, or the effects of infection on the systemic or local circulations.

21.10.8  Infection-associated nephropathies

Glomerulonephritis—​associated with chronic and acute bacterial infections. Shunt nephritis follows colonization of a ventriculoatrial shunt, most commonly with Staphylococcus epidermidis, leading to constitutional symptoms, an acute inflammatory response, and (most characteristically) a type 1 mesangiocapillary glomerulonephritis. Infective endocarditis and other deep-​seated bacterial infections may produce a similar renal picture, but they can also mimic vasculitic syndromes and outcome is dependent on the response of the infection to treatment. Acute postinfectious glomerulonephritis—​see Chapter 21.8.5. Interstitial nephritis—​bacteria that can cause this include leptospira (Weil’s disease), Rickettsia rickettsii (Rocky Mountain spotted fever), legionella, and mycobacteria. Viral infections include hantaviruses (haemorrhagic fever with renal syndrome and nephropathia epidemica) and, almost exclusively following renal transplantation, cytomegalovirus and polyomavirus hominis type 1 (BK) virus. HIV-​associated renal disorders—​these include HIV nephropathy, which is a focal segmental glomerulosclerosis of ‘collapsing’ form, occurring almost exclusively in black patients. Other morphologies are more common in other races, but interstitial disease is also common as a manifestation of infection or of drug toxicity. Hepatitis B virus—​chronic infection is strongly associated with membranous nephropathy; affected individuals are HBeAg and HBsAg positive, usually with coexistent hepatitis; seroconversion from HBeAg positive to HBeAb positive (naturally or induced by treatment) is associated with remission of the renal lesion. Hepatitis C virus—​chronic infection is the commonest cause of mixed essential (type II) cryoglobulinaemia in most populations; it is associated with membranoproliferative glomerulonephritis (MPGN, also described as MCGN), and reduction of viral replication has been associated with disease remission.

Introduction Almost all renal lesions, particularly glomerular lesions, may be associated with infections. In the developed world, infection-​associated nephritis was once predominantly recognized during acute infections occurring in apparently healthy individuals, and this is still the pattern in many countries. However, improvements in living conditions and health care reduce the numbers of healthy people succumbing to complications of infection. Instead, infections occurring on a background of debilitating illnesses and previous medical interventions become more common precipitants of renal disease. In this chapter, glomerular diseases and interstitial diseases associated with infection are considered in turn. Particular attention is given to those glomerulopathies associated with bacterial endocarditis and other chronic bacterial infections, and three viral infections of worldwide importance, HIV, hepatitis B, and hepatitis C.

Pathogenesis Infection-​ associated glomerular disease is usually attributed to trapping of circulating antigen–​antibody complexes in the glomerulus, or to immune responses to pathogen-​derived antigens that become ‘planted’ in the glomerulus. The evidence for deposition

of circulating immune complexes is strong for cryoglobulinaemia, and highly plausible for infections occurring within the vascular system such as bacterial endocarditis. In most other infections the evidence is less clear, and this is probably not a common mechanism of glomerular disease. A direct cytopathic effect on glomerular cells seems likely for some pathogens such as HIV and parvovirus, both of which infect glomerular podocytes and have been associated with ‘collapsing’ focal segmental glomerulosclerosis (FSGS). Interstitial renal disease is often blamed on direct invasion by the microorganism, and for some there is evidence that this is true. The pathogen may cause injury directly, or indirectly by causing cells to express foreign antigens which generate an immune response. More speculatively, an immune response generated to an organism may cross-​react with a remote self-​antigen, triggering autoimmunity through molecular mimicry, but there are no unequivocal examples of this. Infection may also involve the kidney by interfering with the circulation either generally (septic shock) or locally (e.g. by causing thrombotic microangiopathy, as for Escherichia coli O157 or Capnocytophaga canimorsus (previously DF-​ 2)). Occasionally, toxins may be released that harm the kidney directly (e.g. haemoglobin in malaria). Medically administered toxins include antimicrobial agents that impair renal function by crystallization (e.g. aciclovir, indinavir) or by predictable toxicity (e.g. aminoglycosides, amphotericin, and tenofovir), or by idiosyncratic reactions such as acute interstitial nephritis (e.g. penicillins).

Glomerulonephritis associated with chronic and acute bacterial infections Classic acute postinfectious glomerulonephritis is considered in Chapter  21.8.5. This account considers subacute or chronic diseases, although other causes of a ‘classic’ picture are mentioned. Shunt nephritis was first recognized in the 1960s, and it remains the archetype of an immune complex nephritis. The glomerulonephritis occurring in association with infective endocarditis is very similar. Both are caused by subacute infection within the bloodstream, with constant shedding of antigen and formation of antigen–​antibody complexes. Other bacterial infections may cause similar pictures.

Shunt nephritis and similar syndromes of intravascular infection In shunt nephritis, a ventriculoatrial shunt implanted for hydrocephalus becomes colonized by bacteria, usually of low pathogenicity. More common modern equivalents are infected long-​term central venous catheters and other intravascular devices. The syndrome does not occur with ventriculoperitoneal shunts, which are therefore now the preferred neurosurgical option, making shunts now a rare cause of the syndrome. Although Staphylococcus epidermidis has been most commonly implicated in these infections, Propionibacterium acnes or other organisms are sometimes involved. Typically the diagnosis is only appreciated after weeks to months of symptoms of mild to moderate pyrexia and malaise associated with haematuria and proteinuria and progressive renal impairment. Fevers have often been attributed to urinary infection in patients with neurogenic bladders. There may be moderate splenomegaly. Investigations show complement consumption and

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an acute-​phase response with normochromic normocytic anaemia, and variable renal impairment. The renal lesion is characteristically a type 1 membranoproliferative (mesangiocapillary) glomerulonephritis with deposition of multiple immunoglobulins and complement components beneath the endothelium, the classic appearance of a circulating immune complex nephritis. Sometimes the picture is more severe, showing a diffuse proliferative lesion, occasionally with crescents. In other cases, the histological appearances are less pronounced with focal proliferative changes. Antibiotic treatment alone is almost never adequate to cure these infections, which require removal of the intravascular device, followed by its replacement after an interval if it is still required. Delayed diagnosis and delayed removal may lead to more severe and irreversible renal damage, and sometimes to endstage renal failure, but some degree of recovery can follow successful treatment.

Infective endocarditis A similar syndrome can occur in infective endocarditis, as part of which minor degrees of glomerular disease are probably extremely common. In truly subacute endocarditis, symptoms and signs are as seen in shunt nephritis. Typical streptococcal infections are well represented in case reports, but there have been multiple reports involving ‘slow’ infections such as Q fever (Coxiella burnetii), and more unusual causes including chlamydia and fungi. Typical patients in developed countries have shifted from being young patients with rheumatic heart disease, to being elderly with comorbid conditions, long-​ term vascular access devices, pacemakers, etc. Infection of prosthetic or native heart valves may be implicated. Right-​sided endocarditis occurring in intravenous drug abusers may be particularly likely to present as nephritis, because the diagnosis is often delayed. Depletion of serum complement is again diagnostically useful, but, as for shunt nephritis, most other serological and haematological changes are nonspecific. Partial treatment with antibiotics makes diagnosis and management more difficult, as positive blood cultures are usually a key part of proving the diagnosis and selecting appropriate therapy. The pathological lesion is typically similar to that of shunt nephritis, but forms of endocarditis that are acute, rather than subacute (e.g. that associated with Staphylococcus aureus), are more likely to cause glomerulonephritis in a diffuse proliferative pattern, sometimes with crescent formation. Focal changes that are indistinguishable from antineutrophil cytoplasmic antibody (ANCA)-​associated vasculitis have been reported in the literature, and ANCA are detected in some patients. There may be a florid purpuric cutaneous vasculitis (as in Fig. 21.10.8.1), but there may be few or no other signs of vasculitis elsewhere. However, immune deposits are usually present in glomeruli, in contrast to the primary small-​vessel vasculitides. In most cases, the outcome is dependent on the response of the endocarditis to treatment, but renal involvement is a poor prognostic factor for survival, which may be simply because it reflects long-​lasting infection, although recovery from dialysis dependence may occur. Patients with endocarditis are also prone to two other renal lesions: interstitial nephritis related to antibiotics and, in those with disease on the left side of the heart or with right–​left shunts, renal emboli, although glomerulonephritis is a more common cause of urinary abnormalities.

Fig. 21.10.8.1  Cutaneous vasculitis in a patient with Staphylococcus aureus endocarditis.

Deep-​seated bacterial infections Amyloidosis is a well-​recognized consequence of very chronic bacterial (including mycobacterial) and other infections, and is described in Chapters 12.12.3 and 21.10.5. As in reactive amyloidosis of other aetiologies, progression of the renal lesion may be prevented or even partially reversed by treatment of the cause. Deep-​seated infections, particularly abscesses, may also be associated with glomerulonephritis. Although the mechanisms involved are presumably similar to those of shunt nephritis and nephritis associated with endocarditis, blood cultures have often been negative in reported cases. Staphylococcus aureus is the most frequently implicated organism. A wide variety of renal lesions have been described, usually inflammatory/​proliferative and with immunoglobulin deposition. Unsuspected abscesses or other deep-​seated infections are occasionally found only after the renal biopsy appearances trigger a search. Such hidden abscesses are more likely in obese or older people, and in those on corticosteroids or who are immunosuppressed by other means or by disease.

Acute glomerulonephritis and other infections Acute glomerulonephritis resembling poststreptococcal nephritis has been reported in association with a large number of other organisms, including current (as opposed to recent) infection with staphylococci, streptococci, and other bacteria, and with acute viral infections that are usually self-​limiting. These include Epstein–​Barr virus, cytomegalovirus, varicella, measles, mumps, parvovirus, and coxsackieviruses. Some may cause a clinical syndrome that is very similar to poststreptococcal nephritis, while others typically cause a less florid ‘nephritic’ or mixed ‘nephritic/​ nephrotic’ picture. Staphylococcus aureus is particularly associated with a variant of postinfectious glomerulonephritis with prominent nephrotic features and dominant IgA deposition in glomeruli.

Diagnostic difficulties in bacterial infection-​related glomerulonephritis Infection-​related nephritis may present in a very similar manner to nephritis associated with other systemic diseases, notably microscopic polyangiitis and other small-​vessel vasculitides (see

21.10.8  Infection-associated nephropathies

Chapter 21.10.2). As both types of disease process may be associated with fever, a systemic illness, and an acute-​phase response, it is important to consider the possibility of infection in all patients thought to have systemic vasculitis. Blood cultures should be routine. ANCA assays are extremely useful, but it is important to note that ANCA positivity has been recorded in many infections, both by fluorescence and by solid-​phase assays: ANCA are not diagnostic of small-​vessel vasculitides. Renal biopsy is often the most discriminating investigation. Infection-​associated glomerulonephritis is usually (but not invariably) associated with plentiful immunoglobulin deposition, whereas small-​vessel vasculitis is characteristically pauci-​immune. Nonglomerular causes of renal impairment (interstitial nephritis, acute tubular necrosis) are also distinguished by renal biopsy.

Interstitial nephritis associated with infections Bacterial infections Acute bacterial pyelonephritis is usually a florid and painful disorder associated with symptoms of urinary tract infection, as described in Chapter 21.13. Substantial renal impairment is usual only if a single functioning kidney is affected. Occasionally, however, the diagnosis is masked by immunosuppression (e.g. in a transplanted kidney), age, or other factors, and the diagnosis is made by the renal biopsy appearances of neutrophils in the interstitium and in tubules, which are rarely found in any other renal lesions. Acute interstitial nephritis is a key feature of Weil’s disease, a severe form of leptospirosis (see Chapter 8.6.35). Jaundice and renal failure follow a febrile illness caused by infection with Leptospira interrogans. The renal lesion comprises interstitial oedema with predominantly mononuclear infiltrates and foci of tubular necrosis. Renal failure is usually oliguric but may be polyuric. Dialysis may be required for days to weeks, and renal recovery may sometimes be incomplete. Other bacterial infections that may cause a similar pathological picture include Rocky Mountain spotted fever (Rickettsia rickettsii), in which there may be an interstitial nephritis with foci of haemorrhage, and acute Yersinia pseudotuberculosis infection, in which an acute lymphocytic interstitial nephritis has been described in several patients. Legionnaires’ disease (Legionella pneumophila) has been reported to be associated with renal impairment, also with an interstitial nephritis, but in some instances may show a picture of acute tubular necrosis. The same is probably true of other severe pneumonias. Mycobacteria can cause a chronic granulomatous interstitial nephritis (discussed in ‘Mycobacteria’).

Viral infections Hantaviruses Hantaviruses are carried by small rodents, and have been associated with a range of human syndromes that involve the kidneys with varying severity. ‘Haemorrhagic fever with renal syndrome’ (HFRS) is characterized by oliguric renal failure, associated histologically with lymphocytic interstitial nephritis that may be haemorrhagic in severe cases, reflecting the systemic bleeding diathesis. Some patients have been reported to have persistent renal impairment after recovery.

HFRS was originally associated with Hantaan strains of hantavirus in Korea, while milder disease, with less frequent and usually less severe renal impairment and without haemorrhagic diathesis, was associated with the Seoul strain. Milder disease (nephropathia epidemica) recognized in northern Europe and subsequently more widely was associated with the Puumula strain. However, it has become apparent that there are many more subtypes of hantavirus, and the association of a serotype with a particular clinical picture is not rigid. Severe disease with shock, variable haemorrhage, and sometimes pulmonary impairment has been encountered in the Balkans and Greece. Disease with predominantly pulmonary manifestations and shock has been recognized, particularly in North America, although these geographical variations in clinical picture are no more rigid than the strain variations. Ribavirin is active against hantaviruses in vitro, and therapy with ribavirin was found to be effective in HFRS caused by the classic Hantaan strain in China and confirmed in Korea, but there are likely to be strain differences as no benefit could be demonstrated in trials in the pulmonary syndrome in North America, and evidence for value more widely seems weak. Cytomegalovirus, polyomaviruses, and other viruses Cytomegalovirus (CMV) may lie dormant in renal tubular cells, and during new or reactivated infection causes characteristic inclusion bodies. This rarely has a significant impact on renal function outside the setting of renal transplantation, where CMV infection commonly occurs concurrently with acute rejection. Although there is evidence that CMV infection may precipitate rejection, it is also clear that the risk of CMV infection is greatly increased by most types of antirejection therapy. CMV may also rarely cause a florid glomerular lesion characterized by gross endothelial cell damage and swelling, resembling pre-​eclampsia. This has again been recognized almost exclusively in renal transplants, where some believe that the appearances are due to, or complicated by, vascular rejection. Human polyomaviruses (BK and JC) were previously believed to be benign passenger viruses which replicated without causing damage during immunosuppression. However, BK virus has been increasingly recognized as a cause of impaired renal transplant function, usually many months after transplantation. The histological changes of tubulitis closely resemble acute cellular rejection, but further immunosuppression favours further infective damage. Observation of typical inclusion bodies and immunohistochemical studies prove the true cause of the tubulitis, and renal function may improve after reduction of immunosuppressive agents, although renal outcome is often poor despite this. Polymerase chain reaction-​based screening has been introduced in many centres in attempts to make an earlier diagnosis, but there is still no proven antiviral therapy and reduction of immunosuppression is not without risk. A  strategy of combining leflunomide (as a replacement for azathioprine or mycophenolate mofetil), intravenous immunoglobulin, and ciprofloxacin has been tried, but shown no benefit. Polyomavirus renal disease seems to be less common in patients immunosuppressed for reasons other than renal transplantation, but it is being increasingly recognized. A wide range of other viruses and microorganisms have been less regularly associated with interstitial lesions. HIV (considered in the following section) may cause an interstitial nephritis. Another

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condition that is likely to be infective in origin, Kawasaki’s disease, is associated with interstitial nephritis, although glomerular lesions have also been described occasionally.

HIV and renal disease Renal impairment is commonly encountered at some stage of HIV infection. The largest single cause of serious renal disease in this group is the distinct entity of HIV nephropathy. However, this generalization is misleading as this specific diagnosis is largely restricted to black patients, and there are many other causes of renal disease in patients with HIV infection.

FSGS associated with HIV infection (HIV nephropathy) HIV nephropathy is characterized by heavy proteinuria and renal impairment. It is an important cause of endstage renal failure in Africa, but also significant in black adults of working age in the United States of America. Although it has often been described as an initial manifestation of HIV infection, in these circumstances the infection is advanced, with high viral loads and low CD4 counts. Histologically, the appearances are of FSGS of the ‘collapsing’ form, with injury and hypertrophy of glomerular epithelial cells accompanied by variable interstitial inflammation with oedema and microtubular dilatation (Fig 21.10.8.2). The racial (black African) restriction of susceptibility to HIV nephropathy and increased risk of other types of FSGS is due to variants in the APOL1 gene which convey resistance to trypanosomiasis. How they produce their disadvantageous renal effects is not yet known. Without therapy the condition progresses to endstage renal failure rapidly, over weeks to months. Perhaps because it is associated with low CD4 counts, the medium-​term prognosis in the past was poor despite renal replacement therapy, but effective antiviral therapy can alter this.

Non-​FSGS nephropathies in HIV infection FSGS accounts for a minority of HIV-​associated renal disease in most populations. An HIV immune complex glomerulonephritis (HIVICK) has been described, but so have other specific types of renal disease, encompassing almost all types of glomerular lesion, interstitial nephritis, cryoglobulinaemia, and thrombotic microangiopathy. IgA nephropathy has been frequently recorded. Some of these lesions may be directly caused by HIV infection, while others are related to concurrent infections with other microorganisms, and some may be related to therapy. The occurrence of autoimmune phenomena in HIV infection may also be accompanied by an increase in immune-​mediated primary renal diseases of many types. Interstitial nephritis is often but not always related to anti-​HIV drugs. Tenofovir in particular may cause tubular injury with renal impairment and sometimes Fanconi’s syndrome. Aciclovir and indinavir have replaced sulphonamides as common causes of crystal nephropathy. Adjusting the doses of these and other drugs in the setting of renal impairment is problematic. Patients with HIV infection receive many other drugs with predictable nephrotoxicity, and polypharmacy also puts them at risk of allergic reactions.

Highly active antiretroviral therapy and other therapies Highly active antiretroviral therapy (HAART), when instituted early, may arrest the progression of FSGS as well as lowering the mortality of patients with endstage renal failure. Severity of chronic damage on biopsy may be a better prediction of prognosis than serum creatinine. Its effect on non-​FSGS nephropathies may also be beneficial. Patients with any diseases associated with proteinuria should be treated with angiotensin-​converting enzyme inhibitors. Treatment with corticosteroids should probably be considered in patients with HIV-​FSGS who progress despite effective HAART and intensive renoprotective therapy with angiotensin-​converting enzyme inhibitors and blood pressure control. Patients with good control of HIV do well on renal replacement therapies, and several national guidelines now allow and recommend transplantation for patients whose prognosis is of many years. In high-​incidence regions, transplantation of kidneys from HIV-​ positive donors improves organ supply.

Nephropathy associated with hepatitis B virus

Fig. 21.10.8.2  Histology of HIV-​associated nephropathy showing glomerular collapse with a focal sclerosing lesion, microcystic tubular dilatation, and interstitial inflammation (magnification ×200). Reproduced with permission from Naicker S, Paget G. HIV and renal disease. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Courtesy of Prof Stewart Goetsch, University of the Witwatersrand.

Chronic infection with hepatitis B virus (HBV) (see Chapter 8.5.21) is strongly associated with membranous nephropathy, and it is an important secondary cause of the lesion. A  less clear relationship holds with membranoproliferative glomerulonephritis (MPGN, also known as MCGN), while for hepatitis C virus (HCV) the converse is true. Chronic HBV infection is much more common in some regions and racial groups, and the distribution of HBV-​related nephropathy closely follows this distribution. The clinical picture may be complicated by the concurrence of HBV infection by infection with HCV, HIV, or with other organisms, or by the coincidence of significant renal and hepatic disease. HBV membranous nephropathy has a

21.10.8  Infection-associated nephropathies

close relationship with virus multiplication, so affected individuals are usually HBeAg and HBsAg positive, with evidence of hepatitis, although this may be minor. Membranous nephropathy is a more common complication of HBV infection in children, but it is also more benign in this group. The lesion may be static, or in some cases (particularly in adults) associated with progressive deterioration to endstage renal failure. Histopathology is typical of membranous nephropathy, and HBV antigens may be detectable in glomerular deposits. Idiopathic membranous nephropathy is caused by autoantibodies to podocyte surface proteins, usually to the phospholipase A2 (PLA2) receptor, but these are not typically identified in patients with secondary membranous nephropathy, including that associated with HBV. The target in these circumstances may be viral, but it has not been identified. Seroconversion from HBeAg positive to HBeAb positive is associated with remission of the renal lesion, whether the conversion occurs naturally or is induced by treatment. Spontaneous remission of the renal lesion is more likely in children. Antiviral treatment is the appropriate therapy when required, as immunosuppression may increase viral burden. Recently acquired (within months) HBV infection has been associated with classic polyarteritis nodosa (PAN) in some populations, such as in France and North America, but even in these areas HBV-​ PAN is uncommon and apparently decreasing. Furthermore, the association of the two diseases is rare in some countries with low (e.g. the United Kingdom) and with high (e.g. Thailand) rates of HBV carriage, suggesting the involvement of a cofactor. Clinically, the disease is typical of PAN, affecting medium and somewhat smaller vessels but not capillaries, and therefore not usually associated with focal necrotizing or crescentic nephritis. ANCA are not usually detected. Treatment is difficult to balance as immunosuppression (usually with corticosteroids alone) is often indicated, but favours viral replication and exacerbation of liver disease, while remission

(a)

(b)

is associated with seroconversion from HBeAg positivity to HBeAb positivity.

Nephropathy associated with hepatitis C virus Chronic HCV (see Chapter 8.5.22) infection is the commonest cause of mixed essential (type II) cryoglobulinaemia in most populations, and an important cause of MPGN without overt cryoglobulinaemia. The clinical picture includes cutaneous vasculitis, glomerular pathology (mesangiocapillary glomerulonephritis, MCGN), and other manifestations. Cryoglobulins contain quantities of HCV antigens and bound antibody, in addition to monoclonal IgM rheumatoid factors. HCV may also be associated with MCGN in the absence of detectable cryoglobulins. A relationship with membranous nephropathy is also possible, but not proven. As for HBV, reduction of viral replication has been associated with disease remission. Immunosuppression with corticosteroids and sometimes other agents may be required to control disease manifestations caused by vasculitis. B-​cell depletion with anti-​CD20 monoclonal antibodies may help to control the disease if antiviral therapy does not.

Renal sequelae of other chronic infections Amyloidosis Amyloidosis (see Chapter 12.12.3) may be a consequence of all sorts of chronic infection, but of the ‘tropical’ infections is most frequently associated with schistosomiasis, filariasis, or leishmaniasis.

Mycobacteria Mycobacterial infections (see Chapter 8.6.26) cause a chronic granulomatous interstitial nephritis that is characteristically associated with inflammatory and fibrotic abnormalities in the ureters and lower

(c)

Fig. 21.10.8.3  Radiological appearances in urinary schistosomiasis. (a) Plain radiograph showing linear bladder calcification. (b) Retrograde urogram showing contracted bladder with reflux into extremely dilated ureter, and hydronephrosis. (c) Cystogram showing large irregular filling defect in the bladder caused by a tumour. Reproduced with permission from Barsoum RS. Schistosomiasis. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

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urinary tract. Symptoms often relate to lower tract involvement, but the disease may be asymptomatic, and in the earliest stages involvement is presumed to be restricted to the kidneys, with subsequent spread to the lower tract. Sterile pyuria is the rule, and impaired renal function is common at presentation. Imaging by intravenous urography or other techniques will show blunting of calyces, progressing to changes typical of pyelonephritis or papillary necrosis, along with lower tract abnormalities such as ureteric strictures and scarring and contraction of the bladder. Amyloidosis is a well-​recognized secondary complication of mycobacterial infections. Idiosyncratic reactions to antituberculous drugs are another common cause of late renal dysfunction.

Syphilis Congenital syphilis (see Chapter 8.6.37) may cause severe nephrotic syndrome with the histological pattern of membranous nephropathy. This is also the usual pattern when secondary syphilis rarely causes nephrotic syndrome. Both respond to antispirochaetal treatment.

Malaria Plasmodium falciparum infections (see Chapter  8.8.2) are an extremely important cause of acute kidney injury worldwide. This occurs in 1 to 5% of infected patients native to a malarial area, but a higher proportion of nonimmune visitors, and is associated with high mortality (15–​45%). Series from Africa have cast doubt on the existence of a specific chronic malarial nephropathy that was described in earlier literature. Biopsy studies have shown a high incidence of infection-​related glomerulonephritis and of FSGS, but have found little evidence of a distinct malarial disease.

Schistosomiasis Schistosomiasis (Fig. 21.8.10.3; see Chapter  8.11.1) is best recognized for causing disease of the lower urinary tract, but chronic infections associated with hepatosplenomegaly may be associated with glomerular disease after many years. In Schistosoma haematobium infection this is often due to secondary infections with Salmonella spp. rather than directly associated with schistosomal infection. In Schistosoma mansoni infection the relationship is probably usually directly causal, typically causing MPGN.

Filariasis Longstanding filariasis (see Chapter 8.9.2) may also be associated with glomerular lesions. An acute syndrome with tubulointerstitial nephritis has also been described in association with the presence of microfilariae in renal capillaries.

FURTHER READING Arendse CG, et al. (2010). The acute, the chronic and the news of HIV-​ related renal disease in Africa. Kidney Int, 78, 239–​45. Bigé N, et al. (2012). Presentation of HIV-​associated nephropathy and outcome in HAART-​treated patients. Nephrol Dial Transplant, 27, 1114–​21. Bonarek H, et al. (1999). Reversal of c-​ANCA positive mesangiocapillary glomerulonephritis after removal of an infected cysto-​atrial shunt. Nephrol Dial Transplant, 14, 1771–​3. Clementi A, et al. (2011). Renal involvement in leishmaniasis: a review of the literature. Nephrol Dial Transplant Plus, 4, 147–​52.

Conlon PJ, et al. (1998). Predictors of prognosis and risk of acute renal failure in bacterial endocarditis. Clin Nephrol, 49, 96–​101. Daugas E, Rougier JP, Hill G (2005). HAART-​related nephropathies in HIV-​infected patients. Kidney Int, 67, 393–​403. De Vita S, et  al. (2012). A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum, 64, 843–​53. Doe JY, et al. (2006). Nephrotic syndrome in African children: lack of evidence for ‘tropical nephrotic syndrome’? Nephrol Dial Transplant, 21,  672–​6. Elsheikha HM, Sheashaa HA (2007). Epidemiology, pathophysiology, management and outcome of renal dysfunction associated with plasmodium infection. Parasitol Res, 101, 1183–​90. Fabian J, et al. (2013). The clinical and histological response of HIV-​ associated kidney disease to antiretroviral therapy in South Africans. Nephrol Dial Transplant, 28, 1543–​54. Genovese G, et al. (2010). Association of trypanolytic ApoL1 variants with kidney disease in African-​Americans. Science, 329,  841–​5. Haffner D, et  al. (1997). The clinical spectrum of shunt nephritis. Nephrol Dial Transplant, 12, 1143–​8. Krautkrämer E, Zeier M, Plyusnin A (2013). Hantavirus infection:  an emerging infectious disease causing acute renal failure. Kidney Int, 83,  23–​7. Lai AS, Lai KN (2006). Viral nephropathy. Nat Clin Pract Nephrol, 2, 254–​62. Majumdar A, et  al. (2000). Renal pathological findings in infective endocarditis. Nephrol Dial Transplant, 15, 1782–​7. Montseny JJ, et al. (1995). The current spectrum of infectious glomerulonephritis: experience with 76 patients and review of the literature. Medicine (Baltimore), 74,  63–​73. Moudgil A, et al. (2001). Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy. Kidney Int, 59, 2126–​33. Muller E, Kahn D, Mendelson M (2010). Renal transplantation between HIV-​positive donors and recipients. N Engl J Med, 362, 2336–​7. Naqvi R, et al. (2003). Outcome in severe acute renal failure associated with malaria. Nephrol Dial Transplant, 18, 1820–​3. Nasr SH, et al. (2008). Acute postinfectious glomerulonephritis in the modern era: experience with 86 adults and review of the literature. Medicine (Baltimore) 87,  21–​32 Neugarten J, Baldwin DS (1984). Glomerulonephritis in bacterial endocarditis. Am J Med, 77, 297–​304. Nickeleit V, Mihatsch MJ (2006). Polyomavirus nephropathy in native kidneys and renal allografts: an update on an escalating threat. Transpl Int, 19, 960–​73. Perico N, et al. (2009). Hepatitis C infection and chronic renal diseases. Clin J Am Soc Nephrol, 4, 207–​20. Peters CJ, Simpson GL, Levy H (1999). Spectrum of hantavirus infection: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Ann Rev Med, 50, 531–​45. Post FA, et al. (2008). Predictors of outcome in HIV-​associated nephropathy. Clin Infect Dis, 15, 1282–​9. Sneller M, Hu Z, Langford C (2012). A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-​ associated cryoglobulinemic vasculitis. Arthritis Rheum, 64, 835–​42. Turner AN, et al. (eds) (2015). Oxford textbook of clinical nephrology, 4th edition. Chapters 183–​198 and 284. Oxford University Press, Oxford. Watts RA, Scott DG, Mukhtyar C (2015). Secondary vasculitis. In: Vasculitis in clinical practice, pp. 173–​84. Springer International Publishing AG, Cham. Wearne N, et  al. (2012). The spectrum of renal histologies seen in HIV with outcomes, prognostic indicators and clinical correlations. Nephrol Dial Transplant, 27, 4109–​18.

21.10.9  Malignancy-associated renal disease

21.10.9  Malignancy-​associated renal disease A. Neil Turner

Table 21.10.9.1  How malignant disease affects the kidney and urinary tract Mode of involvement

Examples

Direct

Tumours of the renal substance Lymphoma, leukaemia deposits Remote metastases from solid tumours Tumours of the urinary tract, prostate gland, etc.

ESSENTIALS Malignancies can affect the kidneys by direct invasion, metabolic and remote effects of tumour products, deposition of tumour products, triggering of immune reactions, and effects of treatment. Particular malignancy-​ associated renal diseases include the following: Thrombotic microangiopathy—​particularly reported for malignancies of the stomach, pancreas, and prostate, and also with certain chemotherapeutic agents. Minimal-​change nephrotic syndrome—​rarely caused by lymphoma. Membranous nephropathy—​associated with malignancy, usually of solid organs, in 5 to 11% of cases. Malignant disease is typically advanced and obvious when nephrotic syndrome or heavy proteinuria is recognized. Very few treatable and otherwise subclinical tumours are uncovered by investigation in routine clinical practice. Focal necrotizing and crescentic nephritis—​may rarely be associated with malignancy, when they are usually antineutrophil cytoplasmic antibody negative. Proteinuria—​may be caused by agents that modulate interferons or vascular endothelial growth factors.

Introduction Malignant disease may affect the kidney and urinary tract by five broad mechanisms (see Table 21.10.9.1). Acute kidney injury is common in patients with malignancy: in many instances the cause is not specifically related to the malignancy, but it can be, and in many instances several factors combine (Fig. 21.10.9.1).

Direct involvement of the urinary tract Solitary kidney tumours in adults are usually caused by renal cell carcinoma (hypernephroma). Bilateral tumours may occur, but multicentric tumours or bilateral tumours in young patients should lead to suspicion of an inherited disorder, particularly von Hippel–​ Lindau syndrome (see Chapter 21.12; cystic and solid lesions, some malignant) or tuberous sclerosis (see Chapter 21.12; benign lesions), both having autosomal dominant inheritance. Lymphoma and leukaemia may occasionally invade the renal substance on a sufficient scale to cause renal impairment, but it is rare for other tumours to do so. A rare and aggressive renal medullary tumour has been described in young patients with sickle cell trait or disease. These are easily confused with tumours of the collecting system and carry a poor prognosis. The collecting system and lower urinary tract may be affected by transitional cell tumours or by malignancies that may invade the

Local invasion (cervix, colon) Metabolic and remote effects

Hypercalcaemia Hypokalaemia Hyperuricaemia Thrombotic microangiopathy (tumour-​associated thrombotic thrombocytopenic purpura)

Deposition of tumour products

Myeloma kidney (precipitation in tubules)

Immune reaction

Minimal-​change disease (particularly with lymphomas)

Immunoglobulin deposition diseases

Membranous nephropathy (particularly with solid tumours) Rapidly progressive glomerulonephritis and small-​vessel vasculitis Effect of treatment

Tumour lysis syndrome Direct toxicity of drugs Idiosyncratic (e.g. immune) response

tract bilaterally or below the bladder. Transitional cell tumours affecting the bladder are common, and sometimes cause renal manifestations if extensive. Lesions in the ureters and collecting system are less common. They occur multifocally in association with analgesic nephropathy and two conditions caused by aristolochic acid(‘Chinese herb’) nephropathy and Balkan endemic nephropathy (see Chapter 21.9.2).

Metabolic effects of malignancies on the kidney Hypercalcaemia is a feature of many malignancies, both with and without metastasis. Its renal effects are discussed in Chapter 21.14. Hypokalaemia may be a consequence of acute leukaemias or rectal tumours, and may occasionally be severe enough to cause renal dysfunction (see Chapter 21.2.2). Severe hyperuricaemia (>900 µmol/​litre) is characteristically associated with massive cell death occurring following chemotherapy of haematological or solid tumours (tumour lysis syndrome), when it is usually accompanied by marked hyperphosphataemia and often by hypocalcaemia. High serum lactate dehydrogenase levels may also be diagnostically useful. Similar gross hyperuricaemia may be seen following radiotherapy of radiosensitive tumours, or may occur without therapy in malignancies with a very high rate of cell turnover, particularly acute lymphocytic or acute myeloid leukaemia, or poorly differentiated solid tumours. Uric acid levels this high can lead to precipitation within renal tubules and acute kidney injury. Prevention and treatment of tumour lysis syndrome is discussed in Chapter 21.10.5.

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Causes of AKI in a patient with Malignancies Vein

Artery

Prerenal Causes

Renal Vein Thrombosis Renal Arterial Occlusion

• NSAIDS • Contrast • Sepsis • Hypotension • Diarrhea • N/V • Capillary Leak Syndrome

Kidney

lntrarenal Causes

lgM Thrombi, (Waldenstrom's Cryoglobulinaemia), Light Chain Deposition Disease

Artery Stenosis Ureter

ATI from Tubulotoxins

Amyloidosis Drug Crystals

Post-renal Causes

• Lymphadenopathy • Blood Clots • Tumor infiltration & Encasement, Fibrosis

Cast Nephrophathy

Bladder Infiltration in plasma cell leukaemia or lymphoma Nephron

Urethra

Fig. 21.10.9.1  Summary of causes of acute kidney injury (AKI) in patients with cancer. ATI, acute tubular injury; NSAIDs, nonsteroidal anti-​ inflammatory drugs; N/​V, nausea and vomiting. Reproduced with permission from Moeckel GW, Manjunath V, and Perazella MA. Acute kidney injury in the cancer patient. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

Remote effects of malignant tumours on the kidney Thrombotic microangiopathy Thrombotic microangiopathy occurring in association with malignant disease (also known as malignancy-​associated thrombotic thrombocytopenic purpura; see Chapters 22.7.3 and 22.7.5) is often attributed to chemotherapy. It is particularly associated with certain agents (e.g. bleomycin, mitomycin), although isolated reports implicate others. However, in some instances the classic presentation with thrombocytopenia, microangiopathic haemolytic anaemia, and renal failure occurs in association with primary tumours. This has been particularly reported for malignancies of the stomach, pancreas, and prostate. The syndrome is occasionally the presenting sign of malignancy but often occurs in a patient known to have a tumour. In the absence of specific evidence, tumour-​related thrombotic microangiopathy is usually treated in the same way as thrombotic microangiopathy of other types, by plasma exchange for fresh frozen plasma. If the tumour itself is responsive to treatment, microangiopathy generally subsides too. Renal function may be recoverable if the process is halted rapidly, an outcome that is most likely in prostatic carcinoma.

Deposition of tumour products The protean effects of monoclonal overproduction of immunoglobulins, or their component parts, are considered elsewhere (see Chapter 21.10.5). The tubulotoxic effects of freely filtered immunoglobulin light chains may be amplified by hypercalcaemia in myeloma, or by concurrent administration of other nephrotoxins, notably intravenous radiological contrast media or possibly loop diuretics. AL amyloidosis (see Chapters 12.12.3 and 21.10.5) is another possible consequence of monoclonal proliferation of B cells, devastating enough on its own, but it may be associated with myeloma or progress to overt myeloma. A variety of other renal consequences may occur in B-​cell disorders with overproduction of immunoglobulin fragments, notably the light-​ chain (and rarer heavy-​chain) deposition disorders.

Immune reactions Malignant diseases are common, hence on occasions cancer will be associated with nephropathies by chance. There are many case reports in the literature, but some associations have been reported

21.10.9  Malignancy-associated renal disease

consistently and are beyond doubt. The best-​supported linkages between malignancies and intrinsic renal diseases are for minimal-​ change disease and membranous nephropathy, glomerular conditions that are (membranous) or are believed to be (minimal-​change) immunologically mediated. There is also a frequently reported association of malignancy with various types of vasculitis, particularly small-​ vessel vasculitis, which—​ as with glomerulonephritis—​ is usually believed to be immunologically mediated, both because of the typical contexts in which it occurs and because of its usual response to immunosuppressive agents. By contrast, there is little evidence for association of malignancies with primary interstitial renal diseases. Some malignancies are particularly likely to be associated with renal disease. Chronic lymphocytic leukaemia and similar low-​ grade B-​cell tumours are associated with a variety of types of glomerulopathy. Thymomas have frequently been associated with glomerular lesions, usually causing nephrotic syndrome with various histological patterns reported. Minimal-​change nephrotic syndrome Lymphomas, usually Hodgkin’s disease, are rarely associated with minimal-​change nephropathy. The renal lesion is typical in pathological characteristics, and usually also in response to corticosteroid treatment. In exceptional cases, this is the presenting sign of the lymphoma, and it may also herald relapse. More so than with other renal lesions that are putatively associated with malignancy, there is often a close temporal relationship between the occurrence of nephrotic syndrome and the presentation of the tumour. However, there is no way of proving the association in an individual patient, or of suspecting an underlying lymphoma in patients who present with nephrotic syndrome without systemic symptoms. As the association is very rare in comparison to the number of young patients with minimal-​change disease, screening other than by clinical examination and simple investigations is not justified. Less commonly, minimal-​change disease has been associated with solid tumours, and particularly with malignant and benign thymomas. Membranous nephropathy Membranous nephropathy is caused by antibody (autoantibody) formation to any of several molecules on the surface of the podocyte. It has often been associated with malignancies, but membranous nephropathy is not rare and occurs in older patients who are at relatively high risk of malignancy simply on account of their age. Series have shown rates of malignancy from 5 to 11%, although the risk is greater in older patients. However, variation in reporting practice makes published figures difficult to interpret, for example, if tumours that are recognized long after the renal diagnosis are included. Most reported tumours are of solid organs, including almost all types, but haematological malignancies are also implicated. Very often the disease is advanced and obvious when nephrotic syndrome or heavy proteinuria is recognized. In some cases, the nephrotic syndrome or proteinuria lessens after effective treatment of the malignancy. The use of alkylating agents or corticosteroids as treatment for the membranous nephropathy is not recommended in this setting, unless this would be appropriate for treatment of the malignancy itself.

There is controversy about the value of screening for malignancy in patients presenting with membranous nephropathy when malignancy is not apparent from initial investigations. Aside from routine haematological and biochemical investigations, chest radiography, and renal ultrasonography that are needed in all cases of nephrotic syndrome, in older patients it is appropriate to perform careful breast and rectal examination, faecal occult blood screening, and possibly mammography and sigmoidoscopy or colonoscopy. However, in clinical practice, the number of treatable and otherwise subclinical tumours uncovered in this way is low. Systemic vasculitis Focal necrotizing and crescentic nephritis, with or without evidence of small-​vessel vasculitis affecting other organs, may occur in association with malignancy. Some cases may be chance associations of malignancy with typical small-​vessel vasculitis that is not uncommon in older people, but there are sufficient reports of unusual associations to strongly suggest that there is sometimes a causal relationship. As well as true vasculitis, cancer-​related thrombotic microangiopathy and thrombotic events complicating disseminated intravascular coagulation in association with cancer may resemble systemic vasculitis and lead to diagnostic confusion. The most common type of vasculitis to be associated with malignancy is small-​vessel cutaneous vasculitis. In other cases, bowel and other organs including the kidney have been involved by a small-​to medium-​vessel systemic vasculitis, which is usually antineutrophil cytoplasmic antibody (ANCA) negative. However, more typical ANCA-​associated vasculitis has also been associated with malignancy, and there may be a particular relationship between granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) and renal cell carcinoma. Usually the kidney is not involved in cancer-​associated systemic vasculitis, but when it is, the appearances are indistinguishable from those of small-​vessel vasculitis of other aetiologies. Immune deposits in glomeruli are not usual (pauci-​immune). Atrial myomas have been associated with lesions of larger and smaller vessels, and it appears that embolization is not always the explanation for this.

Effects of treatment for malignancy These include the tumour lysis syndrome (discussed earlier and in Chapter 21.10.5), as well as idiosyncratic or predictable reactions to therapeutic agents. On occasions, minimal-​ change disease or other proteinuria-​ causing lesions have been associated with treatment with interferons and with drugs that target vascular endothelial growth factor (VEGF) or its signalling. Anti-​VEGF therapy may also cause thrombotic microangiopathy. The bisphosphonate pamidronate has caused proteinuria and focal segmental glomerulosclerosis, usually when given at high doses in myeloma. Cisplatin may cause tubular damage, predominantly to proximal tubules, and is characteristically associated with features of a renal Fanconi syndrome (see Chapter 21.16), although there can also be significant loss of glomerular filtration rate when severe. Ifosfamide,

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but not cyclophosphamide, is also prone to cause permanent tubular damage. High-​ dose methotrexate and pemetrexed may cause tubular damage. Radiation nephropathy develops slowly and is termed acute if it occurs within 6  months of exposure. Hypertension is usually a prominent feature, and there may be accompanying thrombotic microangiopathy. Chronic radiation nephropathy appears from 1 to 20 years after exposure and typically presents indolently with chronic kidney disease, with imaging revealing small kidneys.

FURTHER READING Bacchetta J, et al. (2008). Paraneoplastic glomerular diseases and malignancies. Crit Rev Oncol Haematol, 70,  39–​58. Biava CG, et al. (1984). Crescentic glomerulonephritis associated with nonrenal malignancies. Am J Nephrol, 4, 208–​14. Dabbs DJ, et al. (1986). Glomerular lesions in lymphomas and leukemias. Am J Med, 80,  63–​70. Goel A, et  al. Renal medullary carcinoma. Radiopaedia. http://​ radiopaedia.org/​articles/​renal-​medullary-​carcinoma Gordon LI, et al. (1999). Thrombotic microangiopathy manifesting as thrombotic thrombocytopenic purpura/​ hemolytic uremic syndrome in the cancer patient. Semin Thromb Hemost, 25, 217–​21. Gupta R, Billis A, Shah RB (2012). Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma: clinicopathologic analysis of 52 cases of rare aggressive subtypes of renal cell carcinoma with a focus on their interrelationship. Am J Surg Pathol, 36, 1265–​78. Gurevich F, Perazella MA (2009). Renal effects of anti-​angiogenesis therapy: update for the internist. Am J Med, 122,  322–​8. Izzedine H, et al. (2006). Drug-​induced glomerulopathies. Exp Opin Drug Saf, 5, 95–​106. Izzedine H, et al. (2010). VEGF signalling inhibition-​induced proteinuria: mechanisms, significance and management. Eur J Cancer, 46, 439–​48. Kurzrock R, Cohen PR, Markowitz A (1994). Clinical manifestations of vasculitis in patients with solid tumors. A case report and review of the literature. Arch Intern Med, 154, 334–​40. Maher ER (2011). Genetics of familial renal cancers. Nephron Exp Nephrol, 118,  e21–​6. Markowitz GS, et  al. (2001). Collapsing focal segmental glomerulosclerosis following treatment with high-​ dose pamidronate. J Am Soc Nephrol, 12, 1164–​72. Markowitz GS, Bomback AS, Perazella MA (2015). Drug-​induced glomerular disease: direct cellular injury. Clin J Am Soc Nephrol, 10, 1291–​9. O’Callaghan CA, et  al. (2002). Characteristics and outcome of membranous nephropathy in older patients. Int Urol Nephrol, 33, 157–​65. Pabla N, Dong Z (2008). Cisplatin nephrotoxicity:  mechanisms and renoprotective strategies. Kidney Int, 73, 994–​1007. Ronco PM (1999). Paraneoplastic glomerulopathies: new insights into an old entity. Kidney Int, 56, 355–​77. Turner AN, et al. (eds) (2015). Oxford textbook of clinical nephrology, 4th edition. Oxford University Press, Oxford. Watts RA, Scott DG, Mukhtyar C (2015). Secondary vasculitis. In: Vasculitis in clinical practice, pp. 173–​84. Springer International Publishing AG, Cham.

21.10.10 Atherosclerotic renovascular disease Philip A. Kalra and Diana Vassallo ESSENTIALS Atherosclerotic renovascular disease (ARVD) refers to atheromatous narrowing of one or both renal arteries and frequently coexists with atherosclerotic disease in other vascular beds. Patients with this condition are at high risk of adverse cardiovascular events, with mortality around 8% per year. Many patients with ARVD have chronic kidney disease, but only a minority progress to endstage kidney disease, suggesting that pre-​existing hypertensive and/​or ischaemic renal parenchymal injury is the usual cause of renal dysfunction. Many patients with ARVD are asymptomatic, but there can be important complications such as uncontrolled hypertension, rapid decline in kidney function, and recurrent acute heart failure (flash pulmonary oedema). Management—​patients with ARVD should receive medical vascular protective therapy just like other patients with atheromatous disease. This involves antiplatelet agents such as aspirin, statins, antihypertensive agents (angiotensin-​ converting enzyme inhibitors or angiotensin receptor blockers are the drugs of choice), optimization of glycaemic control in diabetic patients, and advice/​help to stop smoking. On the basis of randomized controlled trial data, the majority of patients should not be offered revascularization by angioplasty/​stenting for the purpose of improving blood pressure control or stabilizing/​improving renal function. However, there is evidence that a subgroup of patients with specific complications of ARVD (as previously mentioned) may benefit from revascularization.

Introduction Atheromatous disease is common, indeed almost universal in elderly individuals, and it is a multiorgan disease process. Atherosclerotic renovascular disease (ARVD) refers to atheromatous narrowing or occlusion of one or both renal arteries and as expected, occurs more frequently with increasing age and in the presence of cardiovascular risk factors such as diabetes, smoking, and hypertension. Although ARVD is very often asymptomatic and usually discovered incidentally during investigation for extrarenal atherosclerotic disease, haemodynamically significant stenosis in certain patients can lead to important complications such as uncontrolled hypertension, progressive decline in kidney function, and recurrent episodes of acute heart failure (flash pulmonary oedema). The heterogeneous nature of ARVD poses a significant diagnostic and management dilemma to the physician. Despite significant progress in imaging techniques, accurate determination of the haemodynamic significance of a stenosis remains difficult. In addition, percutaneous revascularization carries a risk of complications and does not guarantee improved outcomes. This is probably due to irreversible renal parenchymal damage in the poststenotic kidney, a product of both local (e.g. oxidative stress) and systemic

21.10.10  Atherosclerotic renovascular disease

(e.g. longstanding hypertension, diabetes) insults. This would explain the neutral results of recent large prospective trials in ARVD, which have shown that revascularization does not confer any added benefit to optimal medical therapy in unselected populations. However, there is evidence that subgroups of patients with a ‘high-​ risk’ phenotype, for example, patients with recurrent flash pulmonary oedema, or refractory hypertension in conjunction with rapidly declining renal function, do benefit from revascularization. Identifying these patients in a timely manner remains a considerable challenge. The issue of investigation and treatment of renal artery stenosis (RAS) in the context of the patient presenting with hypertension is discussed in Chapter 16.17.3. This brief chapter focuses more on patients with impairment of renal excretory function (chronic kidney disease) with reduced (and falling) estimated glomerular filtration rate (eGFR) in association with ARVD. The underlying aetiology, genetics, pathogenesis, and histopathology of the major macrovascular RAS lesions in ARVD are broadly as for atherosclerotic disease in general (see Chapter  16.13.1). However, as already mentioned, histopathological changes in the kidneys of patients with chronic kidney disease associated with ARVD can include hypertensive and ischaemic injury, as well as atheroembolic disease. The latter is a recognized cause of acute kidney injury occurring after revascularization.

Epidemiology It is difficult to state the true incidence and prevalence of ARVD because of variability in both the definition and in the enthusiasm with which the diagnosis is pursued. There is no uniform agreement about the precise degree of RAS which constitutes a haemodynamically significant lesion. However, in the context of the patient with gradually failing renal function, in which the causal mechanism might be ‘ischaemic renovascular disease’ (ischaemic nephropathy), many consider that the presence of significant high-​grade RAS (>70% narrowing of both renal arteries, or of the artery to a single functioning kidney) is necessary to make the diagnosis. Most ARVD epidemiological studies have been performed in populations with known atherosclerosis or cardiovascular risk factors, hence leading to selection bias. A  study of administrative claims data from the United States Medicare population over 67  years of age gave an incidence of 3.7/​1000 patient years. The overall prevalence in such patients is around 0.5%. Another study in which healthy individuals over 65 years of age living in the United States of America were screened for ARVD by means of a doppler ultrasound scan reported an incidence of 6.8%. However, the prevalence of ARVD in populations with significant comorbidities is much higher—​unsuspected ARVD has been found in around 25% of patients with peripheral vascular disease and in up to 50% of patients with congestive heart failure. In various studies RAS has been demonstrated in 5 to 22% of patients with endstage renal disease aged over 50 years, but the presence of ARVD here does not always imply causality of the renal dysfunction. Conversely, patients with ARVD usually have evidence of other macrovascular disease such as coronary (67%), peripheral arterial (56%), and cerebrovascular (37%) atherosclerotic disease.

Some atherosclerotic RAS lesions become worse with time, but this is not inevitable, especially since the advent of modern, multitargeted medical management of atherosclerosis, which includes statins and tight risk factor control. Serial imaging studies performed in the pre-​statin era reported a rate of progression to occlusion of up to about 40% over 12 months’ follow-​up, leading to loss of renal function and renal atrophy. However, nowadays, progression to total occlusion occurs much less commonly, and later studies have reported a rate of occlusion of 3% over 3 years.

Clinical features The diagnosis of ARVD should be suspected in any patient with other manifestations of atherosclerosis who presents with stable chronic kidney disease or progressive impairment of renal function, especially in the presence of hypertension that is particularly severe or difficult to control. Other clinical pointers are the presence of abdominal or iliofemoral bruits, significant deterioration in renal function after initiation of treatment with an angiotensin-​ converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), and asymmetry of renal size on imaging (>1.5 cm difference in length of the two kidneys). Flash pulmonary oedema is a well-​described and ‘classic’ manifestation of ARVD, but pulmonary oedema in a patient with ARVD is more usually attributable to concurrent ischaemic cardiac disease. ARVD is now increasingly recognized in association with congestive cardiac failure.

Clinical investigations ARVD can only be confirmed by some form of imaging and the main techniques used include duplex Doppler ultrasonography (very operator dependent) (Figs. 21.10.10.1 and 21.10.10.2), magnetic resonance angiography (either contrast free or with gadolinium, although the latter is contraindicated in patients with an eGFR 50 mg/​mmol), but is bland, without red cells or casts.

Management All patients with ARVD should receive interventions appropriate for any patient with known atherosclerotic disease, including encouragement of and assistance with smoking cessation, aspirin

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Fig 21.10.10.1  Normal right renal artery as assessed by colour Doppler ultrasound. Spectral analysis (bottom of image) shows low resistance waveform in the artery. From https://​www.med-​ed.virginia.edu/​courses/​rad/​gu/​anatomy/​kidneys.html.

(or other antiplatelet agents), statin therapy, blood pressure control, and in patients with diabetes, optimization of glycaemic control. Early studies discouraged the use of ACE inhibitors or ARBs in patients with RAS as they were thought to decrease perfusion pressure across a stenosis and exacerbate renal injury, but subsequent studies confirmed that renin–​angiotensin blockade can both mitigate the intrarenal parenchymal injury that leads to chronic kidney disease in ARVD and improve overall survival by optimizing cardiac (a)

status. In view of this, ACE inhibitors and ARBs are now considered the antihypertensive agents of choice in patients with ARVD. Nonetheless, a minority of patients with bilateral RAS or severe RAS affecting a solitary functioning kidney are at risk of acute kidney injury with such therapy, hence close monitoring of kidney function after initiation of an ACE inhibitor or ARB is essential. Blood pressure and renal chemistry should be checked within 2 weeks of starting renin–​angiotensin blockade in any patient, and especially in those with RAS. Renal function should then be rechecked on a 6-​monthly basis once the patient is receiving a stable maintenance dose, and more frequent monitoring may be required in patients who are on concurrent diuretic therapy or aldosterone antagonists. If, following initiation of an ACE inhibitor or ARB, serum creatinine concentration increases by more than 30% or eGFR declines by more than 25%, and there is no other apparent precipitating cause of acute kidney injury such as dehydration or concurrent nephrotoxic medication (e.g. nonsteroidal anti-​ inflammatory agents), the dose of the ACE inhibitor or ARB may need to be reduced to a previously tolerated level or stopped altogether. Hypotension may cause an acute decline in GFR due to impaired autoregulation in patients with chronic kidney disease or in those with critical RAS receiving an ACE inhibitor or ARB. In the event of an intercurrent illness which can cause hypotension, such as diarrhoea, vomiting, or sepsis, it should be recommended that the ACE inhibitor or ARB are temporarily stopped until the patient has recovered. Such advice is now part of ‘Sick Day rules’ programmes for prevention of acute kidney injury. A key management question concerns whether renal revasculari­ zation with renal artery angioplasty/​stenting is warranted. While there is no doubt that such interventional procedures can produce ‘anatomical cure’ of RAS (Fig. 21.10.10.3), there is a small chance (approximately 3%) of major debilitating complications including groin haematoma, acute kidney injury, cholesterol embolization, arterial dissection, and renal infarction.

(b)

Fig 21.10.10.2  Panel (a) shows a CT angiogram with the red arrow indicating significant stenosis in the right renal artery. Panel (b) shows the colour Doppler ultrasound appearance compatible with the angiographic findings. An elevated peak systolic velocity of 246.6 cm/​s is noted at the area of stenosis. (a) From http://​www.radblazer.com/​renal-​artery-​stenosis-​angiogram/​. (b) From https://​iame.com/​online/​duplex_​and_​color_​doppler_​of_​the_​kidney/​content.php.

21.10.10  Atherosclerotic renovascular disease

(a)

(b)

(c)

Fig 21.10.10.3  An intra-​arterial digital subtraction angiography series showing left renal angioplasty and stent placement. (a) Flush aortogram showing severe (>95%) left renal artery stenosis (arrow); the more distal circulation beyond the stenosis is just visible. (b) The angioplasty catheter (arrow) has traversed the renal artery stenosis. (c) A stent has been deployed (arrow). Courtesy of Professor J. Moss, Gartnavel Hospital, Glasgow.

A number of studies have been carried out over the past two decades to determine whether anatomical improvement translates into clinically useful outcomes for patients, and to assess how revascularization compares with modern multitargeted medical management. Results from small randomized controlled trials showed no clear evidence of benefit for revascularization over conservative medical management. The largest and most recent randomized controlled trials, the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) and Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) studies, provide the most robust data regarding the role of revascularization in the management of patients with ARVD. The United Kingdom-​ based ASTRAL trial randomized 806 patients with ARVD to either medical therapy alone or medical therapy with revascularization. The primary endpoint was change in renal function from baseline and after a median follow-​up of 34 months. Results showed that revascularization had no impact on decline in renal function or on blood pressure control, incidence of cardiovascular events, or mortality (secondary endpoints), and there was a significant complication rate of 7% associated with the procedure. The CORAL study was based in the United States of America (although around 50% of patients were from the rest of the world), and is the largest study in ARVD to date; 947 patients were randomized to stenting and best medical therapy or best medical therapy alone. The primary endpoint was a composite of major cardiovascular events, progressive deterioration in renal function, and death from cardiovascular or renal causes. Again, after a median follow-​up of 43 months, revascularization did not confer any clinical benefit over medical therapy on its own. However, a major criticism of these ARVD trials is the fact that these results may not be entirely generalizable as patients with ‘high-​ risk’ features (e.g. uncontrolled hypertension, rapidly deteriorating renal function, or unstable cardiac status) were specifically excluded. A  recent single-​centre retrospective study looked at 237 patients with at least 50% RAS and one or more ‘high-​risk’ features. Around one-​quarter (24%) of these patients underwent revascularization and their outcomes were compared with those of patients who were treated exclusively medically. Revascularization led to improved clinical outcomes in patients with either flash pulmonary oedema or a combination of rapidly declining kidney function and uncontrolled hypertension. Our recommendation is that there is no benefit in screening asymptomatic patients with chronic kidney disease and/​or hypertension for ARVD, and that most patients found to have ARVD should generally not be referred for revascularization for the purpose of improving blood pressure control or stabilizing/​ improving renal function. There is, however, some evidence that revascularization may play a role in the management of an important subset of patients with certain ‘high-​risk’ features who have not been well-​represented in clinical trials. These include patients with severe RAS and with otherwise unexplained rapid decline in renal function, those with recurrent episodes of flash pulmonary oedema (not explained by cardiac disease), and perhaps those with severe hypertension not adequately controlled by multiple drug treatments (or in whom reduction in arterial pressure leads to significant decline in eGFR). Another subgroup who

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section 21  Disorders of the kidney and urinary tract

could justifiably be treated with revascularization are those who require ACE inhibitors or ARBs because of concomitant heart disease and/​or renal parenchymal injury, but show intolerance of these drugs as manifest by acute kidney injury.

Prognosis Patients with ARVD are at a higher risk of cardiovascular events and death than the general population due to their significant atherosclerotic burden. However, renal function tends to remain stable and only rarely do patients with ARVD require renal replacement therapy due to ARVD progression. Indeed, in the Medicare population in the United States of America, the risk of mortality during follow-​up was almost six times that of requiring renal replacement therapy. Recent trials in ARVD have shed light on the heterogeneous nature of this condition and how prognosis may be quite variable. This is illustrated by the different baseline characteristics of patients enrolled into the ASTRAL and CORAL trials and their slightly divergent outcomes; the average eGFR for ASTRAL was 40 ml/​min per 1.73 m2 whereas that for CORAL was higher, approximately 58 ml/​min per 1.73 m2. As a result, mortality was around 8% per year for ASTRAL, compared to around 4% per year for CORAL, whereas the incidence of endstage kidney disease was 2% per year for ASTRAL and 0.5% per year for CORAL. Nonetheless, the results of both of these trials highlight the steady improvement in the prognosis of ARVD that has occurred over the past few decades, a testament to the reno-​and cardioprotective effects of modern medical therapy.

Future developments Timely identification of individuals who may gain benefit from revascularization remains a very important challenge to clinicians, and recent progress in imaging and diagnostic technology may help address this issue. Novel functional magnetic resonance imaging (MRI) techniques such as blood oxygen level-​dependent (BOLD)-​ MRI may estimate the degree of intrarenal hypoxia and thus help identify critically ischaemic kidneys. MRI has also been used to measure single-​kidney GFR and other perfusion parameters that may correspond to the functional status of the kidney. Indeed, a high single-​kidney GFR-​to-​parenchymal volume ratio has been shown to identify kidneys that may be salvaged by revascularization because they retain viable or ‘hibernating parenchyma’. Progress in biomarker technology over the past decade has stimulated interest in the identification of serum or urine biomarkers, such as neutrophil gelatinase-​associated lipocalin (NGAL), tubular kidney injury molecule-​1 (KIM-​1), or brain natriuretic peptide (BNP), which can

help predict outcomes post revascularization. However, these novel techniques have only been studied under experimental conditions and more research is required to determine whether they can be applied to clinical practice. Increased understanding of the complex pathogenesis of renal parenchymal injury in ARVD has paved the way for novel therapeutic strategies. Cell-​ based therapies have been proposed to counteract the inflammatory milieu and oxidative stress typically found in the poststenotic kidney. These might prevent irreversible loss of renal microvascular architecture and help improve clinical outcomes.

FURTHER READING Bax L, et al. (2009). Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function:  a randomized trial. Ann Intern Med, 150,  840–​8. Cheung CM, et al. (2006). MR-​derived renal morphology and renal function in patients with atherosclerotic renovascular disease. Kidney Int, 69, 715–​22. Cooper CJ, et al. (2014). Stenting and medical therapy for atherosclerotic renal-​artery stenosis. N Engl J Med, 370,  13–​22. Chrysochou C, et  al. (2012). BOLD imaging:  a potential predictive biomarker of renal functional outcome following revascularization in atheromatous renovascular disease. Nephrol Dial Transplant, 27, 1013–​19. Eirin A, Textor SC, Lerman LO (2019). Novel therapeutic strategies for renovascular disease. Curr Opin Nephrol Hypertens, 28, 383–9. Herrmann SMS, Saad A, Textor SC (2014). Management of atherosclerotic renovascular disease after Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL). Nephrol Dial Transplant, 30, 366–​75. Kalra PA, et al. (2005). Atherosclerotic renovascular disease in United States patients aged 67 years or older: risk factors, revascularization, and prognosis. Kidney Int, 68, 293–​301. National Institute for Health and Care Excellence (2013). Acute kidney injury:  prevention, detection and management. Clinical guideline [CG169]. National Institute for Health and Care Excellence, London. National Institute for Health and Care Excellence (2014). Chronic kidney disease: in adults: assessment and management. Clinical guideline [CG182]. National Institute for Health and Care Excellence, London. Ritchie J, et al. (2014). High-​risk clinical presentations in atherosclerotic renovascular disease:  prognosis and response to renal artery revascularization. Am J Kidney Dis, 63, 186–​97. Saad A, et  al. (2013). Stent revascularization restores cortical blood flow and reverses tissue hypoxia in atherosclerotic renal artery stenosis but fails to reverse inflammatory pathways or glomerular filtration rate. Circ Cardiovasc Interv, 6, 428–​35. The ASTRAL Investigators (2009). Revascularisation versus medical therapy for renal-​artery stenosis. N Engl J Med, 361, 1953–​62.

21.11

Renal diseases in the tropics Vivekanand Jha

ESSENTIALS Kidney diseases encountered in tropical areas are a mix of conditions that have a worldwide distribution and those that are secondary to factors unique to the tropics, for example, climatic conditions, infectious agents, nephrotoxic plants, envenomations, and chemical toxins. Cultural factors, illiteracy, superstitions, living conditions, level of access to health care, and nutritional status also affect the nature and course of disease. Knowledge of such conditions and issues is important for medical professionals in all parts of the globe, as ease of travel means that individuals and practices are exported with increasing frequency. Glomerular diseases—​there is a high prevalence of infection-​related glomerulonephritis throughout the tropics, with the pattern of injury dependent upon the nature of the prevalent endemic infection in that region. Important infection-​related glomerulopathies include quartan malarial, schistosomal, and filarial nephropathies. Once established, the course of disease is rarely modified by treatment of underlying infection. Acute kidney injury (AKI)—​ there is a higher prevalence of community-​acquired AKI in the tropics than elsewhere. Medical causes predominate, with diarrhoeal diseases, intravascular haemolysis due to glucose-​6-​phosphate dehydrogenase deficiency, ingestion of toxic plants, snake bites, insect stings, and locally prevalent infections being responsible for most cases, although obstetric causes remain common in some tropical countries. Falciparum malaria and leptospirosis are the most important infectious aetiologies. Use of indigenous herbs and chemicals by traditional healers (‘witch doctors’) are the most important toxic causes of AKI in sub-​Saharan Africa. Chronic kidney disease (CKD)—​although the contributions of diabetes and hypertension are growing, many cases are secondary to glomerular diseases, likely infection related, or have CKD of undetermined aetiology. Many of the latter are agriculture or farm workers presenting with chronic tubulointerstitial nephritis of unknown cause.

Introduction Approximately 40% of the world’s population live in the tropics, geographically defined as the area between the latitudes 23° north

to 23° south. Kidney diseases in tropical areas are a variable mix of globally encountered conditions and those specific to the geopolitical characteristics of the region. Tropical ecobiology strongly influences the pattern and presentation of kidney diseases encountered. Tropics are characterized by high ambient temperature; some regions receive heavy rains, while other areas are arid, with little precipitation. Extreme heat and humidity can lead to unrecognized fluid losses, especially among those engaged in manual labour. Studies have demonstrated that people can lose up to 5 kg of weight during the course of a day and show features of subclinical rhabdomyolysis, both of which can lead to kidney injury. Rains force leaching of minerals and organic compounds from the fragile tropical soil into flowing water, which can leading to waterlogging and contamination of fields with potentially toxic metals. The combination of high temperatures, wet weather, and salinity support growth of a variety of flora and fauna, including potentially nephrotoxic plants, pathogenic microorganisms, and animals that can serve as disease vectors and intermediate hosts. The end result is a high prevalence of water­borne and infectious diseases, many of which are associated with kidney injury. Rains cause a spike in the incidence of nephrotoxic snake bites, since flooding of snake burrows forces their inhabitants to come to the surface. Population migration over millennia has led to accumulation of certain genetic traits that increase kidney disease risk in the tropics. These include glucose-​6-​phosphate dehydrogenase (G6PD) deficiency giving rise to intravascular haemolysis and pigment-​ induced acute kidney injury (AKI); progressive kidney disease in haemoglobinopathies such as sickle cell anaemia and thalassaemias; MYH9 and APOL1 alleles predisposing to HIV-​associated kidney disease; and hypokalaemia, hypercalcaemia, hypocitraturia, and renal tubular acidosis due to inherited defects in tubular transport. Compared to countries in temperate regions, tropical countries are disadvantaged in socioeconomic terms. Except for two small countries (Singapore and Hong Kong), all tropical countries are classified in low-​or middle-​income categories. Poorly developed healthcare systems reduce access of large populations to medical services. Traditional health systems that rely on unproven and potentially harmful therapies flourish in the tropics, some of which are associated with practices that increase kidney disease risk.

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Cultural factors, illiteracy, superstitions, poor living conditions, and nutritional status also affect the nature, presentation, and course of kidney disease. Delayed diagnosis leads to extreme presentations that have been (almost) eliminated in the developed world. For example, it is not uncommon for children with distal renal tubular acidosis to present with marked skeletal deformities and severe growth retardation, or those with posterior urethral valves to go undiagnosed until they are several years old. Acute renal cortical necrosis following septic abortion and placental abruption continues to be seen regularly. Malnutrition exaggerates the impact of kidney disease; a lower degree of protein loss leads to more severe peripheral oedema and serous effusions. Delayed and suboptimal treatment leads to loss of opportunities to implement preventive and/​ or curative therapies, thereby increasing morbidity and mortality. Economic considerations also prevent the implementation of more refined technological solutions. For example, continuous renal replacement therapy is eschewed in favour of cheaper and less complex peritoneal dialysis. In an era of easy transcontinental movement of people, organisms, and materials, all physicians and nephrologists need, more than ever before, to be aware of tropical renal diseases. People who have migrated from the tropics may continue to engage in habits that predispose to kidney disease, even in their new location. Slowly progressive diseases due to past exposures in the tropics may produce delayed clinical manifestations. This chapter highlights the important differences between different syndromes of kidney disease in the tropics and the rest of the world, and discusses some specific renal diseases unique to the tropical regions.

Types of renal disease Glomerular diseases The overall prevalence of glomerulonephritis is reported to be higher in tropical countries than in temperate regions. Surveys from hospitals in sub-​Saharan Africa show that nephrotic syndrome accounts for 0.2 to 4% of all admissions. Primary glomerular diseases account for the majority, but secondary causes are responsible in 40 to 55% of patients in Zimbabwe and Jamaica. There is variation in the epidemiology, aetiology, clinical presentation, and natural history of glomerulonephritis between different tropical countries (Figs. 21.11.1 and 21.11.2). In general, there is a high prevalence of infection-​related glomerulonephritis throughout the tropics, with the pattern of injury dependent upon the nature of the prevalent endemic infection in that region. Minimal-​change disease is as frequent in Asia and North Africa as in the developed world, but is less common in the rest of Africa. In a study from South Africa, minimal-​change disease was responsible for nephrotic syndrome in 75% of children of Indian ancestry, whereas only 13.5% of black children showed this lesion. A  high frequency of proliferative glomerulopathies and steroid resistance is described in paediatric patients from the Democratic Republic of Congo, Zimbabwe, Malawi, Nigeria, Kenya, and Uganda. Membranous nephropathy is seen with a high frequency among children with nephrotic syndrome in countries with a high hepatitis B virus (HBV) carrier rate, and in some areas HBV-​related disease accounts for up to 15% of all membranous nephropathy cases. By

Jamaica Ghana Sudan South Africa Pakistan Papua New Guinea Singapore North India Europe 0%

20%

40%

60%

80%

100%

Minimal change

Membranous

Mesangioproliferative

Diffuse proliferative

Mesangiocapillary

FSGS

Others

Fig. 21.11.1  Prevalence of different types of glomerular lesions in adults with nephrotic syndrome in different parts of the world. FSGS, focal segmental glomerulosclerosis.

contrast, mesangial proliferative forms with IgA deposits seem to be more common in adults with HBV infection. A strong (and likely causal) association has been described between chronic hepatitis C virus (HCV) infection and several chronic glomerular diseases. An autopsy study revealed glomerular lesions in 55% of HCV-​infected individuals, including mesangial proliferative glomerulonephritis (17.6%), membranoproliferative glomerulonephritis (11.2%), and membranous nephropathy (2.7%). Recent population-​based studies have shown a link between the prevalence of HCV infection and proteinuria. The introduction of new treatments for HCV is likely to reduce the prevalence of HCV-​related glomerulonephritis. Postinfectious glomerulonephritis continues to be encountered in high frequency throughout the tropics. In studies from north Africa and the Middle-​East, about 15 to 20% of all paediatric biopsies show diffuse proliferative glomerulonephritis, likely postinfectious. The prevalence of poststreptococcal glomerulonephritis in the Goajiro

United Kingdom South India North India Papua New Guinea Zimbabwe Nigeria South Africa (Blacks) South Africa (Indians) 0%

20%

40%

60%

80%

100%

Minimal change

Membranous

Mesangioproliferative

Diffuse proliferative

Mesangiocapillary

FSGS

Others

Fig. 21.11.2  Prevalence of different types of glomerular lesions in children with nephrotic syndrome in different parts of the world. FSGS, focal segmental glomerulosclerosis.

21.11  Renal diseases in the tropics

Fig. 21.11.3  Map showing areas with a high prevalence of community-​acquired AKI. Areas with a high prevalence of malaria-​associated AKI are shown in maroon, and with intermediate prevalence in yellow; orange indicates areas with a high prevalence of both leptospiral and malarial AKI; textured fill in countries of sub-​Saharan Africa indicates a high prevalence of malarial and herbal remedy-​induced AKI; green indicates AKI of other causes.

Indian community of Venezuela was twice that seen in other parts of the Goajira state.

Acute kidney injury Community-​acquired AKI is the commonest nephrological emergency encountered in the tropics, and referral patterns to dialysis units suggest a higher prevalence of community-​acquired AKI in the tropics than elsewhere. In a large referral hospital in North India, 1.5% of all hospital admissions were referred to the nephrology service for management of moderate to severe AKI. Medical causes predominate, with diarrhoeal diseases, intravascular haemolysis due to G6PD deficiency,

ingestion of toxic plants, snake bites, insect stings, and locally prevalent infections being responsible for most cases, although obstetric causes remain common in some tropical countries (Figs. 21.11.3 and 21.11.4). In a recent global study conducted by the International Society of Nephrology, AKI patients in low-​and low–​middle-​income countries of the tropics were younger than those from rest of the world, although the extent to which this is explained by ascertainment bias remains uncertain. In a study from India, the average age of patients dialysed for AKI was 34.3 years. Dehydration was the most common cause of AKI, followed by infections, pregnancy-​related AKI, and animal envenomation.

100% 90% 80% 70% 60% 50% 40% 30% 20% 10%

a Ar

ge n

tin

a an

Obstetric

Gh

Surgical

S

Af

ric

a

ia ig

Medical

N

Th

ai

la

er

nd

ka an iL Sr

In h ut So

N or

th

In

di

di

a

a

0%

Fig. 21.11.4  Causes of AKI in different tropical countries. Modified from Chugh, Satprija and Jha, Oxford Textbook of Clinical Nephrology, Oxford University Press, Oxford 2005.

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section 21  Disorders of the kidney and urinary tract

Fig. 21.11.5  Tropical countries from where hot spots of chronic kidney disease of undetermined aetiology have been reported (red: definite; yellow: probable).

In contrast to patients with hospital-​acquired AKI seen in temperate countries, the kidney is the sole affected organ in more than 50% of cases at diagnosis. However, when tropical AKI is seen as part of an undifferentiated illness that includes AKI, liver failure, respiratory failure, neurological dysfunction, disseminated intravascular coagulation, and metabolic acidosis, then establishing the cause can be impossible in the absence of specialized facilities. Lack of resources forces a significant proportion of patients with AKI in tropical low-​income countries to go untreated, but the proportion of those receiving treatment who recover is greater than in the developed world, reflecting the relatively young age and absence of any pre-​existing disease in the affected individuals. Saving Young Lives, a collaborative project between the International Society of Nephrology, International Paediatric Nephrology Association, International Society for Peritoneal Dialysis, and Sustainable Kidney Care Foundation, is developing a sustainable programme to treat AKI using peritoneal dialysis in several countries of sub-​Saharan Africa and Southeast Asia.

‘Mini-​epidemics’ of such cases has been reported from several tropical regions in central America (Costa Rica, Guatemala, Nicaragua, El-​ Salvador, Mexico), north America (California), South and Southeast Asia (India, Sri Lanka, Thailand), Middle-​East (Saudi Arabia, Qatar), and Africa (Egypt, Sudan) (Fig. 21.11.5). Dubbed variously CKD of uncertain aetiology (CKDu), chronic interstitial nephritis in agricultural communities (CINAC) and other terms (e.g. mesoamerican nephropathy), the aetiology of this condition has been a subject of intense speculation. The currently favoured postulations include recurrent heat stress with episodes of dehydration and/or rhabdomyolysis, and exposure to agrochemicals, particularly pesticides. Other hypotheses are heavy metals (contaminating drinking water, rice and edible fish), fluoride, tropical infections, dietary peculiarities, consumption of herbal medicines, and abuse of over-​the-​counter medications. See Chapter 21.9.2 for further discussion. Obstructive nephropathy due to urolithiasis is common in Pakistan, Thailand, and parts of India known as ‘stone belts’.

Chronic kidney disease

Kidney diseases specific to the tropics

There are several notable differences in the pattern of chronic kidney disease (CKD) in topical populations compared to those in temperate zones. Tropical patients with endstage renal disease are significantly younger. Although the contribution of diabetes and hypertension to the overall CKD burden in the tropics is growing, a significant proportion develop CKD secondary to glomerular diseases, likely infection related, or have CKD of undetermined aetiology. Many patients come to medical attention for the first time with advanced renal failure and few prior symptoms. Most often, these are individuals from poor socioeconomic background and are agriculture or farm workers who work long hours in hot and humid environments. Investigations reveal minimal proteinuria, bland urinary sediment, and smooth contracted kidneys. Kidney biopsies in a few cases have shown bland tubulointerstitial nephritis.

In addition to nephropathies that have a worldwide distribution, some renal lesions have been described solely in residents of tropical countries. These can be broadly grouped under infectious and toxic categories. Causal relationships are suggested by epidemiological studies, demonstration of a temporal relationship between the inciting event (infection, environmental insult, or toxin exposure) and the development of renal manifestations, and by resolution following treatment of the infection or withdrawal of the insult. Improved diagnostic techniques and appropriately designed experimental studies have provided concrete evidence of a cause-​and-​effect relationship in some instances. Examples include establishment of aristolochic acid as the cause of Balkan endemic nephropathy, and identification of specific infections (e.g. scrub typhus, dengue, and leptospirosis) as the cause of undifferentiated febrile syndromes with

21.11  Renal diseases in the tropics

AKI. Confirmation has been obtained by the demonstration of either the organism or microbial antigens in the renal lesions, and elution of specific antibodies in the case of infections, and toxic compounds in the case of plant and animal toxins. In some cases, animal models have provided insight into the genesis of the lesions.

Infectious causes of renal disease in the tropics Table 21.11.1 shows the various tropical infections that can cause kidney injury.

Malarial renal diseases Malaria, caused by members of the protozoan Plasmodium genus, is endemic in the Indian subcontinent, Middle East, East Asia, Table 21.11.1  Tropical infections associated with kidney injury Class

Organism

Nature of renal lesion

Protozoal

Plasmodium malariae

Glomerulonephritis

Plasmodium falciparum

AKI, TMA

Plasmodium vivax and knowlesi

AKI

Schistosoma mansoni

Glomerulonephritis

Wuchereria bancrofti

Glomerulonephritis

Loa loa

Glomerulonephritis

Onchocerca volvulus

Glomerulonephritis

Mycobacterium leprae

Glomerulonephritis, amyloidosis

Mycobacterium tuberculosis

Glomerulonephritis, interstitial nephritis, destructive inflammation, amyloidosis

Salmonella typhi and paratyphi

Glomerulonephritis

Shigella dystenteriae

AKI, TMA

Brucella abortus

AKI

Burkholderia pseudomallei

AKI

Vibrio cholera and vulnificus

AKI

Orient tsutsugamushi

AKI

Campylobacter jejuni

AKI

Dengue haemorrhagic fever

Glomerulonephritis, AKI

Hantaan virus

AKI

Rift valley fever

AKI

Yellow fever

Glomerulonephritis, AKI

Spotted fever

AKI

HIV

Glomerulonephritis, AKI, TMA

Hepatitis B and C

Glomerulonephritis

Bacterial

Viral

sub-​Saharan Africa, and Central America. Of the five species pathogenic to humans, renal lesions have been described following infections with Plasmodium falciparum, P.  vivax, P.  knowlesi, and P. malariae, but not after P. ovale. Glomerulonephritis is the chief complication of P. malariae infection, whereas the others primarily present with AKI. Malarial AKI Less than 1% of all patients with P. falciparum and P. knowlesi infection develop AKI, but the prevalence increases to 60% in those with severe infection. Nonimmune visitors to an endemic area are more likely to develop severe infection than local residents. Malarial AKI has been reported from the Indian subcontinent, Thailand, Malaysia, and Africa. In recent years, AKI has been encountered in association with P. vivax infection, in particular from the Indian subcontinent. Molecular methods have permitted identification of human infection with P. knowlesi, earlier thought to be limited to macaques in Malaysia, Thailand, Vietnam, Myanmar, and Philippines. Clinical features The initial symptoms are nonspecific and consist of malaise, headache, fatigue, muscle aches, fever, and chills. Nausea, vomiting, and hypotension are frequent in nonimmune individuals. Encephalopathy, acute respiratory distress syndrome, and disseminated intravascular coagulation indicate severe infection. AKI is usually seen by the end of the first week and is nonoliguric in 50 to 75% of cases. Haemolytic anaemia and cholestatic jaundice are frequent accompaniments. The so-​called blackwater fever has seen a resurgence among nonimmune European expatriates, probably due to the reintroduction of quinine and mefloquine into the treatment regimen. Individuals with G6PD deficiency can develop severe haemolysis. Renal failure lasts from a few days to several weeks, with an average of 2 weeks. Investigations show azotaemia, hyponatraemia, hyperkalaemia, and lactic acidosis. Diagnosis requires the demonstration of asexual forms of the parasite in peripheral blood smears stained with Giemsa stain or acridine orange. Morphological features of P.  knowlesi infection resemble those of P. falciparum in the early and P. malariae in the late stages, and accurate identification requires the use of molecular techniques. Test kits for rapid diagnosis of malaria on finger-​prick blood samples are commercially available. These depend upon immunochromatographic detection of malaria antigens such as histidine-​rich protein 2 (PfHRP2), lactate dehydrogenase (pLDH) or aldolase (pAldo). Useful in the field, these tests are relatively insensitive at low levels of parasitaemia and for nonimmune populations. Other problems include false positivity and cross-​reactivity between Plasmodium species. Pathology Acute tubular necrosis, characterized by cloudy swelling and degeneration of tubular cells and casts loaded with malarial pigment, is the most prominent finding. Tubular cells contain haemosiderin granules. Varying degrees of interstitial oedema and mononuclear cell infiltrate are also seen.

Rotavirus, Norwalk agent

AKI

Spirochete

Leptospira icterohaemorrhagica

AKI, AIN, CKD

Pathogenesis

Fungus

Zygomycetes spp.

AKI, renal infarction

Kidney injury is attributed to haemorheological changes induced by the parasite that lead to renal ischaemia. P. falciparum merozoites consume and degrade erythrocyte proteins and alter the red cell

AIN, acute interstitial nephritis; AKI, acute kidney injury; CKD, chronic kidney disease; TMA, thrombotic microangiopathy.

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section 21  Disorders of the kidney and urinary tract

membrane, making the erythrocytes more spherical and less deformable. Cup-​shaped, electron-​dense structures that overlie accretions of histidine-​rich P. falciparum erythrocyte membrane protein and extrude an adhesive protein of high molecular weight are expressed on the erythrocyte membrane and mediate attachment to endothelial cells, causing a phenomenon called ‘cytoadherence’. Infected erythrocytes adhere to uninfected red cells, platelets, monocytes, and lymphocytes. P.  falciparum can also activate the alternate complement pathway and intrinsic coagulation cascade. Increased production of endothelin-​1, increased plasma viscosity secondary to an increase in plasma fibrinogen, and rhabdomyolysis also contribute to the AKI. Contributory factors include volume depletion secondary to capillary leak and haemolysis. Studies from Thailand indicate that prior infestation with helminths protects against malarial AKI. Management Severe falciparum malaria requires supportive care in combination with specific antimalarial treatment (see Chapter  8.8.2). Combination therapies, including artemisinin derivatives, are the norm. Careful fluid management is needed in patients with pulmonary oedema. Prognosis The mortality of malarial AKI is 10 to 40%. Late referral, high parasitaemia, multiorgan involvement, and infection in previously unimmunized subjects portend a poor prognosis. Malarial glomerulopathy Before 1980, nephrotic syndrome was encountered during periods of intense transmission of P.  malariae infection among children in western Nigeria, Uganda, Kenya, Côte d’Ivoire, Sumatra, New Guinea, and Yemen, with plasmodium positivity in 40 to 75% of cases. The prevalence of such quartan malarial nephropathy (the term quartan is used because the fever tends to return at 3-​day intervals) has shown a sharp decline with the eradication of malaria, and the entity does not find a mention in recent reports. Clinical features The nephrotic syndrome develops several weeks after the onset of fever. Nonvisible haematuria is noted in about one-​third of cases. Hypertension develops along with decline in renal function. Hypoalbuminaemia is profound, with values commonly less than 1 g/​dl. The serum cholesterol level tends to be normal or low, reflecting low dietary intake. Serum creatinine is usually normal at presentation. Glomerulonephritis in other malaria infections is usually clinically silent, but nonselective proteinuria, nonvisible haematuria, and casts are noted in 20 to 50% of cases with falciparum malaria. Glomerular lesions are seen at autopsy in about 18% of cases who die with P. falciparum and P. knowlesi infections. Pathology and pathogenesis The morphological appearance of quartan malarial nephropathy is of a mesangiocapillary pattern. Demonstration of malarial antigen in the deposits and binding of specific antibody to circulating malarial antigens suggest an immunological basis for the condition. Experimental studies also support this hypothesis. Environmental

factors such as malnutrition or coinfection with Epstein–​Barr virus may be permissive. The liver may act as a source of continuous antigen supply. Mild endocapillary glomerulonephritis has been described in falciparum malaria. Management Once established, quartan malarial nephropathy follows an inexorably progressive course, culminating in renal failure within 2 to 4 years. Antimalarials and steroids have proved ineffective in arresting progression of kidney disease. Remission has been reported occasionally with cyclophosphamide, but there is no improvement in survival. By contrast, glomerulonephritis associated with falciparum malaria resolves within a few weeks of eradication of infection.

Renal disease in schistosomal infections Schistosomiasis is a chronic infection caused by trematodes (blood flukes) and affects over 300 million people in Asia, Africa, and South America. Of the seven species pathogenic to humans, the most prevalent are Schistosoma haematobium (Africa and the Middle East), S.  mansoni (South America and Africa), and S.  japonicum (China and the Far East). S.  haematobium primarily involves the lower urinary tract, whereas S.  mansoni involves the gastrointestinal tract and portal system, leading to hepatic fibrosis and portal hypertension. Schistosomal glomerulopathy Glomerulonephritis has been described in association with hepatosplenic schistosomiasis produced by S.  mansoni. Reports from autopsy series in Brazil during the 1960s were followed by clinical observations from endemic areas of Africa, Saudi Arabia, and Yemen. Proteinuria has been reported in 1 to 22% of patients infected with S. mansoni and 2 to 5% with S. haematobium infection. Subclinical glomerular lesions were found in about 40% of patients with hepatosplenic schistosomiasis. Clinical features Though described at all ages, glomerulonephritis is most frequent in young adults with overt hepatosplenic disease. Males are affected twice as frequently as females. Peripheral oedema and ascites are the hallmarks; hypertension is seen in 50% of cases, appearing late in the disease. Proteinuria is poorly selective and haematuria uncommon. Complement levels are usually low. Nonspecific antibody production is demonstrated by false-​positive rheumatoid factor or the VDRL (Venereal Disease Research Laboratory) tests. It is important to exclude other causes of nephrotic syndrome before attributing the lesions to schistosomiasis. Diagnosis is confirmed by demonstrating viable eggs in the stool or egg-​containing granulomas in rectal or liver biopsies. Pathology Five patterns of glomerular pathology have been described (Table 21.11.2). The class I lesion is the earliest and most frequent, and is the principal lesion in renal allografts with recurrent schistosomal nephropathy. Class  II lesions are more frequent in patients with concomitant salmonella infection. The frequency of class  III lesions varies from 20% in asymptomatic patients to over 80% in those with overt renal disease. The class IV lesion, seen in 15 to 40% of cases, cannot be distinguished from idiopathic focal segmental

21.11  Renal diseases in the tropics Table 21.11.2  Clinicopathological classification of schistosomal glomerulopathy Class

I

II

Light microscopic pattern

Mesangioproliferative Exudative

III A

IIIB

IV

V

Mesangiocapillary type I

Mesangiocapillary type II

Focal and segmental glomerulosclerosis

Amyloidosis

(a) ‘Minimal lesion’ (b) Focal proliferative (c) Diffuse proliferative Immunofluorescence

Mesangial IgM and C3. Schistosomal gut antigens

Endocapillary C3 Schistosomal antigens

Mesangial IgG, IgA, and C3, schistosomal gut antigen

Mesangial and subepithelial IgG and C3, schistosomal gut antigen (early), IgA (late)

Mesangial IgG, IgM, and IgA

Mesangial IgG

Asymptomatic proteinuria

+++

–​

+

+

+

+

Nephrotic syndrome

+

+++

++

+++

+++

+++

Hypertension

±

–​

++

+

+++

±

Progression to endstage renal disease

±

±

++

++

+++

+++

Response to treatment

±

+++

–​

–​

–​

–​

Modified with permission from Barsoum R, Kidney Int 1993.

glomerulosclerosis on the basis of light microscopy, but immunofluorescence reveals IgA deposition. Class  III and IV lesions are seen in patients with fibrotic livers and associated with severe hypocomplementaemia. Class V prevalence varies from 15 to 40%, with a higher frequency in African patients. This form is not usually affected by hepatic fibrosis. Pathogenesis The glomerulopathy is caused by the immunological reaction to specific schistosomal antigens. Antigens have been demonstrated in the glomeruli of baboons infected with S.  mansoni, and circulating immune complexes have been documented in experimental animals and humans with hepatosplenic disease. Circulating complexes localize in mesangial and subendothelial locations, whereas the extramembranous deposits form in situ. Portocaval shunting prevents hepatic processing of worm antigen and delivers it directly into the systemic circulation. IgM antibodies are seen in most patients with hepatosplenic schistosomiasis alone, but circulating mononuclear IgA-​bearing cells and IgA antibodies predominate in those with glomerular involvement. An isotope switch from IgM-​to IgA-​producing B cells is believed to be responsible for this alteration. An aberrant Th2 cytokine response contributes to organ damage. Genetic factors are thought to play a role; polymorphisms in IL13 and STAT6 genes have been associated with disease severity. The immune reaction may be modified by concomitant infection with salmonella, hepatitis viruses, staphylococci, and mycobacteria. Epidemiological studies have shown clearance of urinary abnormalities following therapy for salmonella alone, suggesting a permissive role of this infection. Management Treatment of schistosomal glomerulopathy is disappointing. Antischistosomal drugs (see Chapter 8.11.1) do not alter the clinical course, which is one of inexorable progression to renal failure.

Steroids or cytotoxic agents are similarly ineffective. Salmonella infection should be looked for and treated in all patients. Schistosomiasis involving the lower urinary tract The adult S. hematobium worm resides and lays eggs in the perivesical venous plexus, where they get trapped in the urinary tract mucosa and incite granuloma formation. Clinical manifestations appear when they coalesce into larger granulomata or polyps that ulcerate and bleed. Over time, fibrosis and calcification set in. The presenting feature is painful haematuria, and characteristic ova with terminal spikes may be seen on urinary examination. Later stages are characterized by symptoms related to reduced bladder volume, obstruction to urine flow at the level of bladder outlet or ureterovesical junction, vesicoureteric reflux, or urinary tract infection. Plain radiology may reveal linear or irregular calcification in the bladder wall, ureter, or seminal vesicles (Fig. 21.11.6). Bladder cancer is a complication of chronic schistosomal cystitis, and develops two to three decades after the initial infection in about 5% of all infected individuals. In Egypt, schistosomal eggs are demonstrated in over 85% of resected bladder cancer specimens. Long-​standing obstruction leads to progressive loss of kidney function; 7 to 20% of the endstage renal disease population in Egypt is secondary to lower tract schistosomiasis.

Renal disease in filarial infection Filarial worms are nematodes transmitted to humans through arthropod bites. Clinical manifestations depend upon the location of microfilariae and adult worms in the tissues. Of the eight filarial species that infect humans, Loa loa, Onchocerca volvulus, Wuchereria bacrofti, and Brugia malayi are associated with kidney disease. Loiasis is prevalent in West and Central Africa and manifests with localized allergic inflammation and swelling. Onchocerciasis (river blindness) is characterized by subcutaneous nodules, a pruritic skin rash, sclerosing lymphadenitis, and ocular lesions. Bancroftian and

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Fig. 21.11.6  Plain radiograph of a patient with S. haematobium infection showing calcification of bladder wall. Courtesy of Professor R. Barsoum.

brugia infections cause febrile episodes associated with acute lymphangitis and lymphadenitis, leading to lymphoedema manifesting as hydrocele and elephantiasis. This form of filariasis is endemic in Africa and South and South-​East Asia. Filarial nephropathy Clinical features

Fig. 21.11.7  Photomicrograph of a kidney biopsy showing microfilariae with parallel-​arranged nuclei throughout their length and covered by a sheath on their external aspect in the glomerular capillary lumen in a patient with lymphatic filariasis (arrows) (periodic acid–​Schiff stain, magnification ×100).

developed after selective catheterization and infusion of D. immitis into one renal artery; the contralateral kidney either remained uninvolved or showed minor lesions, suggesting in situ immune complex formation. Diethylcarbamazine treatment, by killing the parasite, may lead to antigen release into the circulation, thus exacerbating the immune process. A temporal relationship between the administration of this agent and the development of proteinuria has been noted.

Urinary abnormalities have been described in 11 to 25% of cases of loiasis and onchocerciasis, with nephrotic syndrome in 3 to 5%. In a survey in an endemic area, proteinuria was detected in over 50% of patients with lymphatic filariasis, with 25% showing a glomerular pattern of protein loss. The frequencies of proteinuria, nonvisible haematuria, and hypertension are significantly higher in patients with chronic sclerosing filariasis than in those with an acute febrile illness or microfilaraemia. False-​positive rheumatoid factor and anti-​DNA and antiphospholipid antibodies have been described.

Good response to antifilarial therapy with diethylcarbamazine is observed in patients with non-​nephrotic proteinuria and/​or haematuria. The response is inconsistent in those with nephrotic syndrome, when deterioration of renal function may continue despite clearance of microfilariae.

Pathology

Chyluria

Light microscopy reveals a gamut of lesions, including minimal-​ change disease and focal segmental glomerulosclerosis, and mesangial proliferative, mesangiocapillary, and chronic sclerosing glomerulonephritis. Diffuse basement membrane thickening with endocapillary proliferation is the commonest finding. Mononuclear interstitial infiltration and microinfarcts around blood vessels have been demonstrated in patients with loiasis. Microfilariae may be found in the glomerular capillary lumina (Fig. 21.11.7), tubules, and interstitium. Electron microscopy shows widely spaced subepithelial, subendothelial, and intramembranous deposits and spikes. O. volvulus and B. malayi antigens, along with IgM, IgG, and C3 have been demonstrated.

Lymphatic filariasis secondary to W. bancrofti or B. malayi infections leads to fibrosis of lymph glands and dilatation of draining lacteals. Under pressure, the dilated retroperitoneal lacteals rupture into the low-​pressure urinary system, leading to leakage of lymph in urine. The presentation is characterized by passage of milky white urine (Fig. 21.11.8), with or without haematuria. Patients complain of backache, probably caused by distended vessels. Formation of chylous clots may result in acute urinary retention. Prolonged chyluria results in the loss of protein, fat, and lymphocytes in the urine, leading to hypoproteinaemia and lymphopenia. Urinalysis shows proteinuria, and—​if the history of change in urine colour is not elicited—​an erroneous diagnosis of nephrotic syndrome might be made, prompting an unnecessary kidney biopsy. About 80% of cases respond to treatment with diethylcarbamazine and dietary modification. Sclerotherapy using local instillation of povidone iodine, hypertonic dextrose, or silver nitrate is required for resistant cases (or less commonly surgery).

Pathogenesis Glomerulonephritis is likely immune complex mediated. The levels of circulating immune complexes correlate with the adult worm burden. Dogs infected with Dirofilaria immitis develop glomerular lesions similar to human filariasis: glomerular lesions

Management

21.11  Renal diseases in the tropics

(a)

(b)

Fig. 21.11.8  Panel (a) shows milky white urine in a patient with chyluria secondary to lymphatic filariasis and panel (b) shows filling up of ruptured lacteals on retrograde pyelogram.

Renal disease in leprosy Leprosy is a chronic granulomatous disorder caused by the acid-​fast bacillus Mycobacterium leprae. Nephritis was an important cause of death until the 1950s, but is now rare. The main renal lesions encountered are glomerulonephritis, secondary amyloidosis, and tubulointerstitial nephritis. Glomerulonephritis The incidence of glomerulonephritis in leprosy is now less than 2%, but old autopsy series showed lesions in over 50% of cases. Most cases are seen in patients with multibacillary disease and during episodes of erythema nodosum leprosum. Clinical presentation may be as nephrotic syndrome, acute nephritic syndrome, or rapidly progressive renal failure. Hypocomplementaemia is common, and circulating cryoglobulins may be present. Mesangial proliferative and diffuse proliferative glomerulonephritis are the commonest histological lesions. Electron microscopy reveals electron-​dense deposits in the mesangial and subendothelial regions, focal foot-​process widening, glomerular capillary basement membrane reduplication with mesangial interposition, and endothelial cytoplasmic vacuolation. Immunofluorescence reveals granular IgG and C3 deposits in the mesangium and along capillary walls. Circulating immune complexes can be detected in 30 to 75% of patients, and can be of mycobacterial origin or dapsone:antidapsone antibodies. Alternate pathway complement activation by cryoprecipitates can also contribute. Steroids or antileprosy drugs have no effect on the course of glomerular disease. Prednisolone may hasten the recovery of renal function in patients with renal failure during episodes of erythema nodosum leprosum. Amyloidosis Amyloid was documented in 55% of cases in older autopsy and biopsy studies in leprosy cases from the United States of America, 31% from Brazil, and less than 10% from Mexico, Africa, and India. The amyloid is of AA type and is far more frequent in lepromatous than nonlepromatous leprosy. Erythema nodosum leprosum further increases the risk as each episode is associated with a marked elevation

of serum amyloid A protein. Patients with tuberculoid leprosy who have long-​standing and infected trophic ulcers can also develop this complication.

Renal disease in tuberculosis Tuberculosis is endemic throughout the tropics. Concerted efforts to contain the disease have been thwarted by the HIV epidemic and treatment default, leading to a rise in drug-​resistant disease. Seen in less than 10% of all cases with tuberculosis, urinary tract involvement is a relatively late manifestation of disease. Common presenting features are irritative lower urinary symptoms suggestive of infection as a result of ureteric and bladder involvement secondary to seeding of M. tuberculosis into the urine. Urinalysis shows pus cells, but cultures are repeatedly sterile. The presence of sterile pyuria or failure of symptoms to respond to conventional antibacterial treatment should raise the possibility of urinary tract tuberculosis. Systemic symptoms like fever, night sweats, and weight loss are helpful diagnostic clues when present. Only about one-​third of patients show simultaneous pulmonary involvement. Involvement of renal parenchyma takes the form of granulomatous interstitial nephritis and caseous destruction, culminating in small nonfunctioning and often calcified kidneys. An association with glomerulonephritis was postulated in the pre-​antibiotic era, but only occasional recent reports have described immune complex glomerulonephritis and dense-​deposit disease in tuberculosis. A well-​known complication, however, is amyloidosis, which is still seen in a significant proportion of patients in poor countries where the disease remains untreated for long periods. Once established, the course of amyloidosis is unaffected by treatment of the underlying tuberculosis. Imaging (Fig. 21.11.9) provides important diagnostic clues, with about 30% showing dystrophic calcification of the urinary tract (bladder and ureteric walls, or—​ less commonly—​ renal parenchyma). Involvement of the excretory system is delineated better by intravenous urography, CT, or magnetic resonance imaging which shows thickening, irregularity or narrowing of involved segments, and cavities or mass effects secondary to necrosis. Fibrosis and

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section 21  Disorders of the kidney and urinary tract

of the second week, and may last longer than that associated with other causes of AKI. Recent studies suggest that leptospiral infection can persist in humans and may have long-​term adverse effects on kidney function. Molecular techniques have shown asymptomatic urinary shedding of leptospira in areas of high disease transmission, including in those without serological evidence of recent infection. In a recent population-​based study, individuals with previous leptospira exposure had a higher prevalence of CKD stages 3 to 5. Further, those with a higher antibody titre showed a greater decline in estimated glomerular filtration rate on follow-​up. Diagnosis

Fig. 21.11.9  Intravenous pyelogram in a patient with renal tuberculosis. The left kidney is hydronephrotic and the right kidney is nonfunctioning and shows punctuate calcification of the dilated pelvicalyceal system. Courtesy of Professor John Eastwood.

contraction of the bladder gives rise to reduction in capacity—​the classical ‘thimble bladder’. Extrarenal spread can also be identified on imaging. Patients with advanced and bilateral disease have a reduced glomerular filtration rate due to generalized destruction of the parenchyma, but a more common cause for renal failure is urinary tract obstruction due to scarring of the lower tract. Management requires institution of antitubercular therapy according to local guidelines. Obstructive lesions that fail to respond to therapy require surgical correction, including urinary diversion and bladder augmentation surgery.

Renal disease caused by leptospirosis Leptospirosis, the most widespread zoonosis in the world, is an occupational hazard in fishermen, coal miners, and sewage, abattoir, and farm workers throughout the tropics. The pathogenic Leptospira interrogates complex has 30 serogroups and 240 serotypes. Leptospira are shed in the urine by the animal hosts (rats, mice, gerbils, hedgehogs, foxes, dogs, cattle, sheep, pigs, and rabbits) and survive for several weeks in a moist environment. Human infection occurs upon exposure of abraded skin and exposed mucosae to contaminated water, soil, or vegetation. Clinical features Leptospirosis occurs in both sexes and in all age groups. The incidence peaks during or soon after the rainy season, especially following floods. The disease starts with fever, chills, headache, severe muscle aches and tenderness, and dry cough, which terminate with defervescence after 4 to 10 days. Organ involvement is seen in the second phase and takes the form of AKI, cholestatic jaundice, and haemorrhagic manifestations (Weil’s syndrome). AKI occurs in 20 to 85% of cases and is oliguric in 40 to 60%. It is typically mild and nonoliguric in anicteric patients. Renal magnesium and phosphate wasting is common. Diuresis ensues by the end

Diagnosis is based on culture or serology. The organisms can be grown on Fletcher’s or Stuart’s semisolid media from blood during the first phase, and later from urine. Antileptospiral antibodies are detectable in the second phase. A single titre of greater than 1:400 or a fourfold increase is taken as significant. A macroscopic agglutination test or a slide test can be used to screen patients, but these are not specific. The gold standard is the complex microscopic agglutination test that requires maintenance of live leptospira cultures. Other tests include an IgM-​specific dot enzyme-​linked immunosorbent assay (ELISA), complement fixation, serum and salivary ELISA, rapid IgM dipstick ELISA, and gold immunoblot tests. Lately, nucleic acid-​based testing has allowed identification of greater number of cases. Pathology Grossly, the kidneys are swollen and bile stained. The main light-​ microscopic lesion is a tubulointerstitial nephritis, with mononuclear cells and eosinophilic infiltration. Mild and transient mesangial proliferative glomerulonephritis with C3 and IgM deposition is occasionally noted. Pathogenesis Renal involvement results from direct invasion of the renal tissue by the organism and liberation of bacterial enzymes, metabolites, and endotoxins. Addition of leptospira endotoxin to human macrophages induces release of tumour necrosis factor-​α (TNFα). Proximal convoluted tubules show a decrease in expression of sodium/​hydrogen exchanger isoform 3, aquaporin 1, and α-​Na+,K+-​ ATPase. The glycoprotein component of the endotoxin inhibits the renal Na+,K+-​ATPase and apical Na+–​K+–​Cl− cotransporter, leading to potassium wasting. Leptospiral outer membrane proteins have been localized to the proximal tubules and interstitium of infected animals. Recent studies have suggested the involvement of Toll-​like receptor, leading to activation of NF-​κB and mitogen-​activated protein kinases, and enhanced message for inducible nitric oxide synthase, monocyte chemoattractant protein-​1 and TNFα. Leptospiral outer membrane proteins may also induce activation of the transforming growth factor-​ β/​SMAD-​associated fibrosis pathway, leading to accumulation of extracellular matrix. Management Leptospirosis is a self-​limiting disease, and mild cases recover spontaneously. The emphasis is on symptomatic measures, together with correction of hypotension and fluid and electrolyte imbalance. Antibiotic therapy can shorten the duration of fever and hasten amelioration of leptospiruria. Adverse prognostic factors include

21.11  Renal diseases in the tropics

advanced age, pulmonary complications, hyperbilirubinaemia, diarrhoea, hyperkalaemia, and the presence of other infections.

Kidney injury in scrub typhus Scrub typhus, caused by Orientia tsutsugamushi, a Gram-​negative α-​proteobacterium of family Rickettsiaceae, is endemic in Asia, with an estimated 1 million cases occurring annually. The infection is maintained in nature by transovarian transmission in trombiculid mites. Human involvement occurs when people get bitten by infected larvae, leading to inoculation of organisms into the skin. The World Health Organization identifies scrub typhus as a re-​ emerging disease in South-​East Asia and the South-​Western Pacific region, with a fatality rate of 30% in untreated cases. Until recently, renal involvement due to scrub typhus had not received much attention, and a recent systematic review could only find a few case reports specifically describing AKI. However, recent studies from India have shown renal abnormalities in 70 to 80% of cases, and about 50% exhibit AKI, which is an independent predictor of mortality. Vascular endothelial cell injury is thought to be the predominant mechanism. Renal biopsies have shown mild mesangial hyperplasia, acute tubular necrosis, or tubulointerstitial nephritis.

abscesses. Characteristic broad, aseptate hyphae can be demonstrated in material obtained by needle aspiration or biopsy. The only definitive treatment is extensive debridement of affected tissue, which may include bilateral nephrectomy and systemic amphotericin B therapy. This condition carries an extremely poor prognosis. HIV infection Most individuals affected with HIV infection live in the tropical countries of Africa and South Asia. The frequency of renal involvement varies widely in different geographic areas and races, with less than 5% in Asia and Latin America and 25 to 50% in Africa. Renal lesions can be as a direct result of the HIV infection, or indirectly secondary to treatment or associated conditions (Table 21.11.3 and Fig. 21.11.11).

Table 21.11.3  Renal manifestations in of HIV infection Direct renal effects associated with HIV infection Acute kidney injury

• Volume loss (e.g. gastroenteritis, pancreatitis)

Other infective causes of renal disease

• Infections

Zygomycosis

• Myocardial dysfunction (e.g. cardiomyopathy)

Zygomycosis (syn. mucormycosis) is an opportunistic infection caused by the saprophytic fungi of the order Mucorales and genera Rhizopus, Absidia, and Rhizomucor. The spores gain entry into the body through inhalation or cutaneous breach. The fungus primarily spreads through vascular route, leading to thrombosis of large and small arteries and infarction and necrosis of the affected organ. Primary renal zygomycosis has been described from several tropical countries. Patients present with high fever, lumbar pain, pyuria, and oliguric AKI. The initial route of entry of the organism is often uncertain. Diagnosis requires a high index of suspicion and use of imaging. Ultrasonography reveals enlarged kidneys. CT scan appearance is often diagnostic and shows large kidneys with perinephric stranding, large nonenhancing areas indicating infarction (Fig. 21.11.10), along with perirenal and/​or intrarenal

• Liver failure (HIV cholangiopathy or

coinfection with hepatitis B and/​or C); hepatorenal syndrome

Chronic kidney disease

• HIV-​associated nephropathy (HIVAN) • HIV immune complex glomerulonephritis

Electrolyte and acid–​base disorders

• Hyponatraemia (related to SIADH, volume depletion, and adrenal insufficiency)

• Hypernatraemia (related to dehydration) • Hyperkalaemia (related to renal dysfunction, trimethoprim, or IVI pentamidine use and adrenal insufficiency)

• Hypokalaemia (related to diarrhoea and amphotericin B therapy)

• Metabolic acidosis (lactic acidosis secondary

to tissue hypoperfusion, stavudine use or liver disease or kidney failure)

Indirect renal involvement Acute kidney injury

• Toxins, especially traditional herbal medications

• Analgesics, especially nonsteroidal anti-​inflammatory drugs

• Antiretroviral agents, especially tenofovir

(tubular toxicity), ritonavir (exacerbates tenofovir nephrotoxicity), indinavir (crystal formation and obstruction), and stavudine (lactic acidosis and/​or pancreatitis)

Chronic kidney disease

• Metabolic syndrome associated with antiretroviral drug use

• Other chronic kidney disease with incidental HIV infection

Fig. 21.11.10  Contrast-​enhanced CT of the abdomen showing almost complete nonenhancement of the left and minimal patchy contrast enhancement of the right renal parenchyma (suggesting infarction), along with bilateral perinephric stranding (arrows) in a patient with AKI due to bilateral mucormycosis.

IVI, intravenous infusion; SIADH, syndrome of inappropriate antidiuretic hormone secretion. Reproduced with permission from Naicker S, Paget G. HIV and renal disease. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

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Fig. 21.11.11  Photomicrograph of a patient with HIV-​associated nephropathy showing glomerular collapse, focal sclerosis, and microcytic dilatation of tubules. Reproduced with permission from Naicker S, Paget G. HIV and renal disease. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Courtesy of Prof Stewart Goetsch, University of the Witwatersrand.

The presentation of renal disease in HIV infection is the result of a complex interplay between the pheno-​and/​or genotypic variants of the virus, the genetic make-​up of the host, and environmental factors. The viral genes nef and var increase podocyte proliferation and dedifferentiation, and alter podocyte protein expression. HIV-​1 infection induces tubular injury by triggering an apoptotic pathway involving caspase activation and FAS up-​ regulation. Release of a variety of cytokines also affects podocytes and tubular cells. HIV-​associated nephropathy also shows a strong genetic predilection:  people of African ancestry exhibit a 20-​fold increase in relative risk compared with individuals of Caucasian descent. The differential risk has been traced to the presence of pathogenic variants of MYH9 and APOL1 gene variants in this population. A number of studies have shown a direct link between the viral load and development as well as progression of kidney disease. Use of highly active retroviral therapy has had a favourable effect on disease course.

Toxic causes of renal disease in the tropics

Fig. 21.11.12  Contrast-​enhanced CT of the abdomen in a patient with AKI following an Echis carinatus bite showing acute cortical necrosis. The nonenhancing zone of necrotic cortex is limited by the enhancing subcortical rim on the outside (arrows) and the medulla on the inside (arrowheads).

Clinical features The initial symptoms are pain and swelling of the bitten part, followed by blister formation and ecchymosis. Bleeding—​as ooze from fang marks, haematemesis, melaena, or haematuria—​is seen in 65% of cases. Sea-​snake bites cause myonecrosis, which manifests as muscle pains and weakness. Renal failure sets in from within a few hours to as late as 4 days after the bite, and is usually oliguric. A history of passage of ‘Coca-​ Cola’-​ coloured urine, indicating intravascular haemolysis, is obtained in about one-​half of cases, and over 90% show oliguria. Life-​threatening hyperkalaemia may develop in patients with haemolysis or myonecrosis. With effective management, oliguria resolves in 5 to 21 days; persistence indicates the likelihood of renal cortical necrosis (Fig. 21.11.12). Pathology Grossly, the kidney are swollen and exhibit petechial haemorrhages. Light microscopy shows acute tubular necrosis in 70 to 80% of cases. Interstitial oedema, inflammatory cell infiltration, and scattered haemorrhages may be seen. Electron microscopy reveals dense intracytoplasmic bodies in the proximal tubules representing degenerated organelles. Other lesions include acute interstitial nephritis, thrombotic microangiopathy, necrotizing arteritis, and crescentic glomerulonephritis. Acute cortical necrosis is seen in 20 to 25% of cases.

Snake venoms

Pathogenesis

Most of the 450 venomous snake species are found in the tropical and subtropical regions. Renal lesions have been reported following bites by snakes belonging to classes Viperidae (Russell’s viper, saw-​ scaled viper, puff adder, pit viper, and rattlesnakes), Colubridae (boomslang, Bothrops jararaca, gwardar, dugite, and Cryptophis nigrescens), and Hydrophidae (sea snakes). AKI is the most frequent and clinically important effect of envenomation on the kidneys, with most cases seen following viper and sea snake bites. In India, about 13 to 32% of those bitten by Echis carinatus (Russell’s viper) develop AKI. The reported incidence from other countries varies between 1 and 27%.

Renal damage is a cumulative effect of direct nephrotoxicity of venom, hypovolaemia, haemolysis, myoglobinuria, and disseminated intravascular coagulation. Injection of snake venom leads to increased excretion of tubular enzymes in rats. Administration of Russell’s viper venom led to a dose-​dependent decrease in inulin clearance in isolated perfused rat kidney. Destruction of the glomerular filter, lysis of vessel walls, mesangiolysis, and tubular injury have been shown in experimental models. A vasculotoxic factor has been isolated from the venoms of several snakes. Similarities have been noted between the structure of the potent vasoconstrictor endothelin-​1 and the venom of the Israeli burrowing asp.

21.11  Renal diseases in the tropics

Hypotension and circulatory collapse can result from blood loss, release of kinins, or depression of the medullary vasomotor centre or myocardium. Kininogenases are present in crotalid venom. Viper palastinae venom produces depression of the medullary vasomotor centre, whereas Bitis arietans venom causes myocardial depression, arteriolar dilatation, and increased vascular permeability. Phospholipase A  and a basic protein called ‘direct lytic factor’ present in Russell’s viper and E.  carinatus venoms cause intravascular haemolysis and disseminated intravascular coagulation. Microangiopathic haemolytic anaemia can develop following A. rhodostoma, Russell’s viper, E. carinatus, puff adder, and guarder bites. Viper venom activates the coagulation cascade at several levels, leading to rapid thrombin formation.

Other conditions AKI has been reported following stings by scorpion, jellyfish, and giant centipede. Scorpion stings result in disseminated intravascular coagulation and internal bleeding, and these can give rise to intravascular haemolysis.

Plant toxins

The mainstay of management is prompt antivenom administration to cases with evidence of systemic envenomation or local inflammation involving more than 50% of the limb circumference. There is no agreement on the exact dose needed, or duration of therapy. A rule of thumb is to continue administration until the effects of systemic envenoming disappear as shown by normalization of the whole-​blood clotting time. Concomitant measures include replacement of lost blood, maintenance of electrolyte balance, administration of tetanus immunoglobulin, and adequate treatment of pyogenic infection. Maintenance of a high urinary output, as well as alkalinizing the urine, may attenuate renal damage in those with haemolysis.

Tropical communities consume products derived from locally grown plants, either as food or as medicines, and many of these contain nephrotoxic substances. Exposure may be accidental, when a toxic plant is mistaken for an edible one. The insult can be identified quickly when the presentation is acute, but the cause–​effect relationship may be harder to establish in the case of slowly progressive kidney disease. Traditional medicines constitute a special class of nephrotoxins among poor populations in tropical Africa and Asia. In African hospitals, more than 75% of all deaths from acute poisoning and 25 to 60% of all AKI from medical causes are due to traditional medicines. These agents are obtained from traditional healers (‘witch-​doctors’), who wield considerable power. Administration is either by the oral route or as enemas, the latter consisting of mixtures of herbs, barks, roots, leaves, and bulbs, administered through a truncated cow’s horn or hollow reed. Increasing urbanization and industrialization have introduced potent chemicals (e.g. paint thinners, turpentine, chloroxylenol, ginger, pepper, soap, vinegar, copper sulphate, and potassium permanganate) into their armamentarium. AKI has been reported following the use of such enemas: detailed studies are not available, but histology usually shows acute tubular necrosis.

Other animal toxins

Callilepis laureola (impila) poisoning

Bee, wasp, and hornet stings

C. laureola, a herb with a tuberous rootstock, grows in several countries in sub-​Saharan Africa. An extract of the tubers is taken orally or as an enema as a traditional remedy, and is a common cause of AKI in the black South African population. Symptoms appear within 24 h in 40% and within 4 days in 70% of patients. Children and older people show earlier and more severe abnormalities. Abdominal pain and vomiting are followed by hypoglycaemia, convulsions, and jaundice. Histology shows acute tubular necrosis and/​or interstitial infiltration. Atractyloside, an alkaloid in the tuber of the plant, inhibits ATP synthesis and is believed to have nephrotoxic and hypoglycaemic effects. Gastrointestinal fluid loss contributes to the renal dysfunction. Treatment is supportive and includes correction of hypoglycaemia and volume and electrolyte replacement. The mortality rate is over 50%.

Management

Stinging insects belonging to the order Hymenoptera, such as honeybees, yellow jackets, hornets, and paper wasps, are found in most tropical countries. Systemic symptoms develop when an individual is attacked by a swarm of insects and receives a large dose of venom. Manifestations include vomiting, diarrhoea, hypotension, and loss of consciousness. AKI is secondary to haemolysis, rhabdomyolysis, or both. Haemolysis results from the action of a basic protein fraction, melittin, and phospholipase A.  Rhabdomyolysis has been attributed to polypeptides, histamine, serotonin, and acetylcholine. Experimental studies have suggested a direct nephrotoxic role of venom components. Renal biopsy invariably reveals acute tubular necrosis. Carp and sheep bile Acute hepatic and renal failure have been reported following consumption of the raw gallbladder or bile of freshwater and grass carps (Ctenophryngodon idellus, Cyprus cardio, Hypophythalmichthys molitrixn, Mylopharyngodon pisces, and Aristichthys nobles) in Taiwan, South China, Hong Kong, Japan, India, and South Korea, and sheep bile in the Middle East. Initial symptoms include abdominal pain, nausea, vomiting, and watery diarrhoea. Hepatocellular jaundice and AKI occur 48 h after ingestion. Haematuria is noted in 75% of cases. The duration of renal failure ranges from 2 to 3 weeks. Manifestations vary depending upon the varieties of carp and amount of bile ingested. Histology reveals acute tubular necrosis and interstitial oedema.

Djenkol bean poisoning Djenkol beans (Pithecolobium lobatum and P.  jiringa, family Mimosaceae) are considered a delicacy in Indonesia, Malaysia, southern Thailand, and Myanmar (Burma). AKI can occur when raw beans are consumed in large amounts with low fluid intake, and nephrotoxicity has been reported most commonly in the rainy season from Malaysia and Indonesia. Symptoms include dysuria, lumbar pain, hypertension, haematuria, and oligoanuria. The breath and urine emit a characteristic sulphuric odour. Urinalysis shows needle-​like crystals of djenkolic acid, a sulphur-​rich cysteine thioacetal of formaldehyde that forms in the concentrated acidic urine of the distal tubules. Individual susceptibility to the toxic

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effects is variable, possibly related to hydration status or variability in activity of metabolizing enzymes. High fluid intake and urinary alkalinization helps in dissolving the crystals. Most victims recover within a few days. Chronic ingestion can lead to development of djenkolic acid stones. Mushroom poisoning Less than 1% of all mushrooms are toxic. AKI has been observed following the ingestion of mushrooms of the genera Amanita, Galleria, Cortinarius, and Inocybe. Amanita phalloides (death cap) and A. virus (destroying angel) grow commonly in lawns, pastures, on living trees, in basements, plasterboard walls, and flower pots, and may be picked and ingested by inexperienced collectors and children. Initial symptoms are related to the gastrointestinal tract and may result in dehydration and hypotension. The toxic compounds (phallotoxin, amatoxin) inhibit RNA polymerase. Hepatic and renal failure develops after a couple of days. Renal histology shows acute tubular necrosis. Management is supportive; charcoal haemoperfusion is effective in clearing α-​amanitin from circulation and may improve outcome. Overall mortality is over 50%, and exceeds 70% in children. Long-​term ingestion of cortinarius mushrooms has been implicated in chronic renal failure. Details of other toxic plants that have been associated with development of kidney diseases are described in Table 21.11.4.

Chemical nephrotoxins Increasing industrialization has facilitated the access of the poor and poorly educated populations of tropical countries to a variety of chemicals. Poisonings have been reported after accidental ingestion or following attempted suicide or homicide. AKI is a manifestation of toxicity of many of these agents, such as copper sulphate, ethylene glycol, paraphenylenediamine (PPD), paraquat, ethylene dibromide, and hexavalent chromium compounds. Ethylene glycol Ethylene glycol is used as an organic solvent, antifreeze, preservative, and glycerine substitute. It is metabolized in the liver to glyoxylic acid and oxalate, which combines with calcium and gets deposited in the acid milieu of renal tubules as calcium oxalate crystals, leading to AKI. Epidemics of ethylene glycol poisoning in children as a result of substitution of nontoxic propylene glycol with toxic di-​and polyethylene glycols as a vehicle in paediatric syrup preparations have been reported from tropical countries including India, Bangladesh, Nigeria, South Africa, and Haiti. The mortality is high due to underlying diseases and delayed diagnosis:  236 deaths were recorded among 339 children with AKI in Bangladesh during one such epidemic. Paraphenylenediamine PPD is a widely used chemical in Africa, Middle East, and Indian subcontinent as a textile, fur, or hair dye, to colour cosmetics, for temporary tattoos, photographic development, and in gasoline. It is a well-​known skin irritant and may be absorbed from the skin. Being cheap and widely available, it is also used for suicidal purposes. Clinical manifestations include cervicofacial oedema,

chocolate brown-​coloured urine, oliguria, muscular oedema, and shock. The most common renal presentation is as oliguric AKI, perhaps secondary to direct toxicity, rhabdomyolysis, and hypovolaemia, and PPD toxicity is a common cause of AKI in parts of the Indian subcontinent and Africa. Treatment is mostly supportive. Antihistamines and steroids are used in the management of airway oedema. Alkaline diuresis is tried in those with myoglobinuria. PPD is not dialysable. Copper sulphate Copper sulphate is commonly used as a pesticide, in the leather industry, and in making home-​made glue. Its blue colour makes it attractive to children, with risk of inadvertent poisoning, and it is used for suicidal purposes in the Indian subcontinent. Initial symptoms of copper sulphate poisoning consist of a metallic taste, increased salivation, burning retrosternal pain, nausea, vomiting, diarrhoea, haematemesis, and melaena. Jaundice, hypotension, convulsions, and coma indicate severe poisoning. Acute pancreatitis, myoglobinuria, and methaemoglobinaemia have also been reported. Oliguric AKI develops in 20 to 25% of cases and is frequently associated with passage of dark (Coca-​C ola)-​coloured urine, indicating intravascular haemolysis, the risk of which is increased in genetic G6PD deficiency. Renal histology shows acute tubular necrosis with abundant pigmented haemoglobin casts indicating haemoglobinuria. Acute cortical necrosis occurs rarely. Dialysis may be required for renal failure, but is ineffective in clearing copper from the body.

Future challenges In the coming years, tropical societies will face major impacts of climate change and water scarcity on kidney health. Changes in air and ocean temperature will make their impact felt in the tropics during the course of next 10 years, long before changes are noted in the temperate regions. Temperatures in excess of 50°C are already being recorded regularly in the tropics. The number of tropical cyclones is rising year on year. According to the United Kingdom-​based risk analysis firm Maplecroft, the top 10 countries at ‘extreme risk’ from climate change are all tropical countries. The kidneys are particularly vulnerable to the effects of climate change. Dehydration secondary to heat stress will increase the risk of acute as well as chronic kidney injury. Unpredictable rainfall, as seen in the Indian state of Tamil Nadu in 2015, is likely to lead to the re-​emergence of water-​borne and vector-​borne infectious diseases, nullifying the past gains made in infection control. Changes in climate and biodiversity have been linked to increases in zoonotic and vector-​borne disease outbreaks. Changes in vector ecology and water quality will increase the risk of the re-​emergence of previously contained infections or of the emergence of new infections in the tropics. Potential changes in the virulence of organisms is also a possibility, as shown by the emergence of kidney injury in vivax malaria, once considered benign, and of kidney injury in scrub typhus. Degradation of the ecosystem, with air and water pollution, will increase the risk of exposure to environmental toxins.

21.11  Renal diseases in the tropics Table 21.11.4  Plant nephrotoxins in the tropics Plant

Reported from

Active molecule

Renal manifestations

Other manifestations

Averrhoa bilimbi (irumban puli)

South India

Oxalic acid

Intratubular obstruction

Averrhoa carambola (star fruit)

Hong Kong, Taiwan

Oxalate

Intratubular precipitation of oxalate crystals

Vomiting

Callilepis laureola (impila)

Sub-​Saharan Africa

Atractyloside

ATN

Abdominal pain, diarrhoea, vomiting, jaundice, seizures, and coma

Catha edulis (khat leaf)

East Africa, Arab peninsula

S-​cathione, ephedrine

ATN

Hepatotoxicity

Cleistanthus collinus (oduvan)

India

Cleistanthin A and B, collinusin, diphylline

AKI

Hypotension, hypokalaemia, arrhythmia

Colchicum autumnale (meadow saffron)

Turkey

Colchicine

ATN

Haemorrhagic gastroenteritis, muscle paralysis, respiratory failure

Crotalaria laburnifolia (bird flower)

Zimbabwe, Sri Lanka

Pyrrolizidine alkaloids

ATN, HRS

Hepatic veno-​occlusive disease, pulmonary injury, thrombocytopenia

Cupressus funebris Endl (mourning cypress)

Taiwan

Flavonoid

ATN, AIN

AHF, haemolytic anaemia, thrombocytopenia

Dioscorea quartiniana and D. quinqueloba (yam)

Africa, Asia

Dioscorine, dioscin

ATN

Convulsions, encephalopathy

Dodonaea angustifolia (sand olive)

South Africa

Unknown

AIN

Pulmonary embolism

Euphorbia metabelensis, E. paralias (spurge)

Zimbabwe

Irritant chemicals in plant latex

ATN

Thrombocytopenia

Glycyrrhiza glabrata (liquorice)

Several countries

Glycyrrhizic acid

ATN

Rhabdomyolysis, hypokalaemia, hypertension, cardiac arrhythmia

Larrea tridentate (chaparral)

Chile, South Africa

Nordihydroguaiaretic acid, s-​quinone

Renal cysts, renal cell carcinoma

Hepatic failure

Lawsonia alba (henna)

Middle east, North Africa, Pakistan

2-​hydroxy-​1,4-​ naphthoquinone

ATN

Haemolysis

Pithecolobium lobatum and Pithecolobium jiringa (djenkol) beans

South East Asia

Djenkolic acid

Intratubular obstruction and ATN

Lumbar and lower abdominal pain, hypertension

Propolis

Brazil, Taiwan

Unknown

AIN

Contact dermatitis

Rhizoma rhei

Hong Kong

Anthraquinones (emodin, aloe-​emodin)

AIN

None

Securidacea longepedunculata (violet tree, wild wisteria)

Congo, Zambia, Zimbabwe

Methylsalicylate, securinine, ATN saponins

Vomiting, diarrhoea

Sutherlandia frufesces (cancer brush), Dodonaea angustifolia

South Africa

Unknown

AIN

Pulmonary embolism

Takeout roumia

Morocco, Sudan

Paraphenylenediamine

ATN

Rhabdomyolysis

Taxus celebia (Chinese yew)

Asia

Flavonoid

ATN, AIN

Hepatitis, haemolysis, DIC

Thevetia peruviana (yellow oleander)

India, Sri Lanka

Cardiac glycosides

ATN, mesangiolysis

Liver failure, cardiac arrhythmias

Tribulus terrestris

USA, Iran

Unknown

ATN, AIN

Liver failure, encephalopathy

Tripterygium wilfordii Hook F (thunder god vine)

Taiwan

Triptolide

ATN

Diarrhoea, shock

Uncara tomentosa (cat’s claw)

Peru

Alkaloids, flavonols

AIN

Diarrhoea, hypotension, bruising, bleeding gums

AHF, acute hepatic failure; AIN, acute interstitial nephritis, AKI, acute kidney injury; ATN, acute tubular necrosis, DIC, disseminated intravascular coagulation; GI, gastrointestinal; HRS, hepatorenal syndrome.

A decreased ability to excrete, secondary to dehydration, will lead to higher concentrations of such toxins in the kidney, with adverse consequences on kidney health. Combating these challenges will require concerted action on medical as well as societal and political fronts. Anticipating the upcoming challenges and fortifying the health system to address these in a timely manner is a challenge that needs to be tacked urgently.

FURTHER READING Araujo ER, et  al. (2010). Acute kidney injury in human leptospirosis: an immunohistochemical study with pathophysiological correlation. Virchow Arch, 456, 367–​75. Barber BE, et al. (2013). A prospective comparative study of knowlesi, falciparum, and vivid malaria in Sabah, Malaysia: high proportion with severe disease from Plasmodium knowlesi and Plasmodium

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vivid but no mortality with early referral and artesunate therapy. Cain Infect Dis, 56, 383–​97. Barsoum R (2000). Malarial acute renal failure. J Am Soc Nephrol, 11, 2147–​54. Barsoum R (2004). The changing face of schistosomal glomerulopathy. Kidney Int, 66, 2472–​84. Chugh KS, et al. (1994). Acute renal cortical necrosis—​a study of 113 patients. Ten Fail, 16,  37–​47. Cruz LS, et  al. (2009). Snakebite envenomation and death in the developing world. Ethn Dis, 19 Suppl 1, S42–​6. Correa-​Rotter R, et  al. (2014). CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy. Am J Kidney Dis, 63, 506–​20. Daher EF, et al. (2010). Clinical presentation of leptospirosis: a retrospective study of 201 patients in a metropolitan city of Brazil. Bras J Infect Dis, 14,  3–​10. Das BS (2008). Renal failure in malaria. J Vector Borne Dis, 45,  83–​97. Da Silva Junior GB, et al. (2006). Renal involvement in leprosy: retrospective analysis of 461 cases in Brazil. Bras J Infect Dis, 10, 107–​12. Eastwood J, et  al. (2015). Mycobacterial infections:  tuberculosis. In: Turner N, et al. (eds) Oxford textbook of clinical nephrology, 4th edition, pp. 1620–​4. Oxford University Press, Oxford. Isnard A, et al. (2008). Recent advances in the characterisation of genetic factors involved in human susceptibility to infection by schistosomiasis. Cure Genomics, 9, 290–​300. Jayakumar M, et  al. (2006). Epidemiological trend changes in acute renal failure—​a tertiary centre experience from South India. Ten Fail, 28, 405–​10. Jha V (2015). ESRD burden in South Asia: the challenges we are facing. Clin Nephrol, 83,  7–​10. Jha V, Chugh KS (2008). Acute kidney injury in Asia. Semi Nephron, 28, 330–​47. Jha V, Parameswaran S (2013). Community acquired acute kidney injury in the tropics. Nat Rev Nephrol, 9, 278–​90. Jha V, Prasad N (2016). CKD and infectious diseases in Asia Pacific: challenges and opportunities. Am J Kidney Dis, 68, 148–​60. Jha V, Rathi M (2008). Acute kidney injury due to natural medicines. Semim Nephrol, 28, 416–​28. Jha V, et al. (1992). Spectrum of hospital-​acquired acute renal failure in the developing countries—​Chandigarh study. Q J Med, 83, 497–​505. Liyanage T, et al. (2015). Worldwide access to treatment for end stage kidney disease: a systematic review. Lancet, 385, 1975–​82.

Mehta RL, et al. (2015). International Society of Nephrology’s 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology. Lancet, 385, 2616–​43. Mendley SR, et al. (2019). Chronic kidney disease in agricultural communities: report from a workshop. Kidney Int, pii: S00852538(19)30781-1. doi: 10.1016/j.kint.2019.06.024. Minho FM, Zanetti DM, Burdman EA (2005). Acute renal failure after Crotalus duress’s snakebite:  a prospective survey on 100 patients. Kidney Int, 67, 659–​67. Morand S, et  al. (2014). Infectious diseases and their outbreaks in Asia-​Pacific: biodiversity and its regulation loss matter. PLoS One, 9, e90032. Murray KO, et  al. (2015). Mesoamerican nephropathy:  a neglected tropical disease with an infectious ethology? Microbes Infect, 17,  671–​5. Naicker S, Paget G (2015). HIV and renal disease. In: Turner N, et al. (eds) Oxford textbook of clinical nephrology, 4th edition, pp. 1667–​ 75. Oxford University Press, Oxford. Nguansangiam S, et al. (2007). A quantitative ultrastructural study of renal pathology in fatal Plasmodium falciparum malaria. Trop Med Int Health, 12, 1037–​50. Olowu WA, et  al. (2010). Quartan malaria-​ associated childhood nephrotic syndrome: now a rare clinical entity in malaria endemic Nigeria. Nephrol Dial Transplant, 25, 794–​801. Prakash J, et al. (2006). Acute renal failure in pregnancy in a developing country: twenty years of experience. Ren Fail, 28, 309–​13. Rodrigues VL, et al. (2010). Glomerulonephritis in schistosomiasis mansion: a time to reappraise. Rev Soc Bras Med Trop, 43, 638–​42. Rosenberg AZ, et al. (2015). HIV-​associated nephropathies: epidemiology, pathology, mechanisms and treatment. Nat Rev Nephrol, 11, 150–​60. Shalaby SA, et al. (2010). Clinical profile of acute paraphenylenediamine intoxication in Egypt. Toxic Ind Health, 26,  81–​7. Singh SK, et  al. (2008). Milky urine. Chyluria. Kidney Int, 74, 1100–​1. Utah IA, et al. (2005). Factors contributing to maternal mortality in north-​central Nigeria: a seventeen-​year review. Afr J Reprod Health, 9,  27–​40. Wang X, et al. (2014). A two-​fold increase of carbon cycle sensitivity to tropical temperature variations. Nature, 506, 212–​15. Yang HY, et  al. (2015). Overlooked risk for chronic kidney disease after leptospiral infection: a population-​based survey and epidemiological cohort evidence. PLoS Negl Trop Dis, 9, e0004105.

21.12

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

ESSENTIALS There are more than 200 inherited disorders in which the kidney is affected. Many are single gene diseases that affect children, but cases are not restricted to paediatrics and diagnosis is often made in adults. They display a wide range of renal features: cystic, glomerular, tubulointerstitial, vascular, malformative, tumoural, and urolithiasis. Autosomal dominant polycystic kidney disease—​affects about 1/​1000 individuals and accounts for 7% of cases of endstage renal failure in Western countries. Inheritance is autosomal dominant, with mutations in polycystin 1 responsible for 75% of cases and mutations in polycystin 2 accounting for most of the remainder. May present with renal pain, haematuria, urinary tract infection, or hypertension, or be discovered incidentally on physical examination or abdominal imaging, or by family screening, or after routine measurement of renal function. Commonly progresses to endstage renal failure between 40 and 80  years of age. Main extrarenal manifestations are intracranial aneurysms, liver cysts, and mitral valve prolapse. Alport’s syndrome—​ X-​ linked dominant inheritance in 85% of kindreds, with molecular defects involving the gene encoding the α-​5 chain of the type IV collagen molecule. Males typically present with visible haematuria in childhood, followed by permanent nonvisible haematuria, and later by proteinuria and renal failure. Extrarenal manifestations include perceptive deafness of variable severity and ocular abnormalities (bilateral anterior lenticonus is pathognomonic). Carrier women often have slight or intermittent urinary abnormalities, but may develop mild impairment of renal function late in life, and a few develop endstage renal disease. In the autosomal recessive form of Alport’s syndrome, renal disease progresses to endstage before 20 to 30 years of age at a similar rate in both affected men and women. Hereditary tubulointerstitial nephritis—​ nephronophthisis is the most common genetic cause of endstage renal disease in children and young adults, and is a group of autosomal recessive tubulointerstitial nephropathies with multiple, small medullary cysts that appear late in the course of the disease. Eighty per cent of cases are caused by homozygous deletions of the NPH1 gene, which codes for nephrocystin. It presents with polyuria, polydipsia, and growth retardation in early childhood, progressing to endstage renal disease at a mean age of 14 years. In adults, autosomal dominant

tubulointerstitial nephritis, sometimes with gout and medullary cysts, is related to mutations in various genes (UMOD, MUC1, REN, TCF2). Hereditary tumours—​in von Hippel–​Lindau disease, due to mutations in the tumour suppressor gene VHL, renal cysts and bilateral multifocal renal cell carcinomas are found in 70% of cases. Carcinomas are often asymptomatic, should be screened for regularly, and occur at a mean age of 45 years. In tuberous sclerosis, due to mutations in genes encoding hamartin (TSC1) or tuberin (TSC2), multiple and bilateral renal angiomyolipomas may bleed, or induce progressive renal impairment.

Autosomal dominant polycystic kidney disease and other cystic diseases of the kidneys An overview of the most frequent causes of cystic kidney diseases, genetic and nongenetic, is shown in Table 21.12.1.

Autosomal dominant polycystic kidney disease Autosomal dominant polycystic kidney disease (ADPKD) is by far the most frequent inherited kidney disorder, accounting for approximately 7% of cases of endstage renal failure in Western countries. It is one of the most frequent human inherited monogenic diseases (c.1 in 1000 individuals). Diagnosis The diagnosis of ADPKD is mainly based on renal imaging. Ultrasonography, inexpensive and safe, remains the imaging modality of choice to make the diagnosis. One must take into account the presence or absence of a family history of ADPKD, the patient’s age, the number of observed cysts, and their localization and morphology. If unsure, a genetic diagnosis is sometimes offered and differential diagnoses must be explored. Positive diagnosis in a subject at risk of ADPKD This follows screening, usually of asymptomatic children and/​or siblings of an affected individual who have a 50% risk of having inherited ADPKD. Paediatric complications of ADPKD are exceptional and there is no proven benefit to screen for ADPKD in

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Table 21.12.1  Conditions causing cystic kidney diseases Condition

Characteristics

Autosomal dominant diseases Autosomal dominant polycystic kidney disease

Large kidneys (often), numerous diffuse renal cysts, hepatic cysts

Von Hippel–​Lindau (VHL) disease Large kidneys (often), cysts, solid lesions Tuberous sclerosis

Large kidneys (often), cysts, angiomyolipomas

TCF2 mutation (renal cysts and diabetes syndrome)

Medullary cysts; cystic dysplasia ± urinary malformations ± diabetes (MODY type 5)

UMOD, REN, MUC1 mutations

Medullary cysts ± gout

Table 21.12.2  Diagnostic tests for ADPKD Test

Age (years)

To affirm ADPKD

To exclude ADPKD

Renal ultrasonography

15–​39

≥3 cysts (total)

Impossible

40–​59

≥2 cysts in each kidney

0 or 1 cyst in each kidney

Renal MRI

>16

≥10 cysts (total)

75 years in PKD2 disease). PKD1 disease progresses more slowly in women than in men. Control of hypertension may slightly reduce the rate of progression. Extrarenal manifestations Liver cysts develop in 70% of patients, usually later in life than renal cysts. They are more frequent and more diffuse in women than in men. They are usually asymptomatic but may be clinically palpable, and are typically detected by ultrasonography. Liver function tests are usually normal. Liver cyst infection may occur, particularly in patients on dialysis or in transplant recipients. Massive liver involvement can cause severe discomfort in some cases, mostly in women. Cardiovascular abnormalities include intracranial aneurysms and mitral valve prolapse. Subarachnoid haemorrhage or intracerebral bleeding due to rupture of intracranial aneurysm are among the most severe complications of ADPKD and occur in approximately 1 to 2% of patients. Rapid diagnosis and urgent neurosurgical opinion are required. Diagnosis should be suspected early, before complete rupture, in patients with ADPKD with recent and severe headache, or with any transient focal neurological deficit. In cross-​sectional studies performed using noninvasive screening methods such as high-​resolution CT or magnetic resonance angiography, intracranial aneurysms have been found in 7 to 8% of asymptomatic middle-​aged patients with ADPKD. The prevalence is higher in those with a family history of intracranial aneurysm. The risk of rupture is largely dependent on aneurysm size. Routine screening by noninvasive methods is not indicated for all asymptomatic patients with ADPKD, but it seems reasonable in certain subgroups, in particular those with a family history of intracranial aneurysm or subarachnoid haemorrhage, those who have already bled from an aneurysm (since recurrent aneurysm is possible), and possibly those who are to undergo major elective surgery. In high-​ risk groups, screening should be repeated every 5 to 10 years since the cerebral vascular disease is progressive.

Mitral valve prolapse is discovered in 20% of patients with ADPKD by echocardiography, whereas it is found in only 2 to 3% of the general population. Other cardiac valve abnormalities and occasionally artery dissection or aneurysm may also be detected. Other extrarenal abnormalities observed in ADPKD include pes excavatum, colonic diverticula, and abdominal hernias. Pathogenesis Cysts develop only in a few nephrons and only focally, whereas all nephron cells carry the mutated gene. This has been explained by a two-​hit phenomenon which postulates that renal tubular (or liver biliary) cells that are at the origin of cysts bear first the germinal PKD gene mutation, and then acquire a somatic PKD gene mutation involving the other allele, this event occurring at random in a limited number of cells. This explanation does not exclude other mechanisms. The link between the genetic event(s) and cystic fluid accumulation is not known. The disease has an autosomal dominant mode of inheritance, so that the risk of any child of an affected parent carrying the abnormal gene is one in two, new mutations being rare. Mutations affecting polycystin 1 (from the PKD1 gene on the short arm of chromosome 16) are responsible for 75% of cases in the most recent series, with mutations affecting polycystin 2 (from the PKD2 gene on the long arm of chromosome 4) accounting for most of the remainder. Polycystin 1 and polycystin 2 are transmembrane proteins that are able to interact, function together as a nonselective cation channel, and also induce several distinct transduction pathways. The ‘polycystin complex’ may have three different subcellular localizations and associated putative functions: at lateral membranes of the cells (with a role in cell–​cell interaction), at the basal pole of the cell (with a role in cell–​ extracellular matrix interaction), and at the apical primary cilia of the cells (with a role in mechanotransduction of the urinary flux). Treatment—​general and symptomatic High fluid intake and regular follow-​up of blood pressure and renal function are indicated in all patients with ADPKD. The control of hypertension is an essential part of management, achieved with standard antihypertensive agents. Haematuria should be managed conservatively if possible, although bleeding may sometimes be prolonged over several days and even weeks. The relief of pain or abdominal discomfort can be difficult. In addition to symptomatic treatment, surgical renal cyst decompression should be restricted to very selected cases. Surgery is rarely needed in the management of renal stones. Liver cyst aspirations by needle under CT guidance, fenestration, or resection may be needed when massive involvement gives rise to pain; and in very rare cases such patients have come to liver transplantation. Kidney infection requires administration of antimicrobials appropriate for upper urinary tract infection (see Chapter 21.13). In some cases, control of infection is not obtained, most probably because agents penetrate some infected cyst fluids poorly and do not achieve adequate concentration. Lipophilic drugs such as trimethoprim–​ sulphamethoxazole and fluoroquinolones have the best penetration into cyst fluid. Liver cyst infection also requires antimicrobials and drainage if infection is not controlled. Standard medical management of chronic renal failure is indicated, as are renal replacement therapy and kidney transplantation when the patient reaches endstage, the results being similar to those obtained in other renal diseases.

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Treatment—​specific Identification of polycystins and their downstream intracellular dysregulated signalling pathways has provided clues to how the disease develops and thereby to the possibility of specific interventions. Among various molecules, V2 receptor antagonists (tolvaptan), somatostatin analogues (octreotide), and mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) have been tested and shown promise in animal models. A  randomized trial of tolvaptan in patients aged 18 to 50 years, with an estimated glomerular filtration rate greater than 60 ml/​min and total kidney volume greater than 750 mL, demonstrated a reduced rate of annual increase in total kidney volume (2.8% vs 5.5%), a reduced annual rate of decline of renal function (−3.0 µmol/​L vs −4.3 µmol/​L), and reduced rate of reaching a composite endpoint comprising measures of clinical progression and rate of kidney function decline (44 vs 50 events per 100 patient-​years of follow-​ up). Patients who took tolvaptan had a higher rate of adverse events related to aquaresis, but a lower frequency of adverse events related to ADPKD. Elevation of serum alanine aminotransferase to more than 2.5 times normal occurred in 4.9% of patients taking tolvaptan (vs 1.2% controls), and the United States Food and Drug Administration has subsequently issued a safety warning about the possibility of irreversible liver injury associated with the use of the drug. In the United Kingdom the National Institute for Health Care and Excellence have recommended Tolvapatan as an option to slow progression of cyst development and renal failure in patients with CKD stages 2 or 3 who have evidence of rapidly progressing disease, subject to the medication being provided at an agreed discount. Clinical trials of octreotide have shown a tendency for reduction in increase in renal size and decline in glomerular filtration rate, but without the reductions reaching statistical significance and with a suggestion that beneficial effects may be attenuated after 2  years. Clinical trials of everolimus and sirolimus have not shown significant clinical benefit, and these agents have a formidable side effect profile. Genetic counselling The pattern of inheritance of ADPKD means that the offspring of an affected subject each have a 50% risk of having the disease. The disease has a highly variable clinical course, even within a given family. Prenatal diagnosis by gene linkage studies using material derived from chorionic villus sampling has been performed and can be considered if required and if adequate family information is available, but the demand for such prenatal diagnosis has been very low in Western countries. This is explained by the late onset and the variable clinical course of the disease, often relatively benign, which cannot yet be predicted by DNA analysis. Ultrasonography may occasionally show renal cysts in the fetus, but late in pregnancy. Obviously, due to the slow and late development of macrocysts, negative ultrasonography in the fetus (as well as in a child) does not rule out the disease.

Autosomal recessive polycystic kidney disease Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited disease (c.1 in 40  000 individuals), the first manifestations of which appear early in childhood. Mutations at a single locus, polycystic kidney and hepatic disease 1 (PKHD1, located on

chromosome 6), are responsible for all typical forms of ARPKD. The PKDH1 gene product, fibrocystin, is a transmembrane protein localized to the cell primary cilia. Three clinical features characterize this disease: • Its recessive nature:  both heterozygous parents are unaffected, with normal renal ultrasonography; parental consanguinity is found in some families. • Renal cysts derive from the collecting ducts, accounting for the striations in the dilated collecting system seen on MRI. • The renal disease is in most cases associated with congenital hepatic fibrosis: this may be responsible for portal hypertension due to presinusoidal block, or for bacterial angiocholitis due to intrahepatic bile duct dilatation. In children, ARPKD should be differentiated from ADPKD, which can be detected in childhood, even in neonates. Family history and renal ultrasonography in parents are decisive for correct diagnosis. In very rare families with PKD1 disease, renal involvement may be revealed in neonates and may progress to endstage within the first year of life. The diagnosis of ARPKD may be made before birth by antenatal ultrasonography, showing renal enlargement and increased echogenicity (as well as oligohydramnios). However, prenatal diagnosis may be uncertain and, since cystic changes occur in well-​ developed collecting ducts, these are detected only in the second half of pregnancy. When there is huge renal enlargement, pulmonary hypoplasia and respiratory distress may lead to death within hours after birth. With prolonged survival, liver and renal involvement becomes prominent. Gastrointestinal bleeding due to portal hypertension may be life-​threatening and necessitate surgical portocaval shunt. Systemic hypertension is a frequent finding in the first year of life but, surprisingly, it may regress in subsequent years. Urinary tract infection is common. The rate of progression of renal failure is variable:  of those who survive the neonatal period, about 50% reach endstage in childhood, whilst this occurs in adulthood in the remainder.

TCF2 mutation; renal cysts and diabetes syndrome (RCAD) Heterozygous mutations in the TCF2 gene encoding hepatocyte nuclear factor (HNF)-​1β, a DNA transcription factor, were initially described as one of the main molecular causes of maturity-​onset diabetes of the young (MODY) type 5. It now appears that renal anomalies are the key feature of HNF1β mutation phenotype and often precede the onset of diabetes. Renal cysts and progressive renal failure are frequent; glomerulocystic kidney disease and renal hypoplasia have been reported. Abnormal liver function tests, hyperuricaemia, hypomagnesaemia, pancreatic hypoplasia, and urogenital malformations have also been related to HNF1β mutations.

Other hereditary cystic kidney diseases Renal cysts may be found in other autosomal dominant diseases, such as von Hippel–​Lindau disease, tuberous sclerosis, as well as in three recently identified major causes of familial tubulointerstitial nephritis (UMOD, REN, and MUC1 gene mutations) with frequent medullary cysts. Most of these rare condition progress to endstage renal failure. Renal medullary cysts are also found in juvenile nephronophthisis, but not early in the course.

21.12  Renal involvement in genetic disease

Genetic glomerular diseases Glomerular structural diseases In glomerular structural diseases, proteins of podocytes or basement membrane are mutated (Table 21.12.3). X-​linked Alport’s syndrome Basement membranes of glomeruli may be altered by type IV collagen mutations. Six α chains of type IV collagen have been identified so far, with each molecule of type IV collagen being made up of three of these chains, differently associated in various basement membranes. In X-​linked Alport’s syndrome, mutations have been identified in the gene encoding the α-​5 chain that maps to the long arm of the X chromosome. X-​linked Alport’s syndrome is characterized by the association of progressive haematuric hereditary nephritis and bilateral sensorineural hearing loss. Its prevalence is approximately 1 in 5000 individuals. The first renal manifestation is typically visible haematuria, occurring sometimes in the first year of life, recurring during childhood, and followed by permanent nonvisible haematuria. Proteinuria appears later. A nephrotic syndrome, usually moderate, develops in 30 to 40% of patients. In other cases, moderate proteinuria and nonvisible haematuria are the presenting symptoms in adulthood. By electron microscopy, the basement membrane can be abnormally thickened with splitting of the lamina densa, thinned with focal thickening, or diffusely thin. The disease is progressive, leading to renal failure in all affected males, but the rate of progression is heterogeneous from one family to another, although usually homogeneous within a given family. In some, endstage is reached at or before 30 years of age, sometimes in childhood; in others, renal failure progresses to endstage between the ages of 30 and 60 years. Carrier females of X-​linked Alport’s syndrome often have slight or intermittent urinary abnormalities. Some may develop impairment of renal function late in life.

The hearing defect may lead to severe perceptive deafness, but it is often moderate or slight, only detected by audiometric testing. The hearing loss labels a given family, but is not found in all patients with renal disease. Eye abnormalities are detected in 30 to 40% of cases. These include bilateral anterior lenticonus detected by slit-​lamp examination—​a pathognomonic abnormality—​and perimacular or macular retinal flecks that are seen by fundoscopic examination and do not alter visual acuity. Recurrent corneal erosions occur in some patients. Genetic counselling first requires the correct identification of the mode of inheritance. If X-​linked dominant inheritance is documented, affected men will not transmit the disease to their sons, whereas all their daughters will carry the mutant gene; affected women will transmit the mutant gene to 50% of either sons or daughters. DNA analysis may be helpful for genetic counselling in these families. Treatment of hypertension and supportive management of renal failure are indicated in patients with progressive disease. The results of kidney transplantation are similar to those obtained in other renal diseases, but in rare cases antiglomerular basement membrane crescentic glomerulonephritis develops in the graft. It is assumed that this complication is related to alloimmunization to the ‘missing antigen’ introduced by the transplant. Autosomal Alport’s syndromes In the autosomal recessive form, renal disease progresses to endstage before 20 to 30 years of age at a similar rate in both affected men and women. The genes encoding α-​3 or α-​4 chains are mutated. Affected subjects are homozygotes in consanguineous families, or compound heterozygotes in other cases. In families with leiomyomatosis, α-​5 and α-​6 genes, located contiguously on the X chromosome, are both involved in a large deletion. In some families, macrothrombocytopenia is associated with nephritis and hearing defects: mutations involve the MYH9 gene, encoding the nonmuscle myosin heavy chain IIA.

Table 21.12.3  Genetic glomerular structural diseases Disease

Gene (OMIM)

Inheritance

Renal phenotype

Extrarenal phenotype

X linked Alport’s syndrome

COL4A5 (301050)

XL

Nonvisible haematuria (constant) ± episodes of visible haematuria; increasing proteinuria ± nephrotic range, progressive renal failure. Early endstage renal disease (ESRD) in most males

Sensorineural hearing loss; anterior lenticonus and other eye anomalies

Myosin heavy chain 9 (MYH9)

MYH9

AD

Nonvisible haematuria, proteinuria, progressive renal failure

Macrothrombocytopenia Leucocyte inclusions Sensorineural hearing loss Cataract

Nail patella syndrome (osteo-​onychodysplasia)

LMX1B (161200)

AD

Focal and segmental glomerulosclerosis with specific ultrastructural changes of the glomerular basement membrane, in 30% of patients, may progress to ESRD in some

Inconstant. Absence, dysplasia, or hypoplasia of the nails and patella; elbow dysplasia; bilateral iliac horns arising from the anterosuperior iliac crest; eye disease and sensorineural hearing loss possible

Congenital nephrotic syndrome of the Finnish type

Nephrin

AR

Massive proteinuria occurs in utero and persists in infancy. Intense therapy needed: nutritional support to compensate for protein loss; prevention of infection and thrombosis; bilateral nephrectomy; continuous peritoneal dialysis, and finally kidney transplantation

None

Familial focal segmental glomerulosclerosis

Various (see text)

AR or AD

Progressive proteinuria, sometimes nephrotic. May progress to ESRD

None

AD, autosomal dominant; AR, autosomal recessive; XR, X-​linked.

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Benign familial haematuria

Metabolic diseases with glomerular involvement

This condition is characterized by isolated nonvisible haematuria, without proteinuria or progression to renal failure, in both men and women. Renal biopsy usually shows a thin glomerular basement membrane (hence the alternative name thin basement membrane nephropathy) and immunofluorescence studies are negative. The mode of transmission is compatible with autosomal dominant inheritance of mutations involving the α-​3 or α-​4 chain gene.

In metabolic diseases with glomerular involvement, a defect in an enzyme or its cofactor leads to accumulation or deficiency of a specific metabolite. Fabry disease’s, mitochondrial cytopathy, lecithin-​cholesterol acyl transferase (LCAT) deficiency, hepatorenal glycogenosis (glucose-​ 6-​ phosphatase deficiency), and glycogen storage disease type I are the most important diseases in this group (Table 21.12.4).

Familial focal segmental glomerulosclerosis

Fabry’s disease, a rare X-​linked lysosomal storage disease, results from α-​galactosidase A  deficiency. Glycosphingolipid deposition mainly occurs in the cardiovascular and renal system. Hemizygotes males are more severely affected than heterozygote females. The first manifestations are painful acroparaesthesias, appearing in childhood and often prevented by administration of carbamazepine or phenytoin. Angiokeratomas, anhidrosis, and corneal deposits develop subsequently. Ischaemic cerebrovascular complications, cardiac valve abnormalities, myocardial deposition of glycolipids, and coronary events are the most severe manifestations, along with renal involvement. In the kidney, glycolipid deposition involves glomerular epithelial cells, tubular cells, and endothelial and smooth muscle cells of intrarenal arteries. The latter changes are responsible for progressive renal ischaemia. Renal disease is revealed by proteinuria at around 20 years, and then progresses to endstage between 40 and 60 years of age, necessitating regular dialysis and/​or kidney transplantation. Glycolipid deposition does not recur in the renal graft that contains normal α-​galactosidase activity. Diagnosis is based on symptoms, familial history, measurement of α galactosidase activity in leucocytes, demonstration of typical inclusions on a tissue biopsy, and genetic analysis. Two different recombinant enzyme treatments (agalsidase α and agalsidase β) have been available since 2001. Enzyme replacement therapy promotes

Familial focal segmental glomerulosclerosis with either autosomal dominant or autosomal recessive inheritance has been well characterized. Mutation of the NPHS2 gene, which encodes podocin, and mutations of PLCE may cause recessive steroid-​resistant nephrotic syndrome in some families, which can be of early or late onset. Mutations in ACTN4, which encodes α-​actinin-​4, mutations of TRPC6, and mutations of INF2 (which encodes formin) may cause autosomal dominant focal segmental glomerulosclerosis. All these proteins are synthesized and secreted by the podocytes, and interact and regulate plasticity and slit diaphragm permselectivity with other podocyte proteins. Mutations (especially podocin mutations) may be detected in some cases of sporadic steroid-​resistant nephrotic syndrome. Nephrin is localized at the slit diaphragm between podocyte foot processes (which are both absent in affected subjects), and plays a key role in the normal glomerular filtration barrier. Mutations of nephrin are responsible for autosomal recessive congenital nephrotic syndrome. Familial IgA nephropathy For most types of other primary glomerulonephritis, familial cases have been anecdotally reported. The most frequent form, albeit rare, is probably familial IgA nephropathy, either primary (Berger’s disease) or associated with Henoch–​Schönlein purpura.

Fabry’s disease

Table 21.12.4  Genetic glomerular metabolic diseases Disease

Gene (OMIM)

Inheritance

Renal phenotype

Extrarenal phenotype

Fabry’s disease

GLA (301500)

XL

Mostly in men: proteinuria, progressive kidney failure; sometimes tubular dysfunction (polyuria, Fanconi’s syndrome) and renal parapyelic cysts. Glycolipids accumulation observed on light and electron microscopy

Pain (acromelalgia), skin (angiokeratomas, anhidrosis), eye (cornea verticillata), heart (left ventricular hypertrophy, conduction anomalies, valve anomalies, angina), strokes (hearing loss, ataxia, vascular dementia)

Mitochondrial cytopathy, MIDD type

MT-​TL1 (520000)

Mitochondrial

Proteinuria, progressive renal failure (focal segmental glomerular sclerosis, tubulointerstitial nephritis)

Sensorineural hearing loss and diabetes in adults (seek for maternal inheritance); pigmentary retinopathy, ptosis, cardiomyopathy, myopathy, neuropsychiatric symptoms

Lecithin-​cholesterol acyl transferase (LCAT) deficiency

LCAT (245900)

AR

Lipid accumulation occurs in glomerular mesangial cells and progresses to endstage renal disease. Lipid deposition recurs slowly in kidney transplants

Lipid accumulation occurs in the eyes (causing corneal deposits), erythrocyte membranes (leading to low-​grade haemolytic anaemia), arterial walls (contributing to premature atherosclerosis)

Hepatorenal glycogenosis (glucose-​6-​ phosphatase deficiency; glycogen storage disease type I; von Gierke)

G6PC (type a 232200) SLC37A4 (type b 232220)

AR

Early enlarged kidneys Late glomerular hyperfiltration proteinuria, progressive renal failure

Early hypoglycaemia, intolerance to fasting, hepatomegaly, growth retardation, osteopenia, round face, platelet ± neutrophil dysfunction, enteropathy Late hepatic adenomas and carcinomas

AR, autosomal recessive; XR, X-​linked.

21.12  Renal involvement in genetic disease

cell clearance of substrate and improves some clinical parameters (heart, kidney damage, pain, quality of life). However, there is no proven efficacy to date on central nervous system lesions, on cardiac morbidity and mortality, nor on renal damage beyond a certain stage (proteinuria >1 g/​day and/​or estimated glomerular filtration rate 4.4 mmol/​day) may be seen in patients with calcium stones, often caused by a diet high in protein. Hyperuricosuria decreases the solubility of calcium oxalate, and promotes stones. Allopurinol was successful in decreasing stone recurrence in such patients (Table 21.14.3), and a decrease in protein intake would be helpful as well. Calcium phosphate stones Calcium phosphate stones form when supersaturation for calcium phosphate (brushite) in the urine is exceeded. The major determinant of this type of supersaturation is alkaline urine pH (>6.3), coupled with hypercalciuria. These stones are associated with a more destructive renal pathology, and often require more procedures for removal. The cause of the elevated urine pH in these patients is often unclear; few have true distal renal tubular acidosis. Treatment with thiazide to lower urine calcium can prevent recurrent stones. The use of potassium citrate as a treatment for stones requires careful follow-​up to assure that supersaturation with respect to calcium phosphate is not rising, as formation of calcium phosphate stones may worsen.

Nephrocalcinosis Nephrocalcinosis is defined as precipitation of calcium salts in the renal tubules or interstitium. As noted previously, all calcium stones are accompanied by at least some tissue precipitation of calcium phosphate, but the amount is not large, and not yet detectable by current radiological methods. Larger amounts of precipitation may be seen in certain disease states (Table 21.14.2), and particularly in diseases such as distal renal tubular acidosis and primary hyperoxaluria, where deposition of large amounts of mineral in medullary (and occasionally cortical) tissue may lead to renal failure.

Uric acid stones Aetiology and pathogenesis Uric acid stones occur when urine pH is abnormally low. The solubility of undissociated uric acid is only 0.54 mmol/​litre (90 mg/​litre), and at a pH below 5.35 (the pKa) over half the uric acid present is in the undissociated form. Normal daily excretion of uric acid is 3 to 4.8 mmol/​day (500–​800 mg/​day), depending on protein intake, so it is easy to see that acid urine will be supersaturated with respect to uric acid in most cases. Low urinary volume and high uric acid excretion will exacerbate the tendency to uric acid precipitation. Patients with diarrhoea, especially with ileostomy, excrete concentrated, acid urine because of loss of water and bicarbonate in stool; uric acid stones are a common complication of this condition. Low urinary pH and uric acid stones also occur in patients with insulin resistance, as in diabetes or the metabolic syndrome, because insulin resistance is associated with a decreased ability to synthesize ammonia, leading to a lower urinary pH because of the lack of this proton buffer. Increasing body weight is also associated with a low urinary pH, perhaps because of insulin resistance. In diabetic stone formers, as many as 35 to 45% of stones will be composed of uric acid, which is much higher than the 5 to 10% prevalence seen in the general population of stone formers. Patients with gout are frequently obese or diabetic; however, some forms of gout are associated with acid urine pH without the established need for insulin resistance. Certain forms of renal disease result in reduced ammonia production and low pH; chronic lead nephropathy is a well-​known example (saturnine gout). Although a low pH is common in most forms of progressive renal failure, uric acid stones are not.

Diagnosis and treatment Uric acid stones are poorly visualized on standard plain radiographs, although they are easily seen on CT. On intravenous pyelograms they may be seen as filling defects. Alkali treatment to raise urinary pH above 6.2 will solubilize uric acid and can prevent stones. Use of potassium alkali (citrate or bicarbonate) is preferred, as sodium alkali (sodium citrate or sodium bicarbonate) will raise urinary calcium, and possibly blood pressure. Urine pH needs monitoring because excessive elevation may cause calcium phosphate stones, and serum potassium also needs to be monitored to avoid hyperkalaemia, especially in diabetics. Giving doses of 10 to 20 mmol of alkali two to three times a day is usually sufficient to keep the urinary pH at 6 to 6.5. Dietary intake of purine should be moderated if uric acid excretion is elevated, increased fluids are a standard part of stone management, and xanthine oxidase inhibitors play a role in those with hyperuricaemia.

Cystine stones Aetiology and pathogenesis Cystine stones form in patients with inherited defects of dibasic amino acid transport in the proximal tubule, which lead to increased excretion of cysteine, ornithine, lysine, and arginine in the urine (Table 21.14.2). The only clinical outcome of this defect is cystine

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stones, because of the tendency of cysteine molecules to disulphide bond, forming cystine which is significantly less soluble than free amino acids, thus the defect has been termed cystinuria. Cystine stones are found in only 1 to 2% of stone formers, but they are often recurrent, and may become very large, leading to the need for many stone removal procedures. Cystine stones are poorly fragmented by extracorporeal shock-​wave lithotripsy, hence alternative means of stone removal may be needed. Renal function is often reduced, perhaps as the result of the effects of stones and surgery. Stones are not well visualized using plain abdominal radiographs, although they are seen well with CT. Cystinuria has traditionally been regarded as an autosomal recessive disorder, which may be caused by defects in either of two genes, SLC3A1 or SLC7A9, although cystine stone formation has now been reported in some heterozygotes. The proteins encoded by these genes form a heterodimer, which is responsible for cysteine transport in the apical membrane of the proximal tubule, and in the small intestine. Defects in these two genes appear to explain most cases of cystinuria, and they are clinically indistinguishable with respect to age of stone onset, frequency of recurrence, or cystine excretion. Papillary biopsies show crystal deposits that contain cystine and also calcium phosphate in collecting ducts. The degree of interstitial fibrosis and tubular cell injury is quite marked, and accords with reduction of renal function that is more severe than in almost any other stone disease. Cystine stones may begin in childhood, or even in infancy, although presentation may be delayed to adulthood. In a large cohort study, the median age of first stone was 12 years; males appear to be more severely affected than females for reasons that are unclear. Cystinuria should always be looked for when stones present in childhood or adolescence. Preventive therapy should be started as soon as stones are diagnosed, and continued lifelong because of high recurrence rates and severe kidney injury.

Diagnosis and treatment Cystinuria may be diagnosed by stone analysis showing cystine, and the finding of characteristic hexagonal crystals in urine is pathognomonic. All stone formers should have at least one urine sample screened for cystine. Cystine excretion may be transiently elevated in infancy, and diagnosis in this age group is more difficult. Lowering supersaturation of the urine with respect to cystine is the goal of treatment. Cystine solubility is pH dependent, and is higher at alkaline pH, but not very accurately predicted from nomograms. At a pH of 7 to 7.5, solubility can vary from 0.7 to 1.47 mmol/​ litre. A  reasonable goal is to keep urinary cystine concentration below 1 mmol/​litre and urine pH about 7 to 7.5. Management begins with measurement of daily cystine excretion and urinary pH. High fluid intake is a cornerstone of treatment, and the amount needed to achieve a concentration of less than 1 mmol/​ litre can be calculated and prescribed, with fluid intake distributed throughout the day, and in the evening as well. Some patients will require potassium alkali, as potassium citrate or bicarbonate, in divided doses, to improve solubility. Potassium salts are preferred, as sodium intake can raise cystine excretion. Low sodium (100 mmol/​ day) and protein (0.8–​1 g/​kg per day) intake can reduce cystine excretion modestly. If stones recur despite adequate hydration and increase of pH, a cysteine-​binding drug should be added to fluids and alkali to

decrease the concentration of cystine further. Cystine is formed by the linkage of two cysteine molecules by a disulphide bond. Cysteine binding drugs have sulphydryl groups that form mixed disulphides with cysteine, which are more soluble than the homodimer, cystine. d-​Penicillamine (1–​2 g/​day, in three or four divided doses) is one such drug, the penicillamine–​cysteine disulphide being 50 times more soluble than cystine. A second agent, α-​mercaptopropionylglycine (tiopronin, 400–​1200 mg/​day in divided doses), is also effective. Both drugs have side effects, including fever, rash, impaired taste, arthralgias, leucopenia, and proteinuria, but tiopronin is better tolerated, with a lesser incidence and severity of adverse reactions. Captopril has a free sulphydryl group and is thus the antihypertensive of choice in patients with cystinuria. Recurrent stones should be analysed, as patients may form stones containing calcium phosphate due to the alkaline urine pH, which require different treatment.

Struvite stones Struvite (magnesium ammonium phosphate) stones may present with vague flank pain and gradual deterioration of renal function, rather than colic. They form when the kidney is infected with organisms that possess the enzyme urease, such as proteus, providentia, klebsiella, pseudomonas, and enterobacter species. Urease hydrolyses urea to ammonia and CO2, with the ammonia raising the pH of the urine and leading to production of carbonate in the urine. Calcium carbonate coprecipitates with struvite, forming large, branched stones within the kidney. Bacteria adhere to the stone, where they are poorly reached by antibiotics, making urine sterilization impossible when stones are present, hence adequate treatment requires removal of all stone material in addition to appropriate antibiotics. Struvite stones are more common in settings with chronic urological instrumentation, or in patients with neurogenic bladders. In cases where removal of all stone material is not possible, acetohydroxamic acid, a urease inhibitor, has been used to prevent stone recurrence and growth, but its use is limited by serious side effects, including headache, gastrointestinal upset, and thrombophlebitis.

FURTHER READING Abate N, et  al. (2004). The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int, 65, 386–​92. Asplin JR, et  al. (1999). Reduced crystallization inhibition by urine from men with nephrolithiasis. Kidney Int, 56, 1505–​16. Auge BK, Preminger GM (2002). Surgical management of urolithiasis. Endocrinol Metabol Clin North Am, 31, 1065–​82. Barcelo P, et al. (1993). Randomized double-​blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol, 150, 1761–​4. Belostotsky R et al. (2010). Mutations in DHDPSL are responsible for primary hyperoxaluria type III. Am J Hum Genet, 87,  392–​9. Borghi L, et al. (1993). Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences. J Cardiovasc Pharmacol, 22 Suppl 6, S78–​86.

21.14  Disorders of renal calcium handling, urinary stones, and nephrocalcinosis

Borghi L, et al. (1996). Urinary volume, water and recurrences of idiopathic calcium nephrolithiasis:  a 5-​year randomized prospective study. J Urol, 155, 839–​43. Borghi L, et  al. (2002). Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med, 346,  77–​84. Coe FL, Evan A, Worcester E (2005). Kidney stone disease. J Clin Invest, 115, 2598–​608. Curhan GC, et  al. (2001). Twenty-​four-​hour urine chemistries and the risk of kidney stones among women and men. Kidney Int, 59, 2290–​8. Ettinger B, et  al. (1986). Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med, 315, 1386–​9. Ettinger B, et al. (1988). Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not. J Urol, 139, 679–​84. Ettinger B, et al. (1997). Potassium-​magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. J Urol, 158, 2069–​73. Evan AP, et al. (2003). Randall’s plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle. J Clin Invest, 111, 607–​16. Evan AP, et al. (2005). Crystal-​associated nephropathy in patients with brushite nephrolithiasis. Kidney Int, 67, 576–​91. Gambaro G, et  al. (2004). Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms. Am J Kidney Dis, 44, 963–​86. Hofbauer J, et al. (1994). Alkali citrate prophylaxis in idiopathic recurrent calcium oxalate urolithiasis—​a prospective randomized study. Br J Urol, 73,  362–​5. Laerum E, Larsen S (1984). Thiazide prophylaxis of urolithiasis:  a double-​blind study in general practice. Acta Med Scand, 215,  383–​9.

Lieske JC, et al. (2005). International registry for primary hyperoxaluria. Am J Nephrol, 25,  290–​6. Moe OW (2006). Kidney stones: pathophysiology and medical management. Lancet, 367, 333–​44. Paisson R, et al. (2019). Genetics of common complex kidney stone disease: insights from genome-wide association studies. Urolithiasis, 47, 11–21. Pak CY, et  al. (1986). Management of cystine nephrolithiasis with alpha-​mercaptopropionylglycine. J Urol, 136, 1003–​8. Parks JH, Coe FL (2009). Evidence for durable kidney stone prevention over several decades. BJU Int, 103, 1238–​46. Parks JH, et  al. (2004). Clinical implications of abundant calcium phosphate in routinely analyzed kidney stones. Kidney Int, 66, 777–​85. Ryall RL (2004). Macromolecules and urolithiasis: parallels and paradoxes. Nephron Physiol, 98,  37–​42. Sakhaee K, Moe OW (2016). Urolithiasis. In: Skorecki K, et al. (eds) Brenner & Rector’s The kidney (10th edn), pp. 1322–​67. Elsevier, Philadelphia. Sayer JA (2017). Progress in understanding the genetics of calciumcontaining nephrolithiasis. J Am Soc Nephrol, 28, 748–59. Stamatelou KK, et  al. (2003). Time trends in reported prevalence of kidney stones in the United States: 1976–​1994. Kidney Int, 63, 1817–​23. Taylor EN, Stampfer MJ, Curhan GC (2004). Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-​up. J Am Soc Nephrol, 15, 3225–​32. Worcester EM (2002). Stones from bowel disease. Endocrinol Metab Clin North Am, 31, 979–​99. Worcester EM, Coe FL (2010). Clinical practice. Calcium kidney stones. N Engl J Med, 363, 954–​63. Worcester EM, et al. (2006). Reduced renal function and benefits of treatment in cystinuria vs other forms of nephrolithiasis. Br J Urol Int, 97, 1285–​90.

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21.15

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

ESSENTIALS Renal tubular acidosis (RTA) arises when the kidneys either fail to excrete sufficient acid, or are unable to conserve bicarbonate, with both circumstances leading to metabolic acidosis of varying severity with altered serum potassium. Proximal and distal types of RTA can be differentiated according to which nephron segment is malfunctioning. The condition may be secondary (e.g. associated with drugs, autoimmune disease, or diabetes mellitus) or inherited, and there may be renal tract calcification and—​in chronic cases—​metabolic bone disease.

Proximal RTA Aetiology and diagnosis—​the condition may be (1) secondary to generalized proximal tubular dysfunction (part of the renal Fanconi’s syndrome), or rarely (2) due to an inherited mutation of a single transporter (NBC1) located at the basolateral surface of the proximal tubular epithelium. The combination of normal anion gap acidosis with other features of proximal tubular dysfunction such as renal phosphate wasting (and hypophosphataemia), renal glycosuria, hypouricaemia (due to uricosuria), aminoaciduria, microalbuminuria, and other low molecular weight proteinuria suggests the diagnosis. Management—​this requires large quantities (up to 10–​15 mEq/​kg per day) of oral alkali (as bicarbonate or citrate), with (in most cases) potassium supplements to prevent severe hypokalaemia. Associated phosphate and vitamin D deficiencies may also require treatment. Precipitating drugs should be stopped if possible.

Distal RTA Aetiology—​two main classes are differentiated by whether (1)  the acid-​handling cells (α-​intercalated cells) in the collecting ducts are themselves functioning inadequately, in which case there is associated hypokalaemia (this is ‘classic’ distal RTA); or (2)  the main abnormality is of the salt-​handling principal cells in the same nephron segment, in which case hyperkalaemia occurs and the acidosis is a secondary phenomenon. This is hyperkalaemic distal RTA, which is most often secondary to hyporeninaemic hypoaldosteronism (e.g. in diabetes mellitus or critical illness) but may also be reversibly precipitated by drugs such as trimethoprim or ciclosporin.

Diagnosis—​the combination of normal anion gap acidosis with a urine pH higher than 5.5 suggests classic distal RTA, especially if renal tract calcification is present or there is coexistent autoimmune disease. Diagnosis may require an oral urine acidification test if the metabolic abnormalities are partially masked by compensatory mechanisms, when inability to achieve a urine pH less than 5.5 clinches the diagnosis of classic distal RTA. By contrast, urine acidification capacity is normal in hyperkalaemic distal RTA. Management—​ (1) classic distal RTA—​ 1 to 3 mg/​ kg per day of oral alkali (additional supplements should not be required); (2) hyperkalaemic distal RTA—​treatment is with sodium bicarbonate, but fludrocortisone and/​or potassium-​lowering measures may also be necessary. Precipitating drugs should be stopped.

Introduction The kidney plays a key role in the regulation of acid–​base balance and the term ‘renal tubular acidosis’ (RTA) refers to systemic acidosis arising from a tubular ion transport abnormality. On a mixed omnivorous diet, humans produce a net acid load of about 1 mmol/​ kg per day, which must be excreted. Through activity at two main sites in the nephron, the proximal convoluted tubule and the collecting duct, the kidney is able to vary bicarbonate reclamation and net acid excretion such that urine pH can range from about 4.5 to over 8, enabling systemic pH to be closely maintained between 7.35 and 7.45. Failure of these tubular functions can cause very severe acidosis with pH less than 7. The traditional classification of the RTAs is an historical one, based on the order in which the defects were described, but in thinking about the different mechanisms involved it is least confusing to use a tubular location to classify them: • Proximal (former type 2) • Distal, subdivided into ‘classic’ (type 1)  and ‘hyperkalaemic’ (type 4) • Mixed, which usually refers to carbonic anhydrase deficiency (type 3)

21.15  The renal tubular acidoses

Note that RTA excludes the acidosis of chronic kidney disease (which would be a raised anion gap metabolic acidosis), also that within each class of RTA there is then a division into primary (inherited) and secondary types. Primary RTA is directly due to inadequate function of a proton or bicarbonate transporter, and molecular genetic studies have identified a variety of these (as discussed later). In general, disorders associated with RTA that are inherited dominantly are clinically milder and give rise to overactivity or gain of abnormal function of a channel or transporter, whereas those that are recessively inherited are clinically more severe and due to loss-​of-​function genetic defects. Although all the recessive diseases described in this chapter are rare, they are encountered more commonly in areas of the world where parental consanguinity is prevalent, and the investigation of kindreds where affected children are the offspring of such unions of unaffected parents has allowed us to investigate the genetic causes of such disorders, and to understand better the molecular pathophysiology involved. In adult clinical practice, secondary causes of RTA are much commoner than primary, in particular hyperkalaemic distal RTA (dRTA) in association with diabetes mellitus, and classic dRTA in association with autoimmune diseases. Secondary RTA also describes metabolic acidosis arising from other renal ion transporter dysfunctions: the kidney does not carry out any of its myriad homeostatic functions in isolation, and interactions with these other systems form an important part of the overall picture. This is perhaps most marked in the context of salt homeostasis, where the endocrine system—​ particularly the mineralocorticoid axis—​is closely involved, and defects in these pathways can cause hyperkalaemic RTA.

Physiology of renal acid–​base homeostasis To understand the pathophysiology of the different types of RTA, it is helpful to consider normal renal acid–​base balance, again in terms of tubular location. Broadly, this consists of the combination of bicarbonate reabsorption (proximal tubule), proton secretion and bicarbonate generation (collecting duct), and ammonium generation and secretion (proximal tubule and medulla).

Proximal tubule Since the total load of sodium and bicarbonate reaching the glomeruli is freely filtered, the proximal tubule has a considerable reabsorption task to perform, reclaiming 90% (3–​4 mol) of bicarbonate daily from the tubular fluid, with Na+, H+, and HCO3–​ transport linked, as shown in Fig. 21.15.1. Citrate is also reabsorbed by the proximal tubule, which yields additional bicarbonate. Proximal tubular cells are also capable of generating ‘extra’ bicarbonate through the deamination of glutamine to glutamate, then forming α-​ketoglutarate and eventually glucose (Fig. 21.15.1). This produces bicarbonate and ammonium—​the former is reabsorbed and the latter secreted into the tubular lumen. This process is up-​regulated in states of chronic acidosis of nonrenal origin.

Collecting duct Two cell types with distinctly different functions are present in the collecting duct (Fig. 21.15.2). These are principal cells (responsible for salt handling) and intercalated cells (ICs, responsible for maintenance of acid–​base). Within the IC population, many studies—​mostly

Filtrate

H2O + CO2 CA4

H2O + CO2 CA2

HCO3− + H+

H+ + HCO3−

NHE3

Na+

HCO3−

Na+ −

H2PO4

NBC1

Na+

Glutamine

NH4+

NH4+, glucose, HCO3−

lumen

blood

Fig. 21.15.1  Schema of proximal tubular acid–​base movement. H+/​ HCO3–​ movement pathways are shown in red, Na+/​Cl–​ in blue, and ammonium in green. Na+ is absorbed in direct exchange for H+ by the sodium–​proton exchanger NHE3 (encoded by SLC9A3). In the lumen, the H+ and HCO3–​ rapidly form H2O and CO2 under the catalytic influence of membrane-​bound carbonic anhydrase (CA4, encoded by CA4). Having diffused into the cell, CO2 undergoes a reverse reaction (via intracellular CA2, encoded by CA2) to reform bicarbonate, which is then available for Na+/​HCO3–​ reabsorption into the interstitial fluid (and from there into the blood) via the sodium bicarbonate transporter NBC1 (encoded by SLC4A4). Any excess luminal H+ is buffered by filtered phosphate (HPO42–​). Proximal tubular cells also generate ‘extra’ HCO3–​ and ammonium through the deamination of glutamine as shown, the former being reabsorbed and the latter secreted into the tubular lumen. Dopamine antagonizes NHE3 and acetazolamide is a carbonic anhydrase inhibitor.

in rodents—​have described at least two subtypes, α-​ and β-​ICs. α-​ ICs are responsible for coupled apical secretion of protons into the urine and reclamation of bicarbonate across the basolateral surface (Fig. 21.15.2). On the apical surface, the multisubunit proton pump (H+-​ATPase) transfers H+ into the urine. It is of the same type as the H+-​ATPases found ubiquitously in intracellular organelles such as lysosomes, which require a low pH for efficient function. H+-​ATPases are composed of at least 13 different subunits, organized into a membrane-​anchored V0 (‘stalk’) domain (subunits a–​e), through which protons are moved, and a V1 ‘head’ that hydrolyses ATP (subunits A–​H). Apical and intracellular proton pumps can be differentiated by their subunit composition: the α-​IC’s apical renal pumps contain B1 and a4 subunits. In α-​ICs, apical H+-​ATPase function is coupled to basolateral bicarbonate exit (in exchange for chloride) via the anion exchanger AE1 (Fig. 21.15.2), which is structurally similar to the isoform present in the erythrocyte membrane, except that it is a little shorter at the N-​terminal end. Chloride/​bicarbonate exchange is 1:1. β-​ICs essentially reverse the processes of α-​ICs, so they secrete bicarbonate into the urine. It remains unclear whether α-​ and β-​ICs are molecular mirror images of each other or are separate cell types. Two other potential Cl–​/​HCO3–​ exchangers, pendrin (SLC26A4) and AE4, which may reside apically in β-​IC, have been reported in animals. Defects in pendrin cause Pendred’s syndrome of deafness and goitre, but alkalosis is not a feature in either Pendred’s patients or pendrin knockout mice. In any event, the acid load provided by an omnivorous human diet dictates that the great majority of ICs will be α-​ICs.

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A B1 A B1 G3 A E C2

α-intercalated cell

B1

H a4 e2 H+ATPase

D F

d2

ATP ADP

H+

AE1 Cl−

H− + HCO3− CA2

c" c

HCO3−

H2O + CO2

H+

K+ Cl−

K+ principal cell ENaC

MR

Na+ K+

K+ ATP ADP lumen

Na+ blood

Fig. 21.15.2  Collecting duct acid–​base regulation. Intercalated cells are responsible for coupled apical secretion of protons into the urine and reclamation of bicarbonate across the basolateral surface. On the apical surface, the multisubunit proton pump (H+ATPase) transfers H+ into the urine. The various subunits of this pump are shown on the left of the figure: mutations in B1 (ATP6V1B1) and a4 (ATP6V0A4) cause recessive dRTA. Basolateral bicarbonate exit (in exchange for chloride) occurs via the anion exchanger AE1 (SLC4A1). A cartoon of this exchanger is shown on the right of the figure, with R589—​a mutational hotspot for dominant dRTA—​marked with a red dot. There is a second, less structurally complex, P-​type ATPase present on the apical surface and exit routes for K and Cl that are not yet well characterized in humans. The adjacent principal cells (responsible for salt handling) are depicted: electrogenic sodium reabsorption via the epithelial sodium channel ENaC (SCNN1A, -​B, and -​G) takes place in exchange for K+ secretion; this is under the control of aldosterone, acting via the basolateral mineralocorticoid receptor (MR).

There is a second, less structurally complex, P-​type ATPase present apically in α-​ICs, which exchanges protons for K+. In humans, however, the overall contribution of H+/​K+-​ATPase to α-​IC function is not clear.

Clinical presentation RTA can range from being asymptomatic and undetectable without specialized biochemical tests, to presenting with a severe syndrome of failure to thrive in infancy. A  list of causes of RTA is given in Table 21.15.1. The following patients should all be suspected of having RTA: • Recurrent calcium-​ containing (especially calcium phosphate) stone formers, especially if there is a family history of renal stone disease • Individuals with osteomalacia (rickets in children) without other clear explanation • Patients with autoimmune disease, especially Sjögren’s syndrome (see Chapter 19.11.4) and an unexplained low serum potassium and/​or bicarbonate • Infants with osteopetrosis • Unexplained metabolic acidosis

Biochemically, overt RTA is characterized by the presence of a normal anion gap (hyperchloraemic) metabolic acidosis in the setting of either reduced renal net acid secretion (dRTAs) or bicarbonate wasting (proximal RTA), but otherwise normal or near normal renal excretory function (preserved estimated glomerular filtration rate). In dRTA, similar molecular defects can cause mild or severe acidosis, the reasons for which are not well understood. The clinical features of the various types of RTA are summarized in Table 21.15.2.

Proximal RTA Clinical and biochemical features The hallmark of proximal RTA is bicarbonate wasting into the urine. The consequent metabolic acidosis is often less severe than in other types of RTA because as serum bicarbonate falls, a larger proportion of filtered bicarbonate can be reabsorbed more distally, such that an equilibrium is reached at a venous bicarbonate level of around 15 mmol/​litre. The urinary bicarbonate loss from the proximal tubule is usually accompanied by other features of proximal tubular dysfunction (i.e. the renal Fanconi’s syndrome), such as renal phosphate wasting (and hypophosphataemia), renal glycosuria, hypouricaemia (due to uricosuria), aminoaciduria, microalbuminuria, and other

21.15  The renal tubular acidoses

Table 21.15.1  Causes of RTA

Acquired

Proximal RTA

Classic distal RTA

Hyperkalaemic distal RTA

Intrinsic renal disease

Hypokalaemic nephropathy Renal transplant rejection (acute and chronic)

Medullary sponge kidney Nephrocalcinosis

Diabetic nephropathy Interstitial nephritis

Haematological disease

Myeloma

Myeloma

Drugs

Gentamicin Cisplatin Ifosfamide Sodium valproate Zidovudine Tenofovir

Amphotericin Lithium Ifosfamide

Heavy metals/​toxins

Lead Cadmium Mercury Toluene (glue sniffing)

Vanadate

Hormonal

Primary hyperparathyroidism

Pregnancy

Nutritional

Kwashiorkor (protein-​energy malnutrition)

Autoimmune Inherited

Trimethoprim Ciclosporin/​tacrolimus K+-​sparing diuretics (spironolactone and eplerenone) Angiotensin-​converting enzyme inhibitors/​angiotensin receptor blockers Renin inhibitors Heparin

Sjögren’s syndrome

Inherited renal disease

Autosomal dominant Fanconi’s syndrome Autosomal recessive proximal RTA X-​linked (Dent’s disease 1 and 2, but acidosis usually mild and may be absent)

Autosomal dominant dRTA Autosomal recessive dRTA

Inherited syndromes

Cystinosis Tyrosinaemia type 1 Galactosaemia Oculocerebrorenal syndrome (Lowe’s syndrome) Wilson’s disease Hereditary fructose intolerance

Sickle cell anaemia

Pseudohypoaldosteronism type 1 Gordon’s syndrome

Table 21.15.2  Clinical and biochemical features of RTA Proximal RTA

Distal RTA—​dominant/​ sporadic

Distal RTA—​recessive

Mixed RTA

Hyperkalaemic RTA

Usual age of presentation

Childhood (primary) Adult (acquired)

Older/​child/​adult

Infancy/​early childhood

Infancy/​early childhood

Adult

Symptoms/​ signs

Variable including intellectual disability Rarely glaucoma/​ cataracts

Sometimes none Nephrolithiasis Nephrocalcinosis Sometimes rickets/​ osteomalacia

Vomiting/​dehydration Poor growth Early nephrocalcinosis Rickets Sensorineural deafness (early or late onset) Cystic kidneys

Fractures Poor growth Intellectual disability Blindness Osteopetrosis/​fractures Conductive deafness Dental malocclusion

Related to underlying disorder, e.g. diabetes complications

Biochemistry

Mild/​moderate acidosis Normal/​low K+ (if Na+ given)

Mild or compensated acidosis Low/​normal K+

Severe acidosis Low K+

Severe acidosis Low K+

Mild/​moderate acidosis High K+

Minimum urine pH

5.5

>5.5

>5.5

90% at 5  years). In these patients, the issue is of risk of relapse and subsequent progression. This risk increases with a number of factors including depth of invasion (Ta 3 cm

5% risk of malignancy Requires regular imaging follow-​up

III

Indeterminate mass Thick, enhancing wall or septa

50% risk of malignancy Resect

IV

Malignant cystic mass Thick, enhancing wall or septa with enhancing soft tissue component

Malignant Resect

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Patient operable? Met. completely resectable?

Symptomatic Or “Must Act”?

No

Observe

Yes

Yes

MDT Feasible to observe?

Yes

No

Palliate

No Surgery

RT/ablate

Systemic Rx

Observe for 3–6 months

Fig. 21.18.4  Algorithm for management of patients with metastatic renal cancer. MDT, multidisciplinary team; Met., metastasis; RT, radiotherapy; Rx, prescribed treatment.

The patient with distant disease Metastatic renal cancer can behave in a very variable manner: many patients will remain well without any active treatment for long periods, while others will progress quickly and require aggressive intervention. Factors that point to an aggressive tumour include systemic symptoms of weight loss, night sweats, and hypercalcaemia. The most commonly used risk scoring system for advanced disease is the MSKCC score for metastatic renal cell cancer (also available online). This predicts survival based on yes/​no answers to the following questions: (1) time from diagnosis to systemic treatment less than 1 year, (2) haemoglobin less than lower limit of normal, (3) calcium greater than 2.5 mmol/​litre, (4) lactate dehydrogenase (LDH) concentration greater than 1.5 times the upper limit of normal, and (5) performance status less than 80% (Karnofsky). The algorithm will have to be revalidated with the arrival of T-​cell checkpoint inhibitors. A patient with metastatic disease who has a painful and bleed­ing primary lesion may benefit from a palliative nephrectomy. Embolization may be performed to palliate symptoms for patients with advanced symptomatic RCC who are not operable. Surgery also has a role in selected patients with oligometastatic disease (metastatic disease present at just one or two sites). Factors which select patients for a good outcome include a disease-​free interval longer than 12 months, a solitary

site of disease, and age less than 60 years. An algorithm for management of patients with metastatic renal cancer is shown in Fig. 21.18.4. Systemic treatment options have been investigated in a number of first-​, second-​, and third-​line settings. The treatment grid in Table 21.18.5 shows where phase III data have supported various treatment options. Antiangiogenic tyrosine kinase inhibitors targeting vascular endothelial growth factor receptor signalling have an approximately 75% chance of causing tumour shrinkage or reduction, and an approximately 35% chance of causing a partial response by agreed criteria (Response Evaluation Criteria In Solid Tumours, RECIST). Each results in 10 to 14 months of progression-​free survival in the first-​line setting. The combination of the vascular endothelial growth factor antibody bevacizumab with interferon similarly doubles progression-​free survival compared to interferon alone. The toxicities of tyrosine kinase inhibitors need to be considered carefully as these are used in the maintenance setting:  these include hypertension, skin rash, fatigue, stomatitis, and a variety of less common toxicities. The key features of toxicity management are early intervention and use of prophylactic measures. The mammalian target of rapamycin (mTOR) inhibitors temsirolimus and everolimus are of modest benefit and have a

Table 21.18.5  Phase III data of treatment options in metastatic renal cancer Good risk

Intermediate risk

Poor risk

First line

Pembrolizumab + Axitinib Sunitinib Pazopanib Tivozanib Bevacizumab + IFN

Pembrolizumab + Axitinib Nivolumab + Ipilimumab Cabozantinib Sunitinib Pazopanib Tivozanib Bevacizumab + IFN

Pembrolizumab + Axitinib Nivolumab + Ipilimumab Cabozantinib Sunitinib Pazopanib Temsirolimus

Second and third line options

Nivolumab Cabozantinib Axitinib Everolimus Lenvatinib + everolimus

Nivolumab (if no prior immunotherapy) Cabozantinib Axitinib Everolimus Lenvatinib + everolimus

Nivolumab (if no prior immunotherapy) Cabozantinib Axitinib Everolimus Lenvatinib + everolimus

21.18  Malignant diseases of the urinary tract

diminishing role in treatment. The role of immunotherapy is undergoing a renaissance. There is intensive research in the use of novel immunotherapies such as autologous tumour vaccines, and T-​ cell checkpoint inhibitors such as antibodies to PD-​1, PD-​L1, and CTLA4, which relieve the control of autoimmunity and may induce host-​versus-​tumour immune reactions. The PD-​1-​directed antibody, nivolumab, has recently been established as a standard second-​line agent. The most notable feature of treatment is that the 20% of patients whose disease remains under control for at least a year have an excellent chance of prolonged benefit. Combinations of checkpoint inhibitors look particularly effective, albeit with toxicity. In the past year, combinations of immune checkpoint inhibitors with tyrosine kinase inhibitors have shown significant survival benefits and are likely to become the first line standard of care in the near future.

Prostate cancer Epidemiology Prostate cancer is the second most common cause of male cancer deaths in the Western world. It represented 13% of all cancer cases diagnosed in the United Kingdom in 2013, with 47 300 new cases and 10 837 men who died from the disease in 2012. In the United States of America alone, it is estimated that 220 800 men were diagnosed in 2015, with 27 540 men dying of the disease. Age, race, and family history are strong risk factors for developing the disease, with a known higher incidence in African American men.

Aetiology and pathogenesis Prostate cancer is a heterogeneous malignancy, with much genomic diversity. Multiple genome-​wide association studies have reported 77 single nucleotide polymorphisms (SNPs) associated with the condition. Further studies are required to identify whether targeted screening could be performed based on the genetic information obtained from these SNPs. In addition to the familial risk in first-​degree relatives of men with prostate cancer, who have a two-​to threefold higher risk, rare highly penetrant germline mutations are linked to genetic predisposition, such as HOXB13 and BRCA2 in families with a high incidence of breast and ovarian cancer. The genomic diversity of prostate cancer is further confirmed by high-​throughput new-​generation sequencing studies of multi-​focal disease, including the presence of genomic aberration in phenotypically benign prostate tissue, and lethal clonality of metastatic disease associated with phenotypically low-​risk primary cancers. This represents one of the biggest challenges in the management of this common cancer.

Clinical features Most cases of prostate cancer are asymptomatic at presentation, being detected following measurement of serum prostate-​specific antigen (PSA) or after digital rectal examination and subsequent biopsy. Lower urinary tract symptoms are common, but usually attributable to coexisting benign prostatic hypertrophy. Haematuria and haematospermia are uncommon, and more likely to be due to benign prostatic disease. Men with metastatic prostate cancer may present with bone pain, but in healthcare systems where awareness of the disease and screening are prevalent, this presentation has become uncommon.

Screening and diagnosis Screening for prostate cancer remains one of the most controversial public health issues. At present, prostate cancer screening continues to fall short of the World Health Organization criteria described by Wilson and Jungner, with its natural history poorly understood. PSA is a serum protease that is secreted by prostatic epithelium. It is not a specific marker for cancer as there are many nonmalignant processes that also elevate PSA, such as benign prostatic hyperplasia, urinary tract infection, urinary tract instrumentation, ejaculation, and traumatic catheterization. A total PSA cut off value of 3.0 ng/​ml is widely accepted in order to trigger further investigation, as best balancing the risk of missing clinically important cancers with the hazard of subjecting men to unnecessary prostate biopsies to reveal clinically insignificant disease. How men with a borderline elevation of PSA should best be advised is a matter of much debate. One study found that 44% of men with an isolated elevation of PSA had a normal PSA at one or more subsequent annual tests, hence standard advice is that a borderline result should be retested a few weeks later. Age-​adjusted norms for PSA improve the sensitivity and specificity of the measurement in clinical practice. PSA kinetics may be more valuable in making treatment decisions than a single value: a rapidly rising PSA with a short doubling time (even if starting at a very low number) indicates that a man is likely to have high-​risk prostate cancer. More recently, however, it has been shown that a single PSA value of 1 ng/​ml or higher from the age of 45 years may determine the necessity for further and frequent testing. The diagnosis of prostate cancer, suspected following measurement of serum PSA, is established by transrectal ultrasound-​guided biopsy, which in itself can carry morbidity and complications. There is increasing enthusiasm for the use of prebiopsy multiparametric magnetic resonance imaging (mpMRI) in order to identify or exclude ‘significant’ lesions, and facilitate MRI-​transrectal ultrasound fusion biopsies. At present, the use of prebiopsy mpMRI is not widespread in most countries, but is likely to evolve following completion of ongoing clinical trials. Protocols incorporating imaging into screening programmes will need to be evaluated prospectively. Most cases of prostate cancer detectable through PSA-​ based screening are of low-​or intermediate-​risk of progression. Most of these screen-​detected cases may never become lethal during an individual’s lifetime, and it is becoming increasingly apparent that our definition of ‘significant’ versus ‘insignificant’ prostate cancer is inadequate. However, there is compelling evidence from the European Randomised study of Screening for Prostate Cancer (ERSPC) that PSA-​based screening for prostate cancer can yield a significant survival benefit, as well as a reduction in the burden of metastatic disease, albeit at the cost of exposing unacceptably large numbers of men to radical treatment for each life saved. The fact that the ERSPC clearly demonstrated that prostate cancer screening can reduce the future development of advanced metastatic disease can be used as a powerful argument for the introduction of screening. However, it is likely that the screening process could be further refined by the risk stratification of men at the introduction of the screening process, taking into consideration factors such as family history, race, life expectancy, and baseline PSA level, with the subsequent screening protocol modified for individuals based on these risk factors. The frequency with which men may need to be screened may also be influenced by their initial PSA test result within a screening programme protocol. Other developments in the prostate cancer diagnosis pathway, such as

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the use of additional kallikrein markers, targeted screening, and the introduction of mpMRI, may improve the performance of a screening protocol such that the benefits could be increased and the risks reduced. These and other future developments are likely to influence the ratio of risks to benefits in favour of the introduction of screening in due course. In the meantime, men who request PSA testing should only receive the test after careful professional counselling about the potential benefits and harms caused by screening for prostate cancer.

Management and prognosis Clinically localized disease Effective treatments to cure clinically localized prostate cancer are widely available, including different forms of radiotherapy and minimally invasive surgery such as robot-​assisted laparoscopic radical prostatectomy, with excellent outcomes. Since Walsh and Donker first described the anatomy of the prostatic apex, ligaments and nerves that enabled development of nerve-​sparing radical prostatectomy in 1982, morbidity associated with radical surgery has decreased substantially, with reduced rates of postoperative impairment of continence and erectile function. The advent of laparoscopic and robot-​assisted radical prostatectomy brings better visualization and potential improved outcomes, with reduced blood loss and length of hospital stay already reported. The Scandinavian prospective randomized controlled trial (RCT) SPCG-​ 4 comparing radical prostatectomy with watchful waiting demonstrated improved disease-​specific, overall survival and a reduction in disease progression in men receiving surgery. In parallel, the PIVOT (Prostate Intervention Versus Observational Treatment) study in the United States of America showed no benefit of surgery over watchful waiting in men with low-​risk disease and in those above the age of 65 years compared with watchful waiting. Over the last decade, there have been significant developments in the use of radiotherapy to manage localized prostate cancer. Biochemical relapse and survival rates appear similar to surgery and side effects have been reduced, enhanced by sophisticated three-​dimensional conformal or intensity-​modulated systems. The use of brachytherapy has also increased, either as monotherapy or in conjunction with external beam radiotherapy. The addition of neoadjuvant androgen deprivation therapy prior to external beam radiotherapy has also demonstrated improved outcomes in a number of RCTs, and this has become now standard practice globally. Paradoxically, many patients detected to have clinically localized prostate cancer following PSA screening do not require treatment, as their disease is unlikely to cause them harm in the long term, and they are best managed by active surveillance or monitoring, with delayed intervention if necessary. For low-​risk, low-​volume prostate cancer, universal recommendations are that they are suitable for active surveillance, with regular monitoring using PSA measurements, imaging, and repeat biopsies, although there is no consensus about the optimal protocol to maintain patients in a window of curability should their disease progress in due course, and some of these patients can progress while monitored. Other therapeutic options have developed, including the use of partial ablation of the prostate using different forms of energy delivery such as high-​intensity focused ultrasonography, cryotherapy, and vascular targeted photodynamic therapy. The potential advantages are the reduced functional adverse events with equivalent oncological outcomes compared with

conventional radical treatment options. These newer technologies are enhanced by considerable improvement in the reliability of imaging techniques. In the United Kingdom, the NIHR HTA ProtecT (Prostate Testing for Cancer and Treatment) trial is the world’s largest RCT comparing the three major treatment options in screen-​detected prostate cancer—​ surgery, radiotherapy, and active monitoring. Following screening of 82 429 men, 2664 received a diagnosis of localized prostate cancer, and 1643 were randomized. Prostate cancer-​specific mortality was low at 10 years irrespective of treatment (1.5 deaths/​1000 patient-​years in the active monitoring group vs 0.9 surgery vs 0.7 radiotherapy), but surgery and radiotherapy were associated with lower incidences of disease progression (22.9 events/​1000 patient-​years in the active monitoring group vs 8.9 surgery vs 9.0 radiotherapy) and metastases (6.3 events/​1000 patient-​years in the active monitoring group vs 2.4 surgery vs 3.0 radiotherapy). Locally advanced disease When prostate cancer infiltrates tissues into and beyond the prostatic capsule, it is likely to develop into progressive and metastatic disease and requires intervention. While approximately one-​third of men who receive radical treatment for clinically localized disease demonstrate pathological evidence of extracapsular extension, many of these will not require additional treatment, but residual disease after surgery will benefit from salvage external beam radiotherapy. Large RCTs have demonstrated the benefit of androgen deprivation therapy for up to 3 years as an adjunct to radiotherapy in men with clinically locally advanced disease, compared with radiotherapy or androgen deprivation therapy alone. Metastatic disease Aggressive prostate cancer tends to spread to locoregional and distant lymph nodes, and particularly to the axial skeleton. There is a particular affinity between primary prostate cancer epithelial cells and the bone microenvironment, leading to a mixed picture of osteolytic and osteoblastic skeletal lesions. These lead to weakening of the skeletal architecture, deranged bone remodelling, and sequelae such as skeletal pain, pathological fractures, and cord compression. The mainstay of treatment in metastatic prostate cancer is the administration of androgen deprivation therapy to reduce levels of circulating testosterone. This causes apoptosis in prostate cells and remissions in most patients lasting 3 years or longer, after which castration-​resistant disease becomes likely with morbidities leading to death from prostate cancer in due course. Androgen deprivation therapy treatment relies on the interface between prostate cancer cell growth and the androgen receptor axis. The androgen receptor is an intracellular steroid receptor normally present in the cytoplasm when in an inactive state. It is maintained by chaperone binding in an inactive conformation; upon binding to dihydrotestosterone, the androgen receptor changes into its active conformation and is separated from its chaperones. Once in the active conformation, the nuclear localization signal is exposed, leading to the translocation of androgen receptor into the nucleus, where it binds to the androgen response element motifs in the promoter regions of its target genes. In prostate cancer cells, this transactivates the expression of a number of genes responsible for cell proliferation.

21.18  Malignant diseases of the urinary tract

Typically, men with metastatic prostate cancer will receive oral antiandrogens followed by a luteinizing hormone-​releasing hormone agonist, or antagonist without preliminary antiandrogens. Symptomatic relief, particularly of pain, and objective remission in measurable metastatic lesions can be achieved with side effects related to loss of libido and sexual function, and metabolic changes as well as effects on cognitive function. More recently, androgen deprivation therapy has also been associated with an increased risk in cardiovascular events. Once castration-​resistant prostate cancer is established, second-​ line hormone treatment with newer agents such as abiraterone (an androgen synthesis inhibitor) and enzalutamide (a synthetic nonsteroidal antiandrogen) can be used in conjunction with prednisolone, also with cytotoxics such as docetaxel and cabazitaxel, all of which have been shown to improve survival through large-​ scale RCTs. Skeletal-​related events can be delayed and reduced in incidence by modulating osteoclast activity through agents such as bisphosphonates and RANK-​ligand inhibition. Intravenous administration of the bone-​seeking radioisotope radium-​223 has been shown to improve survival and reduce skeletal related events. There is currently one form of immunotherapy approved for the treatment of castration-​resistant prostate cancer: Sipuleucel-​T, generated from the patient’s peripheral blood mononuclear cells. The vaccine relies on the ex vivo activation of antigen-​presenting cells with recombinant PSA. Improved survival was demonstrated of the same order as that obtained by cytotoxic chemotherapy. Other prostate cancer vaccines are undergoing intensive investigation at present, aimed at modulating the immune system to treat this lethal form of the disease.

Likely developments in the near future The management of prostate cancer remains one of the most controversial public health problems. While screening is currently not recommended as a public health policy in any country worldwide, opportunistic PSA testing continues to result in overdetection and overtreatment of indolent cancers, and paradoxically undertreatment in men with unrecognized lethal forms of the disease. Targeted screening in men at high risk of harbouring aggressive prostate cancer, accurate stratification of patients at risk of developing the metastatic and lethal phenotype, and providing precision treatment to individual patients tailored to their specific cancer signatures through novel biomarkers and risk factors all remain challenging tasks for researchers worldwide.

Testicular cancer Introduction Testicular tumours affect predominantly young adult men in whom they are the most common malignant tumours. Most (95%) are germ cell tumours; less commonly they are of stromal cell origin (Sertoli and Leydig cell tumours), lymphomas, or metastases, and tumours may also rarely occur in the rete testis. Testicular germ cell tumours are commonest in the Caucasian population, especially in Northern Europe. There is strong familial predisposition and an increased risk in patients with prior testicular maldescent, testicular atrophy, and other urogenital abnormalities.

Patients with inherited syndromes, including Klinfelter’s and Down’s syndromes, are also at increased risk of testicular cancer. Prevalence has increased markedly over the last 100  years and testicular tumours now affect approximately 1 in 400 European men.

Aetiology, pathogenesis, and pathology The pathogenesis of testicular cancer is thought to involve a noninvasive precursor stage, termed intratubular germ cell neoplasia or carcinoma in situ. Although the natural history of this condition is not completely defined, it would appear that most men with it eventually progress to invasive testicular cancer. The pathology of testicular germ cell tumours is complex. Approximately 50% of patients present with a pure classical seminoma. Seminomas resemble primordial germ cells and are often associated with lymphocytic infiltrate. The remainder are generally classed as nonseminoma germ cell tumours (NSGCTs) and consist of tumours either of tissues of embryonic or extra-​embryonic origin, including yolk sac and placental tissue (choriocarcinoma). The most undifferentiated form of this tumour is termed ‘embryonal carcinoma’. Tumours may be of one subtype or, more frequently, consist of mixed subtypes. Mixtures of nonseminoma and seminoma tumours can also be found (termed combined tumours). The presence of any nonseminomatous element defines a tumour as nonseminoma, and leads to treatment as for nonseminoma.

Clinical features About 90% of testicular germ cell tumours present in men as a lump in the testis, which is usually painless but may less commonly be associated with an ache or episodic pain. About 10% present with symptoms of advanced disease such as back pain (retroperitoneal nodal disease), cough, haemoptysis or shortness of breath (lung metastases), bone pain (skeletal metastases), neck mass (supraclavicular lymph node metastasis), unilateral or bilateral leg swelling (iliac or caval venous thrombosis or obstruction), upper gastrointestinal symptoms (retroperitoneal upper abdominal metastases), or gynaecomastia (raised human chorionic gonadotropin (HCG)).

Assessment Initial investigations consist of a testicular ultrasound examination, where the characteristic appearance of a hypoechoic lesion is usually sufficient to confirm diagnosis (Fig. 21.18.5). Many tumours secrete onco-​ fetal proteins/​ tumour markers (α-​fetoprotein) or β-​HCG (Table 21.18.6). These should be measured when a testicular germ cell tumour is suspected as they have a role in diagnosis, prognostication, and monitoring of disease, although they are not universally present. α-​Fetoprotein is not elevated in seminomas. Once the diagnosis is confirmed, disease extent is assessed by a CT examination of the chest, abdomen, and pelvis. Patients with extensive lung metastases or high HCG levels should receive brain imaging (CT or MRI). PET imaging does not have a routine role, but is occasionally useful for problem-​solving in case of equivocal findings.

Staging Until recently, patients have been staged according to the Royal Marsden system, but this has been supplanted by the TNM staging system (Table 21.18.7). The key division is between stage 1 disease

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Fig. 21.18.5  Ultrasound scan of testis showing lesion of heterogeneous echogenicity replacing most of testis. Courtesy of Addenbrooke’s Hospital, Urology and Radiology departments.

and other stages when metastases are present. For those with metastatic disease, management is defined by the International Germ Cell Collaboration Group (IGCCG) prognostic factor index (Table 21.18.8). Patients with persistently elevated markers and no imaging abnormality are labelled as ‘stage 1M’ and treated as for metastatic disease. Seminomas are divided into good or intermediate classification depending on the presence or absence of nonpulmonary visceral metastases.

Management and prognosis For most patients, initial management consists of an inguinal orchidectomy. The inguinal approach avoids scrotal contamination of tumour and better access for securing the inguinal blood vessels. Patients with an equivocal lesion or an absent testis or atrophic testicular atrophy should be referred for a specialist opinion and consideration be given for undertaking excisional biopsy/​partial orchidectomy. Patients presenting with extensive disease, particularly with lung metastasis in the presence of markedly raised HCG, should be discussed with a specialist oncology service. In this situation, disease can be rapidly progressive and immediate chemotherapy is usually indicated. Stage 1 disease Most patients present with stage 1 disease (seminoma 80–​85%, nonseminoma 70–​75%) and have an expected cure rate of 98 to 99%.

However, despite a normal staging scan on follow-​up, some patients will develop relapse. The key issue in management is whether to follow patients (surveillance with salvage treatment at relapse) or to offer immediate adjuvant therapy. Both approaches achieve similar long-​term survival. The decision is a complex one and depends on the assessment of risk of relapse, and long-​term risks of adjuvant versus more intensive salvage treatment. Considerations are patient preference, ability to comply with surveillance, psychological issues, and (in some healthcare systems) personal financial issues. Surveillance involves regular marker estimations and chest imaging, with intermittent cross-​sectional imaging (Table 21.18.9). Clinical examination is usually performed, but its value is questioned. There is concern about the radiation dose of repeat CT imaging, and to limit such exposure it may be possible to restrict imaging to the retroperitoneal lymph nodal areas, either by CT scan or (increasingly) by MRI. An Medical Research Council trial has shown that imaging at 3 and 12 months may be sufficient for stage 1 NSGCT. If adjuvant treatment is required for seminoma, a single dose of carboplatin AUC7 reduces the risk of recurrence to less than 5%. Radiotherapy was formerly widely used, but is not now recommended because of concern with regard to the long-​term risk of a second malignancy. In NSGCT, two cycles of the ‘BEP’ schedule (see following ‘Metastatic disease’ section) have been shown to reduce the risk of recurrence in high-​risk stage 1 patients to less than 2%, and recent data suggests that one cycle of BEP may be sufficient, with

Table 21.18.6  Testicular tumour markers Marker

Seminoma

Nonseminoma

Other causes of raised marker

α-​Fetoprotein

Never raised

40%

Hepatocellular cancer, gastric cancer, alcohol, other liver disease, hereditary

β-​HCG

15–​20%

40%

Neuroendocrine, bladder, kidney, lung, and rarely other cancers. marijuana, hypogonadism

LDH

40–​60%

40–​60%

Infection, inflammation

21.18  Malignant diseases of the urinary tract

Table 21.18.7  Royal Marsden Hospital (RMH) and TNM staging systems compared Stage group

RMH system

TNM system

I

Testis only

T1–​T4 N0 M0

II

Infra-​diaphragmatic lymph node involvement

T1–​T4 N1–​3 M0

III

Infra-​diaphragmatic lymph node involvement

Any T, any N M1a (nonregional lymph nodes)

IV

Extranodal metastases

Any T, any N M1a (pulmonary metastases) or M1b (nonpulmonary visceral metastases)

In the RMH system, each stage is subcategorized according to the size of abdominal mass that maps onto N1–​3 in the TNM system, i.e. A (N1) 5 cm.

several studies showing a risk of relapse of less than 5%, hence one cycle of BEP is increasingly recommended as the optimal adjuvant treatment. Metastatic disease The mainstay of management of metastatic germ cell tumours has been the BEP schedule (bleomycin 30  000 IU days 1, 8, and 15; etoposide 100 mg/​m2 days 1–​5; cisplatin 20 mg/​m2 days 1–​5; on a 21-​day cycle) This is a highly successful treatment, but should be given without dose reduction or delays to optimize outcomes. Use of supportive treatments (antiemetics, growth factors) is recommended to achieve this, but it does have a significant burden of toxicities, both acute and late (Table 21.18.10). For good prognosis disease, a randomized trial has defined three cycles as the appropriate treatment, and potentially the chemotherapy can be given over 3 days. The exception to this is in stage 2a/​b seminoma, where radiotherapy to the para-​aortic nodes with or without carboplatin is equally effective and may be better tolerated. In intermediate or poor prognosis disease, four cycles of 5-​day BEP is recommended. The outcomes, particularly in poor prognosis disease, remain less than satisfactory. A number of approaches have been tried to improve results, as summarized in Table 21.18.11. To date, however, none have been shown to improve overall survival, but some may improve progression-​free survival. The GETUG study investigated if slow marker decline could be utilized to select patients for dose intensification. In this study, patients with a ‘good’ marker decline (c.20%) who had a better prognosis received BEP chemotherapy and those with a poor marker decline were randomized to dose intensification versus BEP. The dose intensified patients had better progression-​ free survival, lower use of salvage high-​dose chemotherapy, and showed a trend to improved survival.

Residual masses commonly remain following chemotherapy. In NSGCTs, it is recommended that these are completely resected (if >1 cm) as they may harbour residual malignancy (in which case surgery may be curative) or be teratoma differentiated. Though the latter histology is generally regarded as being benign, teratoma differentiated can gradually enlarge and become unresectable, transform to more active germ cell tumour, develop into somatic malignancies, and may be responsible for the phenomenon of late relapse. Seminomas should not develop teratoma differentiated, and routine treatment to residual masses has not been shown to improve outcome. A significant proportion of large (>3 cm) residual masses may, however, harbour residual active seminoma. An FDG-​PET scan taken more than 6 weeks after chemotherapy has shown a high sensitivity for residual disease and is recommended to define subsequent treatments. Salvage treatment About 10% of good prognosis, 20% of intermediate prognosis, and 40 to 50% of poor prognosis patients will go on to develop relapse. Management of these cases is challenging, but usually involves chemotherapy along with aggressive local therapy and/​or high-​ dose chemotherapy. A number of salvage regimens have been described, the most common of which is probably the TIP schedule (paclitaxel 250 mg m2 over 24 h; ifosfamide 1.5 g/​m2 daily, days 2–​5; cisplatin 25 mg/​m2, days 2–​5) given for a total of four cycles. The success of this treatment has been shown to depend on pretreatment prognostic factors (Table 21.18.12), but overall 30% of patients are cured by this approach. The main debate is whether treatment should be consolidated, or replaced in second line by use of high-​dose chemotherapy. An international retrospective study suggested some improvement with immediate high-​dose chemotherapy, but the one European randomized trial of this approach showed no significant advantage. A further trial of cyclical high-​dose chemotherapy (TIGER trial) was launched in 2016. Consolidation of salvage chemotherapy should utilize aggressive surgery and/​or radiotherapy wherever possible. Some patients develop what is termed a late relapse, defined as a relapse more than 2 years after initial treatment. These tumours often secrete α-​fetoprotein and tend to be relatively drug resistant. Surgical excision is the optimal approach. Prognosis Overall, the cure rate of testicular germ cell is favourable, with a 5-​ year survival in the United Kingdom of over 97% rising to over 99% in patients with stage 1 disease. For most patients, the key issues as highlighted are maintaining cures but minimizing long-​term

Table 21.18.8  International Germ Cell Collaboration Group prognostic classification for nonseminomas Category

Criteria

HCG level IU/​litre

α-​Fetoprotein level IU/​litre

LDH × normal

NPVM

Mediastinal primary

Predicted PFS

Good

All of

10

Yes

Yes

41%

Intermediate Poor

Any of

HCG, human chorionic gonadotropin; LDH, lactate dehydrogenase; NPVM, nonpulmonary visceral metastases; PFS, progression-​free survival. a I or marker category plus no nonpulmonary visceral metastases or mediastinal mass.

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Table 21.18.9  Surveillance schedules for stage 1 germ cell tumours Nonseminoma

Seminoma

Year 1

1 months

3 months

Year 2

3 months

3 months

Year 3

4 months

4 months

Year 4

6 months

6 months

Year 5

6 months

6 months

Imaging

3 months, 12 months

6, 12, 18, 24, 36, 48, and 60 months

Table 21.18.12  International Germ Cell Consensus Classification Group-​2 prognostic classification for germ cell tumours undergoing salvage treatment Variable

Markers and clinical review are performed at each visit, and chest radiograph at alternate visits in year 1. Imaging is by CT or MRI, and may be restricted to abdomen in most patients. Source data from Van As et al. Evidence-​based pragmatic guidelines for the follow-​up of testicular cancer: optimising the detection of relapse, Br J Cancer. 2008 Jun 17; 98(12): 1894–​1902.

Histology

Seminoma 1, nonseminoma 0

Primary site

Gonadal 0, retroperitoneal 1, mediastinum 3

Response first line

CR/​PRM− 0, PRM + 1, PD 2

Progression free interval

>3 months 0,