Table Of ContentMacSween’s
Pathology
Liver
of the
Commissioning Editor: Michael Houston
Development Editor: Martin Mellor
Project Manager: Anita Somaroutu
Design: Charles Gray
Illustration Manager: Merlyn Harvey
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MacSween’s
Pathology
Liver
of the
SIXTH EDITION
Alastair D. Burt BSc MD FRCPath FRCP FSB Linda D. Ferrell MD
Professor of Pathology and Dean of Clinical Medicine Professor of Pathology
Newcastle University; Vice-Chair of Anatomic Pathology
Honorary Consultant Histopathologist Director of Surgical Pathology
Newcastle upon Tyne Hospitals NHS Foundation Trust, Department of Anatomic Pathology
Newcastle, UK University of California, San Francisco
San Francisco, CA, USA
Bernard C. Portmann MD FRCPath
Professor Emeritus, King’s College London, School of
Medicine;
Former Lead Consultant Histopathologist, Institute of
Liver Studies,
King’s College Hospital NHS Foundation Trust;
Consultant Histopathologist, The London Clinic
London, UK
For additional online content visit expertconsult.com
Edinburgh London New York Oxford Philadelphia St Louis Sydney Toronto 2012
An imprint of Elsevier Limited
© 2012, Elsevier Limited. All rights reserved.
First edition 1979
Second edition 1987
Third edition 1994
Fourth edition 2002
Fifth edition 2007
The right of A.D. Burt, B.C. Portmann and L.D. Ferrell to be identified as authors of this work has been asserted by them in
accordance with the Copyright, Designs and Patents Act 1988.
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This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as
may be noted herein).
The chapter entitled ‘Hepatic injury due to drugs, herbal compounds, chemicals and toxins’ is in the public domain.
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understand-
ing, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any informa-
tion, methods, compounds, or experiments described herein. In using such information or methods they should be mindful
of their own safety and the safety of others, including parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information
provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recom-
mended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of
practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and
the best treatment for each individual patient, and to take all appropriate safety precautions.
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operation of any methods, products, instructions, or ideas contained in the material herein.
ISBN: 978-0-7020-3398-8
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List of contributors
Jorge Albores-Saavedra MD Andrew D. Clouston MBBS PhD FRCPA
Consultant and Researcher Associate Professor of Molecular and Cellular Pathology
Department of Pathology University of Queensland;
Instituto Nacional de Ciencias Medicas y Nutricion ‘Salvador Managing Partner
Zubiran’ Envoi Specialist Pathologists;
Mexico City, Mexico Visiting Consultant
Royal Brisbane and Women’s Hospital
Arturo Angeles-Angeles MD Brisbane, Queensland, Australia
Chief
Department of Pathology James M. Crawford MD PhD
Instituto Nacional de Ciencias Medicas y Nutricion ‘Salvador Professor and Chair
Zubiran’ Department of Pathology and Laboratory Medicine
Mexico City, Mexico Hofstra North Shore-LIJ School of Medicine
Senior Vice President of Laboratory Services
Pierre Bedossa MD PhD North Shore-Long Island Jewish Health System
Manhasset, NY, USA
Professor of Pathology;
Head of Department of Pathology
Beaujon Hospital and University of Paris-Denis Diderot Linda D. Ferrell MD
Paris, France Professor of Pathology;
Vice-Chair of Anatomic Pathology;
Henry C. Bodenheimer Jr MD Director of Surgical Pathology
Department of Anatomic Pathology
Chairman
University of California, San Francisco
Department of Medicine;
San Francisco, CA, USA
Professor of Medicine
Albert Einstein College of Medicine
Beth Israel Medical Center Zachary D. Goodman MD PhD
New York, NY, USA Director
Hepatic Pathology Research
Elizabeth M. Brunt MD Center for Liver Diseases
Inova Fairfax Hospital
Professor of Pathology and Immunology
Falls Church, VA, USA
Washington University School of Medicine
St Louis, MO, USA
Weei-Yuarn Huang MD PhD FRCPC
Alastair D. Burt BSc MD FRCPath FRCP FSB Assistant Professor
Department of Pathology, Dalhousie University
Professor of Pathology and Dean of Clinical Medicine
Staff Pathologist, QEII Health Science Center
Newcastle University
Halifax, Canada
Honorary Consultant Histopathologist
Newcastle upon Tyne Hospitals NHS Foundation Trust,
Newcastle, UK
vii
List of contributors
Stefan G. Hübscher MBChB FRCPath FSB Antonello Pietrangelo MD PhD
Leith Professor and Professor of Hepatic Pathology Professor of Medicine;
University of Birmingham; Director, Division of Internal Medicine 2
Consultant Histopathologist, and Center for Hemochromatosis
University Hospital Birmingham NHS Foundation Trust, University Hospital of Modena
Birmingham, UK Modena, Italy
David E. Kleiner MD PhD Bernard C. Portmann MD FRCPath
Director, Clinical Operations Professor Emeritus
Laboratory of Pathology King’s College London, School of Medicine;
National Cancer Institute Former Lead Consultant Histopathologist
Bethesda, MD, USA Institute of Liver Studies
King’s College Hospital NHS Foundation Trust;
James H. Lewis MD FACP FACG AGAF London, UK
Professor of Medicine
Division of Gastroenterology; Alberto Quaglia MD, PhD, FRCPath
Director of Hepatology Lead Consultant Histopathologist
Georgetown University Medical Center Institute of Liver Studies
Washington, DC, USA King’s College Hospital NHS Foundation Trust;
London, UK
Sebastian B. Lucas FRCP FRCPath
Professor of Clinical Histopathology Eve A. Roberts MD MA FRCPC
King’s College London School of Medicine Adjunct Professor of Paediatrics, Medicine and Pharmacology
Department of Histopathology University of Toronto
St Thomas’ Hospital Division of Gastroenterology, Hepatology and Nutrition
London, UK The Hospital for Sick Children
Toronto, ON, Canada
Michael P. Manns MD
Professor and Chairman Luigi M. Terracciano MD
Department of Gastroenterology, Hepatology and Professor of Pathology
Endocrinology Head of Molecular Pathology Division
Medical School of Hannover Institute of Pathology
Hannover, Germany University Hospital
Basel, Switzerland
Yasuni Nakanuma MD PhD
Professor and Chairman Neil D. Theise MD
Department of Human Pathology Professor of Pathology;
Kanazawa University Graduate School of Medicine Professor of Medicine (Division of Digestive Diseases)
Kanazawa, Japan Beth Israel Medical Center, Albert Einstein College of
Medicine
Brent A. Neuschwander-Tetri MD New York, NY, USA
Professor of Internal Medicine;
Director, Division of Gastroenterology and Hepatology Richard J. Thompson BA BM BCh MRCP MRCPCH
Saint Louis University Senior Lecturer in Paediatric Hepatology;
St Louis, MO, USA Honorary Consultant
Institute of Liver Studies
Valerie Paradis MD PhD Division of Transplant Immunology and Mucosal Biology
King’s College London School of Medicine at King’s College
Professor of Pathology
Hospital
Pathology Department
London, UK
Beaujon Hospital, Clichy, France
Alan C. Paterson MB BCh PhD FCPath(SA) Ian R. Wanless MD CM FRCPC
Professor of Pathology Professor of Pathology
Consultant in Liver and Gastrointestinal Pathology Dalhousie University
Ampath Trust Halifax, Nova Scotia, Canada
Johannesburg, South Africa
viii
List of contributors
M. Kay Washington MD PhD Sherif R. Zaki MD PhD
Professor of Pathology Chief
Vanderbilt University Medical Center Infectious Diseases Pathology Branch
Nashville, TN, USA Centers for Disease Control and Prevention
Atlanta, GA, USA
Aileen Wee MB BS FRCPath FRCPA
Professor and Senior Consultant Yoh Zen MD PhD FRCPath
Department of Pathology Consultant Histopathologist
Yong Loo Lin School of Medicine, National University of Institute of Liver Studies
Singapore King’s College Hospital NHS Foundation Trust;
National University Hospital London, UK
National University Health System
Singapore
ix
Preface
Liver disease continues to be a major cause of morbidity and mor- diseases, given its importance. We are delighted to have the input
tality worldwide. There are nevertheless, epidemiological changes. of Antonello Pietrangelo, arguably the most experienced scientist
The effects of mass immunization against Hepatitis B are beginning in this field internationally. Here we have adopted a more funda-
to be seen in some parts of the world and the development of more mental approach to classification than that which is included in the
effective antiviral agents are influencing the clinical expression of fifth edition. We also took the decision to combine the coverage of
Hepatitis C infection. In parallel however, there has been an almost alcoholic and non-alcoholic fatty liver disease. While there are some
exponential growth in the prevalence of fatty liver disease, much of differences morphologically, there are more similarities and overlap,
which can be attributed to the progressive rise in obesity levels. In both in histological features and in underlying mechanisms. It is
some countries, there has been a decline in alcohol-induced fatty with great sadness that since the publication of the fifth edition,
liver disease while in others, including the UK, there has been an Pauline Hall passed away. Pauline had contributed to successive
increase. editions with outstanding chapters on alcoholic liver disease and
In terms of the diagnosis of liver disease there have been signifi- Chapter Six is very heavily influenced by her thoughts on this dis-
cant developments since the fifth edition of MacSween’s Pathology order and the many contributions she made to the field.
of the Liver. Non-invasive imaging of the liver has continued to In the chapter including non-viral infectious diseases, we are
develop at a phenomenal pace and we have seen the introduction delighted to have the additional input of Sherif Zaki, who has out-
of techniques such as transient elastography for the assessment of standing expertise and experience in unusual infectious diseases in
fibrosis. Furthermore, surrogate markers of liver fibrosis have been the liver. In the current edition, we also welcome the combined
developed by a number of groups and there are algorithms utiliz- strengths of Kay Washington and Michael Manns with their excel-
ing serum levels of matrix proteins and metalloproteinases. While lent overview of autoimmune hepatitis.
these are seen to be supplementary diagnostic modalities, none Ian Wanless has done much to highlight the importance of
has replaced liver biopsy as the ‘gold standard’. We have continued vascular events in liver disease, and we are delighted to include
to see substantial increases in our understanding of morphological an extended coverage of this and the importance of parenchymal
changes across a whole range of liver diseases, and in particular extinction lesions in the development of cirrhosis in his chapter.
since the fifth edition, there have been very significant advances in The chapter on liver tumours has been written to be consistent
the interpretation of drug-induced liver injury; tumour precursor with the recently published WHO classification. It considers our
lesions; benign hepatic neoplasms; variant malignant tumours; evolving understanding of precursor lesions and novel approaches
and the interpretation of patterns of fibrosis. In addition, new to subtyping hepatocellular adenomas. We have expanded this
anti bodies have been developed and made commercially available chapter to ensure that it is as comprehensive as possible. The editors
to refine the diagnosis of tumours and metabolic disorders. We were also aware of the importance of cytopathology in the diagnosis
felt it was timely therefore for a further edition, drawing on the of liver tumours particularly in Asian centres and we are delighted
expertise of many of the top hepatopathologists from around the to have enlisted the help of Aileen Wee as a contributor to this
globe. chapter.
In this sixth edition, we have made some further changes to the All three of us continue to feel honoured to be responsible for
structure of the book. Chapter One now combines an outline of this textbook and once again wish to pay tribute to the man behind
structure and function of the normal liver with an overview of the the very first edition: Sir Roddy MacSween, whom we all continue
basic pathological processes that can be seen in injury. This chapter to look upon as a great friend and mentor. We have all enjoyed
draws on the introductory chapters from previous editions and we working with our contributors in developing this sixth edition,
are indebted to the authors of these earlier chapters and in particu- which we hope will continue to influence the practice of patho-
lar to the input of Professors Valeer Desmet and Tania Roskams. logists and clinicians involved in the care of patients with liver
Chapter Two was designed to take a fresh look at technical aspects disease. It has once again also been a pleasure to collaborate with
of liver pathology, introducing some ‘new kids on the block’. Some the publishing teams in Elsevier.
of these approaches enhance existing morphological techniques,
while some are likely to be complementary in the diagnostic arena. Alastair D. Burt Newcastle
The editors took the decision in this edition to separate out Bernard C. Portmann London
disorders of iron overload from all other genetic and metabolic Linda D. Ferrell San Francisco
xi
Acknowledgements
Acknowledgements of illustrations from previous publications or (Newcastle), Elisabeth Portmann (London) and Caren Hale (San
of modification to illustrations and diagrams and acknowledge- Francisco). As always, preparation of a book this size and type is a
ment of original photographic material and microscopic material time-consuming business, and we would like to thank our respec-
is appropriately made in each chapter and figure legends. tive families for their patience and support during the more fraught
We would like to take the opportunity to thank our administra- times in the development of this sixth edition. We would like to
tive assistants who have helped with the preparation of manuscripts thank our publishers and typesetters for their help and encourage-
and figures and who have contributed to the chores of proofreading, ment at all times and in particular Martin Mellor, Michael Houston
and in particular we are grateful for the help of Emma Reynolds and Anita Somaroutu.
xiii
Anatomy, pathophysiology and basic
1
mechanisms of disease
James M. Crawford and Alastair D. Burt
CHAPTER CONTENTS Steatosis 37
Cholestasis 38
Introduction 2
Mallory–Denk bodies 41
Development of the liver 2
Cell death 42
General features 2
Apoptosis 42
Vascular arrangements 2
Necrosis 44
Hepatocytes and sinusoidal cells 4
Regeneration 45
The bile duct system 4
Regeneration of mature liver cells 45
Haemopoiesis 5
The role of progenitor cells 48
Molecular control of liver development 5
Fibrosis 49
Macroanatomy of the liver 6
Hepatic stellate cells 50
Microanatomy of the liver 7
Portal tract fibrogenesis 51
Anatomy of the hepatic microcirculation 8
Epithelial–mesenchymal transition 51
Regulation of the hepatic microcirculation 8
Bone marrow-derived myofibroblast precursors 51
Functional heterogeneity in the liver 12
Regulation of fibrogenesis 52
Ultrastructural anatomy of the hepatocyte 13
Vascular remodelling 54
The hepatic sinusoid and the sinusoidal cells 19
Endothelial porosity 54
The biliary system 23
Vascular thrombosis 54
Other constituent tissues 26
Sinusoidal blood flow 54
General concepts of liver injury and repair 30
Angiogenesis, arterial and venous changes 56
Inflammation 31
Zonation 56
The innate immune system 32
Cirrhosis 57
The adaptive immune system 33
Parenchymal extinction 58
Recruitment and influx of inflammatory cells 34
Reversibility of fibrosis/cirrhosis 58
Inflammation of portal tracts 34
The liver in biopsy and autopsy specimens 59
Granulomas 36
Hepatocellular injury 36
Ballooning degeneration 37
©2012 Elsevier Ltd
DOI: 10.1016/B978-0-7020-3398-8.00001-5
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