Viral Hepatitis E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 2016

Veröffentlichungsjahr: 2013

Beschreibung

The 4^th edition of Viral Hepatitis covers comprehensively the entire complex field of infections caused by all of the different hepatitis viruses, which affect many millions of people throughout the world with considerable morbidity and mortality.

Howard Thomas and Arie Zuckerman are joined by Anna Lok from the USA and Stephen Locarnini from Australia as Editors.  They have recruited leading researchers and physicians from many countries, who have produced an authoritative account of current knowledge and research on this important infection, including new insights into immune response to HBV and HCV. 

The result is a comprehensive account on all aspects of viral hepatitis, including rapid advances in the diagnosis, management, treatment and prevention of a complex infection, which in the case of hepatitis B, C and D may lead to severe complications including chronic hepatitis, cirrhosis and hepatocellular carcinoma.

The latest edition of Viral Hepatitis offers an essential resource of current information for hepatologists, gastroenterologists, infectious diseases specialists and other clinicians, researchers, public health physicians and National and International Health Authorities.

Leseprobe

Table of Contents

Title page

Copyright page

List of Contributors

Preface

Section I: Introduction to Liver Biology

Chapter 1: Liver regeneration and fibrosis

Introduction

Liver turnover and regeneration

Stem cells and liver cancer (founders and propagators)

Liver fibrosis

Chapter 2: Hepatic immunology

Overview of liver immunology

Innate immunity

Adaptive immunity

The liver is a unique immune organ

Section II: Hepatitis A Virus

Chapter 3: Structure, molecular virology, natural history, and experimental models

Introduction

HAV structure and molecular virology

Natural history of HAV

HAV experimental models

Conclusion

Chapter 4: Epidemiology and prevention

Epidemiology

Prevention

Future directions in hepatitis A prevention

Acknowledgment

Section III: Hepatitis B Virus and Other Hepadnaviridae

Chapter 5: Structure and molecular virology

HBV morphology, life cycle, and genome organization

Hepatitis B viral proteins

HBV life cycle

Attachment, membrane fusion, and entry

Conclusion

Chapter 6: Epidemiology and prevention

Epidemiology

Prevention

Conclusion

Chapter 7: Other Hepadnaviridae (Avihepadnaviridae (DHBV) and Orthohepadnaviridae (WHV))

Hepadnaviridae: Introduction and comparative virology

Avihepadnaviridae: Classification

Avihepadnaviridae: The exogenous replication strategy

Development of antihepadnaviral agents: The experimental model of DHBV

Future challenges for the development of therapies for chronic HBV: The role of covalently closed circular DNA (cccDNA) inhibitors and animal model testing

Endogenous avian hepadnaviruses: Deep evolutionary origins

Extrahepatic DHBV infection: Role of germ line infection and integration

Intrahepatic pathogenesis of hepadnaviral infection: Insights from animal models

Orthohepadnaviridae: The woodchuck model

The woodchuck is a preclinical model for new therapeutic strategies in CHB

Cloning and characterization of components of the woodchuck immune system

Development of immunological tools in the woodchuck model

Combination of antiviral treatment and vaccination

Electroporation: A new strategy to improve immune response in therapeutic vaccination

New strategies for treatment of chronic hepadnaviral infection

Vaccination against hepatitis D virus (HDV) infections

What can we learn from the woodchuck model?

Acknowledgments

Chapter 8: Molecular variants of hepatitis B surface antigen (HBsAg)

Introduction

The surface gene and subtypes

Surface variants

Variants associated with active immunization

Variants associated with passive immunization

Antigenic characterization

Immune escape at the T cell level

HBsAg mutants and clinical outcomes

HBsAg mutants in liver transplantation settings

Diagnostic issues

Variants associated with antiviral therapy

Pre-S and S variants and chronic hepatitis

Conclusion

Chapter 9: Molecular variants of the precore, core, and core promoter regions of hepatitis B virus, and their clinical significance

Introduction

Virus biology and evolution

Precore variants

Basal core promoter variants

Other variants

Emergence of variants during chronic infection

Core gene variants

Mechanisms of emergence of variants

Concluding remarks

Chapter 10: Natural history of chronic hepatitis B virus infection

Introduction

Clinical presentations

Phases of chronic HBV infection

Adverse sequelae and mortality

Summary and conclusion

Acknowledgments

Chapter 11: Extrahepatic manifestations of hepatitis B infection

Introduction

Background

Polyarteritis nodosa

Renal manifestations

Cutaneous manifestations of HBV

Hematologic manifestations

Neurologic manifestations

Ocular manifestations

Conclusions

Chapter 12: Hepatitis B and hepatocellular carcinoma

Introduction

Epidemiological association between HBV and HCC

The HBV genome

Oncogenic properties of viral proteins

Viral integrations in HCC

Genetic and epigenetic alterations in HBV-related HCC

Conclusions

Chapter 13: Murine models and human studies of pathogenesis of chronic hepatitis B

Introduction

HBV transgenic mouse models

Hydrodynamically transfected HBV mouse models

Chimeric mouse models

Murine models for assessing HBV treatments

Relevance to HBV infection in humans

Conclusions

Chapter 14: Treatment of hepatitis B

Introduction

Treatment goals

Indications for HBV treatment

Safety and efficacy of approved HBV drugs

Conclusions and future perspectives

Chapter 15: Liver transplantation for chronic hepatitis B and C

Liver transplantation for chronic hepatitis C

Liver transplantation for hepatitis B

Section IV: Hepatitis C Virus

Chapter 16: Structure and molecular virology

Introduction

The HCV virion

Structural proteins

Nonstructural proteins and virus replication

The 5′ terminal UTR

The 3′ terminal UTR

Chapter 17: Epidemiology and prevention

Introduction

Transmission mechanisms and groups at risk for HCV infection

Global prevalence of HCV infection among the general population

Epidemiological trends

Genotype distribution

Summary

Chapter 18: The immune response to HCV in acute and chronic infection

Introduction

Genetic considerations

Antibody responses

Dendritic cells and macrophages

NK cells

T cell responses

Failure of immune responses in acute and chronic HCV infection

Evasion from innate responses

Evasion from NK cell responses

Evasion from humoral immune responses

Evasion from T cell responses

Summary

Chapter 19: Animal models of hepatitis C virus infection

Introduction

The contribution of the chimpanzee model in the pre-HCV era

The role of the chimpanzee model in the discovery of HCV

The contribution of the chimpanzee model in the post-HCV era

Interactions among hepatitis viruses in chimpanzees

Lack of protective immunity against re-infection or superinfection with HCV

Small-animal models for the study of HCV infection

Chapter 20: Extrahepatic manifestations of hepatitis C virus infection

Introduction

Mixed cryoglobulinemia

Insulin resistance as an extrahepatic manifestation

Dermatological diseases

Porphyria cutanea tarda

Oral lichen planus

Other EHMs

Summary

Chapter 21: Central nervous system complications of hepatitis C virus infection

Introduction

CNS involvement in HCV-related vasculitis

Evidence for a cerebral effect in HCV infection

Brain imaging

Virological studies

Detection of HCV RNA in the CNS

Conclusions

Chapter 22: In vitro replication models

Genome organization and replication cycle of HCV: a 2-minute course

HCV cell culture systems

Host cell permissiveness

Host range of HCV replication

Infection of primary cells

Applications of HCV cell culture systems

Conclusion

Acknowledgments

Chapter 23: Natural history of chronic HCV infection and non-invasive assessment of hepatic fibrosis

Natural history of chronic HCV infection

Non-invasive assessment of hepatic fibrosis

Conclusion

Chapter 24: Hepatitis C and hepatocellular carcinoma

Introduction

Clinical aspects of HCV-induced HCCs

Liver inflammation, fibrosis, and HCC development

Molecular hepatocarcinogenesis and HCV infection

Genetic changes

HCV infection and malignancies other than HCC

Conclusions and perspectives

Acknowledgments

Chapter 25: Treatment of hepatitis C

Introduction

HCV treatment, objectives, and outcome

The new standard of care in chronic hepatitis C treatment

Triple therapy combining the PEG-IFN/RBV backbone with a ketoamide NS3/4A protease inhibitor

Challenges in the management of chronic hepatitis C patients treated with the new standard of care

Who should be treated for chronic hepatitis C?

Factors influencing response to antiviral therapy

Special patient populations

Management of patients with advanced liver disease who fail to achieve SVR on a protease inhibitor–based regimen

Novel agents in clinical development

Interferon-sparing regimens and future perspectives

Chapter 26: Development of anti-HCV drugs

Introduction

HCV viral life cycle

Direct-acting antivirals

Host-targeted antivirals (HTAs)

Alternative interferons

Conclusion

Section V: Hepatitis D Virus

Chapter 27: Structure and molecular virology

Introduction

HDV genome and classification

The HDV life cycle

Virus–host interactions

Conclusions

Chapter 28: Epidemiology and natural history

Epidemiology of hepatitis D

Natural history of hepatitis D

Chapter 29: Treatment of hepatitis D

Introduction

Challenges in treatment of hepatitis D

Goals of treatment

Efficacy of therapy

HDV latency

Future therapies?

Conclusions

Section VI: Hepatitis E Virus

Chapter 30: Structure and molecular virology

Introduction

Virion properties

Taxonomy and classification

Genomic organization

HEV proteins and their function

Stages of HEV replication

Virion structure

Conclusion and future prospects

Acknowledgment

Chapter 31: Epidemiology, experimental models, and prevention: zoonotic aspects of hepatitis E

Introduction

General epidemiology and genetic heterogeneity

Epidemiology: zoonotic aspect

Experimental models

Prevention

Chapter 32: Clinical and pathological features, and diagnosis

Introduction

Clinical features

Treatment of HEV

Pathological features

Diagnostic tests and caveats in interpretation

Section VII: Clinical Aspects of Viral Liver Disease

Chapter 33: Clinical and diagnostic aspects of viral hepatitis

Introduction

Hepatitis A

Hepatitis B

Hepatitis C

Hepatitis E

Chapter 34: Treatment of acute hepatitis, severe acute hepatitis, and acute liver failure

Introduction

Definition of and discrimination between acute hepatitis, severe acute hepatitis, and fulminant hepatitis (or acute liver failure)

Etiology of acute hepatitis and acute liver failure, and etiology-specific treatment options

Viral hepatitis, acute hepatitis, and acute liver failure

Hepatitis viruses: HAV to HGV

Other viral infections that can cause acute hepatitis and acute liver failure

Prognosis and indication for liver transplantation

General treatment and prophylaxis recommended for patients with fulminant hepatitis and acute liver failure

The future

Conclusion

Chapter 35: Hepatitis and hemophilia

Introduction

Clotting factor concentrates

Rates of infection

Investigation of liver disease

The natural history of hepatitis C in hemophilia

Hepatocellular carcinoma

Antiviral therapy

Liver transplantation

Prevention

Chapter 36: Hepatitis in persons infected with HIV

Hepatitis A virus infection

Hepatitis B virus infection

Hepatitis C virus infection

Hepatitis D virus (HDV) infection

Hepatitis E virus (HEV) infection

Hepatitis GBV-C

Summary

Chapter 37: Migration, hepatitis B, and hepatitis C

Introduction

People on the move

Population movement and health

Population movement and viral hepatitis

Emerging HBV and HCV patterns

Substance abuse and migrants

Migrants and sex work

Prevention and management of viral hepatitis

Real barriers to care and treatment

HBV vaccination

Conclusions

Chapter 38: Occupational aspects of hepatitis

Hepatitis B and C viruses

Occupational acquisition of HBV by workers

Hepatitis C

Hepatitis A

Hepatitis D

Hepatitis E

Compensation for occupationally acquired infection

Chapter 39: Neonatal and pediatric infection

Neonatal viral hepatitis

Acute hepatitis in older children

Chapter 40: Management of hepatocellular carcinoma

Background

The diagnostic algorithm

Tumor staging

The treatment algorithm

Assessment of tumor response

Conclusions and perspectives

Chapter 41: Application of molecular biology to the diagnosis of viral hepatitis

Introduction

Molecular biology methods

Clinical use of virologic methods in hepatitis B

Clinical use of virologic methods in hepatitis C

Clinical use of virologic methods in other types of hepatitis

Conclusion

Chapter 42: Disinfection and sterilization

Introduction

Regulation of chemical germicides

Definitions

Factors that influence germicidal activity

Inactivation of hepatitis viruses

Sterilization, disinfection, and housekeeping in the laboratory

Conclusions

Chapter 43: Evolution of hepatitis viruses

Introduction

Genetic variability of hepatitis viruses – classification into genotypes

Virus evolution and selection pressures

Origins of hepatitis viruses

Practical implications of virus variability

Summary

Index

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Library of Congress Cataloging-in-Publication Data

Viral hepatitis / edited by Howard C. Thomas … [et al.]. – 4th ed.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-0-470-67295-2 (alk. paper) – ISBN 978-1-118-63727-2 (ebook online product) – ISBN 978-1-118-63730-2 (ePDF) – ISBN 978-1-118-63731-9 (eMobi) – ISBN 978-1-118-63733-3 (ePub)

I. Thomas, H. C. (Howard C.)

[DNLM: 1. Hepatitis, Viral, Human. 2. Hepatitis Viruses. WC 536]

616.3'623–dc23

2013001678

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Cover image: High detailed hepatitis virus view isolated with clipping path (Image ID: 42546331). © CLIPAREA l Custom media / Shutterstock

Cover design by Garth Stewart

List of Contributors

Seyed Moayed Alavian PhD

Professor of Gastroenterology and Hepatology

Middle East Liver Diseases Center (MELD)

Tehran, Iran

Malcolm R. Alison PhD, DSc

Professor of Stem Cell Biology

Centre for Tumour Biology

Barts Cancer Institute

Barts and The London School of Medicine and Dentistry

London, UK

Nadia Amharref PhD

Postdoctoral Fellow

Oak Ridge Institute for Science and Education (ORISE) Research Participation Program

Center for Biologics Evaluation and Research

US Food and Drug Administration

Bethesda, MD, USA

Majid Amiri MD, PMP, AFSA

Associate Professor of Medicine

Service d'HépatoGastroentérologie

Hôpital de la Croix Rousse

Hospices Civils de Lyon;

Centre de Recherche en Cancérologie de Lyon

Lyon, France

Ralf Bartenschlager PhD

Professor of Virology

Department of Infectious Diseases

Molecular Virology

University of Heidelberg

Heidelberg, Germany

Antonio Bertoletti MD

Director, Infection & Immunity Program

Singapore Institute for Clinical Sciences

A*STAR;

Program of Emerging Viral Diseases

Duke-NUS Graduate Medical School;

Department of Medicine

Yong Loo Lin School of Medicine

National University of Singapore

Singapore

Hubert E. Blum MD

Professor of Medicine

Department of Medicine II

University Hospital of Freiburg

Freiburg, Germany

Walter W. Bond MS

Consulting Microbiologist

RCSA, Inc.

Lawrenceville, CA, USA

Johanna Bruneau PhD

Postdoctoral Fellow

University of Massachusetts Medical School

Worcester, MA, USA

Marie Annick Buendia PhD

Directeur de Recherche Emeritus

INSERM U.785

Hepatobiliary Center, Paul Brousse Hospital

University Paris-Sud

Villejuif, France

Sandra Bühler PhD

Scientific Coordinator

Department of Infectious Diseases

Molecular Virology

University of Heidelberg

Heidelberg, Germany

Jens Bukh MD

Professor

Copenhagen Hepatitis C Program (CO-HEP)

Department of Infectious Diseases and Clinical Research Centre

Copenhagen University Hospital, Hvidovre;

Department of International Health, Immunology and Microbiology

University of Copenhagen

Copenhagen, Denmark

Manuel Carballo PhD, MPH

Executive Director

International Centre for Migration, Health and Development

Geneva, Switzerland

William F. Carman MBBCh, MMed(Virology), PhD, FRCPath

Professor (ret.)

Fast Track Diagnostics

Junglinster, Luxembourg

Laurent Castera MD, PhD

Senior Lecturer

Service d'Hépatologie

INSERM U733 CRB3

Université Denis Diderot Paris-VII

Hôpital Beaujon

Assistance Publique-Hôpitaux de Paris

Clichy, France

Stéphane Chevaliez PharmD, PhD

Assistant Professor

National Reference Center for Viral Hepatitis B, C and D

Department of Virology

Hôpital Henri Mondor

Université Paris-Est

Créteil, France

Raymond T. Chung MD

Vice Chief, Gastroenterology

Director of Hepatology

Associate Professor of Medicine

Massachusetts General Hospital

Boston, MA, USA

Alessia Ciancio MD, PhD

Division of Gastroenterology

University of Torino

Torino, Italy

Rowan Cody BA, MPH

Research Officer

International Centre for Migration, Health and Development

Geneva, Switzerland

Massimo Colombo MD

Professor of Gastroenterology

A.M. & A. Migliavacca Center for Liver Disease

1st Division of Gastroenterology

Fondazione IRCCS Ca' Granda Maggiore Hospital

University of Milan

Milan, Italy

Markus Cornberg MD

Consultant Physician

Department of Gastroenterology, Hepatology and Endocrinology

Hannover Medical School

Hannover, Germany

Benjamin Cowie MB BS, PhD, FRACP

Epidemiologist and Physician

WHO Regional Reference Laboratory for Hepatitis B;

Victorian Infectious Diseases Reference Laboratory (VIDRL);

Victorian Infectious Diseases Service

Royal Melbourne Hospital;

Department of Medicine

University of Melbourne

Melbourne, VIC, Australia

Matthew E. Cramp MB BS, MD, FRCP

Consultant Hepatologist and Honorary Professor of Hepatology

South West Liver Unit

Derriford Hospital;

Plymouth University Peninsula School of

Medicine and Dentistry

Plymouth, UK

Payam Dindoost MD, PhD

Professor

Middle East Liver Diseases Center (MELD)

Tehran, Iran

Geoffrey Dusheiko MD, MB, BCh

Professor of Medicine

UCL Institute for Liver and Digestive Health

Royal Free Hospital

London, UK

Patrizia Farci MD

Chief, Hepatic Pathogenesis Section

Laboratory of Infectious Diseases

National Institute of Allergy and Infectious Diseases (NIAID)

National Institutes of Health (NIH)

Bethesda, MD, USA

Martin S. Favero PhD

Johnson & Johnson

Irvine, CA, USA

Stuart J. Forbes MB, ChB, PhD, FRCP(Ed)

Professor of Transplantation and Regenerative Medicine and Consultant Hepatologist

MRC Centre for Regenerative Medicine

The University of Edinburgh

Edinburgh, UK

Daniel M. Forton MB, BS, PhD, FRCP

Consultant Hepatologist and Senior Lecturer

St Georges University of London

London, UK

Ed Gane MB, ChB, MD, FRACP, MNZM

Professor and Hepatologist

New Zealand Liver Transplant Unit

Auckland City Hospital

Auckland, New Zealand

Markus Gess MB, BS, MRCP

Consultant Gastroenterologist

Kingston General Hospital

Surrey, UK

Loïc Guillevin MD

Professor of Medicine

Head of the Department of Internal Medicine

Assistance Publique-Hôpitaux de Paris

Hôpital Cochin

Université Paris-Descartes

Paris, France

Svenja Hardtke PhD

Projektmanagement HepNet Study-House

Department of Gastroenterology, Hepatology and Endocrinology

Hannover Medical School

Hannover, Germany

Angelos Hatzakis MD, PhD

Professor of Epidemiology and Preventative Medicine

Director, Department of Hygiene, Epidemiology and Medical Statistics

Athens University Medical School

Athens, Greece

Michael Houghton BSc, PhD

Professor

Department of Medical Microbiology and Immunology

University of Alberta

Rexall Centre for Health Research

Edmonton, AB, Canada

Dale J. Hu MD, MPH

Director, International Emerging Infections Program

US CDC Office, US Embassy

Beijing, China

Massimo Iavarone MD, PhD

Physician

A.M. & A. Migliavacca Center for Liver Disease

1st Division of Gastroenterology Fondazione IRCCS Ca' Granda Maggiore Hospital

University of Milan

Milan, Italy

William L. Irving MA, MB, BChir, MRCP, PhD, FRCPath

Professor of Virology and Honorary Consultant

Department of Microbiology

University Hospital

Queen's Medical Centre

Nottingham, UK

Jerome Jacques PhD

Postdoctoral Fellow

Oak Ridge Institute for Science and Education (ORISE) Research Participation Program;

Center for Biologics Evaluation and Research

US Food and Drug Administration

Bethesda, MD, USA

Seyed Mohammad Jazayeri MD, PhD

Associate Professor

Hepatitis B Laboratory, Department of Virology

School of Public Health

Tehran University of Medical Sciences

Tehran, Iran

Juandy Jo MD, PhD

Research Fellow

Program of Emerging Viral Diseases

Duke-NUS Graduate Medical School

Singapore

Gerardo G. Kaplan PhD

Senior Investigator

Center for Biologics Evaluation and Research

US Food and Drug Administration

Bethesda, MD, USA

Peter Karayiannis BSc, PhD, FIBMS, FRCPath(Virology)

Reader in Molecular Virology

Hepatology & Gastroenterology Section

Department of Medicine

Imperial College London

London, UK

Deirdre A. Kelly MD, FRCPI, FRCP, FRCPCH

Professor of Paediatric Hepatology

The Liver Unit

Birmingham Children's Hospital NHS Trust

Birmingham, UK

Megan Kelly BS, MPH

MPH Candidate

Tulane University School of Public Health and Tropical Medicine

New Orleans, LA, USA

Salim I. Khakoo MD

Professor of Hepatology

Director of Biomedical Research (IFLS)

Faculty of Medicine

University of Southampton

Southampton General Hospital

Southampton, UK

Krishnamurthy Konduru PhD

Staff Scientist

Laboratory of Emerging Pathogens

Center for Biologics Evaluation and Research

US Food and Drug Administration

Bethesda, MD, USA

Hellan K. Kwon MD

Assistant Professor of Medicine

Division of Gastroenterology and Hepatology

University of Michigan Health System

Ann Arbor, MI, USA

Yun-Fan Liaw MD

Professor of Medicine

Liver Research Unit

Chang Gung Memorial Hospital

Chang Gung University College of Medicine

Taipei, Taiwan

Cui Li Lin MD

Fellow in Gastroenterology and Hepatology

Warren Alpert Medical School of Brown University

Providence, RI, USA

Stephen A. Locarnini MBBS, BSc(Hons), PhD, FRCPath

Head, Research & Molecular Development

Victorian Infectious Diseases Reference Laboratory

Melbourne, VIC, Australia

Volker Lohmann PhD

Group Leader

Department of Infectious Diseases

Molecular Virology

University of Heidelberg

Heidelberg, Germany

Anna S.F. Lok MD

Alice Lohrman Andrews Research Professor in Hepatology

Director of Clinical Hepatology

Professor of Internal Medicine

Associate Chair for Clinical Research, Department of Internal Medicine

University of Michigan Health System

Ann Arbor, MI, USA

Souphalone Luangsay PhD

Research Associate

Lyon University

Cancer Research Center of Lyon (CRCL)

INSERM

Lyon, France

Benjamin Maasoumy MD

Physician and Research Fellow

Department of Gastroenterology, Hepatology and Endocrinology

Hannover Medical School

Hannover, Germany

Janice Main MB ChB FRCP(Edin & Lond)

Reader and Consultant in Infectious Diseases and General Internal Medicine

Department of Medicine

Imperial College London

St Mary's Hospital Campus

London, UK

Mike Makris MA, MB BS, MD, FRCP, FRCPath

Reader in Haemostasis and Thrombosis

Department of Cardiovascular Science

University of Sheffield;

Sheffield Haemophilia and Thrombosis Centre

Royal Hallamshire Hospital

Sheffield, UK

Mohanraj Manangeeswaran PhD

Postdoctoral Fellow

Oak Ridge Institute for Science and Education (ORISE) Research Participation Program

Center for Biologics Evaluation and Research

US Food and Drug Administration

Bethesda, MD, USA

Michael P. Manns MD

Professor and Chairman

Department of Gastroenterology, Hepatology and Endocrinology

Hannover Medical School

Hannover, Germany

Brendan McCarron MBChB, MRCP

Consultant Physician

South Tees Hospitals NHS Foundation Trust

Middlesbrough, UK

Michael J. McGarvey BA, BSc, PhD

Reader in Molecular Virology

Department of Medicine

Faculty of Medicine

Imperial College London

St Mary's Hospital Campus

London, UK

Brian J McMahon MD, MACP

Scientific Program and Clinical Director

Liver Disease and Hepatitis Program

Alaska Native Tribal Health Consortium;

Guest Researcher

Arctic Investigations Program

Centers for Disease Control and Prevention

Anchorage, AK, USA

Xiang-Jin Meng MD, PhD

Professor of Molecular Virology

Center for Molecular Medicine and Infectious Diseases

Department of Biomedical Sciences and Pathobiology

Virginia Polytechnic Institute and State University (Virginia Tech)

Blacksburg, VA, USA

Juan I. Esteban Mur MD, PhD

Professor of Medicine

Liver Unit

Hospital Universitari Vall d'Hebron (HUVH)

Universitat Autonoma de Barcelona

CIBERehd Instituto de Salud Carlos III

Barcelona, Spain

Siham Nakamura BS

Postbac Fellow

Oak Ridge Institute for Science and Education (ORISE) Research Participation Program

Center for Biologics Evaluation and Research

US Food and Drug Administration

Bethesda, MD, USA

Fortune Ncube BSc, BMed Sci, BM BS, DRCOG, MSc PHM, FFPHM, FRIPH

Consultant Epidemiologist, PHM Bloodborne Viruses

Head of BBV Section

HIV and Sexually Transmitted Infections Department

Public Health England

London, UK

Francesco Negro MD

Adjunct Professor

Divisions of Clinical Pathology and Gastroenterology and Hepatology

University Hospital

Geneva, Switzerland

Subrat Kumar Panda MD, FASc, FNA, FAMS, JC Bose National Fellow

Professor and Head of Pathology

All India Institute of Medical Sciences

Ansari Nagar, New Delhi, India

Jean-Michel Pawlotsky MD, PhD

Director, National Reference Center for Viral Hepatitis B, C and D

Chief, Department of Biology

Head, Department of Virology, Bacteriology, and Hygiene

Head, Research Team “Pathophysiology and Therapy of Chronic Viral Hepatitis”

Hôpital Henri Mondor

Université Paris-Est

Créteil, France

Josep Quer PhD

Senior Researcher

Liver Unit, Laboratori Malalties Hepatiques

Vall d′Hebron Institut de Recerca (VHIR)

Hospital Universitari Vall d'Hebron (HUVH)

Universitat Autonoma de Barcelona

CIBERehd Instituto de Salud Carlos III

Barcelona, Spain

Mario Rizzetto MD

Professor of Gastroenterology

Molinette Hospital

Torino, Italy

Christophe Rodriguez PharmD, PhD

Fellow

National Reference Center for Viral Hepatitis B, C and D

Department of Virology

Hôpital Henri Mondor

Université Paris-Est

Créteil, France

Michael Roggendorf Prof. Dr.med.

Director (Emeritus)

Institute for Virology

University Hospital of Essen

University of Duisburg-Essen

Essen, Germany

Esperance Schaefer MD, MPH

Instructor in Medicine

Gastroenterology Unit

Massachusetts General Hospital

Harvard Medical School

Boston, MA, USA

Cyril Sieberhagen MB, ChB, MRCP(UK)

Clinical Research Fellow

South West Liver Unit

Derriford Hospital;

Plymouth University Peninsula School of

Medicine and Dentistry

Plymouth, UK

Peter Simmonds BM, PhD, FRCPath

Infection and Immunity Division

The Roslin Institute

University of Edinburgh

Edinburgh, UK

Alastair D. Smith MB, ChB

Associated Professor

Division of Gastroenterology

Duke University

Durham, NC, USA

Donald B. Smith BSc, PhD

Postdoctoral Scientist

Centre for Immunity, Infection and Evolution

Ashworth Laboratories

University of Edinburgh

Edinburgh, UK

Philip R. Spradling, MD

Medical Epidemiologist

Division of Viral Hepatitis

Centers for Disease Control and Prevention

Atlanta, GA, USA

Gyongyi Szabo MD, PhD

Professor

Associate Dean for Clinical and Translational Sciences

Vice Chair for Research

Department of Medicine

University of Massachusetts Medical School

Worcester, MA, USA

Anthony Tanoto Tan PhD

Research Fellow

Program of Emerging Viral Diseases

Duke-NUS Graduate Medical School

Singapore

Simon Taylor-Robinson MD FRCP

Professor in Translational Medicine

Clinical Dean

Department of Medicine

Imperial College London

St Mary's Hospital Campus

London, UK

Robert Thimme MD

Heisenberg Professor for Hepatology

Leading Attending

Department of Medicine II

University Medical Center Freiburg

Freiburg, Germany

Howard C. Thomas BSc, PhD, FRCP, FRCPath, FMedSci

Emeritus Professor of Hepatology

Department of Medicine

Imperial College London

London, UK

Hans L. Tillmann MD

Associate Professor

Duke Clinical Research Institute and Division of Gastroenterology

Duke University

Durham, NC, USA

Pierre Tiollais MD

Professor

Unite d'Organisation Nucleaire et Oncogenese

INSERM U.579

Institut Pasteur

Paris, France

C.Y. William Tong MD, FRCP, FRCPath

Consultant Virologist and Honorary Senior Lecturer

Department of Infectious Diseases

Guy's and St Thomas' NHS Foundation Trust;

King's College London School of Medicine

London, UK

Christian Trépo MD, PhD

Professor

Service d'HépatoGastroentérologie

Hôpital de la Croix Rousse

Hospices Civils de Lyon;

Centre de Recherche en Cancérologie de Lyon

Lyon, France

Satya Pavan Kumar Varma PhD

Research Officer

Department of Pathology

All India Institute of Medical Sciences

Ansari Nagar, New Delhi, India

Jack R. Wands MD

Jeffrey and Kimberly Greenberg-Artemis and Martha Joukowsky

Professor in Gastroenterology and Medical Science

Director, Division of Gastroenterology and Hepatology and the Liver Research Center

Warren Alpert Medical School of Brown University

Providence, RI, USA

Heiner Wedemeyer MD

Professor

Department of Gastroenterology, Hepatology and Endocrinology

Hannover Medical School

Hannover, Germany

Christoph Welsch MD

Senior Research Fellow

Department of Internal Medicine I

J.W. Goethe University Hospital

Frankfurt am Main, Germany

Chelsea Q. Xu BS

Research Associate

The Liver Research Center/Rhode Island Hospital

Warren Alpert Medical School of Brown University

Providence, RI, USA

Stefan Zeuzem MD

Professor of Medicine

Chief, Department of Internal Medicine I

J.W. Goethe University Hospital

Frankfurt am Main, Germany

Fabien Zoulim MD, PhD

Professor of Medicine

Head of Hepatology Department

Hospices Civils de Lyon;

Head of Viral Hepatitis Research Team

Lyon University

Cancer Research Center of Lyon (CRCL)

INSERM

Lyon, France

Arie J. Zuckerman MD, DSc, FRCP, FRCPath, FMedSci

Emeritus Professor of Medical Microbiology

Formerly Principal and Dean

Royal Free Hospital School of Medicine, and later

Royal Free and University College Medical School

University College London

London, UK

Preface

Viral hepatitis remains a major public health problem throughout the world. Hepatitis A virus infects 1–90% or more of the human population, and it varies according to the socioeconomic, sanitary, and public health infrastructure of each country. Hepatitis B virus has infected one-third of the world population, with between 350 and 400 million carriers of the virus, many of whom progress to chronic liver disease and hepatocellular carcinoma. Hepatitis C virus is estimated to have infected 150–200 million people (probably a gross underestimate), with about 80% infected persistently, and this leads to serious sequelae including primary liver cancer. Infection with hepatitis D virus also occurs throughout the world and is hyperendemic in some countries, and hepatitis E is common and epidemic in a number of non-industrialized regions, with increasing evidence of zoonotic spread and sporadic infection in many countries.

Progress on all aspects of viral hepatitis is remarkably rapid, with many thousands of published accounts of original studies, and the mountain of new information is often bewildering and may be difficult to access. The pressing need for a fourth edition became clear, and the text has been revised and updated. The chapter on the history of hepatitis has been omitted (which is somewhat unfortunate because the future evolves from the past) in order to provide space for several new topics.

The fourth edition of Viral Hepatitis is designed to include a balanced and carefully distilled account of the more recent advances in this field written by a constellation of internationally recognized experts from many countries. We acknowledge their outstanding contributions, including those made by our two new co-editors, Professor Anna Lok and Professor Stephen Locarnini.

We hope that the book will prove useful to virologists, immunologists, specialists in infectious diseases, hepatologists, gastroenterologists, and, of course, public health and occupational health physicians and aspiring scientists. It is a book for those addressing the management and prevention of an important common infection and its associated liver diseases, which affect a large proportion of the world's population.

Howard C. Thomas

and

Arie J. Zuckerman

Section I

Introduction to Liver Biology

Chapter 1

Liver regeneration and fibrosis

Stuart J. Forbes1 and Malcolm R. Alison2

1MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK

2Centre for Tumour Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, London, UK

Summary

In a healthy adult liver, the rate of cell turnover is very low. Following acute liver injury, restoration of parenchymal mass is achieved by proliferation of normally mitotically quiescent hepatocytes. However, chronic liver injury results in the loss of this proliferative capacity of the hepatocytes, as increasing numbers of cells become senescent. In this situation, there is activation of hepatic progenitor cells (HPCs) from within the intrahepatic biliary tree. These bipotential cells are capable of supplying biliary cells and hepatocytes. In animal models, there is some controversy regarding the relative contribution to parenchymal regeneration from these two compartments, but human studies are compatible with the suggestion that as the severity and chronicity of the liver injury increase, immature progenitor cells contribute more to regeneration than mature hepatocytes. We are now beginning to understand the molecular signals and niche requirements that govern their cell fate. Alongside the parenchymal regeneration in chronic liver injury, there is a stereotypical wound-healing response with activation of hepatic stellate cells (HSCs) into scar-forming myofibroblasts and deposition of collagen. This change in the extracellular matrix (ECM) affects the regenerative capacity of the liver, and excess scar tissue can impair liver regeneration from either hepatocytes or HPCs.