Zakim and Boyer's Hepatology. A textbook of liver disease. Volume1

1463 Pages·188.619 MB·English

by  Boyer Thomas D., Wright T.L., Manns M.P.

An affiliate of Elsevier Inc.
© 2006, Elsevier Inc. All rights reserved.
First published 2006
First edition 1982
Second edition 1990
Third edition 1996
Fourth Edition 2003
No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form
or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior
permission of the Publishers. Permissions may be sought directly from Elsevier’s Health Sciences Rights
Department, 1600 John F. Kennedy Boulevard, Suite 1800, Philadelphia, PA 19103-2899, USA: phone:
([phone]; fax: [phone]; or, e-mail: [email protected]. You may also
complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting
‘Support and contact’ and then ‘Copyright and Permission’.
ISBN-13: 978-1-4160-3258-8
ISBN-10: 1-4160-3258-4
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
Library of Congress Cataloging in Publication Data
A catalog record for this book is available from the Library of Congress
Notice
Medical knowledge is constantly changing. Standard safety precautions must be followed, but as
new research and clinical experience broaden our knowledge, changes in treatment and drug therapy
may become necessary or appropriate. Readers are advised to check the most current product
information provided by the manufacturer of each drug to be administered to verify the
recommended dose, the method and duration of administration, and contraindications. It is the
responsibility of the practitioner, relying on experience and knowledge of the patient, to determine
dosages and the best treatment for each individual patient. Neither the Publisher nor the author
assume any liability for any injury and/or damage to persons or property arising from this
publication.
The Publisher
Printed in Canada
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Working together to grow
libraries in developing countries
www.elsevier.com | www.bookaid.org | www.sabre.org
To the memory of Ralph Wright, MA, MD, DPhil, FRCP.
A leading first generation hepatologist, clinical scientist, teacher
and father of one of the editors.
Contributors
Paul C Adams MD Heike Bantel MD Jordi Bruix MD
Professor of Medicine Department of Gastroenterology and Director
Department of Medicine Hepatology Liver Unit IMD
London Health Sciences Centre – University Hannover Medical School Hospital Clinic Provincial
Campus Hannover, Germany Catalonia, Spain
London, ON, Canada
Angeline Bartholomeusz MD
Kathleen M Campbell MD
Research and Molecular Development
Aijaz Ahmed MD Assistant Professor
Victorian Infectious Diseases Reference
Gastroenterology Fellow Division of Gastroenterology, Hepatology and
Laboratory
Hepatology Nutrition
North Melbourne, VIC, Australia
Stanford University Medical Center Cincinnati Children’s Hospital Medical
Palo Alto, CA, USA Center
Marina Berenguer MD
Cincinnati, OH, USA
Adjunct Professor
Karl E Anderson MD Department of Digestive Medicine
Professor of Preventive Medicine and Hospital Universitari La Fe Martin Caselitz MD
Community Health, Valencia, Spain Consultant
Department of Preventive Medicine and Medical Clinic II
Community Health Annika Bergquist MD PhD Klinikum Deggendorf
University of Texas Medical Branch Clinical Assistant Deggendorf, Germany
Galveston, TX, USA Department of Gastroenterology and
Hepatology John P Cello MD
Miguel R Arguedas MD MPH Karolinska University Hospital Professor of Medicine and Surgery
Assistant Professor Huddinge, Sweden Division of Gastroenterology, Hepatology and
Gastroenterology – School of Medicine Clinical Nutrition
Birmingham, AL, USA Henri Bismuth MD San Francisco General Hospital
Director San Francisco, CA, USA
Henri Bismuth Hepatobiliary Institute
Vicente Arroyo MD
Villejuif, France
Professor of Medicine, Director Institute for Naga Chalasani MD
Digestive Disease Associate Professor of Medicine
Herbert L Bonkovsky MD
Hospital Clinic i Provincial Division of Gastroenterology/ Hepatology
Director of Clinical Research, the Lowell P.
Universitat de Barcelona Indiana University School of Medicine
Weicker, Jr.
Barcelona, Spain Indianapolis, IN, USA
General Clinical Research Center, and the
Clinical Trials Unit
Veronica A Arteaga MD Professor of Medicine and Molecular, Microbial, Judy Chang BSc
Doctor of Medicine and Structural Biology Department of Microbiology and Immunology
Department of Surgery Farmington, CT, USA The University of Melbourne
Cedars-Sinai Medical Center Parkville, VIC, Australia
Los Angeles, CA; Thomas D Boyer MD
Clinical Researcher Director Linda J Chen MD
New England Hepatobiliary Disease Center Arizona Liver Institute Clinical Instructor
Dartmouth-Hitchcock Medical Center University of Arizona Division of Transplantation, Department of
Lebanon, NH, USA Tucson, AZ, USA Surgery
Stanford University School of Medicine
Rizwan Aslam MD ChB MRCP FRCR Ulrika Broomé MD PhD Stanford, CA, USA
Associate Professor of Medicine
Assistant Clinical Professor
Department of Gastroenterology and
Department of Radiology Xin Chen PhD
Hepatology
University of California, San Francisco Assistant Professor
Karolinska University Hospital
San Francisco, CA, USA Department of Biopharmaceutical Sciences
Huddinge, Sweden
University of California, San Francisco
Soon Koo Baik MD San Francisco, CA, USA
Robert S Brown MD MPH
Associate Professor of Medicine
Chief of Clinical Hepatology Medical Director
Department of Medicine Massimo Colombo MD
Center for
Yonsei University Wonju College of Medicine Professor of Gastroenterology and
Columbia University College of Physicians and
Wonju, Korea Endocrinology
Surgeons
Maggiore Hospital and University of Milan
New York, NY, USA
William F Balistreri MD Milan, Italy
Director Concepció Bru MD
Division of Paediatric Gastroenterology / Senior Consultant, Associate Professor of Diane W Cox PhD CCMG FRSC
Nutrition Radiology Professor and Chair
University of Cincinnati BCLC Group Department of Medical Genetics
Children’s Hospital Medical Centre Diagnosis Imaging Centre University of Alberta
Cincinatti, OH, USA Barcelona, Spain Edmonton, AB, Canada
ix
Contributors
Oscar W Cummings MD Scott L Friedman MD Mónica Guevara MD
Associate Professor of Pathology Professor of Medicine Associate Investigator
Department of Pathology and Laboratory Division of Liver Diseases Liver Unit
Medicine Mount Sinai School of Medicine Institute of Digestive Diseases
Indiana University School of Medicine New York, NY, USA Hospital Clinic Institut d’Investigacions
Indianapolis, IN, USA Biomediques (IDIBAPS)
Hans Fromm MD Barcelona, Spain
John T Cunningham MD Professor of Medicine;
Professor of Clinical Medicine Director Françoise Imbert-Bismut MD
Section of Gastroenterology and Hepatology Dartmouth-Hitchcock Hepatopancreaticobiliary Department of Biochemistry
University of Arizona School of Medicine Disease Center Hôpital de la Salpétrière
Tucson, AZ, USA Lebanon, NH, USA Paris, France
Sanjeev Gupta MD
Christopher P Day MD PhD FRCP
Paul J Gaglio MD Professor of Medicine and Pathology
Professor of Liver Medicine
Associate Clinical Professor of Medicine (in Departments of Medicine and Pathology
Department of Gastroenterology and
Surgery) Albert Einstein College of Medicine
Hepatology
Center for Liver Disease and Transplantation Bronx, NY, USA
The Medical School
Columbia University College of Physicians and
University of Newcastle upon Tyne
Surgeons Elizabeth J L Heathcote MD
Newcastle upon Tyne, UK
New York, NY, USA Professor of Medicine
Toronto Hospital (Western)
Laurie D DeLeve MD PhD
Guadalupe Garcia-Tsao MD Toronto, ON, Canada
Professor of Medicine
Professor of Medicine
Division of Gastrointestinal and Liver Diseases Kristel Hunt MD
Section of Digestive Diseases
University of Southern California Gastroenterology Fellow
Yale University School of Medicine
Keck School of Medicine Division of Liver Diseases
Yale, CT, USA
Los Angeles, CA, USA Mount Sinai School of Medicine
New York, NY, USA
R Brian Doctor PhD Fayez K Ghishan MD
Associate Professor Horace W. Steele Endowed Chair in Pediatric John Hunter MD
Division of Gastroenterology and Hepatology Research Professor and Chairman
Department of Medicine Professor and Head, Department of Department of Surgery, L223
University of Colorado Health Sciences Center Pediatrics Oregon Health Services University
Denver, CO, USA Director, Steele Memorial Children’s Research Portland, OR, USA
Center
Scott A Elisofon MD University of Arizona Health Sciences Hartmut W Jaeschke PhD
Advanced Hepatology Fellow Center Professor of Pharmacology
Division of Gastroenterology Tucson, AZ, USA Associate Director
Hunnewell Ground Liver Research Institute
Children’s Hospital Boston Kathleen M Giacomini PhD University of Arizona College of Medicine
Boston, MA, USA Professor and Chair Tucson, AZ, USA
Department of Biopharmaceutical Sciences
Eric Esrailian MD MPH University of California, San Francisco Peter L M Jansen MD
Clinical Instructor of Medicine San Francisco, CA, USA Professor of Medicine
Division of Digestive Diseases Liver Center
David Geffen School of Medicine at UCLA Division of Gastroenterology and Hepatology
Pere Ginés MD
Los Angeles, CA, USA Academic Medical Center
Associate Professor of Medicine
Amsterdam, The Netherlands
Liver Unit
Carlos O Esquivel MD PhD
Institute for Liver Research Birgir Johannsson MD
The Arnold and Barbara Silverman Professor of
Hospital Clinic i Provincial Infectious Disease Fellow
Pediatric Transplantation
Universitat de Barcelona Division of Infectious Diseases
Professor of Surgery and Chief, Division of
Barcelona, Spain The University of Iowa
Transplantation
Iowa City, IA, USA
Stanford University School of Medicine
Steven Goldschmid MD
Stanford, CA, USA
Associate Professor of Clinical Medicine Maureen M Jonas MD
Chief Associate Professor of Pediatrics
Gregory T Everson MD
Section of Gastroenterology and Division of Gastroenterology
Professor of Medicine; Director of Hepatology
Hepatology Harvard Medical School
University of Colorado School of Medicine and
University of Arizona School of Medicine Children’s Hospital
Health Sciences
Tucson, AZ, USA Boston, MA, USA
Denver, CO, USA
Dean P Jones PhD
Michael B Fallon MD Gregory J Gores MD Professor of Medicine
Associated Professor of Medicine Professor of Medicine Department of Biochemistry
Med – Gastroenterology Mayo Medical School Emory University
University of Alabama at Birmingham Rochester, MN, USA Atlanta, GA, USA
Birmingham, AL, USA
Albert K Groen PhD Emmet B Keeffe MD
Diana M Flynn MB Bch Associate Professor Professor of Medicine, Chief of Hepatology,
Consultant in Paediatric Gastroenterology Department of Medical Biochemistry Co-Director
John Radcliffe Hospital Academic Medical Center Stanford University Medical Center
Oxford, UK Amsterdam, The Netherlands Palo Alto, CA, USA
x
Contributors
Deirdre A Kelly MD FRCP FRCPI FRCPH Keith D Lindor MD Brent Neuschwander-Tetri MD
MB BA Professor of Medicine Professor of Internal Medicine
Professor of Paediatric Hepatology Division of Gastroenterology and Hepatology Division of Gastroenterology and Heptology
The Liver Unit Mayo Medical School, Clinic and Foundation Saint Louis University Liver Center
Birmingham Children’s Hospital Rochester, MN, USA St. Louis, MO, USA
Birmingham, UK
Josep M Llovet, MD Matthew Nichols MD
Percy A Knolle MD Senior Research Associate Fellow in Gastroenterology and Hepatology
Professor of Molecular Medicine and BCLC Group. Liver Unit, Digestive Disease University of Colorado Health Sciences Center
Immunology Institute Denver, CO, USA
Mount Sinai School of Medicine
Institute for Molecular Medicine and
Barcelona, Spain
Experimental Immunology David H Perlmutter MD
University of Bonn Professor Pediatrics/Cell Biology
Stephen Locarnini MD
Bonn, Germany Department of Pediatrics
Divisional Head
Washington University
Research & Molecular Development
Jina Krissat MD Victorian Infectious Diseases Reference Pittsburgh, PA, USA
Surgical Registrar Laboratory
Hepatobiliary and Pancreatic Surgery Unit North Melbourne, VIC, Australia Robert P Perrillo MD
The Royal London Hospital Director, Gastroenterology and Hepatology
London, UK Robert S McCuskey PhD Section of Gastroenterology and Hepatology
Professor and Head of Cell Biology and Ochsner Clinic Foundation
Manoj Kumar MD DM Anatomy; New Orleans, LA, USA
Senior Research Associate Professor of Physiology;
Department of Gastroenterology Professor of Pediatrics Thierry Poynard MD PhD
GB Pant Hospital Department of Cell Biology and Anatomy Professor of Medicine
New Delhi, India College of Medicine, University of Arizona Department of Hepato-Gastroenterology
Tucson, AZ, USA University of Paris VI
Paris, France
Douglas R LaBrecque MD Michael P Manns MD
Director, Liver Services Professor of Medicine
Jorge Rakela MD
Internal Medicine Liver Services Head, Department of Gastroenterology and
Professor of Medicine
University of Iowa Hospitals and Clinics Hepatology
Department of Internal Medicine
Iowa City, IA, USA Zentrum Innere Medizin and Dermatologie
Mayo Clinic
Medizinische Hochschule Hannover
Scottsdale, AZ, USA
Konstantinos Lazaridis MD Hannover, Germany
Assistant Professor of Medicine
Charles M Rice PhD
Center for Basic Research in Digestive Enrique J Martinez MD FACP
Maurice R and Corinne P Greenberg Professor;
Diseases Associate Professor of Clinical Medicine
Head, Laboratory of Virology and Infectious
Division of Gastroenterology and Hepatology Center for Liver Diseases
Disease;
Mayo Clinic College of Medicine University of Miami
Scientific and Executive Director
Rochester, MN, USA Miami, FL, USA
Center for the Study of Hepatitis C
Darius Moradpour MD The Rockefeller University
Samuel S Lee MD Associate Professor of Medicine New York Presbyterian Hospital
Professor of Medicine Division of Gastroenterology and Hepatology New York, NY, USA
Liver Unit
Centre Hospitalier Universitaire Vaudois
Department of Medicine
Lausanne, Switzerland Mario Rizzetto MD
University of Calgary
Professor of Gastroenterology
Calgary, AB, Canada Kevin D Mullen MB FRCPI Department of Gastroenterology
Professor of Medicine at University of Torino – Molinette
Jay H Lefkowitch MD Case Western Reserve University; Torino, Italy
Professor of Clinical Pathology Consultant of Gastroenterology
College of Surgeons and Physicians of Gastroenterology and Hepatology Division Eve A Roberts MD FRCPC
Columbia University MetroHealth Medical Center Professor of Paediatrics, Medicine and
New York, NY, USA Cleveland, OH, USA Pharmacology
Division of Gastroenterology, Hepatology and
Satheesh Nair MD
Riccardo Lencioni MD Nutrition
Medical Director of Liver Transplantation
Associate Professor of Radiology The Hospital for Sick Children
Ochsner Clinic Foundation
Department of Oncology, Transplants and Toronto, ON, Canada
New Orleans, LA, USA
Advanced Technologies in Medicine
Division of Diagnostic and Interventional Russell Nash MD Don C Rockey MD
Radiology Assistant Professor Chief, Division of Digestive and Liver Diseases;
University of Pisa Department of Pathology Professor of Medicine
Pisa, Italy University of Colorado Health Sciences Center University of Texas at Southwestern Medical
Denver, CO, USA Center
Sharon Lewin MD Dallas, TX, USA
Director, Infectious Diseases Unit; James Neuberger DM FRCP
Professor, Department of Medicine Consultant Physician, Professor of Medicine Juan Rodés MD
Monash University Liver Unit Professor of Medicine
The Alfred Hospital Queen Elizabeth Hospital Hospital Clinic
Melbourne, VIC, Australia Birmingham, UK Barcelona, Spain
xi
Contributors
Hector Rodriguez-Luna MD Maria H Sjogren MD MPH Dominique-Charles Valla MD
Associate Consultant Chief Professor of Hepatology, University of Paris 7
Division of Transplantation Medicine Department of Clinical Investigation Head, Federation Medico-Chirurgicale
Mayo Clinic Walter Reed Army Medical Center d’HepatoGastroentologie
Phoenix, AZ, USA Washington, DC, USA Hospital Beaujon
Paris, France
Jack T Stapleton MD
Sammy Saab MD MPH
Professor and Director Rebecca W Van Dyke MD
Associate Professor of Medicine and Surgery
Division of Infectious Diseases Professor of Medicine
Division of Digestive Diseases
The University of Iowa and Gastroenterology Division
David Geffen School of Medicine at UCLA
The Iowa City VA Medical Center University of Michigan School of Medicine
Los Angeles, CA, USA
Iowa City, IA, USA Ann Arbor, MI, USA
Arun J Sanyal MBBS MD Stephen F Stewart MBChB BSc PhD MRCP Hugo E Vargas MD
Charles Caravati Professor of Medicine Consultant Hepatologist Associate Professor of Medicine
Chairman: Division of Gastroenterology, Department of Gastroenterology and Mayo Clinic College of Medicine
Hepatology and Internal Medicine Hepatology Phoenix, AZ, USA
Medical College of Virginia School of Clinical Medical Sciences
Richmond, VA, USA The Medical School Siegfried Wagner MD
University of Newcastle upon Tyne Professor and Physician-in-Chief
Newcastle upon Tyne, UK Medical Clinic II
S K Sarin MD DM FNA FNASc
Klinikum Deggendorf
President, Asian Pacific Association Study of
Doris B Strader MD Deggendorf, Germany
Liver;
Associate Professor of Medicine
Adjunct Professor, Molecular Medicine, JNU;
Division of Gastroenterology/Hepatology Jack R Wands MD
Professor and Head
Fletcher Allen Health Care Jeffrey and Kimberly Greenberg-Artemis and
Department of Gastroenterology
Burlington, VT, USA Martha Joukowsky Professor in
GB Pant Hospital
Gastroenterology and the Professor of
New Delhi, India
Christian P Strassburg MD Medical Science
Assistant Professor in Experimental Brown University;
Thomas D Schiano MD Gastroenterology (Privatdozent) Director,
Associate Professor of Medicine; Department of Gastroenterology, Hepatology Division of Gastroenterology and the Liver
Medical Director, Adult Liver Transplantation; and Endocrinology Research Center
Director of Clinical Hepatology Hannover Medical School Rhode Island Hospital
Division of Liver Diseases Hannover, Germany Providence, RI, USA
Mount Sinai School of Medicine
New York, NY, USA R Todd Stravitz MD C Mel Wilcox MD
Associate Professor of Medicine Professor of Medicine
Leonard B Seeff MD Section of Hepatology Division of Gastroenterology and Hepatology
Senior Scientist for Hepatitis Research Virginia Commonwealth University University of Alabama at Birmingham
Liver Disease Research Branch Richmond, VA, USA Birmingham, AL, USA
National Institute of Diabetic
Digestive and Kidney Diseases (NIDDK) Yee-Li Sun MD Teresa L Wright MD
Bethesda, MD, USA Resident Staff Physician
Department of Radiology Veterans’ Affairs Medical Center
University of California, San Francisco San Francisco, CA, USA
Shobha Sharma MD
San Francisco, CA, USA
Assistant Professor of Pathology Judy Yee MD
Department of Pathology Jayant A Talwalkar MD MPH Associate Professor and Vice Chairman
Emory University Hospital Assistant Professor of Medicine Department of Radiology
Atlanta, GA, USA Mayo Clinic College of Medicine University of California, San Francisco;
Rochester, MN, USA Chief, Radiology Service
Steven I Shedlofsky MD Veterans’ Affairs Medical Center
Marcos Lins Andrade Professor Ruedi Thoeni MD San Francisco, CA, USA
Division of Digestive Diseases and Nutrition Chief
University of Kentucky GI Radiology Mahmoud M YousfiMD
Lexington, KY, USA University of California, San Francisco Assistant Professor of Medicine
San Francisco, CA, USA Department of Internal Medicine
Mayo Clinic
Oren Shibolet MD
Christian Trautwein MD Scottsdale, AZ, USA
Lecturer in Medicine
Professor of Medicine
The Liver Unit
Department of Gastroenterology, Hepatology
Hadassah University Hospital
and Endocrinology
Jerusalem, Israel
Zentrum Innere Medizin
Hannover, Germany
Daniel Shouval MD
Professor of Medicine; Daniel Tseng MD
Director, Liver Unit Minimally Invasive Surgery Fellow
Hadassah University Hospital Oregon Health and Science University
Jerusalem, Israel Portland, OR, USA
xii
Preface
The first edition of Hepatology appeared in 1982. The creation of cles and judge the quality of ‘reviews’. Hepatology and the figures
the book came from a desire of Drs Zakim and Boyer to write a will be available on the Elsevier web site in a searchable and down-
textbook on liver disease in which both pathophysiology and clini- loadable format to those who purchase the book.
cal material were presented in a manner that allowed the reader to This edition continues the tradition of changing authors and
understand current issues but, more importantly, to prepare the adding new chapters to cover areas not previously discussed in detail
reader for new developments in the discipline of hepatology. David in the previous edition. Fifty-one of the chapters have new or addi-
Zakim was the driving force behind the first edition and his expert- tional authors compared to the previous edition. We also have added
ise in understanding the basic science behind the clinical diseases 20 new chapters that cover subjects such as hepatotoxicity from
was critical to the success of the book. With his leadership Hepa- herbal preparations, pediatric viral hepatitis and pharmacogenomics
tologymet the goals set in the first and subsequent editions. David that were not in the previous edition. These new chapters reflect
Zakim has now retired from academic medicine and for this book our commitment to keeping Zakim and Boyer’sHepatologycurrent
to continue to be one of the leading books in the field of liver disease and providing the reader with the latest advancements in liver
it was essential that new editors be added. Drs Teresa Wright and disease as well as the influence of the new editors. Although we con-
Michael Manns are world leaders in hepatology with broad clinical tinue to have chapters on basic pathophysiology, we are focusing
expertise and outstanding research credentials. They continue the more and more on the clinical aspects of the discipline of hepatol-
tradition established by Dr Zakim that a textbook should help in ogy. This evolution of the past 25 years reflects the advances in the
understanding a patient’s disease by providing fundamental knowl- field and the increasing number of treatment options available to the
edge of the pathophysiology of the disease process. Thus, their addi- practicing physician for the management of hepatobiliary disorders.
tion as editors allows Zakim and Boyer’s Hepatologyto continue to Lastly, the presentation of the book has been enhanced by drawing
evolve in this fifth edition. many of the figures in color, making the tables more pleasing to the
With the advent of the electronic age and ready availability of eye and placing the color plates within the chapters rather than
summaries of published works there has been a move away from grouping them throughout the book. We believe these latter changes
reading source material and an increasing reliance on opinion arti- will make the book easier to use and more readable. The editors
cles frequently published with the support of the pharmaceutical hope that this book will be of help to modern hepatologists and
industry. These ‘reviews’ are brief and cover the essentials but lack gastroenterologists around the world, as well as to physicians of
depth. In this environment books such as Zakim and Boyer’s Hepa- other specialties and fellows in training, in order to increase their
tology play an increasingly important role. The authoritative chap- knowledge for the benefit of their patients.
ters in the book cover a subject in depth and give the reader both
the basic and clinical information they need to grasp the area of Thomas D. Boyer
interest. With a thorough understanding of an area gained by reading Teresa L. Wright
one or two chapters, the reader can then better understand new arti- Michael P. Manns
xiii
Acknowledgements
A book of this size involves numerous individuals in its creation. We equal importance during the production of Zakim and Boyer’s
are grateful to all of the contributors for their timely delivery of the Hepatology. Their work has lead to a book with a new and exciting
manuscripts and the excellence of the chapters that they have appearance, from the cover by illustrator Richard Tibbitts, to the
written. This book would never have been published without the tables, to the high quality color plates that are now distributed
professional staff at Elsevier. Karen Bowler has been instrumental in within the chapters. We realize that there are numerous other
the creation of this edition of Zakim and Boyer’s Hepatology. She people at Elsevier who have contributed to Zakim and Boyer’s
was there at the first meetings with the new editors and has been Hepatology and we are all grateful for their efforts as well.
there to solve problems and encourage all of us to make the best Lastly, we would like to thank our families who have supported
book possible. Claire Bonnett and Kathryn Mason have been of us during the genesis of this book.
xv
Section I: Pathophysiology of the Liver
1
ANATOMY OF THE LIVER
Robert S. McCuskey
Abbreviations
CGRP calcitonin gene-related peptide IgA immunoglobulin A NPY neuropeptide Y
Da daltons LAL liver-associated lymphocytes RER rough endoplasmic reticulum
DNA deoxyribonucleic acid LD low density SER smooth endoplasmic reticulum
GERL granules or secondary lysosomes LGL large granular lymphocytes SOM somatostatin
HD high density IL interleukin SP substance P
HMS hepatic microvascular subunits NK natural killer Tf transferrin
ICAM intercellular adhesion molecule nNOS neuronal nitric oxide VIP vasoactive intestinal peptide
Protein Synthesis
INTRODUCTION
Hepatocytes synthesize proteins for hepatic and non-hepatic use.
OVERVIEW OF THE STRUCTURE AND FUNCTION Proteins for hepatic use include a wide variety of liver-specific
enzymes that carry out the many synthetic and detoxifying func-
OF THE LIVER
tions of the liver. Proteins secreted by hepatocytes include all of
The liver is the largest organ in the body. In humans it is separated
the major plasma proteins except immunoglobulins (synthesized
incompletely into lobes, covered on their external surfaces by a thin
by plasma cells), e.g. albumin, transferrin, prothrombin, fibrinogen,
connective tissue capsule. The liver is composed of several cell types,
lipoproteins and complement proteins.
which interact with each other but are adapted to performing
specific functions. The principal cell type is the hepatic parenchymal
Glucose Homeostasis
cell, loosely referred to as the hepatocyte, which accounts for 60%
Hepatocytes help to maintain blood glucose levels. In response to
of the total cell population and 80% of the volume of the organ.
pancreatic islet hormones hepatocytes synthesize glycogen from
Hepatocytes are organized into plates or laminae that are intercon-
glucose or break down glycogen and release glucose (glycogenoly-
nected to form a continuous three-dimensional lattice (Figure 1-1).
sis); hepatocytes can also synthesize glucose from other sugars (e.g.
Between the plates of hepatocytes are spaces occupied by hepatic
fructose) and from amino acids (gluconeogenesis).
sinusoids, the large-bore fenestrated capillaries of the liver that
nourish each parenchymal cell on several sides (Figure 1-1). Metabolism of Drugs and Toxins
The sinusoidal space, and non-parenchymal cells associated with
Hepatocyte enzymes metabolize drugs and toxins delivered to the
sinusoids, comprises the majority of the remaining liver volume. The
liver from the gut via the portal circulation.
non-parenchymal cells include sinusoidal endothelial cells, perisinu-
The functions of the hepatic non-parenchymal cells are:
soidal stellate cells (fat-storing cells of Ito), and intraluminal Kupffer
cells. An interconnecting network of minute intercellular channels Kupffer Cells
form bile canaliculi, which course between adjacent hepatocytes
• Phagocytosis of bloodborne toxicants and particulates such as
(Figure 1-1A). These receive the bile secreted from hepatocytes and
bacteria from the circulation.
then drain through short bile ductules (cholangioles) partially lined
• Secretion of mediators (e.g. inflammatory mediators) that affect
by cuboidal epithelial cells to bile ducts.
the function of adjacent cells and cells in distant sites.
Hepatocytes carry out most of the functions generally associated
• Production of beneficial and toxic substances that contribute to
with the liver. They extract and process nutrients and other
host defense as well as liver injury.
materials from the blood, and they produce both exocrine and
endocrine secretions, as follows: Sinusoidal Endothelial Cells
These form a leaky barrier between the parenchymal cells and the
Bile Synthesis and Secretion
blood flowing in sinusoids. The endothelial cells are fenestrated and
Hepatocytes synthesize bile acids from cholesterol; these function act as a sieve to prevent red blood cells and other cellular compo-
in the lumen of the small intestine to emulsify fats. nents from interacting with hepatocytes, while allowing rapid access
Bilirubin, a toxic metabolite generated from the breakdown of to the other substances in the blood.
hemoglobin, is excreted by hepatocytes as follows. Insoluble biliru-
bin is produced as a byproduct of red blood cell breakdown in the Stellate Cells
spleen; it circulates in the blood complex to albumin, and is taken • Storage of vitamin A and other fat-soluble vitamins.
up from the blood hepatocytes, conjugated to a soluble form, then • Stellate cells when activated synthesize collagen, thus they are
secreted into bile canaliculi. important in the development of cirrhosis.
33