Table Of ContentPattern Recognition Series
Series editors:
Kevin O. Leslie and Mark R. Wick
Practical Breast Pathology
Kristen A. Atkins and Christina S. Kong
Practical Cytopathology
Andrew S. Field and Matthew A. Zarka
Practical Hepatic Pathology, 2nd Edition
Romil Saxena
Practical Orthopedic Pathology
Andrea T. Deyrup and Gene P. Siegal
Practical Pulmonary Pathology, 2nd Edition
Kevin O. Leslie and Mark R. Wick
Practical Renal Pathology
Donna J. Lager and Neil A. Abrahams
Practical Skin Pathology
James W. Patterson
Practical Soft Tissue Pathology
Jason L. Hornick
Practical Surgical Neuropathology
Arie Perry and Daniel J. Brat
Practical Hepatic Pathology
A Diagnostic Approach
Second Edition
Romil Saxena, MD, FRCPath
Professor of Pathology and Laboratory Medicine
Professor of Medicine, Division of Gastroenterology and Hepatology
Indiana University School of Medicine
Indianapolis, Indiana
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
PRACTICAL HEPATIC PATHOLOGY: A DIAGNOSTIC APPROACH,
SECOND EDITION ISBN: 978-0-323-42873-6
Copyright © 2018 by Elsevier, Inc. All rights reserved.
Chapter 23: Liver Injury Due to Drugs and Herbal Agents by David E. Kleiner is in the public domain.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechani-
cal, including photocopying, recording, or any information storage and retrieval system, without permission in
writing from the publisher. Details on how to seek permission, further information about the Publisher’s permis-
sions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright
Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher (other
than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
understanding, 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 information, 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 recommended 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.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liabil-
ity for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise,
or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
Previous edition copyrighted 2011.
Library of Congress Cataloging-in-Publication Data
Names: Saxena, Romil, editor.
Title: Practical hepatic pathology : a diagnostic approach / [edited by]
Romil Saxena.
Other titles: Pattern recognition series.
Description: Second edition. | Philadelphia, PA : Elsevier, [2018] |
Series:
Pattern recognition series | Includes bibliographical references and index.
Identifiers: LCCN 2016056540 | ISBN 9780323428736 (hardcover : alk. paper)
Subjects: | MESH: Liver Diseases—pathology | Liver Diseases—diagnosis |
Liver—pathology
Classification: LCC RC846.9 | NLM WI 700 | DDC 616.3/6207—dc23 LC record
available at https://lccn.loc.gov/2016056540
Content Strategist: Kayla Wolfe
Senior Content Development Specialist: Margaret Nelson
Publishing Services Manager: Patricia Tannian
Senior Project Manager: Claire Kramer
Design Direction: Amy Buxton
Printed in China.
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Dedicated to my mum
I wish I had appreciated you more
and understood you better
But I blew the chance
and now you are gone . . .
Contributors
Edson Abdalla, MD, PhD Kevin E. Bove, MD
Assistant Professor Professor
Departments of Infectious Disease and Gastroenterology Department of Pathology
Hospital das Clinicas University of Cincinnati College of Medicine
University of São Paulo School of Medicine Staff Pathologist
São Paulo, Brazil Department of Pathology
Cincinnati Children’s Hospital
Venancio Avancini Ferreira Alves, MD, PhD Cincinnati, Ohio
Professor
Department of Pathology Naga Chalasani, MD
University of São Paulo School of Medicine David W. Crabb Professor and Director
Director Division of Gastroenterology and Hepatology
CICAP–Anatomic Pathology Indiana University School of Medicine
Hospital Alemão Oswaldo Cruz Indianapolis, Indiana
São Paulo, Brazil
Luca Di Tommaso, MD, FIAC
Charles Paul Balabaud, MD Humanitas University
Professor, Service d’Hépatologie Gastroentérologie Biomedical Sciences and Humanitas Research Hospital Pathology
Hôpital Saint André Unit
University Victor Segalen Rozzano, Milan, Italy
Bordeaux, France
Maria Irma Seixas Duarte, MD, PhD
Pierre Bedossa, MD, PhD Professor of Pathology
Pathlogy Department Departamento de Patologia
Beaujon Hospital Faculdade de Medicina da Universidade de São Paulo
Paris, France São Paulo, Brazil
Paulette Bioulac-Sage, MD M. Isabel Fiel, MD, FAASLD
Professeur Emérite Professor of Pathology
Université de Bordeaux The Lillian and Henry M. Stratton-Hans Popper Department of
Bordeaux, France Pathology
Icahn School of Medicine at Mount Sinai
Mauro Borzio, MD New York, New York
Gastroenterology Unit
Azienda Ospedaliera di Melegnano Nora Frulio, MD
Vizzolo Predabissi, Milan, Italy Department of Diagnostic and Interventional Radiology
Saint André and Haut Levèque (Centre Magellan) University
Hospitals
Bordeaux, France
vii
Contributors
Marwan Ghabril, MD David E. Kleiner, MD, PhD
Associate Professor of Medicine Chief, Post-Mortem Section
Division of Gastroenterology and Hepatology Laboratory of Pathology
Department of Medicine National Cancer Institute
Indiana University School of Medicine Bethesda, Maryland
Indianapolis, Indiana
Paul Y. Kwo, MD
Annette S. H. Gouw, MD, PhD Professor of Medicine
Professor of Pathology Director of Hepatology
Department of Pathology and Medical Biology Stanford University School of Medicine
University Medical Center Groningen Palo Alto, California
University of Groningen
Groningen, The Netherlands Carolin Lackner, MD
Institute of Pathology
Christopher Griffith, MD Medical University of Graz
Assistant Professor of Clinical Medical and Molecular Genetics Graz, Austria
Division of Clinical and Biochemical Genetics
Indiana University School of Medicine Richard S. Mangus, MD, MS, FACS
Indianapolis, Indiana Associate Professor of Surgery
Surgical Director of Small Bowel and Multivisceral Transplantation
Maria Guido, MD, PhD Surgical Director of Pediatric Liver Transplantation
Associate Professor of Pathology Indiana University School of Medicine
Department of Medicine-Anatomic Pathology Unit Indianapolis, Indiana
University of Padova
Padova, Italy Rebecca A. Marks, MD
Staff Pathologist
Maha Guindi, MD Pathology and Laboratory Medicine
Director, Gastrointestinal and Liver Pathology Fellowship Program Richard L. Roudebush VA Hospital
Clinical Professor of Pathology Indianapolis, Indiana
Department of Pathology and Laboratory Medicine
Cedars Sinai Medical Center Evandro Sobroza de Mello, MD, PhD
Los Angeles, California Assistant Professor
Department of Pathology
Bryan E. Hainline, MD, PhD University of São Paulo School of Medicine
Director, Clinical and Biochemical Genetics Senior Pathologist
Medical and Molecular Genetics CICAP–Anatomic Pathology
Indiana University School of Medicine Hospital Alemão Oswaldo Cruz
Indianapolis, Indiana São Paolo, Brazil
Stefan G. Hübscher, MB ChB, FRCPath Raffaella A. Morotti, MD
Leith Professor and Professor of Hepatic Pathology Professor of Pathology
Institute of Immunology and Immunotherapy Department of Pathology
University of Birmingham Yale School of Medicine
Birmingham, United Kingdom New Haven, Connecticut
Prodromos Hytiroglou, MD Amaro Nunes Duarte Neto, MD, PhD
Professor Infectious Diseases and Pathologist Specialist
Department of Pathology Departamento de Patologia e Disciplina de Emergências Clínicas
Aristotle University Medical School Faculdade de Medicina da Universidade de São Paulo
Thessaloniki, Greece São Paulo, Brazil
Sanjay Kakar, MD Valérie Paradis, MD, PhD
Professor of Pathology Pathology Department
Chief, Gastrointestinal-Hepatobiliary Pathology Service Beaujon Hospital
Director, Gastrointestinal-Hepatobiliary Pathology Fellowship Paris, France
Program
University of California, San Francisco Young Nyun Park, MD, PhD
San Francisco, California Department of Pathology
Yonsei University College of Medicine
Seoul, South Korea
viii
Contributors
Alberto Quaglia, MD, PhD, FRCPath Arief Antonius Suriawinata, MD
Consultant Histopathologist and Honorary Reader Section Chief of Anatomic Pathology
Institute of Liver Studies Department of Pathology and Laboratory Medicine
King’s College Hospital Dartmouth-Hitchcock Medical Center
London, United Kingdom Lebanon, New Hampshire
Professor of Pathology and Laboratory Medicine
Massimo Roncalli, MD, PhD Geisel School of Medicine
Humanitas University Hanover, New Hampshire
Biomedical Sciences and Humanitas Research Hospital
Pathology Unit A. Joseph Tector, MD, PhD
Rozzano, Milan, Italy Professor of Surgery
Director, Xenotransplant Program
Natalia Rush, MD University of Alabama at Birmingham
Indiana University School of Medicine Birmingham, Alabama
Indianapolis, Indiana
Temel Tirkes, MD
Pierre Russo, MD Assistant Professor of Radiology
Professor of Pathology and Laboratory Medicine University of Indiana School of Medicine
University of Pennsylvania School of Medicine Indianapolis, Indiana
Director, Division of Anatomic Pathology
Children’s Hospital of Philadelphia Raj Vuppalanchi, MD
Philadelphia, Pennsylvania Associate Professor of Medicine
Division of Gastroenterology
Kumaresan Sandrasegaran, MD Department of Medicine
Associate Professor of Radiology Indiana University School of Medicine
Indiana University School of Medicine Indianapolis, Indiana
Indianapolis, Indiana
Kay Washington, MD, PhD
Angelo Sangiovanni, MD Professor of Pathology
Division of Gastroenterology and Hepatology Vanderbilt University Medical Center
Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico Nashville, Tennessee
University of Milan
Milan, Italy Matthew M. Yeh, MD, PhD
Professor of Pathology
Romil Saxena, MD, FRCPath Adjunct Professor of Medicine
Professor of Pathology and Laboratory Medicine Director, Gastrointestinal and Hepatic Pathology Program
Professor of Medicine, Division of Gastroenterology and Hepatology University of Washington School of Medicine
Indiana University School of Medicine Seattle, Washington
Indianpolis, Indiana
Lisa M. Yerian, MD
Amedeo Sciarra, MD Vice Chair, Staff Affairs, and Department of Anatomic Pathology
Department of Pathology Cleveland Clinic
Humanitas Clinical and Research Center Cleveland, Ohio
Humanitas University
Rozzano, Milan, Italy Arthur Zimmermann, MD
Professor of Medicine, Emeritus
Christine Sempoux, MD, PhD University of Bern
Professor of Pathology Bern, Switzerland
Service of Clinical Pathology
Lausanne University Hospital
Institute of Pathology
Lausanne, Switzerland
ix
Series Preface
It is often stated that anatomic pathologists that task. Because a panoply of patterns is dif-
come in two forms: “Gestalt”-based individu- ficult to approach mentally from a practical
als, who recognize visual scenes as a whole, perspective, we have asked our contributors to
matching them unconsciously with memorial- be complete and yet to discuss only principal
ized archives, and criterion-oriented people, interpretative images. Our goal is eventually to
who work through images systematically in provide a series of monographs that, in combi-
segments, tabulating the results—internally, nation with one another, will allow trainees and
mentally, and quickly—as they go along in practitioners in pathology to use salient mor-
examining a visual target. These approaches phologic patterns to reach with confidence final
can be equally effective, and they are probably diagnoses in all organ systems.
not as dissimilar as their descriptions would suggest. In reality, even As stated in the introduction to the PPPDA text, the evaluation of
“Gestaltists” subliminally examine details of an image, and if asked spe- dominant patterns is aided secondarily by the analysis of cellular com-
cifically about particular features of it, they are able to say whether one position and other distinctive findings. Therefore, within the context
characteristic or another is important diagnostically. of each pattern, editors have been asked to use such data to refer the
In accordance with these concepts, in 2004 we published a text- reader to appropriate specific chapters in their respective texts.
book entitled Practical Pulmonary Pathology: A Diagnostic Approach We have also stated previously that some overlap is expected
(PPPDA). That monograph was designed around a pattern-based between pathologic patterns in any given anatomic site; in addition,
method, wherein diseases of the lung were divided into six categories specific disease states may potentially manifest themselves with more
on the basis of their general image profiles. Using that technique, one than one pattern. At first, those facts may seem to militate against the
can successfully segregate pathologic conditions into diagnostically value of pattern-based interpretation; however, pragmatically they do
and clinically useful groupings. not. One often can narrow diagnostic possibilities to a few entities
The merits of such a procedure have been validated empirically by using the pattern method, and sometimes a single interpretation will
the enthusiastic feedback we have received from users of our book. In be obvious. Both outcomes are useful to clinical physicians caring for
addition, following the old adage that “imitation is the sincerest form a given patient.
of flattery,” since our book came out other publications and presenta- It is hoped that the expertise of our authors and editors, together
tions have appeared in our specialty with the same approach. with the high quality of morphologic images they present in this Else-
After publication of the PPPDA text, representatives at Elsevier, most vier series, will be beneficial to our reader-colleagues.
notably William Schmitt, were enthusiastic about building a series of
texts around pattern-based diagnosis in pathology. To this end, we have Kevin O. Leslie, MD
recruited a distinguished group of authors and editors to accomplish Mark R. Wick, MD
xi
Preface
Most organs have a limited repertoire of responses to injury, and recog- Liver diseases of childhood provide unique diagnostic challenges by
nition of these patterns forms the cornerstone of our daily practice of constantly raising the specter of those nebulous “metabolic diseases.”
surgical pathology. It is known that a “good eye” is the defining attribute Because not all metabolic diseases are common, not all childhood
of a good pathologist. However, the limited morphologic expression of diseases are metabolic in nature, and metabolic diseases may present
injury means that there is overlap of patterns and histopathologic find- in adults, this text adopts a pragmatic approach by discussing com-
ings among different diseases and that more than one pattern or feature mon childhood diseases in Chapter 5 and the most common metabolic
may exist at any given time. The “good eye,” therefore, does not simply diseases individually in Chapters 8 through 12. The remaining spec-
recognize a pattern or finding but seeks out the dominant pattern while trum of metabolic diseases is outlined as a pattern-based diagnostic
simultaneously ignoring distracting secondary features. This process is approach in Chapter 7, which is complemented by Chapter 6, which
best exemplified by the ubiquitous eosinophil, which receives a lot of details biochemical and genetic methodologies that assist in establish-
press in drug-induced hepatitis and allograft rejection, but which may ing the final diagnosis. With the same principle in mind, the most com-
be present in a wide variety of other conditions. The bright granules mon liver diseases (eg, inflammatory and biliary) are detailed in their
scream for attention and promise a peg to hang one’s hat on, but the own individual chapters.
astute eye looks past them if they are not pertinent to the underlying This book does not dwell on matters pathophysiologic beyond what
pattern. Once the primary pattern is identified, the roving (but still is necessary to enhance the understanding of liver disease. To this end,
“good”) eye next hunts for additional features that help to formulate metabolism of drugs and xenobiotics (Chapter 22) and the molecular
the final diagnosis. physiology of bile formation and secretion (Chapter 29A) are indis-
This seemingly effortless and intuitive approach, honed over years pensable to the appreciation of drug-induced liver injury (Chapter 23)
of training and experience, has been recapitulated in the present book, and diseases caused by mutations in genes that encode bile canalicular
as it is in every other volume of this series. The dominant patterns of transporters and enzymes involved in bilirubin metabolism (Chapter
injury recognized under low magnification are listed, followed by addi- 29B). Finally, because liver transplantation is performed almost ubiq-
tional findings that lead to the specific diagnosis. Detailed informa- uitously and biopsies from allografts are now routinely encountered in
tion on the diagnostic entity is found in the cross-referenced chapter, daily practice, this text includes a section detailing the clinical aspects
along with a discussion of differential diagnoses, which further guides (Chapter 37) and pathology (Chapter 38) of liver transplantation.
the pathologist down the right path. The chapters themselves are not This second edition includes a new section on evolving concepts to
intended to be encyclopedic in their approach but are rather oriented keep readers abreast of changing paradigms in the practice of hepatol-
toward those who want to learn enough about liver disease without ogy. The possibility of regression of fibrosis and its recognition (Chap-
reaching dizzying heights of scholarship. The text is further embel- ter 40) heralds a promising era in the fight against liver disease, typified
lished with ample tables, boxes, images, and an extensive virtual slide by the introduction of direct-acting antiviral agents against hepatitis
box to make this process as straightforward and rewarding as possible. C infection. Primary liver cell carcinomas that do not respect the con-
Section I of this text starts off with a chapter that presents the basic ventional dichotomy of hepatocellular or cholangiocytic differentiation
framework for microscopic examination of liver biopsies and elabo- but demonstrate biphenotypic differentiation instead (Chapter 39) are
rates on basic terms and elemental lesions. This is followed by Section increasingly encountered. Elucidation of their clinical characteristics
II, which comprises three outstanding chapters that provide an over- and prognosis requires, first and foremost, recognition and documen-
view of clinical features of liver diseases, interpretation of laboratory tation of these tumors in pathology reports. Finally, there is a strong
tests, and radiologic findings in liver diseases. Together, these two sec- movement within the clinical and pathology communities for thought-
tions aim to impart a solid foundation for understanding the essentials ful reconsideration of the term cirrhosis and its misleading connotation
of the practice of hepatopathology. of a uniform, homogenous, and irreversible disease (Chapter 41).
xiii
