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
Copyright © 2018 by Elsevier, Inc. All rights reserved.
Chapter 23: Liver Injury Due to Drugs and Herbal Agents by
ISBN: 978-0-323-42873-6
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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.
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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
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David E. Kleiner is in the public domain.
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 Assistant Professor
Departments of Infectious Disease and Gastroenterology
Hospital das Clinicas
University of São Paulo School of Medicine
São Paulo, Brazil
Venancio Avancini Ferreira Alves, MD, PhD Professor
Department of Pathology
University of São Paulo School of Medicine
Director
CICAP–Anatomic Pathology
Hospital Alemão Oswaldo Cruz
São Paulo, Brazil
Charles Paul Balabaud, MD
Professor, Service d’Hépatologie Gastroentérologie
Hôpital Saint André
University Victor Segalen Bordeaux, France
Pierre Bedossa, MD, PhD Pathlogy Department
Beaujon Hospital
Paris, France
Paulette Bioulac-Sage, MD Professeur Emérite
Université de Bordeaux
Bordeaux, France
Mauro Borzio, MD Gastroenterology Unit
Azienda Ospedaliera di Melegnano
Vizzolo Predabissi, Milan, Italy
Kevin E. Bove, MD Professor
Department of Pathology
University of Cincinnati College of Medicine Staff Pathologist
Department of Pathology
Cincinnati Children’s Hospital
Cincinnati, Ohio
Naga Chalasani, MD
David W. Crabb Professor and Director
Division of Gastroenterology and Hepatology
Indiana University School of Medicine
Indianapolis, Indiana
Luca Di Tommaso, MD, FIAC
Humanitas University
Biomedical Sciences and Humanitas Research Hospital Pathology Unit
Rozzano, Milan, Italy
Maria Irma Seixas Duarte, MD, PhD
Professor of Pathology
Departamento de Patologia
Faculdade de Medicina da Universidade de São Paulo
São Paulo, Brazil
M. Isabel Fiel, MD, FAASLD Professor of Pathology
The Lillian and Henry M. Stratton-Hans Popper Department of Pathology
Icahn School of Medicine at Mount Sinai
New York, New York
Nora Frulio, MD
Department of Diagnostic and Interventional Radiology
Saint André and Haut Levèque (Centre Magellan) University
Hospitals
Bordeaux, France
vii
Marwan Ghabril, MD
Associate Professor of Medicine
Division of Gastroenterology and Hepatology
Department of Medicine
Indiana University School of Medicine
Indianapolis, Indiana
Annette S. H. Gouw, MD, PhD
Professor of Pathology
Department of Pathology and Medical Biology
University Medical Center Groningen
University of Groningen
Groningen, The Netherlands
Christopher Griffith, MD
Assistant Professor of Clinical Medical and Molecular Genetics
Division of Clinical and Biochemical Genetics
Indiana University School of Medicine
Indianapolis, Indiana
Maria Guido, MD, PhD
Associate Professor of Pathology
Department of Medicine-Anatomic Pathology Unit
University of Padova
Padova, Italy
Maha Guindi, MD
Director, Gastrointestinal and Liver Pathology Fellowship Program
Clinical Professor of Pathology
Department of Pathology and Laboratory Medicine
Cedars Sinai Medical Center
Los Angeles, California
Bryan E. Hainline, MD, PhD
Director, Clinical and Biochemical Genetics
Medical and Molecular Genetics
Indiana University School of Medicine
Indianapolis, Indiana
Stefan G. Hübscher, MB ChB, FRCPath
Leith Professor and Professor of Hepatic Pathology
Institute of Immunology and Immunotherapy
University of Birmingham
Birmingham, United Kingdom
Prodromos Hytiroglou, MD
Professor
Department of Pathology
Aristotle University Medical School
Thessaloniki, Greece
Sanjay Kakar, MD
Professor of Pathology
Chief, Gastrointestinal-Hepatobiliary Pathology Service
Director, Gastrointestinal-Hepatobiliary Pathology Fellowship Program
University of California, San Francisco
San Francisco, California
David E. Kleiner, MD, PhD
Chief, Post-Mortem Section
Laboratory of Pathology
National Cancer Institute
Bethesda, Maryland
Paul Y. Kwo, MD
Professor of Medicine
Director of Hepatology
Stanford University School of Medicine
Palo Alto, California
Carolin Lackner, MD
Institute of Pathology
Medical University of Graz
Graz, Austria
Richard S. Mangus, MD, MS, FACS
Associate Professor of Surgery
Surgical Director of Small Bowel and Multivisceral Transplantation
Surgical Director of Pediatric Liver Transplantation
Indiana University School of Medicine
Indianapolis, Indiana
Rebecca A. Marks, MD
Staff Pathologist
Pathology and Laboratory Medicine
Richard L. Roudebush VA Hospital
Indianapolis, Indiana
Evandro Sobroza de Mello, MD, PhD
Assistant Professor
Department of Pathology
University of São Paulo School of Medicine
Senior Pathologist
CICAP–Anatomic Pathology
Hospital Alemão Oswaldo Cruz
São Paolo, Brazil
Raffaella A. Morotti, MD
Professor of Pathology
Department of Pathology
Yale School of Medicine
New Haven, Connecticut
Amaro Nunes Duarte Neto, MD, PhD
Infectious Diseases and Pathologist Specialist
Departamento de Patologia e Disciplina de Emergências Clínicas
Faculdade de Medicina da Universidade de São Paulo
São Paulo, Brazil
Valérie Paradis, MD, PhD
Pathology Department
Beaujon Hospital
Paris, France
Young Nyun Park, MD, PhD
Department of Pathology
Yonsei University College of Medicine
Seoul, South Korea
viii
Contributors
Alberto Quaglia, MD, PhD, FRCPath
Consultant Histopathologist and Honorary Reader
Institute of Liver Studies
King’s College Hospital
London, United Kingdom
Massimo Roncalli, MD, PhD
Humanitas University
Biomedical Sciences and Humanitas Research Hospital
Pathology Unit
Rozzano, Milan, Italy
Natalia Rush, MD
Indiana University School of Medicine
Indianapolis, Indiana
Pierre Russo, MD
Professor of Pathology and Laboratory Medicine
University of Pennsylvania School of Medicine
Director, Division of Anatomic Pathology
Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania
Kumaresan Sandrasegaran, MD
Associate Professor of Radiology
Indiana University School of Medicine
Indianapolis, Indiana
Angelo Sangiovanni, MD
Division of Gastroenterology and Hepatology
Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico
University of Milan
Milan, Italy
Romil Saxena, MD, FRCPath
Professor of Pathology and Laboratory Medicine
Professor of Medicine, Division of Gastroenterology and Hepatology
Indiana University School of Medicine
Indianpolis, Indiana
Amedeo Sciarra, MD
Department of Pathology
Humanitas Clinical and Research Center
Humanitas University
Rozzano, Milan, Italy
Christine Sempoux, MD, PhD
Professor of Pathology
Service of Clinical Pathology
Lausanne University Hospital
Institute of Pathology
Lausanne, Switzerland
Arief Antonius Suriawinata, MD
Section Chief of Anatomic Pathology
Department of Pathology and Laboratory Medicine
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire
Professor of Pathology and Laboratory Medicine
Geisel School of Medicine
Hanover, New Hampshire
A. Joseph Tector, MD, PhD
Professor of Surgery
Director, Xenotransplant Program
University of Alabama at Birmingham
Birmingham, Alabama
Temel Tirkes, MD
Assistant Professor of Radiology
University of Indiana School of Medicine
Indianapolis, Indiana
Raj Vuppalanchi, MD
Associate Professor of Medicine
Division of Gastroenterology
Department of Medicine
Indiana University School of Medicine
Indianapolis, Indiana
Kay Washington, MD, PhD
Professor of Pathology
Vanderbilt University Medical Center
Nashville, Tennessee
Matthew M. Yeh, MD, PhD
Professor of Pathology
Adjunct Professor of Medicine
Director, Gastrointestinal and Hepatic Pathology Program
University of Washington School of Medicine
Seattle, Washington
Lisa M. Yerian, MD
Vice Chair, Staff Affairs, and Department of Anatomic Pathology
Cleveland Clinic
Cleveland, Ohio
Arthur Zimmermann, MD
Professor of Medicine, Emeritus
University of Bern
Bern, Switzerland
Contributors ix
It is often stated that anatomic pathologists come in two forms: “Gestalt”-based individuals, who recognize visual scenes as a whole, matching them unconsciously with memorialized archives, and criterion-oriented people, who work through images systematically in segments, tabulating the results—internally, mentally, and quickly—as they go along in examining a visual target. These approaches can be equally effective, and they are probably not as dissimilar as their descriptions would suggest. In reality, even “Gestaltists” subliminally examine details of an image, and if asked specifically about particular features of it, they are able to say whether one characteristic or another is important diagnostically.
In accordance with these concepts, in 2004 we published a textbook entitled Practical Pulmonary Pathology: A Diagnostic Approach (PPPDA). That monograph was designed around a pattern-based method, wherein diseases of the lung were divided into six categories on the basis of their general image profiles. Using that technique, one can successfully segregate pathologic conditions into diagnostically and clinically useful groupings.
The merits of such a procedure have been validated empirically by the enthusiastic feedback we have received from users of our book. In addition, following the old adage that “imitation is the sincerest form of flattery,” since our book came out other publications and presentations have appeared in our specialty with the same approach.
After publication of the PPPDA text, representatives at Elsevier, most notably William Schmitt, were enthusiastic about building a series of texts around pattern-based diagnosis in pathology. To this end, we have recruited a distinguished group of authors and editors to accomplish
that task. Because a panoply of patterns is difficult to approach mentally from a practical perspective, we have asked our contributors to be complete and yet to discuss only principal interpretative images. Our goal is eventually to provide a series of monographs that, in combination with one another, will allow trainees and practitioners in pathology to use salient morphologic patterns to reach with confidence final diagnoses in all organ systems.
As stated in the introduction to the PPPDA text, the evaluation of dominant patterns is aided secondarily by the analysis of cellular composition and other distinctive findings. Therefore, within the context of each pattern, editors have been asked to use such data to refer the reader to appropriate specific chapters in their respective texts.
We have also stated previously that some overlap is expected between pathologic patterns in any given anatomic site; in addition, specific disease states may potentially manifest themselves with more than one pattern. At first, those facts may seem to militate against the value of pattern-based interpretation; however, pragmatically they do not. One often can narrow diagnostic possibilities to a few entities using the pattern method, and sometimes a single interpretation will be obvious. Both outcomes are useful to clinical physicians caring for a given patient.
It is hoped that the expertise of our authors and editors, together with the high quality of morphologic images they present in this Elsevier series, will be beneficial to our reader-colleagues.
Kevin O. Leslie, MD
Mark R. Wick, MD
xi
Series Preface
Most organs have a limited repertoire of responses to injury, and recognition of these patterns forms the cornerstone of our daily practice of surgical pathology. It is known that a “good eye” is the defining attribute of a good pathologist. However, the limited morphologic expression of injury means that there is overlap of patterns and histopathologic findings among different diseases and that more than one pattern or feature may exist at any given time. The “good eye,” therefore, does not simply recognize a pattern or finding but seeks out the dominant pattern while simultaneously ignoring distracting secondary features. This process is best exemplified by the ubiquitous eosinophil, which receives a lot of press in drug-induced hepatitis and allograft rejection, but which may be present in a wide variety of other conditions. The bright granules scream for attention and promise a peg to hang one’s hat on, but the astute eye looks past them if they are not pertinent to the underlying pattern. Once the primary pattern is identified, the roving (but still “good”) eye next hunts for additional features that help to formulate the final diagnosis.
This seemingly effortless and intuitive approach, honed over years of training and experience, has been recapitulated in the present book, as it is in every other volume of this series. The dominant patterns of injury recognized under low magnification are listed, followed by additional findings that lead to the specific diagnosis. Detailed information on the diagnostic entity is found in the cross-referenced chapter, along with a discussion of differential diagnoses, which further guides the pathologist down the right path. The chapters themselves are not intended to be encyclopedic in their approach but are rather oriented toward those who want to learn enough about liver disease without reaching dizzying heights of scholarship. The text is further embellished with ample tables, boxes, images, and an extensive virtual slide box to make this process as straightforward and rewarding as possible.
Section I of this text starts off with a chapter that presents the basic framework for microscopic examination of liver biopsies and elaborates on basic terms and elemental lesions. This is followed by Section II, which comprises three outstanding chapters that provide an overview of clinical features of liver diseases, interpretation of laboratory tests, and radiologic findings in liver diseases. Together, these two sections aim to impart a solid foundation for understanding the essentials of the practice of hepatopathology.
Liver diseases of childhood provide unique diagnostic challenges by constantly raising the specter of those nebulous “metabolic diseases.” Because not all metabolic diseases are common, not all childhood diseases are metabolic in nature, and metabolic diseases may present in adults, this text adopts a pragmatic approach by discussing common childhood diseases in Chapter 5 and the most common metabolic diseases individually in Chapters 8 through 12. The remaining spectrum of metabolic diseases is outlined as a pattern-based diagnostic approach in Chapter 7, which is complemented by Chapter 6, which details biochemical and genetic methodologies that assist in establishing the final diagnosis. With the same principle in mind, the most common liver diseases (eg, inflammatory and biliary) are detailed in their own individual chapters.
This book does not dwell on matters pathophysiologic beyond what is necessary to enhance the understanding of liver disease. To this end, metabolism of drugs and xenobiotics (Chapter 22) and the molecular physiology of bile formation and secretion (Chapter 29A) are indispensable to the appreciation of drug-induced liver injury (Chapter 23) and diseases caused by mutations in genes that encode bile canalicular transporters and enzymes involved in bilirubin metabolism (Chapter 29B). Finally, because liver transplantation is performed almost ubiquitously and biopsies from allografts are now routinely encountered in daily practice, this text includes a section detailing the clinical aspects (Chapter 37) and pathology (Chapter 38) of liver transplantation.
This second edition includes a new section on evolving concepts to keep readers abreast of changing paradigms in the practice of hepatology. The possibility of regression of fibrosis and its recognition (Chapter 40) heralds a promising era in the fight against liver disease, typified by the introduction of direct-acting antiviral agents against hepatitis C infection. Primary liver cell carcinomas that do not respect the conventional dichotomy of hepatocellular or cholangiocytic differentiation but demonstrate biphenotypic differentiation instead (Chapter 39) are increasingly encountered. Elucidation of their clinical characteristics and prognosis requires, first and foremost, recognition and documentation of these tumors in pathology reports. Finally, there is a strong movement within the clinical and pathology communities for thoughtful reconsideration of the term cirrhosis and its misleading connotation of a uniform, homogenous, and irreversible disease (Chapter 41).
xiii
Preface
Preface
As with the first edition, I hope that the style and organization of this volume, along with its text, images, and a comprehensive virtual slide box, will assist in unmasking the hepatophile who might be surreptitiously lurking among the readers. For the staunch hepatophobes, however, the aim is to assist in establishing, with minimum distress, an accurate diagnosis of liver biopsies that may surreptitiously creep
under their microscopes. In these twin goals, I hope we have achieved some measure of success.
Romil Saxena, MD, FRCPath Indiana University School of Medicine
Indianapolis
xiv
Pattern-Based Approach to Diagnosis
Morphologic patterns of liver injury can be reasonably divided into seven categories. Although not essential in every case, the following algorithm aids in identifying the dominant pattern,
especially in challenging or tricky cases, because it systematically examines architecture, portal tracts, and lobular parenchyma, in that order.
PATTERN
PATTERN 4
(The bubbly liver)
PATTERN 5 Near-normal appearance (Calm but not quiet)
PATTERN 6
PATTERN
The differential diagnoses for each of the patterns in the preceding algorithm are detailed in individual tables on the subsequent pages. These tables are practical rather than being rigorously academic, and they approach liver diseases from all plausible morphologic perspectives to aid the reader in formulating the correct diagnosis. Some examples follow:
l A biopsy from a hepatocellular adenoma (Pattern 7) consisting of benign hepatocytes may be mistaken on casual examination for near-normal liver (Pattern 5), unless one notices the lack of portal structures by first assessing architecture. However, the tables are
so constructed that should one fail to notice the absence of portal tracts and end up along the path of near-normal liver (Pattern 5), the table for this pattern will still lead the reader to the correct diagnosis because it lists hepatocellular adenoma as a diagnostic consideration.
l The pathognomonic ductal plate remnants of congenital hepatic fibrosis do not strictly represent a ductular reaction but effectively mimic it. It is therefore not difficult for the uninitiated eye to perceive them as a form of ductular reaction, and thus congenital hepatic fibrosis is listed in the table of “ductular reaction.”
xix
Normal lobular architecture (uniformly distributed portal tracts and central veins) No No Yes Yes Yes Portal tracts expanded Cellular infiltrates PATTERN 1 Portal cellular infiltrates (The blue portal tract)
2 Ductular reaction
PATTERN
(The bilious portal tract)
3 Lobular injury (The distressed lobule)
Steatosis
Fibrosis
(The scarred liver)
7 Mass lesion (A pushy kind of guy) Ductular reaction Lobular injury Steatosis Near-normal appearance Fibrosis Mass lesion No No No No Yes Yes Yes Yes Yes Yes Romil Saxena, MD, FRCPath
l Similarly, because bridging necrosis can sometimes be mistaken for bridging fibrous septa, it is listed in Pattern 6 (fibrosis) in addition to Pattern 1.
l Fibrotic tumors are listed in tables for both patterns, namely “fibrosis” and “tumors.”
l Although fibrosis is the final consequence of several chronic disease processes, it may be the most prominent finding in a liver biopsy and is therefore included as an independent pattern. The pattern of the underlying disease may or may not always be discernible.
The tables are further constructed to facilitate evaluation of biopsy specimens (a major objective of this text) in which changes can be notoriously patchy or nonrepresentative. Thus:
l Focal nodular hyperplasia finds mention in several tables because the visualized pattern depends on the area of the lesion that is sampled by the biopsy needle. The tables account for these natural variations in morphology and lead the reader to the correct diagnosis irrespective of the area that is actually sampled.
l The pathognomonic features of certain diseases, such as the granulomatous cholangiodestructive lesion of primary biliary cholangitis (PBC) or the occluded central veins of sinusoidal obstruction syndrome/veno-occlusive disease, may be very focal and not always present in a biopsy sample. However, a biopsy sample from a patient with PBC may show other features, such as lymphocytic cholangitis, ductular reaction, or bile duct loss, that are highly suggestive of the diagnosis. Therefore PBC is listed as a diagnostic consideration under all these features.
Finally, some diseases receive mention in several tables because they inherently display divergent patterns of injury. Thus:
l Injury due to Wilson disease may appear as chronic hepatitis (pattern of “portal cellular infiltrates”), appear as steatohepatitis (pattern of “steatosis”), or show minimal change (pattern of “nearnormal appearance”).
l Alpha-1 antitrypsin deficiency may demonstrate chronic hepatitis (pattern of “portal cellular infiltrates”), ductular reaction (pattern of “ductular reaction”), or steatosis (pattern of “steatosis”).
While using the tables, there are a few important points to keep in mind:
l More than one disease pattern may be present in a biopsy; in such cases, it is best to identify and work with the dominant pattern. For instance, a mild degree of ductular reaction may be seen in severely active chronic viral hepatitis along with the dominant pattern of portal cellular infiltrates. Similarly, a mild portal infiltrate may accompany a dominant pattern of lobular injury, and, conversely, mild lobular injury may accompany a dominant pattern of portal cellular infiltrates.
l Although there are diseases common to both children and adults, and to the native and transplanted liver, others are specific to children (eg, biliary atresia) or the allograft (eg, rejection). Information about age and transplantation aids the diagnostic process.
l Diagnostic accuracy will be maximized when the tables are used in conjunction with the cross-referenced chapters because the latter highlight close differential diagnoses as well as atypical features and uncommon clinical situations. In addition, as in all disciplines of surgical pathology, diagnoses should be rendered in the appropriate clinical context.
l Liver injury due to drugs and herbals may mimic almost any known liver disease; therefore drug-induced liver injury remains a differential diagnostic consideration in almost every case. Although establishing causal relationships and excluding competing causes of injury form an important part of the diagnostic algorithm (see Chapter 23), a good histologic clue of drug-induced liver injury is a pattern of injury that does not fit into known patterns or that which shows overlapping patterns.
Pattern-Based Approach to Diagnosis xx
Pattern Diseases to Be Considered
Portal cellular infiltrates (The blue portal tract)
Viral hepatitis
Hepatotropic viruses
Nonhepatotropic viruses
Recurrent or de novo viral hepatitides, post-transplantation
Nonviral infections
Neonatal hepatitis
Recurrent or de novo autoimmune hepatitis
Recurrent primary biliary cholangitis
Sarcoidosis
Ductular reaction (The bilious portal tract)
Lobular injury (The distressed lobule)
Biliary tract obstruction
Biliary stricture
Biliary atresia
Neonatal hepatitis
Alagille syndrome (early)
Alpha-1 antitrypsin deficiency
Cystic fibrosis
Recurrent primary biliary cholangitis
Sarcoidosis
Primary sclerosing cholangitis
Secondary sclerosing cholangitis
Recurrent sclerosing cholangitis
Ischemic cholangiopathy
Acute viral hepatitis
Nonviral infections
Autoimmune hepatitis
Wilson disease
Alpha-1 antitrypsin deficiency
Neonatal hepatitis
Tyrosinemia
Hereditary fructose intolerance
Galactosemia
Citrin deficiency
Zellweger syndrome
Glycogen storage diseases
Urea cycle defects
Lysosomal storage diseases
Cholesterol ester storage disease
Mitochondriopathies
Progressive familial intrahepatic cholestasis, 1 and 2
Bile acid synthetic defects
Reye syndrome, postviral
Steatosis (The bubbly liver)
Alcoholic steatohepatitis
Nonalcoholic steatohepatitis
Alcoholic foamy degeneration
Reye syndrome, postviral
Fatty acid oxidation defects
Acute fatty liver of pregnancy
Malnutrition
Cystic fibrosis
Wilson disease
Alpha-1 antitrypsin deficiency
Mitochondriopathies
Urea cycle defects
Niemann-Pick disease
Glycogen storage disease I, III, and VI
Wilson disease
Alpha-1 antitrypsin deficiency
Tyrosinemia
Cellular rejection
Idiopathic chronic hepatitis, post-transplantation
Drug-induced liver injury
Extramedullary hemopoiesis
Lymphoma/leukemia
Post-transplant lymphoproliferative disease
Recurrent biliary disease, post-transplantation
Fibrosing cholestatic hepatitis B and C
Progressive familial intrahepatic cholestasis, 2 and 3
Alcoholic steatohepatitis
Budd-Chiari syndrome
Systemic infections, sepsis
Ascending cholangitis
Total parenteral nutrition
Drug-induced liver injury
Mimics
Congenital hepatic fibrosis
Caroli disease
Focal nodular hyperplasia
Diabetes mellitus
Hemophagocytic lymphohistiocytosis
Malignant infiltration
Preservation–reperfusion injury
Late cellular rejection (central perivenulitis)
Ischemic injury
Drug-induced injury
Alcoholic steatohepatitis
Nonalcoholic steatohepatitis
Genetic hemochromatosis
Secondary hemosiderosis
Perinatal/neonatal hemochromatosis
Chronic passive congestion
Budd-Chiari syndrome
Veno-occlusive disease/sinusoidal obstruction syndrome
Sickle cell disease
Graft-versus-host disease
Chronic rejection
Hereditary fructose intolerance
Tyrosinemia
Galactosemia
Lysosomal storage disorders
Cholesterol ester disease
Citrin deficiency
Drug-induced liver injury
Mass lesions with steatosis
Focal steatosis
Focal nodular hyperplasia
Hepatocellular adenoma
Dysplastic nodule
Hepatocellular carcinoma
Pattern-Based Approach to Diagnosis xxi
Pattern Diseases to Be Considered
Near-normal appearance (Calm but not quiet)
Gaucher disease
Niemann Pick disease, type C
Glycogen storage diseases
Diabetes mellitus
Wilson disease
Reye syndrome, postviral
Urea cycle defects
Lysosomal storage diseases
Cholesterol ester storage disease
Amyloidosis
Light chain disease
Dubin-Johnson syndrome
Malaria
Schistosomiasis
Leishmaniasis
Toxoplasmosis
Human immunodeficiency virus infection
Sinusoidal malignant infiltration
Cholestasis of pregnancy
Cholestasis due to systemic infections
Paraneoplastic cholestasis
Benign recurrent intrahepatic cholestasis
Fibrosis (The scarred liver)
Chronic viral hepatitis
Autoimmune hepatitis
Alcoholic steatohepatitis
Nonalcoholic steatohepatitis
Genetic hemochromatosis
Secondary hemosiderosis
Perinatal/ neonatal hemochromatosis
Primary biliary cholangitis
Sarcoidosis
Primary sclerosing cholangitis
Secondary sclerosing cholangitis
Ischemic cholangiopathy
Biliary strictures, long-standing
Biliary atresia
Alagille syndrome
Glycogen storage disorders I, III, IV, and VI
Alpha-1 antitrypsin deficiency
Cystic fibrosis
Wilson disease
Indian childhood cirrhosis
Tyrosinemia
Citrin deficiency
Hereditary fructose intolerance
Galactosemia
Gaucher disease
Progressive familial intrahepatic cholestasis 1
Alagille syndrome
Idiopathic adulthood ductopenia
Alpha-1 antitrypsin deficiency
Congestive heart failure
Budd-Chiari syndrome
Veno-occlusive disease
Sickle cell disease
Resolving hepatitis
Regressing cirrhosis
Compression from adjacent mass lesion
Nodular regenerative hyperplasia
Phenylketonuria
Cystinosis
Urea cycle defects
Aminoacidopathies
Preservation–reperfusion injury
Hepatocellular nodules
Large regenerative nodule
Low-grade dysplastic nodule
Hepatocellular adenoma
Very well-differentiated (early) hepatocellular carcinoma
Niemann-Pick disease
Progressive familial intrahepatic cholestasis, 2 and 3
Progressive familial intrahepatic cholestasis 1 (late)
Zellweger syndrome
Polycystic liver disease
Congenital hepatic fibrosis
Caroli disease
Budd-Chiari syndrome
Congestive heart failure
Hereditary hemorrhagic telangiectasia
Congestive syphilis
Leishmaniasis
Schistosomiasis
Tumors with fibrosis
Fibrolamellar carcinoma
Sclerosing hepatocellular carcinoma
Bile duct adenoma
Biliary hamartoma
Cholangiocarcinoma
Biphenotypic primary liver carcinoma (hepatocholangiocarcinoma)
Epithelioid hemangioendothelioma
Sclerosing cavernous hemangioma
Focal nodular hyperplasia
Metastatic carcinoma
Mimic: Bridging necrosis/multiacinar collapse
xxii
Pattern-Based Approach to Diagnosis
Pattern Diseases to Be Considered
Mass lesion (A pushy kind of guy)
Hepatocellular lesions
Focal nodular hyperplasia
Hepatocellular adenoma
Large regenerative nodule
Dysplastic nodule
Hepatocellular carcinoma
Fibrolamellar carcinoma
Hepatoblastoma
Transitional liver cell tumor
Gland-forming lesions
Bile duct adenoma
Biliary hamartoma
Cholangiocarcinoma
Mixed hepatocellular–glandular lesions
Hepatoblastoma
Nested stromal epithelial tumors
Mixed hepatobiliary carcinoma
Mesenchymal lesions
Mesenchymal hamartoma
Undifferentiated embryonal sarcoma
Hepatobiliary rhabdomyosarcoma
Infantile hemangioendothelioma
Cavernous hemangioma
Epithelioid hemangioendothelioma
Angiosarcoma
Angioleiomyoma
Inflammatory/myofibroblastic tumor
Miscellaneous mesenchymal tumors
Cystic lesions
Solitary (nonparasitic) bile duct cyst
Ciliated hepatic foregut cyst
Polycystic liver disease
Mucinous cystic neoplasm
Intraductal papillary neoplasm
Pyogenic abscess
Parasitic abscess
Hydatid cyst
Hematopoietic lesions
Langerhans cell histiocytosis
Lymphoma
Hodgkin disease
Metastases
Pattern-Based Approach to Diagnosis xxiii
Pattern 1 Portal Cellular Infiltrates (“The Blue Portal Tract”)
Elements of the pattern: The hallmark of this pattern is expansion of portal tracts by a cellular infiltrate, which thus appear “blue.” The portal inflammation may be accompanied by varying degrees of lobular inflammation and hepatocyte damage (eSlide P.1).
Pattern-Based Approach to Diagnosis xxiv
Additional Findings
Mature lymphocytes ± lymphoid aggregates
Mild azonal steatosis, biliary duct epithelial damage
Severe interface and/or lobular activity
Bridging necrosis/multiacinar collapse
Diagnostic Considerations
Hepatitis C
Recurrent or de novo hepatitis C, post-transplantation
Autoimmune hepatitis
Recurrent or de novo autoimmune hepatitis, post-transplantation
Viral hepatitis with immunocompromise
Drug-induced injury
Autoimmune hepatitis
Recurrent or de novo autoimmune hepatitis, post-transplantation
Hepatitis B with superinfection or coinfection of hepatitis D virus
Viral hepatitis with immunocompromise
Acute flare of hepatitis C
Wilson disease
Drug-induced injury (alone or superimposed on viral hepatitis)
Chapter:Page
Ch. 15:225
Ch. 38:645, 654
Ch. 21:310
Ch. 38:648, 653
Ch. 17: 251
Ch. 23:331
Ch. 21:311
Ch. 38:648, 653
Ch. 13:198
Ch. 17:251
Ch. 13:192
Ch. 8:128
Ch. 23:331
Ground-glass cells/inclusions
Morula cells
Focal lesions (in few or some portal tracts), damaged bile ducts ± bile duct loss
Lymphocytic cholangitis (lymphocytes within bile ducts) ± duct damage
Hepatitis B
Recurrent or de novo hepatitis B, post-transplantation
Drug-induced injury
Hepatitis D infection
Primary biliary cholangitis
Recurrent primary biliary cholangitis
Primary biliary cholangitis
Recurrent biliary cholangitis
Autoimmune hepatitis
Recurrent or de novo autoimmune hepatitis, post-transplantation
Hepatitis C
Recurrent or de novo hepatitis C, post-transplantation
Drug-induced injury
Concentric periductal inflammation, focal lesions (in few or some portal tracts)
Punched out areas of necrosis ± nuclear inclusions
Eosinophilic nuclear inclusions
Hepatocytes with many glycogenated nuclei, nuclear pleomorphism, binucleation, mild steatosis
Intracytoplasmic globules in periportal hepatocytes
Marked cholestasis, pseudoacinar change of hepatocytes, pericellular fibrosis
Severe cholestasis, giant cells
Steatosis ± microgranular (red granular) hepatocytes
Primary sclerosing cholangitis
Recurrent sclerosing cholangitis
Secondary sclerosing cholangitis
Adenovirus hepatitis
Herpesvirus hepatitis
Cytomegalovirus hepatitis
Wilson disease
Alpha-1 antitrypsin deficiency
Tyrosinemia
Neonatal hepatitis
Mitochondriopathies
Ch. 14:213
Ch. 38:647, 654
Ch. 14:219;
Ch. 23:363
Ch. 13:198
Ch. 26:410
Ch. 38:649
Ch. 26:410
Ch. 38:649
Ch. 21:311
Ch. 38:645, 654
Ch. 15:225
Ch. 38:645, 654
Ch. 23:353
Ch. 27:425
Ch. 38:650
Ch. 27:430
Ch. 13:202; Ch. 38:658
Ch. 13:202
Ch. 13:200; Ch. 38:657
Ch. 8:127
Ch. 9:136
Ch. 6:92; Ch. 7:120
Ch. 5:77
Ch. 6:98; Ch. 7:106; Ch. 17:259
Table continues on following page.
Pattern-Based Approach to Diagnosis xxv
Pattern 1 Portal Cellular Infiltrates (“The Blue Portal Tract”)
Additional Findings
Mature lymphocytes ± lymphoid aggregates—cont.
Sinusoidal lymphoid infiltrate
Plasma cell predominant
None of the preceding specific patterns
Diagnostic Considerations
Hepatitis C
Recurrent or de novo hepatitis C
Epstein-Barr virus hepatitis
Visceral leishmania
Leukemia/lymphoma
Drug-induced injury
Hepatitis B
Recurrent or de novo hepatitis B, post-transplantation
Hepatitis C
Mononuclear cells (lymphocytes, plasma cells) with eosinophils
eosinophils
Focal lesions (in few or some portal tracts), damaged bile ducts ± bile duct loss
Severe interface and/or lobular activity
Chapter:Page
Ch. 15:225 Ch. 38:643, 654 Ch. 13:199; Ch. 38:658 Ch. 17:249; Ch. 18:272 Ch. 36:592
23:353
Ch. 14:213 Ch. 38:647, 654
Ch. 15:225
Recurrent or de novo hepatitis C, post-transplantation Ch. 38:643, 654
Autoimmune hepatitis
Ch. 21:310
Recurrent autoimmune hepatitis Ch. 38:648
Primary biliary cholangitis
Recurrent primary biliary cholangitis
Wilson disease
Human herpesvirus 6
Sclerosing cholangitis in children
Drug-induced hepatitis
Late cellular rejection
Idiopathic chronic hepatitis, post-transplantation
Celiac disease
Rheumatoid diseases
Primary biliary cholangitis
Recurrent primary biliary cholangitis
Autoimmune hepatitis
Recurrent or de novo autoimmune hepatitis Drug-induced injury
Ch. 26:410
Ch. 38:650
Ch. 8:127
Ch. 13:201; Ch. 38:657
Ch. 5:71
Ch. 23:331
Ch. 38:638
Ch. 38:654
Ch. 3:49; Ch. 21:314
Ch. 3:48
Ch. 26:412
Ch. 38:649
Autoimmune hepatitis
Recurrent or de novo autoimmune hepatitis
Primary biliary cholangitis
Recurrent primary biliary cholangitis
Drug-induced hepatitis
Immature myeloid and/or erythroid precursors Extramedullary hemopoiesis
Pattern-Based Approach to Diagnosis xxvi Pattern
Portal
(“The Blue Portal
Cont.
1
Cellular Infiltrates
Tract”)—
Ch.
Ch.
Ch.
Ch.
No specific
Hepatitis A Ch. 13:197 Autoimmune hepatitis Ch. 21:310
hepatitis Ch. 38:648,
Plasma
Ch. 38:653
Ch.
21:310
38:648, 653
23:331, 352
pattern
Recurrent or de novo autoimmune
653
cell hepatitis
Drug-induced hepatitis
23:331, 352
Ch.
Ch.
Ch.
Ch.
Ch.
Ch.
Hodgkin
Ch.
21:310
38:648, 653
26:410
38:649
23:331 Mixed infiltrate mononuclear,
± neutrophils Endotheliitis, bile duct damage Acute cellular rejection
38:634 Large atypical cells
disease
36:593
Ch. 1:16
Hodgkin
Ch.
Ch.
None of the preceding findings Drug-induced hepatitis
disease Indeterminate rejection
23:331 Ch. 36:593
38:634
Continued
Predominantly eosinophils Parasitic infections Ch. 18:275
Pattern-Based Approach to Diagnosis xxvii
Focal lesions (in
± bile
loss Primary biliary cholangitis Recurrent primary biliary cholangitis Ch. 26:410 Ch. 38:650 Large fibrosing granulomas Sarcoidosis Ch. 20:302 Necrosis, no fibrosis Infections Ch. 19:291 Numerous eosinophils Parasites Drug-induced injury Ch. 18:275; Ch. 19:295 Ch. 23:353 Mixed inflammatory infiltrate, large atypical cells Hodgkin disease Ch. 19:298; Ch. 36:593 None of the preceding findings Infections Hodgkin disease Drug-induced hepatitis Idiopathic Ch. 19:290 Ch. 36:592 Ch. 23:275 Ch. 19:298 Atypical lymphoid cells Lymphoma/leukemia Epstein-Barr virus hepatitis Post-transplant lymphoproliferative disease Ch. 36:592 Ch. 13:199; Ch. 38:658 Ch. 38:655
Additional Findings Diagnostic Considerations Chapter:Page Granulomas
few or some portal tracts), damaged bile ducts
duct
Pattern 2 Ductular Reaction (“The Bilious Portal Tract”)
Elements of the pattern: The hallmark of this pattern is expansion of portal tracts by a ductular reaction composed of variable degrees of edema, fibrosis, bile ductular proliferation, and an inflammatory infiltrate that is composed mainly of neutrophils and/or lymphocytes. Visible cholestasis may or may not be present (eSlide P.2).
Pattern-Based Approach to Diagnosis xxviii
Pattern 2 Ductular Reaction (“The Bilious Portal Tract”)
Pattern-Based Approach to Diagnosis xxix Additional Findings Diagnostic Considerations Chapter:Page Edema ± bile plugs ± cholestasis, no fibrosis Biliary atresia Ch. 5:72 Biliary stricture Ch. 27:429; Ch. 38:658 Systemic infections, sepsis Ch. 1:26; Ch. 3: 49; Ch. 18:266 Neutrophils within bile duct epithelium and lumen Ascending cholangitis Ch. 18:266 Liver fluke infestation, fascioliasis Ch. 18:281 Liver fluke infestation, clonorchiasis Ch. 18:282 Ascariasis Ch. 18:275 Ductular cholestasis Sepsis Ch. 1:26; Ch. 18:266 Concentric periductal inflammation, concentric periductal fibrosis Primary sclerosing cholangitis Recurrent sclerosing cholangitis Secondary sclerosing cholangitis Ischemic cholangiopathy Ch. 27:425 Ch. 38:650 Ch. 27:430 Ch. 38:658 Large bile duct casts, parasites Recurrent pyogenic cholangitis Ch. 18:282; Ch. 27:429 Periductal granulomas Primary biliary cholangitis Ch. 26:410 Recurrent primary biliary cholangitis Ch. 38:649 Sarcoidosis Ch. 20:302 Drug-induced injury Ch. 23:353 Large fibrosing granulomas Sarcoidosis Ch. 20:302 Lymphocytic cholangitis Primary biliary cholangitis Ch. 26:410 Recurrent primary biliary cholangitis Ch. 38:649 Drug-induced injury Ch. 23:353 Loss of bile ducts Alagille syndrome 5:4 Ch. 5:70 Alpha-1 antitrypsin deficiency Ch. 9:136 Primary biliary cholangitis Ch. 26:410; Ch. 38:435 Recurrent primary biliary cholangitis Ch. 28:439; Ch. 38:649 Primary sclerosing cholangitis Ch. 27:425; Ch. 28:436 Recurrent sclerosing cholangitis Ch. 28:429; Ch. 38:650 Secondary sclerosing cholangitis Ch. 27:430; Ch. 38:436 Ischemic cholangitis Ch. 28:440; Ch. 38:655 Drug-induced injury Ch. 23:336 Sarcoidosis Ch. 20:302; Ch. 28:437 Minimal ductular reaction, marked cholestasis, degenerative/senescent biliary epithelial changes Chronic rejection Ch. 38:638 Graft-versus-host disease Ch. 28:439 Ballooning change, numerous Mallory hyalin ± steatosis Alcoholic steatohepatitis Ch. 24:376
Table continues on following page.
Pattern-Based Approach to Diagnosis xxx Additional Findings Diagnostic Considerations Chapter:Page Intracytoplasmic globules Alpha-1 antitrypsin deficiency Ch. 9:136 Inspissated pink or orange material in bile ducts/ductules Cystic fibrosis Ch. 10:145 Lobular inflammation and injury (cholestatic hepatitis) Drug-induced injury Ch. 23:353 Hepatitis A Ch. 13:197 Hepatitis E Ch. 13:197 Ballooned hepatocytes, cholestasis, perisinusoidal fibrosis Fibrosing cholestatic hepatitis B Ch. 38:648 Fibrosing cholestatic hepatitis C Ch. 38:645 Multinucleated hepatocytes (giant cells) Neonatal hepatitis Ch. 5:77 Biliary atresia Ch. 5:72 Bile acid synthetic defects Ch. 7:106; Ch. 29B:460 Progressive familial intrahepatic cholestasis 2 Ch. 29B:456 Ductal structures with open lumina ± bile plugs ± fibrosis Congenital hepatic fibrosis Ch. 25:397 Ductal plate malformation Ch. 25:394 Dilated ducts with ductal plate malformation Caroli disease Ch. 25:399 Centrilobular dilatation and congestion Budd-Chiari syndrome Ch. 30:468 Compression from adjacent mass lesion Ch. 3:43; Ch. 30:467 Fibrous septa with irregularly thickened vessels Focal nodular hyperplasia Ch. 32:512 Pattern
Ductular
Continued
2
Reaction (“The Bilious Portal Tract”)—Cont.
Pattern-Based Approach to Diagnosis xxxi
Findings
Considerations Chapter:Page
additional findings Biliary atresia Ch. 5:72 Biliary stricture Ch. 27:429; Ch. 38:655 Systemic infections, sepsis Ch. 1:26; Ch. 3:49; Ch. 18:266 Progressive familial intrahepatic cholestasis 3 Ch. 29B:497 Alagille syndrome Ch. 5:80 Drug-induced injury Ch. 23:353 Primary sclerosing cholangitis Ch. 27:425 Secondary sclerosing cholangitis Ch. 27:430 Recurrent sclerosing cholangitis Ch. 38:650 Human immunodeficiency virus cholangiopathy Ch. 17:250 Primary biliary cholangitis Ch. 26:410 Recurrent primary biliary cholangitis Ch. 38:649 Acute humoral rejection Ch. 38:635 Total parenteral nutrition Ch. 3:50 Budd-Chiari syndrome Ch. 30:468 Nonspecific change Ch. 1:26
Additional
Diagnostic
No
Pattern 3 Lobular Injury (“The Distressed Lobule”)
Elements of the pattern: The hallmark of this pattern is lobular injury, which is as prominent as (if not more so) any accompanying portal tract changes. Lobular injury is variably manifested as inflammation, hepatocyte damage, hepatocyte necrosis, congestion, cholestasis, and regeneration. When present, the accompanying portal changes consist of variable degrees and combinations of ductular reaction with or without bile duct damage (eSlide P.3).
Pattern-Based Approach to Diagnosis xxxii
Additional Findings
Lobular disarray, ballooned hepatocytes, apoptotic bodies
Ground-glass cells/inclusions
Diagnostic Considerations
Acute viral hepatitis
Drug-induced injury
Recurrent or de novo acute hepatitis C, post-transplantation
Recurrent or de novo acute hepatitis B, post-transplantation
Hepatitis B
Glycogen storage disease, type IV
Lafora disease
Post liver or bone marrow transplantation
Total parenteral nutrition
Alcohol-related liver disease
Drug-induced injury
Multinucleated hepatocytes (giant cells) Neonatal hepatitis
Biliary atresia
Alagille syndrome
Alpha-1 antitrypsin deficiency
Progressive familial intrahepatic cholestasis 2
Bile acid synthetic defects
Zellweger syndrome
Autoimmune hepatitis
Multinucleated hepatocytes (giant cells), hemosiderin deposition, cell damage/necrosis
Enlarged, pale hepatocytes
Dyscohesive hepatocytes
Microgranular (red granular) hepatocytes
Ballooned hepatocytes, cholestasis, no inflammation
Perinatal/neonatal hemochromatosis
Tyrosinemia
Glycogen storage disease
Reye syndrome, postviral
Urea cycle defects
Diabetes mellitus
Lysosomal storage diseases
Cholesterol ester storage disease
Drug-induced injury
Leptospirosis
Human immunodeficiency virus mitochondriopathy
Chapter:Page
Ch. 5:77
Ch. 5:72
Ch. 5:80
Ch. 9:136
Ch. 29B:456
Ch. 7:116; Ch. 29B:460
Ch. 6:93; Ch. 7:120
Ch. 21:312
Ch. 5:77; Ch. 7:122; Ch. 29B:460
Ch. 6:92; Ch. 7:120
Ch. 6:92; Ch. 7:115
Ch. 7:108
Ch. 7:108
Ch. 3:49
Ch. 7:111
Ch. 7:112
Ch. 23:363
18:268
Mitochondriopathies Ch. 17:259
Fibrosing cholestatic hepatitis B
Fibrosing cholestatic hepatitis C
Ch. 6:98; Ch. 7:106
Ch. 38:648
Ch. 38:645
Table continues on following page.
Pattern-Based Approach to Diagnosis xxxiii
Pattern 3 Lobular Injury (“The Distressed Lobule”)
Ch.
Ch.
Ch. 13:192 Ch. 23:351
38:643, 654
38:647, 654
Ch.
3:50 Ch. 24:381 Ch. 14:219; Ch. 23:363 Morula cells Hepatitis D virus Ch. 13:198 Punched out necrosis ± nuclear inclusions Adenovirus hepatitis Herpesvirus hepatitis Ch. 13:202; Ch. 38:658 Ch. 13:202 Neutrophilic microabscesses Cholangitis Syphilis Cytomegalovirus hepatitis Ch. 18:266 Ch. 18:268 Ch. 13:200; Ch. 38:657
Ch. 19:295 Granulomas Infections Sarcoidosis Drug-induced injury Idiopathic Ch. 18:267; Ch. 19:289 Ch. 20:302 Ch. 23:353 Ch. 19:298
Ch. 14:214, 219 Ch. 6:94; Ch. 7:115 Ch. 7:116
7:116 Ch.
Eosinophilic abscess/infiltrate Visceral larva migrans Capillariasis Strongyloidosis Other parasitic infections Ch. 18:276 Ch. 18:277 Ch. 18:277 Ch. 18:275;
Ch.
Additional Findings
Ballooned hepatocytes, neutrophils, Mallory hyalin
Centrilobular ballooned hepatocytes ± cholestasis
Pseudoacinar change of hepatocytes
Deposition of hemosiderin
Perivenular inflammation, endotheliitis, necrosis
Centrilobular sinusoidal dilatation, congestion
Diagnostic Considerations
Alcoholic hepatitis
Nonalcoholic steatohepatitis
Drug-induced injury
Preservation–reperfusion injury
Tyrosinemia
Citrin deficiency
Galactosemia
Hereditary fructose intolerance
Biliary atresia
Neonatal hepatitis
Genetic hemochromatosis
Secondary hemosiderosis
Wilson disease
Tyrosinemia
Perinatal/neonatal hemochromatosis
Recurrent autoimmune hepatitis
Recurrent primary biliary cholangitis
Late cellular rejection (central perivenulitis)
Congestive heart failure
Budd-Chiari syndrome
Veno-occlusive disease/sinusoidal obstruction syndrome
Sickle cell disease
Drug-induced injury
Compression from adjacent mass lesion
Occluded central veins
Centrilobular sinusoidal dilatation, congestion + ductular reaction
Centrilobular necrosis without inflammation
Midzonal necrosis without inflammation
Hemorrhagic necrosis
Bridging necrosis; multiacinar collapse
Erythrophagocytosis
Veno-occlusive disease/sinusoidal obstruction syndrome
Drug-induced injury
Compression from adjacent mass lesion
Budd-Chiari syndrome
Vascular ischemia
Chronic rejection
Drug-induced injury (eg, acetaminophen)
Yellow fever virus
Viral hemorrhagic fevers
Toxemia of pregnancy
Hyperacute humoral rejection
Portal hyperperfusion syndrome
Autoimmune hepatitis
Recurrent or de novo autoimmune hepatitis
Hepatitis B with superinfection or coinfection of hepatitis D virus
Viral hepatitis with immunocompromise
Acute flare of hepatitis C
Drug-induced injury (alone or superimposed on viral hepatitis)
Wilson disease
Leptospirosis
Rickettsial infections
Hemophagocytic lymphohistiocytosis
Chapter:Page
Ch. 24:376
Ch. 12:172
Ch. 23:357
Ch. 38:633
Ch. 7:120
Ch. 7:110
Ch. 7:110
Ch. 6:98; Ch. 7:111
Ch. 5:72
Ch. 5:77
Ch. 11:156
Ch. 11:158
Ch. 8:127
Ch. 7:120
Ch. 5:77; Ch. 7:122; Ch. 29B:460
Ch. 38:648
Ch. 38:649
Ch. 38:642
Ch. 30:469
Ch. 30:468
Ch. 30:472
Ch. 30:473
Ch. 23:361
Ch. 3:43; Ch. 30:467
Ch. 30:472
Ch. 23:361
Ch. 3:43; Ch. 30:467
Ch. 30:468
Ch. 30:479; Ch. 38:655
Ch. 38:638
Ch. 1:23; Ch. 23:353
Ch. 13:204
Ch. 13:203
Ch. 30:474
Ch. 38:635
Ch. 38:636
Ch. 21:312
Ch. 38:648, 653
Ch. 13:198
Ch. 17:251
Ch. 13:198
Ch. 23:331
Ch. 8:128
Ch. 18:269
Ch. 18:270
Ch. 1:18;
Ch. 17:249;
Ch. 30:467
Pattern-Based Approach to Diagnosis xxxiv
Lobular Injury (“The Distressed Lobule”)—Cont.
Pattern 3
Continued
Additional Findings
Prominent Kupffer cells with particulate material
Prominent Kupffer cells with storage material
Diagnostic Considerations
Malaria
Leishmaniasis
Human immunodeficiency virus infection
Hemophagocytic lymphohistiocytosis
Niemann-Pick disease, type C
Farber disease
Gaucher disease
Cholesterol ester storage disease
Sinusoidal infiltrate of lymphoid cells
Hepatitis C
Recurrent hepatitis C, post-transplantation
Epstein-Barr virus hepatitis
Visceral leishmaniasis
Leukemia/lymphoma
Drug-induced injury
Sinusoidal infiltrate by nonlymphoid cells
Bland cholestasis (no inflammation or ductular reaction)
Cholestasis with loss of intrahepatic bile ducts
Metastatic carcinoma (eg, breast carcinoma, melanoma)
Angiosarcoma
Epithelioid hemangioendothelioma
Drug-induced injury
Paraneoplastic cholestasis
Preservation–reperfusion injury
Progressive familial intrahepatic cholestasis 1
Benign recurrent intrahepatic cholestasis
Cholestasis of pregnancy
Systemic infections, sepsis
Alagille syndrome
Alpha-1 antitrypsin deficiency
Idiopathic adulthood ductopenia
Drug-induced injury
Graft-versus-host disease
Chronic rejection
Cholestasis with degenerative/senescent biliary epithelial changes
Pink amorphous material in sinusoids, around vessels, or in nerves
Chronic rejection
Graft-versus-host disease
Amyloidosis
Light chain deposition disease
Chapter:Page
Ch. 18:274
Ch. 17:249; Ch. 18:272
Ch. 17:248
Ch. 1:18; Ch. 17:249; Ch. 30:467
Ch. 6:95; Ch. 7:112
Ch. 7:112
Ch. 6:92; Ch. 7:112
Ch. 7:112
Ch. 15:225
Ch. 38:643
Ch. 13:199
Ch. 17:249; Ch. 18:272
Ch. 36:592
Ch. 23:353
Ch. 36:597
Ch. 36:587
Ch. 36:585
Ch. 23:353
Ch. 3:51
Ch. 38:633
Ch. 29B:456
Ch. 29B:460
Ch. 29B:461
Ch. 1:26:
Ch. 3:49;
Ch. 18:266
Ch. 5:80
Ch. 9:138
Ch. 28:138
Ch. 23:356
Ch. 28:439
Ch. 38:638
Ch. 38:638
Ch. 28:439
Ch. 30:480
Ch. 30:481
Pattern-Based Approach to Diagnosis xxxv
Pattern 4 Steatosis (“The Bubbly Liver”)
Elements of the pattern: The hallmark of this pattern is lipid accumulation (steatosis) in hepatocytes. The lipid appears as clear vacuoles that may be macrovesicular, microvesicular, or mixed in size. Steatosis may or may not be accompanied by ballooning change, Mallory hyaline, portal inflammation, lobular inflammation, and fibrosis (eSlide P.4).
Pattern-Based Approach to Diagnosis xxxvi
Additional Findings
Exclusively microvesicular steatosis
Ballooned hepatocytes, Mallory hyalin ± neutrophils
Nuclear pleomorphism, binucleated cells, glycogenated nuclei
Enlarged, pale hepatocytes
Microgranular (red granular) hepatocytes
Pseudoacinar change of hepatocytes
Intracytoplasmic globules in periportal hepatocytes
Cholestasis with ductular reaction
Diagnostic Considerations
Reye syndrome, postviral
Acute fatty liver of pregnancy
Fatty acid oxidation defects
Niemann-Pick disease, types A and B
Alcoholic foamy degeneration
Drug-induced injury
Alcoholic steatohepatitis
Nonalcoholic steatohepatitis
Drug-induced injury
Wilson disease
Wilson disease
Methotrexate use
Reye syndrome, postviral
Glycogen storage disease, types I, III, and VI
Urea cycle defects
Lysosomal storage diseases
Cholesterol ester storage disease
Diabetes mellitus
Drug-induced injury
Mitochondriopathies
Human immunodeficiency virus mitochondriopathy
Citrin deficiency
Hereditary fructose intolerance
Galactosemia
Alpha-1 antitrypsin deficiency
Total parenteral nutrition
Inspissated pink or orange material in bile ducts/ductules Cystic fibrosis
No portal tracts
Irregularly distributed portal tracts, portal tracts far apart
Focal lesion
Fibrous septa with abnormal, thickened vessels
Pericellular fibrosis
Macrovesicular or mixed steatosis without any of the preceding additional findings
Hepatocellular adenoma
Focal nodular hyperplasia
Dysplastic nodule
Hepatocellular carcinoma
Large regenerative nodule
Low-grade dysplastic nodule
Early hepatocellular carcinoma
Focal nodular hyperplasia
Focal steatosis
Focal nodular hyperplasia
Nonalcoholic steatohepatitis
Alcoholic steatohepatitis
Wilson disease
Citrin deficiency
Hereditary fructose intolerance
Galactosemia
Malnutrition
Alcohol use
Nonalcoholic fatty liver disease
Diabetes mellitus
Cystic fibrosis
Urea cycle defects
Lysosomal storage diseases
Cholesterol ester storage disease
Mitochondriopathies
Citrin deficiency
Hereditary fructose intolerance 6:10, 7:11
Human immunodeficiency virus infection
Chapter:Page
Ch. 7:108
Ch. 7:106
Ch. 6:92; Ch. 7:105
Ch. 6:95; Ch. 7:112
Ch. 24:375
Ch. 23:357
Ch. 24:376
Ch. 12:172
Ch. 23:357
Ch. 8:127
Ch. 8:127
Ch. 23:358
Ch. 7:108
Ch. 6:92; Ch. 7:108
Ch. 6:93; Ch. 7:108
Ch. 6:92; Ch. 7:111
Ch. 7:112
Ch. 3:51
Ch. 23:364
Ch. 6:98; Ch. 7:106
Ch. 17:259
Ch. 6:93; Ch. 7:110
Ch. 6:98; Ch. 7:111
Ch. 7:110
Ch. 9:136
Ch. 3:52
Ch. 32:515
Ch. 32:510
Ch. 31:490
Ch. 33:532
Ch. 1:6
Ch. 31:490
Ch. 31:490
Ch. 32:510
Ch. 36:592
Ch. 32:510
Ch. 12:175
Ch. 24:379
Ch. 8:127
Ch. 6:93; Ch. 7:110
Ch. 6:98; Ch. 7:111
Ch. 7:110
Ch. 7:105; Ch. 12:181
Ch. 24:375
Ch. 12:170
Ch. 3:51
Ch. 10:145
Ch. 7:108
Ch. 6:92; Ch. 7:111
Ch. 7:112
Ch. 6:98; Ch. 7:106
Ch. 6:93; Ch. 7:110
Ch. 6:98; Ch. 7:111
Ch. 17:257
Pattern 4 Steatosis (“The Bubbly Liver”)
Preservation–reperfusion damage Ch.
Lipopeliosis
38:633
Ch. 10:145
xxxvii
Pattern 5 Near-Normal Appearance (“Calm but Not Quiet”)
Elements of the pattern: The hallmark of this pattern is absence of the most common features of liver disease, namely, inflammation, lobular injury, necrosis, steatosis, duct damage, ductular reaction, and fibrosis. Subtle changes are seen on closer examination at higher magnification (eSlide P.5).
Approach to Diagnosis xxxviii
Pattern-Based
Additional Findings
Glycogenated nuclei
Ground-glass cells/inclusions
Enlarged, pale hepatocytes
Pink amorphous material in sinusoids, around vessels or in nerves
Attenuated portal vein radicals, absence of portal veins
Deep brown/black pigment in hepatocytes
Black pigment in Kupffer cells and/or macrophages
Prominent Kupffer cells with particulate material
Prominent Kupffer cells with storage material
Sinusoidal infiltrate of lymphoid cells
Sinusoidal infiltrate by nonlymphoid cells
Diagnostic Considerations
Normal up to 15 years of age
Diabetes mellitus
Nonalcoholic fatty liver disease
Wilson disease
Hepatitis B
Glycogen storage disease, type IV
Lafora disease
Post-liver or bone marrow transplantation
Total parenteral nutrition
Chronic alcohol consumption
Adaptive change to medications
Diabetes mellitus
Glycogen storage diseases
Reye syndrome, postviral
Urea cycle defects
Lysosomal storage diseases
Cholesterol ester storage disease
Amyloidosis
Light chain deposition disease 30:17
Obliterative portal venopathy
Portal vein thrombosis
Schistosomiasis
Dubin-Johnson syndrome
Drug-induced injury
Malaria
Schistosomiasis
Thorotrast
Drug-induced injury
Malaria
Leishmaniasis
Human immunodeficiency virus infection
Gaucher disease
Niemann-Pick disease, type C
Farber disease
Cholesterol ester storage disease
Hepatitis C
Epstein-Barr virus hepatitis
Visceral leishmaniasis
Leukemia/lymphoma
Drug-induced injury
Metastatic carcinoma (eg, breast carcinoma, melanoma)
Angiosarcoma
Epithelioid hemangioendothelioma
Chapter:Page
Ch. 1:14
Ch. 3:51
Ch. 12:173
Ch. 8:127
Ch. 14:214, 219
Ch. 6:94, Ch. 7:115
Ch. 7:116
Ch. 7:116
Ch. 3:52
Ch. 24:381
Ch. 14:219; Ch. 23:363
Ch. 3:51
Ch. 6:94; Ch. 7:115
Ch. 7:108
Ch. 6:93; Ch. 7:108
Ch. 6:92; Ch. 7:111
Ch. 7:112
Ch. 30:480
Ch. 30:481
Ch. 30:477
Ch. 30:473
Ch. 18:278
Ch. 29B:462
Ch. 23:364
Ch. 18:274
Ch. 18:274
Ch. 23:364
Ch. 23:364
Ch. 18:274
Ch. 17:249; Ch. 18:272
Ch. 17:248
Ch. 6:92; Ch. 7:112
Ch. 6:95; Ch. 7:112
Ch. 7:112
Ch. 7:112
Ch. 15:225
Ch. 13:199
Ch. 17:249; Ch. 18:272
Ch. 36:592
Ch. 23:353
Ch. 36:597
Ch. 36:587
Ch. 36:585
Table continues on following page.
Pattern-Based Approach to Diagnosis xxxix
Pattern 5 Near-Normal Appearance (“Calm but Not Quiet”)
Additional Findings
Bland cholestasis (no inflammation or ductular reaction)
Cholestasis with loss of intrahepatic bile ducts
Diagnostic Considerations
Drug-induced injury
Cholestasis of pregnancy
Progressive familial intrahepatic cholestasis 1
Preservation–reperfusion injury
Systemic infections, sepsis
Benign recurrent intrahepatic cholestasis
Paraneoplastic cholestasis
Alagille syndrome
Idiopathic adulthood ductopenia
Drug-induced injury
Alpha-1 antitrypsin deficiency
Graft-versus-host disease
Chronic rejection
Cholestasis with degenerative/senescent biliary epithelial changes
Sinusoidal dilatation, congestion
Occluded central veins
Centrolobular sinusoidal dilatation, congestion + ductular reaction
Vaguely nodular architecture without fibrosis, alternate plate atrophy and hyperplasia
Eggs, parasites
Iron deposition
Scattered spotty necrosis, prominent Kupffer cells, mild portal inflammation
Scattered apoptosis, ballooned cells, glycogenated nuclei, mild inflammation, mild steatosis
Minimal ductular reaction, portal fibrosis
Scattered clusters of pigmented macrophages
Chronic rejection
Graft-versus-host disease
Congestive hepatopathy
Budd-Chiari syndrome
Veno-occlusive disease/sinusoidal obstruction syndrome
Sickle cell disease
Compression from adjacent mass lesion
Drug-induced injury
Veno-occlusive disease/sinusoidal obstruction syndrome
Drug-induced injury
Compression from an adjacent mass lesion
Hepatocellular adenoma, inflammatory type
Nodular regenerative hyperplasia
Parasitic infections
Normal in periportal hepatocytes of neonates
Genetic hemochromatosis
Secondary hemosiderosis
Nonspecific reactive hepatitis
Celiac disease
Rheumatoid disease
Systemic infection, sepsis
Wilson disease
Primary sclerosing cholangitis
Resolving hepatitis
Drug-induced injury
Chapter:Page
Ch. 23:353
Ch. 29B:461
Ch. 29B:456
Ch. 38:633
Ch. 1:26; Ch. 3:51; Ch. 18:266
Ch. 29B:460
Ch. 3:51
Ch. 5:80
Ch. 28:443
Ch. 23:356
Ch. 9:138
Ch. 28:439
Ch. 38:638
Ch. 38:638
Ch. 28:439
Ch. 30:469
Ch. 30:468
Ch. 30:472
Ch. 30:473
Ch. 30:467, 473
Ch. 23:361
Ch. 30:472
Ch. 23:361
Ch. 3:51; Ch. 30: 467
Ch. 32:518
Ch. 3:50; Ch. 23:362; Ch.30:479; Ch. 38:659
Ch. 18:275
Ch. 7:123
Ch. 11:156
Ch. 11:158
Ch. 3:50: Ch. 18:266
Ch. 3:50: Ch. 18:266
Ch. 3:50
Ch. 18:266
Ch. 8:127
Ch. 27:425
Ch. 1:18;
Ch. 13:193
Ch. 23:355
Pattern-Based Approach to Diagnosis xl
Near-Normal Appearance (“Calm but Not Quiet”) Cont.
Pattern 5
Continued
