Atlas of Liver Pathology E-Book
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Description

The Atlas of Liver Pathology, by Drs. Gary C. Kanel and Jacob Korula, provides the visual guidance you need to accurately diagnose all forms of liver disease. Organized by disease type, it points out major histological features, updates disease parameters with new images and diagrams, and helps you understand the clinical aspects of each disease. This text provides quick and convenient reference to virtually all of the liver disorders commonly seen today. Nine-hundred-plus high-quality, full-color images capture the gross and histological presentation of liver pathology ideal for comparison to the specimens you encounter in practice.

  • Interpret liver specimens systematically by first considering the morphology, the differential diagnoses, and then the clinical features, including descriptions of the clinical and biologic behavior, treatment, and prognosis.

Quickly and easily retrieve the information you need using a templated format that includes concise, bulleted text and abundant tables.

  • Ensure accurate diagnoses with the help of 900+ full-color, high-quality images which capture the gross and histological presentation of liver pathology.
  • Keep up with the latest findings on newly recognized liver diseases as well as rare disorders such as Langerhans cell histiocytosis, Leishmaniasis, Niemann-Pick disease, Lymphangioma, Pheochromocytoma, Infection-associated (reactive) hemophagocytic syndrome, and glycogen storage diseases.
  • Find tables that cover rare diseases and disorders throughout the book.
  • Obtain assistance with liver biopsy interpretation through greatly expanded coverage including differential diagnostic tables in a new section of the book, increased images, and more.
  • Confidently recognize the major characteristics and distinguishing features of various diseases by examining the revised section on "Clinical and Biologic Behavior."

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Date de parution 29 novembre 2010
Nombre de lectures 1
EAN13 9781455706266
Langue English
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Atlas of Liver Pathology
Third Edition

Gary C. Kanel, M.D.
Professor of Clinical Pathology, Keck School of Medicine, University of Southern California
Associate Pathologist, Los Angeles County + USC Medical Center and USC University Hospital, Los Angeles, California

Jacob Korula, M.D.
Comprehensive Liver Disease Center, St. Vincent Medical Center, Los Angeles, California
Copyright © 2011, Elsevier Inc.
Saunders
Front Matter

Atlas of Liver Pathology
Third Edition
Gary C. Kanel, M.D.
Professor of Clinical Pathology, Keck School of Medicine, University of Southern California
Associate Pathologist, Los Angeles County + USC Medical Center and USC University Hospital, Los Angeles, California
Jacob Korula, M.D.
Comprehensive Liver Disease Center, St. Vincent Medical Center, Los Angeles, California
Copyright

1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
ATLAS OF LIVER PATHOLOGY THIRD EDITION ISBN: 978-1-4377-0765-6
Copyright © 2011, 2005, 1992 by Saunders, an imprint of Elsevier Inc.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, 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 permissions 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).

Notice
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 liability 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.
Library of Congress Cataloging-in-Publication Data
Kanel, Gary C.
Atlas of liver pathology/Gary C. Kanel, Jacob Korula. -- 3rd ed.
p.; cm.
Liver pathology
Includes bibliographical references and index.
ISBN 978-1-4377-0765-6 (hardcover: alk. paper)
1. Liver--Diseases--Atlases. I. Korula, Jacob. II. Title. III. Title:
Liver pathology.
[DNLM: 1. Liver Diseases--pathology--Atlases. 2. Biopsy--Atlases. 3. Diagnosis, Differential--Atlases. WI 17]
RC846.9.K35 2011
616.3’62--dc22
2010034856
Executive Publisher: William Schmitt
Senior Developmental Editor: Andrew Hall
Publishing Services Manager: Patricia Tannian
Senior Project Manager: Kristine Feeherty
Design Direction: Steven Stave
Printed in the United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Dedication
To our families who support us and our colleagues who teach us much
Preface
Although over a decade passed between the publication of the first and second editions of the Atlas of Liver Pathology, the rapid development in understanding the pathophysiologic concepts of diseases and identifying variations in morphologic features of these diseases necessitates a third edition over a much shorter time span.
The new diagnostic tools leading to more sophisticated laboratory testing have been a hallmark in learning the etiology and pathophysiology of diseases. Where before morphologic changes were ascribed to various liver disorders without a good understanding of their significance, the advent of new testing procedures such as genome sequencing much better helps us understand what we see under light microscopy. An excellent example is the ongoing research in liver tumors that examines cellular signaling pathways and molecular profiling, identifies individual genes and gene groups associated with higher instances of the development of hepatocellular carcinoma in cirrhotic livers, and correlates all of the above with the morphology seen in liver biopsy specimens.
The changes in the updated third edition include the use of gross images of various liver diseases with direct correlation with the light microscopy. In addition, the total number of images has increased by approximately 50% from the second edition. What has also been added is a second section addressing specific morphologic changes in table format and listing the various liver diseases associated with these changes. This section, which has been updated from our previous book, Liver Biopsy Evaluation, specifically aids the reader in arriving at diagnoses and differential possibilities solely on morphology, then referring the reader to the text and images of the specific diseases in the first part of the book.
We hope that this new edition will be successful in providing pathologists, clinicians, and students a better understanding of liver pathology and disease concepts and will be a useful practical tool. The overall aim does not change from the previous editions: to offer a concise illustrative text in liver and hepatobiliary pathology.

Gary Kanel, M.D.

Jacob Korula, M.D., Los Angeles, California
Table of Contents
Front Matter
Copyright
Dedication
Preface
Part I: Liver and Hepatobiliary Pathology with Clinical Correlations
Chapter 1: General Aspects of the Liver and Liver Diseases
Chapter 2: Viral Hepatitis
Chapter 3: Cholestasis and Biliary Tract Disorders
Chapter 4: Alcoholic and Non-Alcoholic Fatty Liver Diseases
Chapter 5: Drug- and Toxin-Induced Liver Cell Injury
Chapter 6: Vascular Disorders
Chapter 7: Infectious Disorders, Non-Viral
Chapter 8: Developmental, Familial, and Metabolic Disorders
Chapter 9: Diseases of Hepatic Iron and Copper Metabolism
Chapter 10: Neoplasms and Related Lesions
Chapter 11: Transplantation
Chapter 12: Miscellaneous Conditions
Part II: Liver Biopsy Evaluation: Morphology with Differential Diagnoses
Chapter 13: Introduction
Chronic Liver Diseases: Staging and Grading Systems
Index
Part I
Liver and Hepatobiliary Pathology with Clinical Correlations
Chapter 1 GENERAL ASPECTS OF THE LIVER AND LIVER DISEASES

THE NORMAL LIVER 3
Embryology 3
Gross Anatomy 3
Microanatomy 5
STEM CELLS 9
COMMON PIGMENTS 11
SYSTEMATIC APPROACH IN LIVER BIOPSY INTERPRETATION 12
GENERAL CLINICAL CONSIDERATIONS OF ACUTE AND CHRONIC LIVER DISEASES 12
Acute Hepatic Injury 12
Chronic Hepatic Injury 15

The Normal Liver

Embryology
( Figs 1-1 through 1-5 )
1. The hepatic primordium anlage first appears toward the end of the third week of gestation as a hollow midline outgrowth of the endodermal epithelium (hepatic diverticulum) .
2. Eventually the diverticulum enlarges (proliferation of hepatoblasts) , projects cranially into the mesoderm of the septum transversum, and eventually develops into the hepatic parenchyma.
3. The proliferating endodermal cells form solid anastomosing cords, vesicles, and cribriform tubules that form luminal structures (precursor of the biliary canaliculi).
4. The hepatoblasts (progenitor cells) by way of rapid growth eventually develop into hepatic cords that initially are thickened at birth (muralium multiplex) but eventually evolve into trabeculae one cell thick (muralium simplex) , with those cords adjacent to the portal mesenchyme becoming the ductal plates . These progenitor cells also can generate into both mature hepatocytes and ductules, and they can express markers of both ( α-fetoprotein for liver cells and cytokeratins 7 and 19 for duct epithelium).
5. The mesoderm of the septum transversum forms the lesser omentum, falciform, coronary and triangular ligaments, and hepatic (Glisson’s) capsule.
6. The vascular network , derived from the vitelline and umbilical veins, occurs at the same time as the proliferation of the hepatoblasts, with the cords and vessels anastomosing and forming the hepatic sinusoids.
7. By the fifth week, most of the major vessels (right and left umbilical veins, transverse portal sinus, ductus venosus, portal vein) are identified.
8. The biliary system develops from membranous infoldings occurring between the junctional complexes between individual hepatoblasts, appearing initially only as thin intercellular spaces. Bile canaliculi are first seen at week 6, with bile synthesis occurring by week 9 and bile secretion by week 12, at which time a distinct lumen is apparent.
9. Invasion of these double-layered tubular ductal cells into the portal mesenchyme forms an anastomosing network that is not fully formed by birth; after birth, remodeling occurs, forming the interlobular bile ducts .
10. Hematopoiesis begins in the mesoderm at approximately 6 weeks’ gestation; it is most active during the sixth and seventh months but then rapidly decreases and is usually absent by 1 month of age.
11. The perisinusoidal (Ito, stellate) cells and Kupffer cells appear by 3 months’ gestation.
12. The individual cell functions occur at different time periods during fetal development. They include synthesis of the following:
a. α-Fetoprotein , which is in high quantities at birth and is initially present by 1 month gestation
b. Glycogen , which is seen by 2 months, with glycogen synthesis by 3 months
c. Fat , occurring at the same time as glycogen
d. Hemosiderin (iron pigment) , which is most evident during active hematopoiesis

Figure 1-1 Embryonic development . The drawing to the left represents a 9-mm embryo that is approximately at the 36th day of gestation. The liver originates from the hepatic diverticulum and projects cranially into the septum transversum and caudally into the abdominal wall. The drawing to the right represents a slightly older embryo. The falciform ligament can now be seen between the liver parenchyma and the anterior abdominal wall.
(From Langman J. Medical Embryology. 2nd ed. Baltimore: Williams & Wilkins, 1969, with permission.)

Figure 1-2 Embryonic development . The portal tract demonstrates the mesenchymal framework composed of spindle cells intermixed with a few scattered immature erythroid and myeloid precursors. Three small ductules are present at the border of the portal tract and parenchyma at the left of the field. The adjacent periportal zone of the lobule shows prominent extramedullary hematopoiesis within the sinusoids.

Figure 1-3 Embryonic development . This developing ductule at the edge of the portal structure shows extension through the limiting plate, joining up with the canals of Hering that are partly lined by hepatocytes and ductules (cholangioles).

Figure 1-4 Embryonic development . Prominent extramedullary hematopoiesis is seen within the sinusoids, with the erythroid precursors most abundant in this field. The hepatic cords are up to two cells thick, with the individual hepatocytes showing scantier cytoplasm than seen in the fully developed liver.

Figure 1-5 Embryonic development . The fetal hepatocytes characteristically demonstrate abundant α - fetoprotein within the cytoplasm. (Immunoperoxidase stain for α-fetoprotein.)

Gross Anatomy
( Fig. 1-6 )
1. The liver in the adult takes up most of the right upper quadrant of the abdomen, measures approximately 15 to 20 cm in width, and weighs from 1200 to 1800 g , depending on the person’s overall body size. At birth, however, the liver is proportionately larger compared to the adjacent thoracic and abdominal viscera.
2. The liver anatomically has four lobes (right, left, caudate, and quadrate), with the right lobe accounting for ½ to 2 3 of the total liver volume; however, functionally both the right and left lobes are approximately equal in size and are divided by a line extending from the middle of the gallbladder fossa inferiorly to the inferior vena cava superiorly.
3. There are eight functional hepatic segments , each demarcated by the vascular and biliary drainage:
a. Lateral divisions of the right lobe (segments VI and VII)
b. Medial divisions of the right lobe (segments V and VIII)
c. Medial division of the left lobe (segment IV)
d. Lateral divisions of the left lobe (segments II and III)
e. Caudate lobe (segment I)
4. The hepatoduodenal ligament connects the liver to the superior aspect of the duodenum and supports the hilar vessels and ducts. The transverse fissure divides the right lobe from the caudate lobe, and the umbilical fissure , located to the left of the quadrate lobe, is bordered on the right by the gallbladder.
5. The falciform ligament , formed from the peritoneal layer and extending between the liver and the anterior abdominal wall, separates into the superior layer of the coronary ligament and the left triangular ligament; the ligamentum teres , located along the lower edge of the falciform ligament, contains the obliterated umbilical vein remnant.
6. The portal vein , the main route of vascular drainage of the gastrointestinal tract, develops from the merger of the superior mesenteric and splenic veins, receives blood from the coronary and cystic veins, and is divided into the right and left branches .
7. The hepatic vein is composed of three major tributaries (right, middle, and left intrahepatic branches) and drains blood flow from the right, left, and quadrate lobes into the inferior vena cava. The caudate lobe drains directly into the inferior vena cava.
8. The hepatic artery is a branch of the celiac artery, ascends along the hepatoduodenal ligament, and is divided into the right hepatic artery , the left hepatic artery , and the middle hepatic artery .
a. The right hepatic artery is seen behind the common hepatic duct after giving rise to the cystic artery.
b. The left hepatic artery passes upward and to the left in the porta hepatis.
c. The middle hepatic artery feeds the quadrate lobe.
9. The biliary system , which originates from the bile canaliculi, can grossly be visualized by the larger interlobular and interlobar branches. It is fed by the hepatic artery and its branches.
10. The lymphatic channels are divided into the deep and superficial branches, and the nerve supply is seen immediately adjacent to the main hepatic artery and portal vein and is divided into parasympathetic and sympathetic fibers. Many of the nerve fibers terminate on endothelial cells lining the smallest arteriolar segments and along Kupffer and stellate cells and hepatocytes.

Figure 1-6 Anatomic and functional subdivisions . The eight functional anatomic segments of the liver are demonstrated in this drawing. Each individual segment has its own blood supply and biliary drainage. The subdivisions include the right lateral (segments VI and VII) and medial (segments V and VIII) divisions, the left medial (segment IV) and lateral (segments II and III) divisions, and the caudate lobe (segment I).
(From Moore KL, Dalley II AF. Clinically Oriented Anatomy. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 1999, with permission.)

Microanatomy
( Figs 1-7 through 1-14 )
1. The basic architecture includes the portal tracts, sinusoids, and outflow vessels (terminal hepatic venules and veins), all of which are evenly spaced throughout all lobes of the liver.
2. The portal tracts are composed of the following:
a. Interlobular bile ducts: Usually one and occasionally two per portal structure and seen immediately adjacent to the small hepatic artery and arteriole segments (from which they receive their blood supply)
b. Hepatic arterioles: Most often singly present and drain blood into the sinusoidal network
c. Portal venules: Usually a single vascular structure that provides direct communication with the sinusoids
d. Fibroconnective tissue (collagen): Provides support for the major portal structures
e. Cellular inflammatory cells: Composed of scanty numbers of lymphocytes, which can at times be sparsely seen in healthy livers
3. The parenchyma in the adult comprises almost 4 5 of the total hepatic volume and is composed predominantly of one-cell thick liver cell cords and plates with adjacent sinusoids that are lined by endothelial , Kupffer , and stellate (Ito) cells . The sinusoids then drain into the terminal hepatic venules .
4. The hepatocytes comprise approximately 2 3 of the total number of cells within the liver, measure 25 to 40 μm in diameter, and are arranged in one-cell thick hepatic cords and plates that have three distinct cell membrane boundaries: sinusoidal (basolateral) , lateral (intercellular) , and canalicular . The gap junctions represent the two adjacent liver cell membranes having a distinct 2- to 4-μm gap where there is communication between cells for transport of various components such as metabolites. Desmosomes , intermediate junctions , and tight junctions further play roles in cell membrane resilience and permeability.
5. The hepatocyte is composed of a nucleus and cytoplasm .
a. The centrally located nucleus measures approximately 10 μm in diameter and contains nucleoli and clumped chromatin. The nuclear membranes have apertures (pores) that provide communication between the nucleus and cytoplasm. From one to six nucleoli may be present, their number and size in direct proportion to their degree of activity. The nucleus is usually single, although bilobed forms may be seen in elderly patients as well as in liver cells undergoing active reduplication and regeneration. In addition, variation in nuclear size can occur (nuclear anisocytosis), with enlarged nuclei in the perivenular zone (zone 3 of Rappaport) sometimes seen, especially in the elderly patient population.
b. The cytoplasm comprises approximately 90% of the volume of the liver cell and contains various functional components. In addition, the overall superstructure of the cell is maintained by various filaments, including the microfilaments , microtubules , and intermediate filaments, each with its own special functions. The various intracellular components are outlined in Table 1-1 .
c. Other intracellular components that can be seen on light microscopy include various pigments (lipochrome, hemosiderin, bile), lipids (macrovesicular and microvesicular fat), and glycogen (within both nuclei and cytoplasm).
6. Kupffer cells are oval to oblong sinusoidal lining cells with stellate cytoplasm that function as tissue macrophages. Originally derived from the circulation, these cells eventually attach to the sinusoidal borders and overlie but do not form junctional complexes with the underlying endothelial lining cells. Their primary functions include phagocytosis and eventual clearance of particulate material and endotoxins, clearance of senescent erythrocytes and degenerating cellular components, sequestration of antigens, and clearance of immune complexes.
7. Endothelial cells are flattened, elongated sinusoidal cells that contain numerous cytoplasmic projections and clustered fenestrae or gaps ranging from 0.1 to 0.2 μm in diameter. These structures function by filtering the sinusoidal blood of various macromolecules by receptor-mediated anisocytosis, enabling certain substances such as glycoproteins direct contact with the hepatocyte, while excluding larger cellular compounds.
8. Stellate (perisinusoidal, Ito, “fat-storing”) cells , seen along the perisinusoidal liver cell recesses within the space of Disse, contain variably sized lipid droplets that have high concentrations of vitamin A (retinoyl palmitate, demonstrated by autofluorescence on frozen tissue sections). These cells synthesize extracellular matrix by way of cytokine activation and resultant transformation to myofibroblasts in response to liver injury.
9. Pit cells (liver-associated lymphocytes) are T cells distributed within the sinusoids in loose contact with the Kupffer and endothelial cells and rarely within portal tracts. They act as natural lymphocyte-activated killer (NK) cells and are often seen in direct contact with the endothelium in response to various immunologic processes (e.g., viral hepatitis, cellular post-transplant rejection).
10. Stroma (extracellular matrix) supports the basic hepatic architectural arrangement, produces intercellular cohesion, and effects cellular differentiation. Glisson’s capsule overlies the liver and is composed of hypocellular dense collagen. Five basic types of collagen are present, with types I and III representing more than 95% of the total collagen. In addition, various noncollagenous glycoproteins that are responsible for collagen adhesion and stability include laminin , fibronectin , and elastin . The laydown of these stromal elements is often triggered by stellate cell activation in instances of liver cell injury.
11. The biliary network , whose main function is to transport bile synthesized by the hepatocyte into the gastrointestinal tract, can be subdivided into the following:
a. Biliary canaliculi: Located along the intercellular spaces between the liver cells, 0.5 to 1.0 μm in diameter, lined by microvilli; sometimes difficult to see on routine histology but can be highlighted using polyclonal carcinoembryonic antigen (pCEA) and CD10 immunoperoxidase stains
b. Ducts (canals) of Hering (cholangioles): Derived from liver cells at the portal tract limiting plate and have both liver cell and ductal ultrastructural and histochemical features; aid in communication with the portal interlobular bile ducts
c. Interlobular bile ducts: 15 to 20 μm in diameter; lined by a single layer of cuboidal cells having discrete round nuclei, scanty eosinophilic cytoplasm, and discrete basement membranes; supplied by the smaller hepatic artery branches and peribiliary plexus
d. Interlobar and septal ducts: More than 100 μm in diameter; have a fibrous wall lined by a single layer of cuboidal to columnar epithelium, with the nuclei located toward the basement membrane
e. Segmental ducts: Up to 800 μm in diameter; lined by columnar mucus-secreting epithelium and have a distinct fibromuscular wall; form the major hilar ducts (up to 1.5 mm in diameter) and branch into the main right and left hepatic ducts.
12. The main vascular network can be subdivided into the following:
a. Portal veins: Sequentially develop interlobar, segmental, interlobular, and preterminal vein branches, with the terminal portal venules measuring approximately 20 to 30 μm in diameter and seen in the smaller triangular portal tracts
b. Hepatic arteries: Accompany the portal vein, divide within the smaller portal tracts into the periportal and peribiliary plexus, and provide blood supply to the accompanying interlobular bile ducts by way of small capillaries that are layered around the ducts
c. Outflow vessels (terminal hepatic venules and veins, sublobular and hepatic veins): Provide vascular drainage from the sinusoids into the inferior vena cava
13. The space of Disse lies between the hepatocyte and the endothelial cells and forms a space often not well appreciated on routine light microscopy on biopsy material; it houses the stellate or perisinusoidal cells (Ito cells).
14. The hepatic lymph channels are derived from the space of Disse as well as from capillary leakage from the peribiliary plexus. Their main function is to drain excess proteinaceous fluid from the interstitial hepatic spaces, with the majority of lymphatics leaving the liver at the porta hepatis and along Glisson’s capsule.
15. The neural network is composed of both parasympathetic and sympathetic branches, with small nerve segments sometimes seen within the larger portal tracts and toward the hepatic hilum.
16. On the basis of vascular injection studies, the hepatic vascular unit (hepatic acinus) can be subdivided into three segments:
a. Simple acinus: Smallest functional unit, centering around the preterminal portal venule, hepatic arteriole, and terminal bile ductules and divided into three zones (zones of Rappaport):
i. Periportal (zone 1), which includes the limiting plate
ii. Midzone (zone 2)
iii. Perivenular (zone 3), with the terminal hepatic venule at its outer lateral margin
b. Complex acinus: Derived from three adjacent simple acini that are fed by the preterminal portal vein and hepatic arterial branches
c. Acinar agglomerate: Composed of four complex acini that are fed by a portal venous branch that measures 300 to 1200 μm in diameter
17. Metabolic markers (alkaline phosphatase activity) instead of morphology alone have also been used to further subclassify the architectural arrangement into primary and secondary modules based more on three-dimensional arrangements of the hepatocytes and its microcirculation.
18. The various structural and functional components represent liver cell heterogeneity, with specialized liver cell functions seen within the various parenchymal zones. These functions are manifestations of nutrient and hormonal gradients, and they reflect both variations in the sinusoidal vascular perfusion and oxygen concentration gradients and variations in the expression of certain enzyme activities through gene expression. The functional heterogeneity applies not only to the hepatocytes but also to the sinusoidal and perisinusoidal spaces, Kupffer and endothelial cells, extracellular matrix, and bile duct epithelial cells. Examples are shown in Tables 1-2 and 1-3 .

Figure 1-7 Normal hepatic architecture . This three-dimensional reconstruction of the normal hepatic architecture shows that the liver cell plates, rather than simply radiating from a terminal hepatic venule (as seen on light microscopy), are actually a labyrinth of intercommunicating plates and sinusoids. The diagram also shows the various communications of the portal structures (portal vein, bile duct, hepatic artery) with the adjacent lobule.
(From Sherlock S, Dooley J. Diseases of the Liver and Biliary System. 11th ed. West Sussex, UK: Wiley-Blackwell, 2002, with permission.)

Figure 1-8 Basic lobular architecture . Blood flows from the portal tract (right of the field) into the hepatic sinusoids and leaves the lobule via the terminal hepatic (“central”) venule (left of the field).

Figure 1-9 Portal tract . The major components of a portal tract consist of a hepatic arteriole, portal venule, and one to two interlobular bile ducts.

Figure 1-10 Portal tract . Communication of a portal venule with an adjacent periportal sinusoid at the lower right of the field is seen. The portal tract normally has some degree of collagen fibers, staining blue in this field, supporting its major vascular and biliary components. (Trichrome stain.)

Figure 1-11 Parenchyma . The hepatic cords are one cell thick and are lined by both Kupffer and endothelial cells. The sinusoids drain into the terminal hepatic venule.

Figure 1-12 Parenchyma . This stain of the reticulin fibers lining the hepatic sinusoids shows the orderly liver cell plates to be one cell thick. (Reticulin stain.)

Figure 1-13 Biliary canaliculi . The immunoperoxidase stain of the CD10 surface glycoprotein CALLA (common acute lymphoblastic leukemia-associated antigen) highlights the normal biliary canaliculi, which are located at the intercellular spaces between the hepatocytes. Often these canaliculi are not apparent on routine light microscopy in a healthy liver. The polyclonal CEA immunoperoxidase stain can also demonstrate these normal canaliculi. (Immunoperoxidase stain for CD10.)

Figure 1-14 Simple hepatic acinus and zonal arrangements . Although the hepatic lobule on routine hematoxylin and eosin–stained slides appears to have the outflow vessels located toward the center of the lobule (“central” venules), in fact the outflow vessels functionally are located at the periphery (terminal hepatic venules). This diagram denotes the location of the three hepatic zones with relationship to the portal structures and the vascular blood flow. PT, Portal tract; ThV, terminal hepatic venule.
(Data from Rappaport AM. The microcirculatory acinar concept of normal and pathological hepatic structure. Beitr Pathol. 1976;157:215–243; and Roskams T, Desmet VJ, Verslype C. Development, structure and function of the liver. In: Burt AD, Portmann BC, Ferrell LD, eds. MacSween’s Pathology of the Liver. 5th ed. Elsevier, 2007.)
Table 1-1 Liver Cell Ultrastructure STRUCTURE DESCRIPTION FUNCTION Mitochondria Up to 2200/liver cell; oval to oblong, ranging from 0.4–3.5 μm, with outer and inner membranes Oxidative phosphorylation, fatty acid metabolism, urea and citric acid cycle Endoplasmic reticulum (ER) Convoluted network of cisternae, saccules, tubules, vesicles; divided into rough ER (located around the nucleus) and smooth ER (meshwork of tubules that communicate with Golgi apparatus) Rough ER: protein synthesis Smooth ER: bile acid and lipid synthesis; cytochrome P450 enhancement of drug/toxin metabolism Golgi apparatus 40–60/cell; polarized, parallel, flattened to dilated saccules and vesicles that are 1 μm in diameter; seen most often next to the nucleus and biliary canaliculi Bile secretion, carbohydrate integration into proteins, membrane synthesis/repair, production of secretory vacuoles for protein transport and excretion Lysosomes Electron-dense pleomorphic single membrane–bound vesicles, seen adjacent to biliary canaliculi; divided into primary and secondary variants Actively involved in phagocytosis; various degradation functions of acid phosphatase, esterases, proteases, lipases Peroxisomes (microbodies) Round to oval, single membrane, 0.2–1.3 μm in diameter Oxidation and degradation of numerous substrates, with formation of hydrogen peroxides; oxidation of long-chain fatty acids
Table 1-2 Liver Cell Structural Zonal Variations ZONE 3 (PERIVENULAR) ZONE 1 (PERIPORTAL) Mitochondria round; less numerous and smaller; fewer inner membranes Mitochondria oval and oblong; larger diameter, volume, and number; greater cristae area Prominent peroxisomes Rough endoplasmic reticulum more abundant Bile canaliculi with fewer microvilli; smaller in diameter Bile canaliculi with numerous microvilli; larger in diameter Lysosomes numerous Kupffer cells numerous Sinusoids form parallel vessels that open into terminal hepatic venules; are wider (30 μm) and fewer in number Sinusoids form interconnecting polygonal network; are smaller (6 μm), more tortuous, and more numerous in number Surface area of smooth endoplasmic reticulum larger Abundant Golgi-rich volume Endothelial cells more numerous but smaller; increase in number of fenestrations and porosity Endothelial cells larger; endothelial fenestrations larger but less numerous Larger nuclear volumes Numerous large granular lymphocytes (“pit” cells) Increase in number of microbodies   Slight increase in stellate (Ito) cells ∗   Predominant collagen types I, III, VI  
∗ Zone distribution varies considerably depending on the nutritional state.
Table 1-3 Liver Cell Functional Zonal Variations ZONE 3 (PERIVENULAR) ZONE 1 (PERIPORTAL) Glycolysis Gluconeogenesis Glycogen synthesis from glucose Glycogen synthesis from lactate Lipogenesis β-Oxidation of fatty acids Removal of ammonia from blood by glutamine Amino acid catabolism Detoxification, biotransformation of the majority of drugs and toxins (cytochrome P450 enzymes) ∗ Urea synthesis Ketogenesis Cholesterol synthesis Bile acid synthesis Bile acid secretion Bile salt–independent fraction of bile formation; bile acid uptake (sodium independent) Bile salt–dependent fraction of bile formation; bile acid uptake (sodium dependent) Glucuronidation   Mixed function oxidase   Increase in Kupffer cell phagocytic activity  
∗ Certain drugs and toxins (e.g., allyl formate, phosphorus) and their metabolites may cause liver cell injury in zone 1 because of different pathophysiologic mechanisms.

Stem Cells
( Fig. 1-15 )
1. Primitive stem cells (“oval” cells in experimental models), located in the periportal zone near the canals of Hering, are pleural-potential in their differentiation capabilities.
2. Hepatocytes show a striking ability to regenerate (e.g., as a result of massive liver cell necrosis, after partial hepatectomy for tumor); the availability and activation of these stem cells makes regeneration possible. These cells give rise to ductular cells located at the border of the portal tracts and the parenchyma (along the ductal plate) that may differentiate into hepatocytes or ducts and that can express markers of both ( α-fetoprotein for liver cells and cytokeratins 7 and 19 for ducts). The presence of numerous ductules along the borders of the portal tracts in instances of fulminant hepatitis is an example.
3. Although initial reports showed that hepatocytes and cholangioles may be derived from extrahepatic circulating stem cells of probable bone marrow origin, more recent data suggest that liver cell generation from bone marrow stem cells does not occur through a process of true differentiation but rather by cell fusion of these bone marrow stem cells with nascent mature cells in the target tissue.
4. The hepatic stellate cells, which normally play an important role in the development of hepatic fibrosis, have recently been shown to experimentally express a stem/progenitor cell surface marker and exhibit properties of pluripotent progenitor cells, with precursor potential in the development of both endothelial cells and hepatocytes.


Figure 1-15 Stem cells . In instances of severe liver cell injury, hepatocytes show a striking ability to regenerate as a result of activation and proliferation of stem cells that give rise to ductular epithelium along the ductal plates located at the border of the portal tracts and parenchyma, as seen in this image of fulminant hepatitis (massive hepatic necrosis) from acute viral hepatitis.

Common Pigments
( Figs 1-16 through 1-19 )

Figure 1-16 Lipochrome . This pigment, also referred to as “wear and tear” pigment, is finely to coarsely granular and light to dark brown; it is seen more concentrated in the hepatocytes within the perivenular zone (zone 3 of Rappaport).

Figure 1-17 Intracellular bile . Bile pigment can be seen in various cholestatic disorders within the cytoplasm of the hepatocytes and appears as fine, irregular green to green-yellow droplets.

Figure 1-18 Intracanalicular bile . Bile can be identified within dilated canaliculi as green to green-yellow pigment in various cholestatic liver diseases associated with impairment of biliary drainage.

Figure 1-19 Hemosiderin . A, This coarsely granular golden brown pigment is composed of red blood cell degradation remnants. In this image, hemosiderin can be seen within all of the hepatocytes. B, Because hemosiderin pigment can sometimes resemble lipochrome pigment on routine hematoxylin and eosin staining, a positive intensely blue iron stain confirms the presence of hemosiderin. (Perl’s iron stain.)
Various pigments can be seen on liver biopsy. Following are the three most common pigments:
1. Lipochrome (lipofuscin) pigment appears as fine to coarse brown granules and is derived from an increase in lysosomal activity and intracellular condensation of various cellular remnants. It most often appears within enlarged lysosomes and is usually more frequently seen in hepatocytes located within the perivenular zone (zone 3 of Rappaport). Its presence does not denote liver disease or dysfunction; this pigment is commonly seen in the liver tissue of elderly patients.
2. Bile is present as clumped green to green-yellow globules that stain positive with Hall’s stain for bilirubin. Usually the presence of intracellular bile is also accompanied by intracanalicular bile. Most cholestatic conditions also demonstrate this pigment more commonly in the perivenular zone (zone 3 of Rappaport).
3. Hemosiderin pigment is coarsely granular and golden brown, is best highlighted by Perl’s iron stain, and represents red blood cell degradation remnants. This pigment, in contrast to bile or lipochrome, is first laid down in the periportal zone (zone 1 of Rappaport).
Other pigments include the lipochrome-like pigment (seen in Dubin-Johnson syndrome; Fig. 8-45B ), anthracotic pigment (seen more frequently in city dwellers; Fig. 5-52 ), protoporphyrin (present in erythropoietic protoporphyria; Fig. 8-62 ), and hemozoin pigment (seen in malaria from Plasmodium falciparum infection; Fig. 7-44 ). Table 1-4 shows a comparison of some of the more common pigments.

Table 1-4 Presence of Pigments and Their Characteristics

Systematic Approach in Liver Biopsy Interpretation
( Figs 1-20 through 1-29 )

Figure 1-20 Portal lymphocytic infiltrates . Lymphocytes can be seen expanding the portal tract. These cells in this example are not oriented toward any of the portal structures.

Figure 1-21 Focal necrosis . Necroinflammatory change in this field consists of a small cluster of lymphocytes and hyperplastic Kupffer cells engulfing the damaged hepatocytes.

Figure 1-22 Focal necrosis . Focal necroinflammatory change of hepatocytes can also be highlighted with this stain, which accentuates the ceroid accumulations from the engulfed hepatocytes within macrophages and enlarged Kupffer cells as a coarse dark purple pigment. (DiPAS.)

Figure 1-23 Apoptosis . One form of liver cell injury (apoptosis) shows shrunken hepatocytes that have eosinophilic cytoplasm and small pyknotic nuclei (Councilman bodies, acidophil bodies) that are eventually extruded from the liver cell plates and phagocytized by adjacent Kupffer cells.

Figure 1-24 Fatty change . Fat globules are termed macrovesicular when they are larger than the hepatocyte nuclei and microvesicular when the fat droplets are the same size or smaller than the nuclei.

Figure 1-25 Kupffer cell hyperplasia . The Kupffer cells are more numerous in this field than normally seen, with easily recognizable plump elongated nuclei and moderate eosinophilic cytoplasm, the cells hugging the surface of the hepatic cords.

Figure 1-26 Nuclear anisocytosis . Variably sized liver cell nuclei can be seen. This feature more frequently occurs in the perivenular zone and in the elderly patient population.

Figure 1-27 Glycogenated nuclei . The “empty” nuclei of hepatocytes are in fact loaded with glycogen, which is water-soluble and removed on tissue processing, leaving the nuclei clear.

Figure 1-28 Peribiliary glands . These small clusters of benign ducts and glands are commonly seen within the walls of large hilar and extrahepatic bile ducts. The glands may be serous or mucinous and rarely can show communication with the larger duct lumen.

Figure 1-29 Surgical hepatitis . Clusters of neutrophils are evident in the perivenular zone, are frequently seen in biopsies performed intraoperatively, and are secondary to surgical manipulation in long abdominal surgical procedures. These neutrophils are also commonly seen immediately beneath Glisson’s capsule.
Individual morphologic changes are seldom by themselves diagnostic of any particular liver disease; however, assessing the whole complex of changes leads to a better assessment of the diagnostic possibilities. It is therefore important that the pathologist and clinician take an organized approach in reading and interpreting liver biopsy results. Even when a clinical diagnosis is known, all aspects of liver morphology should be approached in biopsy assessment so that an unexpected or additional diagnosis is not missed. Table 1-5 shows a systematic approach in liver biopsy evaluation . In addition, Figs 1-20 through 1-29 show examples of nonspecific morphologic features that can be seen in a variety of liver diseases. The multiple tables in Part II of this book list the various liver diseases associated with individual morphologic features.
Table 1-5 Systematic Approach in Liver Biopsy Interpretation Basic Architecture
• Intact, distorted (bridging fibrosis, incomplete/complete septa, cirrhosis with regenerative nodules) Portal Tracts
• Fibrosis (degree)
• Inflammatory infiltrates: degree, various and predominant cell types, spillover/periportal interface activity (“piecemeal” necrosis)
• Bile ducts, ductules: number, appearance, periductal fibrosis, inflammatory cells oriented to ducts, duct loss (ductopenia)
• Portal veins/venous radicles: number, size, thrombosis, inflammation (endothelialitis)
• Arterioles/arteries: thickness, inflammation (arteritis)
• Miscellaneous: for example, foreign particles, granulomas, tumor within vessels/lymphatics Parenchyma
• Cord-sinusoid pattern: intact, distorted
• Necroinflammatory infiltrates: degree, predominant cell type, zonal accentuation
• Fatty change: degree, macrovesicular and microvesicular, zonal distribution
• Glycogenated nuclei
• Mallory bodies
• Pigments: bile, lipochrome, hemosiderin, others
• Granulomas: epithelioid, “inflammatory”
• Inclusions: nuclear, cytoplasmic
• Kupffer cells: hyperplastic, hypertrophic
• Sinusoids: dilation, congestion/hemorrhage, collagen deposition (zone predominance), red blood cell extravasation into hepatic cords
• Tumor, other mass lesions: for example, abscess Use of Routine and Special Stains
• Hematoxylin and eosin stain for all routine biopsies
• Masson trichrome to elucidate collagen
• Reticulin to evaluate maintenance of the lobular architecture and liver cell plates
• Periodic acid—Schiff (PAS) after diastase digestion (DiPAS) to identify α 1 -antitrypsin inclusions, ceroid pigment in sinusoidal macrophages and Kupffer cells
• Iron within liver/Kupffer cells, portal macrophages, duct epithelium
• Orcein for copper-binding protein, hepatis B virus “ground glass” cells
• Others (e.g., PAS, Gomori methenamine silver, acid fast for microorganisms; rubeanic acid, rhodanine for copper) Use of Special Techniques
• Immunohistochemical stains (e.g., viral, tumor markers)
• In situ hybridization (e.g., post-transplant Epstein-Barr virus infection) Identification of Artifacts
• Inappropriate, inadequate formalin fixation (discohesion, shrinkage of liver cells)
• Formalin pigment precipitates
• Crush artifact of liver tissue
• Biopsy fragmentation (not related to severe fibrosis)

General Clinical Considerations of Acute and Chronic Liver Diseases
Diseases affecting the liver present as either an acute or a chronic process, where progressive damage leads to steady deterioration in hepatic function, eventually resulting in end-stage liver disease with hepatic failure. The following are various clinical and laboratory features seen in both acute and chronic liver disease.

Acute Hepatic Injury

1. Acute injury is manifested as hepatocellular damage with variable impairment in bile flow.
2. Hepatocellular injury is characterized by elevations of serum transaminases, the degree of elevation depending on the severity or type of injury.
3. Cholestasis presents with elevation of serum bilirubin levels, approximately half of which is conjugated, with or without elevation in alkaline phosphatase activity.
4. Fatty change is sometimes seen acutely with toxin or drug exposure, or it is idiopathic (e.g., Reye’s syndrome, acute fatty liver of pregnancy). Necrosis and inflammation are most often mild, and consequently serum transaminases are only slightly elevated.
5. Varying combinations of types of injury may be present. For example, fatty infiltration and cholestasis may accompany hepatocellular necrosis, seen in certain types of drug-induced injury.

Clinical features of acute hepatic injury

1. Patients can be asymptomatic, or marked malaise, nausea, vomiting, and anorexia may develop, depending on the severity of the acute injury.
2. Recovery is usually heralded by the rapid return of appetite, absence of gastrointestinal symptoms, and improved energy levels.
3. Hepatic failure is characterized by the presence of encephalopathy and/or renal failure (provided renal injury is not directly induced by the agent producing the hepatic injury).
4. Fulminant hepatic failure, regardless of the etiology, is present when the duration from onset of injury or infection to hepatic failure is up to and including 8 weeks, whereas late-onset or subacute fulminant hepatic failure is present when the duration exceeds 8 weeks.
5. Serum aminotransferases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) are moderately to markedly elevated (1000s to >10,000 IU/L) depending on the severity of the injury. The degree of transaminase elevation does not predict the outcome of the disease. An elevation in lactate dehydrogenase (LDH) suggests injury in certain conditions (e.g., ischemia, drug toxicity, or infiltrative processes).
6. Mild to moderate elevations of serum total bilirubin are usually seen but may be markedly elevated (20 to 25 mg/dL), as, for example, in the cholestatic phase of viral hepatitis.
7. Serum alkaline phosphatase is usually mildly to moderately elevated.
8. Prothrombin activity is decreased ( prothrombin time prolonged) in acute hepatic injury, the severity of the abnormality directly related to the degree and extent of injury. A persistent and marked decrease in the prothrombin activity in acute hepatic injury carries a poor prognosis, with mortality often exceeding 80%.

Chronic Hepatic Injury

1. The injurious process continues unabated, resulting in repetitive phases of injury and repair.
2. Elevation of serum transaminases usually signifies hepatocellular injury and may vary depending on the etiology of the disease process. Elevations in alkaline phosphatase usually suggest biliary tract involvement, cholestasis, or infiltrative processes. Gamma-glutamyl transpeptidase (GGT) is nonspecific, and elevations in GGT do not aid in specific diagnosis except in rare clinical situations; for instance, elevations of GGT corroborate alcoholism in patients who surreptitiously drink alcohol. Elevations in serum bilirubin in hepatocellular processes suggest more serious disease and thus are of clinical value in assessing severity.
3. Collagen laid down as part of the reparative process leads to distortion of hepatic architecture, resulting in hepatic fibrosis and leading eventually to cirrhosis over a period of many years.

Clinical features of chronic hepatic injury

1. Clinical features of chronic liver disease depend on the extent of progression of the liver disease.
2. Symptoms may be related to the activity of the underlying etiology. For example, in autoimmune hepatitis, fatigue, malaise, arthritis, and skin rash may reflect the immune disturbance. If cirrhosis is present, decompensation with ascites, hepatic encephalopathy, and/or variceal hemorrhage may occur.
3. Patients with significant chronic liver disease demonstrate stigmata such as vascular spiders or spider angiomata, palmar erythema, clubbing, leukonychia (white nails), Dupuytren’s contracture, and parotid enlargement, which may not all be present in a given patient. Rarely, patients with advanced cirrhosis may not demonstrate any of these features.
4. Gynecomastia and testicular atrophy are seen in some male patients with chronic liver disease.
5. Abdominal wall collaterals develop in portal hypertension as the result of portal-systemic communications.
6. Muscle wasting is due to significant hepatic impairment in protein synthesis, characteristically involves the face and extremities, and is usually seen in advanced liver disease.
7. Hypoalbuminemia is usually due to decreased hepatic protein synthesis but may be due to increased proteinuria seen in conditions associated with liver disease, such as hepatitis C–related membranoproliferative nephropathy.
8. Ascites is the intra-abdominal formation of fluid exuding from the liver surface and is due to intrahepatic portal hypertension and associated impairment in renal sodium excretion. Ascites that is resistant to diuretic therapy is termed refractory ascites.
9. Spontaneous bacterial peritonitis is infection of ascitic fluid and usually occurs in patients with decompensated liver disease.
10. Hepatic encephalopathy develops as a result of worsening hepatic function with or without portal-systemic shunting.
11. Collaterals (varices), occurring commonly in the esophagus and stomach and rarely in the rectum or within adhesions, develop as a consequence of advanced portal hypertension. Hemorrhage from esophageal and gastric varices is a potentially fatal complication with increased mortality (≥50%) in severe liver disease.
12. Hepatic transplantation is offered to patients with fulminant hepatic failure who are not likely to survive and for those with advanced cirrhosis and liver failure.

References

Fausto N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology . 2004;39:1477-1487.
Geller S.A., Petrovic L.M. Biopsy Interpretation of the Liver , 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2009.
Kanel G.C., Korula J. Atlas of Liver Pathology , 2nd ed. London: Saunders; 2005.
Kanel G.C. Liver: anatomy, microscopic structure, and cell types. Yamada T., Alpers D., Kalloo A.N., et al, editors. Textbook of Gastroenterology, 5th ed, vol 2. West Sussex: Wiley-Blackwell, 2009;2057-2072.
Kanel G.C. Liver: anatomy, microscopic structure, and cell types . Yamada T., Alpers D., Kalloo A.N., et al, editors. Atlas of Gastroenterology, 5th ed, vol 1. West Sussex: Wiley-Blackwell, 2009;615-622.
Phillips M.J., Poucell S., Patterson J., et al. The Liver. An Atlas and Text of Ultrastructural Pathology . New York: Raven Press; 1987.
Rockey D.C., Caldwell S.H., Goodman Z.D., et al. Liver biopsy. Hepatology . 2009;49:1017-1044.
Roskams T., Desmet V.J., Verslype C. Development, structure and function of the liver. In: Burt A.D., Portmann B.C., Ferrell L.D., editors. MacSween’s Pathology of the Liver . 5th ed. London: Churchill-Livingstone; 2007:1-73.
Roskams T.A., Theise N.D., Balabaud C., et al. Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers. Hepatology . 2004;39:1739-1745.
Teutsch H.F. The modular microarchitecture of human liver. Hepatology . 2005;42:317-325.
Thorgeirsson S.S., Grisham J.W. Hematopoietic cells as hepatocyte stem cells: a critical review of the evidence. Hepatology . 2006;43:2-8.
Zhao R., Duncan S.A. Embryonic development of the liver. Hepatology . 2005;41:956-967.

References
The complete reference list is available online at www.expertconsult.com
Chapter 2 Viral Hepatitis

MAJOR HEPATOTROPIC VIRUSES: A, B, δ, C, E, G, “NON-A THROUGH NON-G” 16
Acute Viral Hepatitis 16
Chronic Viral Hepatitis 27
SYSTEMIC VIRAL INFECTIONS WITH HEPATIC INVOLVEMENT 39
Epstein-Barr Virus 39
Cytomegalovirus 41
Herpes Simplex Virus 43
Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 45
RARE SYSTEMIC VIRAL INFECTIONS WITH HEPATIC INVOLVEMENT 47
Lassa Fever 47
Yellow Fever 48
Echovirus (Enterovirus) 49
OTHER VIRUSES THAT MAY CAUSE LIVER DAMAGE 50

Major Hepatotropic Viruses: A, B, δ, C, E, G, “Non-A Through Non-G”

Acute Viral Hepatitis

Typical Form (Spotty Necrosis)
( Figs 2-1 through 2-13 )

Figure 2-1 Acute viral hepatitis . A and B. These two images from the same biopsy demonstrate prominent portal lymphocytic infiltrates with some degree of “spillover” of the inflammatory cells into the adjacent periportal zone without true periportal interface inflammatory activity (“piecemeal” necrosis). Interlobular bile ducts are normal in number with occasional cholangioles present.

Figure 2-2 Acute viral hepatitis . The parenchyma shows variable hydropic change of hepatocytes and diffuse necroinflammatory change, the inflammatory cells chiefly lymphocytes. Kupffer cell hyperplasia is present.

Figure 2-3 Acute viral hepatitis . Medium power shows mild hydropic change, spotty liver cell necrosis, and Kupffer cell hyperplasia. A mild lymphocytosis can also be seen within the sinusoids.

Figure 2-4 Acute viral hepatitis . Moderate necroinflammatory change, the inflammatory cells chiefly lymphocytes, is seen in the perivenular zone on high power. The liver cells show variable hydropic change, making it difficult to visualize the hepatic sinusoidal network.

Figure 2-5 Acute viral hepatitis . This field demonstrates spotty necrosis with phagocytosis of the necrotic liver cells by the hypertrophic Kupffer cells. The small eosinophilic cytoplasmic droplets seen in the center of the field represent increase in lysosomal activity within the Kupffer cells. A prominent lymphocytic infiltrate is also seen within the sinusoids and hepatic cords.

Figure 2-6 Acute viral hepatitis, apoptosis . A, Diffuse necroinflammatory changes are seen, with spotty necrosis and hypertrophic Kupffer cells. Toward the left of the field, occasional hepatocytes show a more intense eosinophilic cytoplasm with smaller pyknotic nuclei (apoptosis). A similar but smaller cell with a flattened degenerating nucleus is seen in the bottom right. B, Higher power shows an apoptotic cell with small nuclear remnants and intensely eosinophilic cytoplasm. This cell has been extruded from the hepatic cord and is now being phagocytized within a plump Kupffer cell.

Figure 2-7 Acute viral hepatitis . Cholestasis is seen within a dilated canaliculus in the center of the field.

Figure 2-8 Acute viral hepatitis: hepatitis A virus (HAV) . The portal tract shows numerous plasma cells, a feature sometimes prominent with acute HAV infection.

Figure 2-9 Acute viral hepatitis: hepatitis B virus (HBV) + δ . The necroinflammatory change is prominent, with perivenular confluent necrosis and liver cell dropout evident in the center of the field.

Figure 2-10 Acute viral hepatitis, severe (reticulin) . The perivenular (zone 3) confluent necrosis that can be seen in severe cases of acute viral hepatitis is associated with liver cell necrosis, dropout, and collapse of the reticulin framework, this latter feature highlighted with this reticulin stain. When this morphologic feature is striking, patients usually present with fulminant hepatitis.

Figure 2-11 Acute viral hepatitis: hepatitis E virus (HEV) . The portal tract exhibits a mild lymphocytic infiltrate. Prominent ductular (cholangiolar) proliferation and ectasia are present, and many of the ductules contain bile plugs.

Figure 2-12 Acute viral hepatitis: hepatitis E virus (HEV) . A, The parenchyma shows a mild lymphocytic infiltrate with Kupffer cell hyperplasia. Cholestasis is prominent, the hepatocytes often arranged in rosettes around the bile within the dilated biliary canaliculi. B, The canaliculi are markedly dilated and contain prominent bile plugs. In contrast to the parenchymal changes seen in the preceding figure, the hepatocytes are hydropic without liver cell necrosis or lobular inflammation.

Figure 2-13 Acute viral hepatitis, non-A through non-G . Syncytial giant cell transformation is seen in a biopsy from an adult who clinically presented with signs and symptoms of an acute hepatitis. The diagnosis rests on the exclusion of other causes of acute hepatitis.

Major morphologic features

1. All portal tracts exhibit a moderate to marked predominantly lymphocytic infiltrate.
2. Focal necrosis and apoptosis occur in all zones of all lobules, with associated hepatocytolysis and hydropic ballooning changes (lytic necrosis) of the liver cells. In early-stage disease, these changes are more prominent in the perivenular zone (zone 3 of Rappaport).
3. Variable but often prominent lymphocytic inflammatory infiltrates are seen within the lobules.
4. Phagocytosis of damaged liver cells by macrophages and Kupffer cells is present.

Other features

1. The basic lobular architectural pattern (portal tracts–terminal hepatic venules–portal tracts) is maintained, although in more severe cases there may also be perivenular liver cell dropout and focal perivenular collapse of the reticulin framework ( confluent necrosis; refer to discussion under “Fulminant Hepatitis”).
2. Apoptotic cells (Councilman bodies, acidophil bodies) frequently occur in all zones and consist of hepatocytes with shrunken eosinophilic cytoplasm and small pyknotic nuclei; these cells are seen either within the trabeculae or phagocytized by Kupffer cells after extrusion into the perisinusoidal space. Usually the late-stage apoptotic cells are devoid of nuclei.
3. Cholestasis may be present, often with perivenular (zone 3) accentuation.
4. Kupffer cell hyperplasia is present and is often prominent.
5. Although spillover of lymphocytes from portal tracts into the adjacent periportal zones is seen, true periportal or interface hepatitis (“piecemeal necrosis”) is not a manifestation.
6. The portal and lobular lymphocytes, usually T cells, can sometimes be seen attached to endothelial cells of portal and terminal hepatic venules.
7. Portal tracts may also exhibit variable degrees of infiltration by plasma cells, macrophages, and rarely eosinophils.
8. Although the portal inflammation commonly involves all of the portal tracts, at times there may be some variation in the degree of inflammation from one portal tract to another.
9. Bile duct and cholangiolar proliferation can be present but is generally mild.
10. Cytologic injury to interlobular bile ducts can occur at times but is not prominent (the exception being acute hepatitis C virus (HCV) infection; see discussion later in this chapter).
11. With resolution:
a. Residual spotty clusters of pigment-laded (ceroid-laden) macrophages may be seen ( tombstone lesions that are periodic acid-Schiff (PAS)-positive after diastase digestion [DiPAS]).
b. Hydropic regenerative activity of liver cells occurs, with slight thickening of the liver cell plates (best appreciated on the reticulin stain) and increased mitotic activity of hepatocytes. Note that in the elderly patient population there may be some degree of impairment in liver cell regeneration; this is associated with a poorer prognosis.
c. Eventually (months later) mild, nonspecific portal and lobular inflammatory changes can occur; these usually resolve by 1 year.
12. All types of acute hepatitis secondary to the hepatotropic viruses (A, B, δ, C, E, G, and “non-A through non-G”) basically exhibit similar morphologic features, as described previously; however, the individual subtypes may also show the following:
a. Hepatitis A virus (HAV)
i. Portal plasma cells may at times be prominent.
ii. Inflammation and necrosis may be more prominent in the periportal than in the perivenular zones.
iii. Perivenular cholestasis may be striking in comparison with only mild lobular inflammation, mimicking a drug-induced cholestatic hepatitis versus other causes of cholestasis such as benign recurrent intrahepatic cholestasis (refer to further discussion of this liver disorder in Chapter 8 ).
b. Hepatitis B virus (HBV)
i. Lymphocytic lobular inflammation may show close contact with injured hepatocytes, with lymphocytes occasionally identified within the cell cytoplasm (emperipolesis).
c. HBV and δ
i. The degree of inflammation and necrosis is often more prominent than in acute HBV infection alone. In approximately ⅓ of cases, a fulminant hepatitis with confluent necrosis may occur.
ii. Microvesicular fatty change within liver cells has been described.
d. HCV
i. Portal lymphocytic infiltrates often show lymphoid aggregate and follicle formation, occasionally with germinal centers.
ii. Interlobular bile ducts may be noted within the centers of these lymphoid aggregates, with lymphocytes occasionally infiltrating beneath the duct basement membrane, associated with cytologic damage of the duct epithelium (epithelial hyperplasia, vacuolization, nuclear irregularity).
iii. Although rare, granulomatous-type necrosis can be seen within the lobules, without true epithelioid granuloma formation.
iv. A sinusoidal lymphocytosis may also be present.
Note: The first two described features may be a sign of impending progression to chronicity.
e. Hepatitis E virus (HEV)
i. Cholangiolar (ductular) proliferation may be seen, sometimes associated with bile plugs within the dilated cholangioles that also may be surrounded and focally infiltrated by neutrophils.
ii. Acinar changes (dilated canaliculi) often containing bile can sometimes be appreciated within the lobules.
iii. The degree of lobular inflammation is generally mild; however, infrequently a severe necroinflammatory process can occur, with inflammation of the portal and terminal hepatic venules reported.
f. Hepatitis G virus (HGV)
i. In general, the portal and lobular inflammation and the lobular necrosis are milder than what is seen with the other hepatotropic viruses.
ii. There is some question whether acute HGV infection does, in fact, cause a histologically apparent acute hepatitis, with many believing it is more a passenger virus.
g. Other types (non-A through non-G)
i. Giant cell transformation of hepatocytes has been described.
ii. In some cases, paramyxovirus has been identified within the cytoplasm by electron microscopy.
iii. Viruses such as transfusion-transmitted virus (TTV) and SEN virus (SEN-V) , both single-stranded circular DNA viruses, are postulated to play some part in inducing or enhancing acute hepatitis in certain patient populations; however, there is no convincing evidence to date that these viruses play any significant or primary role.

Special stains

1. PAS after diastase digestion (DiPAS): Cytoplasmic intralysosomal granules in macrophages and Kupffer cells are prominent in areas of necrosis and in portal macrophages.
2. Reticulin: Condensation of reticulin fibers may be seen in the perivenular zones secondary to liver cell necrosis and dropout in the more severe cases.
3. Perl’s iron: Hemosiderin may be seen in macrophages and Kupffer cells in areas of necrosis.

Immunohistochemistry

1. Hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBcAg): Surface and core antigen staining in acute viral hepatitis type B is always negative. Positive staining for either antigen in biopsies exhibiting changes of acute hepatitis is indicative of either (1) a replicative (active) phase of early chronic hepatitis B, where the portal fibrosis is minimal and easily missed, or (2) an acute non-B or drug-induced hepatitis in a patient with underlying early-stage chronic hepatitis type B.
2. Delta antigen: In acute hepatitis B with acute δ infection, liver cell nuclei exhibit variable and often prominent degrees of positive staining.

Differential diagnosis

1. Drug-induced liver cell injury (e.g., isoniazid, rifampin; refer to Table 5-4 ): The morphologic features secondary to hepatotoxicity by certain drugs and toxins that elicit both a portal and lobular inflammatory reaction may be similar to those seen in acute viral hepatitis; however, in some instances the degree of portal lymphocytic infiltrates may be less prominent than in classic acute viral hepatitis. In addition, scattered admixed eosinophils within the portal tracts often favor drug-induced injury. Finally, with some exceptions (e.g., the cholestatic phase of acute viral hepatitis types A and E), the degree of intralobular cholestasis in drug-induced cholestatic hepatitis usually outweighs the degree of portal and lobular inflammation.
2. Early stages of chronic viral hepatitis: Both early and relatively active stages of chronic viral liver disease may resemble the morphologic features seen in acute viral hepatitis, especially in small biopsies with few portal tracts or with only segments of portal areas for evaluation. For hepatitis type B, the presence of stainable HBV antigens (HBsAg, HBcAg) by immunohistochemical techniques in the cytoplasm and nucleus, respectively, is a useful tool in the diagnosis of early chronic HBV infection. Similarly, the presence of HBsAg and anti-HBc immunoglobulin G (IgG) in the absence of anti-HBc IgM in serum samples also points to chronic hepatitis type B. Of note is that the presence of distinct portal lymphoid aggregates and follicles in acute viral hepatitis type C is believed to be an indicator that the disease will most likely progress to chronicity.
3. Early stages of autoimmune hepatitis: The degree of portal and lobular inflammation in the early stages of autoimmune hepatitis may resemble that seen in acute viral hepatitis; however, the portal and lobular plasma cell component and the presence of definite periportal interface inflammatory activity are signs suggesting an autoimmune process. In addition, most of the time, some degree of portal fibrosis may also be present in early autoimmune liver disease. This feature is best highlighted on trichrome and Sirius red stains for collagen.
4. Epstein-Barr virus (EBV), cytomegalovirus (CMV) hepatitis: Both of these viruses may produce acute hepatitis (refer to “Epstein-Barr Virus” and “Cytomegalovirus” later in this chapter), with portal lymphocytic infiltrates and diffuse lobular necroinflammatory changes. The differences from acute viral hepatitis are as follows:
a. EBV and CMV tend to cause less individual liver cell damage, without the characteristic ballooning hydropic changes and apoptosis seen in typical acute viral hepatitis.
b. The degree of necroinflammatory changes and elevations of the serum aminotransferases (seldom greater than 500 IU/L) are considerably less in acute EBV and CMV infections than in typical acute viral hepatitis.
c. Sinusoidal lymphocytosis, although sometimes a feature present in acute viral hepatitis (particularly HCV), is usually quite prominent in EBV and CMV infection, with the lymphocytes frequently enlarged and atypical.
d. CMV often causes a granulomatous type of necrosis. The granulomas sometimes contain true epithelioid histiocytes, a feature not seen in typical acute viral hepatitis. Although acute HCV infection may rarely cause some degree of “granulomatous” necrosis, true epithelioid cells are not present.
e. In the immunocompromised patient (e.g., status post-chemotherapy or liver transplantation), the presence of CMV nuclear and cytoplasmic inclusions in liver cells, Kupffer cells, and/or duct epithelium is a useful marker for CMV infection.
f. A positive Epstein-Barr-encoded RNA (EBER)-1 DNA probe and demonstration of specific EBV-specific proteins (Epstein-Barr nuclear-associated antigens) are useful markers for EBV infection in certain settings.
5. Wilson disease: Wilson disease, an autosomal recessive inherited disorder associated with increased hepatic copper deposition (see Chapter 9 ), may present in the early stages with an acute hepatitis picture similar to that seen in acute viral hepatitis. Confluent necrosis may be seen as well. The presence of Mallory bodies, glycogenated nuclei, increased hepatic copper (rubeanic acid and rhodanine stains on liver biopsy, copper quantification on liver tissue), as well as low serum ceruloplasmin levels and increased urinary copper excretion are helpful indicators pointing toward a diagnosis of Wilson disease.

Clinical and biologic behavior
( Tables 2-1 and 2-2 )
1. Acute viral hepatitis may present clinically with jaundice, but frequently it is not associated with hyperbilirubinemia (anicteric hepatitis).
2. Prodromal signs may include low-grade fever, arthralgias and myalgias, and anorexia.
3. Significant elevations of serum transaminases occur, are usually greater than 500 IU/L, and may at times range from 1000 to 10,000 IU/L. The alkaline phosphatase is usually mildly elevated. Mild leukopenia and thrombocytopenia are also common.
4. Children usually tend to be anicteric and asymptomatic, and adults, especially elderly individuals, may develop a more severe course.
5. Although serum transaminases are lower in anicteric and asymptomatic forms of acute hepatitis, the degree of transaminase elevations does not correlate with outcome or prognosis.
6. A cholestatic phase may follow acute hepatitis due to HAV and HEV infection and is characterized by jaundice and pruritus. Pruritus is sometimes intractable and may last for weeks or months.
7. In acute hepatitis due to HAV, relapses may occur 30 to 60 days after the initial illness and mimic a biphasic hepatic disorder.
8. The absence of gastrointestinal symptoms, improvement in prothrombin time, and improved overall sense of well-being indicate recovery.
9. Chronic hepatitis generally occurs less frequently following acute symptomatic (icteric) hepatitis.
10. The hepatitis D virus (HDV, δ) requires the HBV virus for both acute and chronic infection. Patients with acute HDV infection may present in two ways:
a. In acute HBV and HDV coinfection, resolution of acute hepatitis B is followed by a second biphasic episode of hepatitis. This is due to suppression of HDV during the initial HBV infection.
b. In acute HDV superinfection of chronic HBV infection, the ensuing hepatitis usually has a severe chronic accelerated course.
11. The type of preexisting HBV infection may be important in determining the outcome of HDV superinfection. Active HBV viral replication (hepatitis B e antigen [HBeAg] positive, HBV DNA positive) appears more likely to be associated with a severe acute illness, presumably related to high viral levels. The propensity to develop chronic HDV infection is more likely in cases of low-level replication (anti-HBe positive, HBV DNA <10 5 copies/ml).
12. Symptomatic hepatitis occurs in only about 15% of patients with acute HCV, which is usually diagnosed in the setting of postexposure surveillance or seroconversion in high-risk populations (e.g., health care providers, injection drug users). Elevations in serum transaminases in acute HCV can be as high as 10 times the upper limit of normal. Jaundice is rare; however, there is a higher likelihood of clearance of the hepatitis virus in symptomatic jaundiced patients. Overall, the infection clears in about 30% to 35% of patients, meaning chronic infection develops in about 65% to 70% of patients. Fulminant hepatitis almost never occurs. Patients in whom the virus clears have strong virus-specific CD4+ T-cell reactivity within the first few weeks of infection. Because HCV antibody levels are seen 12 weeks after infection, early diagnosis requires testing for HCV RNA by polymerase chain reaction (PCR).
13. The hepatotropic viruses HBV, HCV, and HDV cause both an acute and chronic hepatitis and are discussed in more detail in this chapter under “Chronic Viral Hepatitis”; however, the enteric hepatic viruses HAV and HEV are associated with only acute infection (rare examples of HEV chronicity).
a. Viral hepatitis type A
i. The HAV is a single-stranded 7.6-kb positive sense nonenveloped RNA virus with three viral capsid proteins (VP1, VP2, and VP3). It causes acute infection with clearance and complete immune response and has fulminant, relapsing, and cholestatic presentations. There are three genotypes: 1A, 1B, and 2.
ii. The virus replicates in the gastrointestinal tract, enters the portal circulation, accesses the hepatocytes through the space of Disse, and replicates in the cytoplasm in membrane-bound replication complexes. The virus is excreted via the biliary canalicular membrane (because of lack of a lipid envelope) and into feces, where shedding can occur for 30 days, providing a source of infection in person-to-person contact. Elimination of the infection occurs by a T-cell-medicated cytokine response, and immunity is established by neutralizing antibodies.
iii. Vaccination confers immunity in almost 100% of patients.
b. Viral hepatitis type E
i. The HEV is a single-stranded 7.2-kb RNA virus with the RNA genome expressed in ORF proteins (ORF1, ORF2, and ORF3). There are two genotypes (1 and 2) that occur worldwide, mostly in the developing countries.
ii. Recently genotypes 3 and 4 have been noted in swine and humans, and genotype 4 has been shown to be a zoonotic source of subclinical infection in developed countries. The infection presumably occurs from the ingestion of infected meat.
iii. Pregnant women appear to be susceptible to infection, with high mortality in India for unclear reasons.
iv. Chronic HEV leading to cirrhosis has been reported in organ transplant recipients in both developing and developed countries.
v. Two vaccines are in development using 56 kD ORF 2 protein; their efficacy against HEV infection is 85% to 95%.
14. Some of the basic but important pathophysiologic concepts of viral hepatitis include the following:
a. The obligatory hepatotropic viruses initially bind to liver cell surface molecules, whereby antibodies against the viruses may either initiate phagocytic clearance via opsonization or inhibit viral attachment and penetration within the cell, with eventual viral clearance.
b. The viruses that do enter the hepatocyte elicit an immune reaction that clears the virus in two ways: (1) by destroying the cell containing the virus and (2) by secreting antiviral cytokines that directly inhibit viral gene expression and replication without cell destruction.
c. The principal mechanism rests with the function of CD8+ cytotoxic T lymphocytes, although other cells, including CD4+ T cells, macrophages and neutrophils, natural killer (NK) cells, and various lymphokines and cytokines, also play a role in viral-related liver cell injury.
d. The eventual necrosis of infected cells is also accompanied by antibody-associated neutralization of circulating virus and inhibition of liver cell reinfection.
e. Although the cytotoxic T lymphocytes are the principal determinate in destroying the infected cells, nondestructive mechanisms that also eliminate the virus are mandatory in eventual viral eradication and liver cell regeneration.
f. Chronicity results when the curative response is only partial, whereby the immune mechanism does not entirely eliminate the virus and can occur via either decreased CD8+ activity (resulting in a persistent but active chronic hepatitis) or total absence of CD8+ activity (chronic “carrier” state).

Table 2-1 Clinical and Biologic Behavior of Hepatotropic Viruses

Table 2-2 Serologic Diagnoses of Acute and Chronic Viral Hepatitis

Treatment and prognosis

1. Although resolution of acute hepatitis is the rule, the development of fulminant or submassive necrosis is associated with a poor prognosis, leading to mortality in more than 80% of patients. In these patients, liver transplantation should be considered, provided these patients do not have comorbid conditions that would preclude a successful outcome.

Fulminant Hepatitis
p0520( Figs 2-14 through 2-22 )

Figure 2-14 Fulminant hepatitis, massive (panlobular) hepatic necrosis . A, The liver is slightly small (1100 g) and has a wrinkled capsule as a result of significant loss of the liver volume from severe panlobular liver cell necrosis in this example of fulminant hepatitis from acute hepatitis A virus (HAV) infection. B, Cut section shows striking hemorrhage in the lobules, which microscopically showed almost total loss of the hepatocytes.

Figure 2-15 Fulminant hepatitis, submassive hepatic necrosis . The liver is small (580 g). The hepatic lobes show numerous bulging regenerative nodules representing hepatocytes that survived the acute hepatitis and that are attempting to replace the damaged liver.

Figure 2-16 Fulminant hepatitis, hepar lobatum . A, The liver shows large deep scars within both the right and left lobes, with marked bulging as a result of liver cell regeneration (hepar lobatum) in this example of fulminant hepatitis secondary to acute hepatitis A virus (HAV) infection. B, Cross section shows the deep fibrous scars encompassing hilar vessels. The parenchyma shows a somewhat mottled pattern. Microscopy from this liver showed the portal tracts within the nodules to have little, if any, fibrosis.

Figure 2-17 Fulminant hepatitis . This low-power image from a section taken from the liver in Figure 2-14 shows marked wrinkling of Glisson’s capsule due to panacinar necrosis and liver cell dropout. The parenchyma stains a vague light blue from condensation of the reticulin framework and not from true fibrosis. (Trichrome.)

Figure 2-18 Fulminant hepatitis . A, The basic portal-perivenular architectural pattern is intact, with the portal tracts of normal size; however, there is prominent liver cell necrosis and dropout surrounding a terminal hepatic venule in the upper left of the field. B, Three portal tracts can be seen closely approximating each other as a result of striking confluent necrosis and almost total liver cell dropout in the corresponding lobules between these portal tracts. (Trichrome.)

Figure 2-19 Fulminant hepatitis . A portal tract and the adjacent parenchyma are present. The portal tract shows prominent lymphocytic infiltrates and bile ductular proliferation. The parenchyma shows striking liver cell necrosis with dropout of all the hepatocytes (massive hepatic necrosis). Lobular lymphocytic infiltrates and Kupffer cell hyperplasia are prominent.

Figure 2-20 Fulminant hepatitis . A higher-power view of a portal tract shows prominent lymphocytic infiltrates similar to that seen in typical nonfatal acute viral hepatitis. Bile ductular proliferation is prominent.

Figure 2-21 Fulminant hepatitis . A, Medium-power view of the parenchyma shows total liver cell dropout with lymphocytic infiltrates and Kupffer cell hyperplasia. Proliferating ductules are seen at the edges of the field and represent activation and proliferation of stem cells in the reparative process. B, High-power view shows the collapsed parenchyma to be composed of hyperplastic Kupffer cells, macrophages, residual apoptotic hepatocytes, and lymphocytes.

Figure 2-22 Fulminant hepatitis . Residual spared hepatocytes are seen in this field (submassive hepatic necrosis).

Major morphologic features: subtypes

1. Confluent (submassive) hepatic necrosis: Portal and parenchymal changes are similar to those seen in acute viral hepatitis, but with prominent perivenular liver cell necrosis, cell dropout, and collapse of the reticulin framework. Bridging necrosis may also be seen adjoining adjacent perivenular zones or extending from the perivenular to the periportal zones. The term submassive is best used when the degree of confluent necrosis is quite striking and involves dropout of most, but not all, hepatocytes.
2. Panlobular, panacinar (massive) hepatic necrosis: Portal inflammation and diffuse lobular necroinflammatory change with associated liver cell dropout and lobular collapse involving all liver cells in all zones occur.

Other features

1. The lobular architectural pattern remains intact, with the perivenular and midzones showing extensive liver cell dropout and lobular collapse of the reticulin framework.
2. The areas of confluent necrosis contain abundant hypertrophic Kupffer cells and macrophages that phagocytize the damaged liver cells; these macrophages often contain abundant ceroid (DiPAS) pigment.
3. Portal tracts show a predominantly lymphocytic infiltrate, sometimes with occasional plasma cells, with mild proliferation of interlobular bile ducts.
4. Prominent proliferation of cholangioles (ductules, transformed or “metaplastic” ducts, neocholangioles) that sometimes contain bile plugs are often seen at the edges of the portal tracts; these ectatic cholangioles represent progenitor cells capable of transforming into duct epithelium or hepatocytes.
5. Portal tracts sometimes will appear close together due to the confluent necrosis and dropout of hepatocytes, substantially decreasing the volume of liver parenchyma between portal tracts.
6. Confluent necrosis involving the periportal zones often demonstrates viable but damaged hepatocytes “trapped” in and among the areas of necrosis.
7. Cholestasis can be present within the lobules and may be prominent in areas where the hepatocytes are still present; however, in the areas of confluent necrosis, cholestasis may be absent.
8. In instances associated with severe confluent necrosis with marked liver cell regeneration, fibrous scars representing the collapsed parenchyma can be seen adjacent to large, grossly bulging regenerative nodules, the liver then having a potato-like appearance (hepar lobatum).
9. Progression to chronic liver disease with fibrosis and cirrhosis does not usually occur with resolution of the hepatitis; however, those biopsies showing confluent necrosis with portal-perivenular bridging are more often associated with disease progression compared with biopsies showing only perivenular-perivenular bridging necrosis.

Special stains

1. PAS after diastase digestion (DiPAS): Cytoplasmic intralysosomal granules are quite prominent in macrophages and Kupffer cells in areas of necrosis secondary to phagocytosis of necrotic liver cells.
2. Masson trichrome, orcein, Verhoeff’s Van Gieson, Sirius red stains: The portal tracts, which normally contain the doubly refractile type I mature collagen fibers, stain dark blue, whereas the lobular areas of collapse, with condensation of reticulin fibers (type III collagen), stain a light blue using Masson trichrome stain. In addition, the orcein and Van Gieson stains for elastic tissue fibers, and the Sirius red stain for collagen, are usually negative in areas of confluent necrosis. These stains can be helpful in differentiating fulminant hepatitis arising in a nonfibrotic liver from severe fibrosis or cirrhosis that errantly is diagnosed because on hematoxylin and eosin (H&E) stain, the areas of collapse may resemble true fibrous bands.
Note: The reticulin stain helpfully demonstrates the areas of lobular collapse by staining the type III collagen; however, reticulin fibers are also normally present to some degree within portal structures, meaning portal fibrosis and even cirrhosis rather than lobular collapse can also be highlighted by this stain. Therefore, the Masson trichrome and other stains listed here are more helpful in distinguishing the difference between true fibrosis and lobular collapse.

Immunohistochemistry

1. HBsAg, HBcAg: Surface and core antigens in fulminant acute viral hepatitis secondary to HBV infection are always negative. If there is any positive cytoplasmic or nuclear staining, then acute “fulminant” hepatitis arising in a patient with underlying early-stage chronic HBV or a severe reactivation of chronic HBV hepatitis is present.
2. Delta antigen: In cases of fulminant hepatitis secondary to HBV and acute δ infection, the δ antigen is present in the nuclei of viable liver cells.
3. Cytokeratins (particularly CK7, CK8, CK18, and CK19): Staining of the proliferating cholangioles is enhanced.

Differential diagnosis

1. Drug-induced liver cell injury (e.g., isoniazid, ketoconazole; see Table 5-5 ): Many drugs that cause acute hepatitis may also be associated with fulminant hepatitis (confluent submassive or massive hepatic necrosis). Sometimes the degree of portal inflammation in drug-induced fulminant hepatitis is not as prominent as that seen in acute viral infection.
2. Wilson disease: This autosomal recessive inherited disorder associated with increased hepatic copper deposition may rarely present with jaundice, hemolysis, and renal failure and histologically may resemble the features of fulminant hepatitis secondary to the hepatotropic viruses. The presence of Mallory bodies, prominent irregular cytoplasmic clumps (lysosomes), glycogenated nuclei, and increase in stainable copper (rubeanic acid stain) and often copper-binding protein (orcein stain) in viable hepatocytes are helpful clues in distinguishing fulminant Wilson disease from a viral etiology.
3. Autoimmune hepatitis: Patients with this liver disease may present with an acute, rapidly progressive course, with histologic changes of confluent (submassive) hepatic necrosis and marked portal and lobular inflammation. In autoimmune hepatitis, however, some degree of portal fibrosis is usually also present. In addition, the plasma cell infiltrates in autoimmune hepatitis are usually quite prominent.
4. Chronic hepatitis with severe fibrosis, cirrhosis: Areas of confluent bridging necrosis with regenerative activity of viable hepatocytes in fulminant hepatitis may mimic on H&E stain active but chronic hepatitis with bridging fibrosis. The trichrome stain showing a loose light blue staining pattern and the absence of elastic tissue fibers (using orcein or Verhoeff’s Van Gieson stains) are features of confluent necrosis and not true fibrosis. In addition, a Sirius red stain for collagen is usually negative in areas of confluent necrosis.
5. Extrahepatic bile duct obstruction: The prominent proliferation of cholangioles that sometimes contain bile plugs in fulminant hepatitis can resemble, in part, the ductular changes associated with extrahepatic bile duct obstruction; however, the interlobular bile ducts, which occur adjacent to hepatic arteriole segments and show prominent proliferation, ectasia, periductal edema, and sometimes acute cholangitis in bile duct obstruction, are normal appearing in fulminant hepatitis. In addition, confluent necrosis is not a feature seen in bile duct obstruction.

Clinical and biologic behavior

1. The prevalence of fulminant hepatitis from viral hepatitis (types A, B, C, and E) overall is less than 1%; however, during epidemics of acute HEV, the mortality in infected pregnant women in India is 10% to 20%, compared with Egypt, which has no increased mortality. The probability of fulminant hepatitis developing in type B hepatitis with HDV coinfection is increased. Fulminant hepatitis with acute HCV is extremely rare.
2. A high prevalence of HDV markers (21% to 50%) among patients with fulminant hepatitis B indicates that the severe hepatitis results from cumulative damage by the two viruses.
3. This severe form of acute viral hepatitis is clinically heralded by the persistence of gastrointestinal symptoms (e.g., nausea, vomiting, dyspepsia), prolonged prothrombin time, and features of early encephalopathy (drowsiness, lethargy, and asterixis).
4. Ascites, lower extremity edema, renal failure, gastrointestinal bleeding, disseminated intravascular coagulation, hypoglycemia, sepsis, hypovolemia, adult respiratory distress syndrome, and cerebral edema may complicate the course of fulminant hepatitis.
5. In fulminant hepatitis B virus infection, significant exponential elevations of α-fetoprotein are more often associated with improved survival.
6. Patients who recover do not develop any form of chronic liver disease. Of note, during the early stages, large regenerative nodules may irregularly form, mimicking a cirrhotic liver on imaging and gross examination. Upon resolution, these nodules coalesce and eventually disappear.
7. Biopsies are generally not performed in these patients because of low prothrombin time unless done by the transjugular route. Overall, biopsies are usually not useful to predict recovery.
8. A number of pathophysiologic processes play a role and include the following:
a. Immune-mediated injury (most important with HBV infection; fulminant hepatitis often occurs in the absence of detectable HBV because of the low level of viral replication)
b. Injury from activation of cytokines, tumor necrosis factor (TNF), and interleukins (IL-1 and IL-6)
c. Direct liver cell injury by lymphocytes, fibroblasts, and monocytes
d. Tissue hypoxia (decreased hepatic perfusion secondary to disturbance in the microvasculature; capillary obstruction from debris such as actin filaments and collagen)
e. Endotoxin-induced damage

Treatment and prognosis

1. The prognosis and outcome depend on the type of hepatitis, the presence of underlying liver disease, and the patient’s age. For example, coexisting HBV and HDV infections have a greater probability of a severe course, and consequently, a poorer prognosis, than seen with HBV infection alone.
2. Older individuals tend to have a more protracted and severe course compared with younger patients, with mortality approaching 100% in persons older than 40 years.

Chronic Viral Hepatitis
( Figs 2-23 through 2-52 )

Figure 2-23 Chronic viral hepatitis, cirrhosis . A, The external surface of the liver from a patient with chronic viral hepatitis resulting from hepatitis B virus (HBV) infection is coarsely nodular, the nodules measuring from less than 1 to up to 2 cm in greatest dimension (macronodular). B, Cut section shows the nodules to be well demarcated; the largest nodule in this image measures 9 mm in diameter. The nodules appear green as a result of marked cholestasis.

Figure 2-24 Chronic viral hepatitis, early stage, relatively inactive . A and B. These two portal tracts from the same biopsy show expansion by lymphocytes; fibrosis is minimal or absent. No periportal interface inflammatory activity (“piecemeal” necrosis) is present.

Figure 2-25 Chronic viral hepatitis, early stage, minimally active . The parenchyma shows diffuse mild hydropic change with rare spotty necrosis.

Figure 2-26 Chronic viral hepatitis, active . The portal tract shows lymphocytes spilling out into the periportal region, surrounding individual and small groups of hepatocytes (periportal interface inflammatory activity, “piecemeal” necrosis), a morphologic indicator of active disease.

Figure 2-27 Chronic viral hepatitis, active . High-power view of the periportal zone shows periportal interface inflammatory activity (“piecemeal” necrosis).

Figure 2-28 Chronic viral hepatitis, active . Lymphocytes can be seen spilling out of the portal tracts at the edges of the field and surrounding individual and small group of hepatocytes (periportal interface inflammatory activity), a feature characteristic of the active stage of the disease.

Figure 2-29 Chronic viral hepatitis, active . Periportal interface inflammatory activity is present, with the hepatocytes exhibiting cytoplasmic eosinophilia as a result of prominence of the mitochondria (oxyphilic change); these types of cells are sometimes seen in chronic viral hepatitis.

Figure 2-30 Chronic viral hepatitis . Nuclear anisocytosis and mild fatty change are seen.

Figure 2-31 Chronic viral hepatitis . The periportal hepatocytes show variability in the nuclear size (anisocytosis), with some of the nuclei pleomorphic, an example of large cell dysplastic change usually evident in cirrhotic nodules but sometimes occurring in fibrotic livers as well.

Figure 2-32 Chronic viral hepatitis . Variability in the same field of cell size, cytoplasmic changes, and the degree of inflammation are often characteristic of chronic viral hepatitis. The lobule to the left of the field shows no inflammation; rather, it exhibits diffuse hydropic change of the hepatocytes secondary to liver cell regeneration. The lobule to the right shows fatty change, prominent nuclear anisocytosis of hepatocytes, and a mild lymphocytic infiltrate.

Figure 2-33 Chronic viral hepatitis: hepatitis B virus (HBV) + δ . The degree of lobular necroinflammatory activity can sometimes be diffuse and is often seen in chronic HBV with associated δ virus infection, as this example demonstrates.

Figure 2-34 Chronic viral hepatitis: hepatitis B virus (HBV) . Hepatocytes that have a ground-glass appearance can be seen in ½ to ⅔ of cases of chronic viral hepatitis caused by HBV infection. They are usually scattered within the lobules (A), but at times may be diffuse (B).

Figure 2-35 Chronic viral hepatitis: hepatitis B virus (HBV) + δ . The ground-glass cells in chronic HBV infection with or without δ coinfection may also demonstrate a clearing (“halo” effect) immediately adjacent to the ground-glass inclusions, as seen in this image.

Figure 2-36 Chronic viral hepatitis: hepatitis B virus (HBV) . The ground-glass cell shown on high power is due to proliferation of the endoplasmic reticulum synthesizing the hepatitis B surface antigen particles.

Figure 2-37 Chronic viral hepatitis: hepatitis B virus (HBV), electron microscopy . This ground-glass cell on electron microscopy shows proliferation of tubular and spherical particles (22 nm) located within the endoplasmic reticulum, representing the hepatitis B surface antigen (HBsAg). The small spherical particles (27 nm) located within the liver cell nucleus at the upper left of the field represent hepatitis B core antigen (HBcAg). An arrow (upper field) notes hepatitis B core particles immediately outside a nuclear pore. The other arrows show larger spherical double-ringed (42 nm) Dane particles representing the complete hepatitis B virus. L, Lipid; m, mitochondria; p, peroxisomes.
(From Phillips MJ et al: The Liver. An Atlas and Text of Ultrastructural Pathology. New York: Raven Press, 1987; with permission from Lippincott Williams & Wilkins.)

Figure 2-38 Chronic viral hepatitis: hepatitis B virus (HBV) . The surface antigen particles may be numerous or spotty and often vary from one lobule to another. A, Almost all the hepatocytes take up a diffuse strong cytoplasmic staining in this medium-power field. B, The cytoplasmic staining in this higher-power field is intense but focal, with relative sparing of the liver cell nuclei. (Immunoperoxidase stain for HBsAg.)

Figure 2-39 Chronic viral hepatitis: hepatitis B virus (HBV) . The core antigen most characteristically is present within the hepatic nuclei. In active disease, cytoplasmic staining can often be seen as well. (Immunoperoxidase stain for HBcAg.)

Figure 2-40 Chronic viral hepatitis: hepatitis B virus (HBV) + δ . In chronic HBV with coexisting δ infection, the δ antigen can be seen within the liver cell nuclei. (Immunoperoxidase stain for δ antigen.)

Figure 2-41 Chronic viral hepatitis: hepatitis B virus (HBV) . Orcein stain, most often useful for staining copper-binding protein, can also demonstrate diffuse cytoplasmic staining of the hepatitis B surface antigen.

Figure 2-42 Chronic viral hepatitis: hepatitis C virus (HCV) . A, A benign lymphoid aggregate is seen within the portal tract. B, This lymphoid aggregate also contains a small reactive germinal center.

Figure 2-43 Chronic viral hepatitis: hepatitis C virus (HCV) . The lymphoid aggregate contains an interlobular bile duct that shows some cytologic distortion; the duct is also infiltrated by lymphocytes.

Figure 2-44 Chronic viral hepatitis: hepatitis C virus (HCV) . The centrally located duct within the lymphoid aggregate shows minimal cytologic damage.

Figure 2-45 Chronic viral hepatitis: hepatitis C virus (HCV) . Periportal arachnoid fibrosis is seen in this field and is often present in chronic HCV infection. (Trichrome.)

Figure 2-46 Chronic viral hepatitis: hepatitis C virus (HCV) . Fatty change is common in chronic HCV infection, is usually mild, and is seen in this image with associated mild necroinflammatory change.

Figure 2-47 Chronic viral hepatitis, intravenous (IV) drug abuser . Chronic viral hepatitis associated with IV drug abuse can sometimes demonstrate in liver biopsies the injectant material, which is most concentrated within the portal tracts. A, The portal tract on low power shows scattered lymphocytes and histiocytes. A suggestion of crystalline material is seen at this magnification. B, High power of the same portal tract demonstrates abundant crystalline material that is predominantly free within the stroma.

Figure 2-48 Chronic viral hepatitis, intravenous (IV) drug abuser . A, High power of a portal tract in a long-term IV drug abuser shows classic extracellular crystalline material. B, The crystals in the same field are best demonstrated and confirmed by their strong birefringence under polarized light.

Figure 2-49 Chronic viral hepatitis, bridging fibrosis . A and B. These two images demonstrate portal fibrosis with portal-to-portal bridging, without complete regenerative nodule formation. (Trichrome.)

Figure 2-50 Chronic viral hepatitis, cirrhosis . The fibrous bands with regenerative nodule formation can be seen from this explanted liver. The nodules are well demarcated, without appreciable periseptal intrasinusoidal collagen deposition. (Trichrome.)

Figure 2-51 Chronic viral hepatitis, cirrhosis . The regenerative nodules are well demarcated, with the fibrous septa exhibiting a mild lymphocytic infiltrate.

Figure 2-52 Chronic viral hepatitis, cirrhosis . An increase in portal venous radicals within the fibrous septa as a result of portal hypertension is characteristically seen in cirrhotic livers of almost any cause. A diffuse lymphocytic infiltrate and scattered bile ducts and ductules are also present.

Major morphologic features

1. Portal lymphocytic infiltrates are present, with variable periportal inflammatory activity (periportal interface hepatitis, “piecemeal” necrosis) consisting of lymphocytes spilling over into the adjacent periportal zones and surrounding individual and small groups of hepatocytes (“trapped” liver cells).
2. Lobular necrosis, inflammation, hydropic change, and apoptosis away from the periportal zones occur and are often irregularly distributed from one lobule to the next.
3. Although the portal tracts in early-stage disease may show little, if any, fibrosis and may only appear expanded because of the prominent inflammatory infiltrates, with time portal fibrosis with bridging (portal-to-portal and portal-to-perivenular) and cirrhosis (fibrous septa and regenerative nodule formation) eventually occur.

Other features

1. The degree of portal and periportal inflammatory activity varies from one portal tract to the next.
2. Bile duct and cholangiolar proliferation may be present but are not prominent, except in instances of severe liver cell injury.
3. Cholestasis may be seen in the more severe and active stages of the disease.
4. “Reactivation” of hepatitis may occur. This is associated with active viral replication and can be associated with a diffuse necroinflammatory change, sometimes with perivenular confluent necrosis, that may histologically mimic acute viral hepatitis.
5. The liver cells adjacent to areas of necroinflammatory change may appear hydropic as a result of liver cell regeneration; these groups of liver cells often have a cobblestone pattern and form cords two to three cells thick (best appreciated on the reticulin stain).
6. Focal nuclear anisocytosis and dysplasia of hepatocytes can occasionally be seen and are usually more obvious in the periportal zones.
7. Kupffer cell hyperplasia is seen to variable degrees.
8. Periportal or periseptal hepatocytes occasionally have a prominent cytoplasmic eosinophilia ( oncocytic or oxyphilic change) secondary to proliferation of mitochondria.
9. In intravenous drug users, particulate polarizable birefringent material may be seen within the portal tracts and occasionally within Kupffer cells and represents the injectant used (e.g., talc, silicon). These crystalline inclusions seldom elicit a histiocytic response.
10. In the cirrhotic stage, the regenerative nodules are often “macronodular” (>3 mm in diameter); however, both micronodules (≤3 mm in diameter) and “mixed” macronodules and micronodules may also be seen.
11. In the cirrhotic liver, enlarged regenerative nodules (macronodules when >8 mm in greatest dimension) that show nuclear and cytoplasmic atypia (“dysplastic” nodules) may occur and may require further investigation for transformation to hepatocellular carcinoma (see “Regenerative Lesions” in Chapter 10 ).
12. All of the aforementioned histologic changes can be seen with any of the hepatotropic viruses associated with chronic hepatitis (B, δ, C, G, non-A through non-G); however, the subtypes may also show the following on routine stains:
a. HBV
i. “Ground-glass” cells are present in 1 2 to ⅔ of the cases; these hepatocytes have a diffusely finely granular eosinophilic cytoplasm, sometimes with a thin “clear” space adjacent to the cell membrane, and represent proliferation of the endoplasmic reticulum synthesizing the 22-nm HBsAg particles. There is no particular zonal predominance for these cells; in fact, the ground-glass cells can cluster and sometimes be prominent in one regenerative cirrhotic nodule but be absent in others.
ii. The liver cell nuclei can sometimes have a sanded, finely granular appearance as a result of the presence of HBcAg.
iii. Portal and lobular plasma cell infiltrates can be prominent at times.
iv. The degree of liver cell dysplasia and oxyphilic (oncocytic) cellular changes are more frequently seen when compared to the other hepatotropic viruses.
v. Development of hepatocellular carcinoma is frequent over time and may occur in both fibrotic and cirrhotic livers.
b. HBV and δ
i. The degree of periportal interface inflammatory activity is usually more prominent than with chronic HBV infection alone.
ii. Occasional hepatocytes may exhibit microvesicular fat.
iii. Progression to hepatocellular carcinoma is uncommon.
c. HCV
i. Portal lymphoid aggregates and follicles, sometimes exhibiting germinal centers, are seen in more than ½ of the cases.
ii. Interlobular bile ducts may be seen within the center of the lymphoid aggregates and exhibit variable cellular atypia, with lymphocytes hugging up against the duct basement membrane and sometimes infiltrating into the duct epithelium itself.
iii. Variable but usually mild macrovesicular fatty change is common.
iv. Glycogenated liver cell nuclei, intrasinusoidal collagen deposition, and variable degrees of stainable iron are usually present.
v. Some degree of sinusoidal lymphocytosis may occur.
vi. Progression to hepatocellular carcinoma is common and occurs most frequently in the cirrhotic stage.
d. HGV
i. The degree of portal and lobular inflammation is usually mild.
ii. Fibrosis is not a feature associated with chronic HGV infection alone; if portal fibrosis is present, then concurrent HBV or HCV infection should be strongly suspected.
iii. There is some question as to whether chronic HGV infection alone, without coinfection with HBV or HCV, causes histologic changes of a chronic viral hepatitis or simply represents a carrier state.
e. Non-A through non-G
i. Giant cell transformations of hepatocytes have been reported, similar to those also described in the acute phase.
Note: Chronic HEV infection has been reported in immunosuppressed patients after liver transplantation, with case reports of progression to cirrhosis.

Special stains

1. In chronic HBV infection, cytoplasmic staining of the HBsAg particles in ground-glass cells can be demonstrated using the following stains:
a. Orcein (brown)
b. Victoria blue (blue)
c. Aldehyde fuchsin (purple)
2. Masson trichrome: This stain for collagen enhances visualization of the degree of fibrosis and can more easily help depict sinusoidal collagen deposition.
3. PAS after diastase digestion (DiPAS): Increases in lysosomal activity and deposition of ceroid pigment in areas of necrosis are highlighted.
4. Reticulin stain: The liver cell plates one to two cells thick in the regenerative cirrhotic nodules can best be appreciated, and this stain is helpful in dysplastic foci to rule out hepatocellular carcinoma where the liver cell plates are thicker and/or the reticulin stain shows decreased to absent staining (see “Hepatocellular Carcinoma” in Chapter 10 ).

Immunohistochemistry

1. HBsAg: The cytoplasm of ground-glass cells in chronic HBV infection shows either uniform or perinuclear staining. Cytoplasmic staining can also be seen in cells that do not have the characteristic ground-glass appearance on H&E stain. Less frequently, linear membrane staining can also be present and is usually associated with active viral replication.
2. HBcAg: Nuclear staining of hepatocytes is present and often prominent in association with active viral replication. In some instances, staining of the cytoplasm may also be seen. In immunocompromised patients (e.g., acquired immunodeficiency syndrome, post-transplantation, dialysis), the vast majority of the nuclei may show strong positive staining.
3. Delta antigen:
a. In acute δ infection superimposed on chronic HBV infection, variable degrees of nuclear staining of hepatocytes are present with an even distribution from one lobule to the next; staining of coexisting HBsAg may also occur but is uncommon in acute δ infection.
b. In chronic δ infection, variable nuclear staining of hepatocytes with an irregular distribution from one lobule to another is characteristic; suppression of HBcAg, not HBsAg, commonly occurs.
4. HBeAg: Nuclear staining is seen that parallels HBcAg nuclear staining.
5. HCV: Cytoplasmic staining of hepatocytes using monoclonal antibodies directed against HCV core polypeptides is positive in up to 75% of cases; however, it is important to exclude background cytoplasmic staining in these cases. In addition, there does not appear to be a correlation with staining and the presence or absence of inflammatory activity.

Histologic disease grading and staging
Histologic staging (degree of fibrosis) and grading (degree of necroinflammatory activity) has become a very useful tool for the clinician in deciding whether patients with chronic viral hepatitis should be treated with antiviral therapy. The recommended histologic sign-out description first states the etiology of hepatitis (e.g., chronic hepatitis C), followed by the degree of fibrosis (e.g., portal fibrosis with bridging) and the degree of activity (e.g., mildly active), with appropriate numerical codes using the particular classification and scoring system used. Some of the more popular grading and staging systems are listed in Table 2-3 and are described in detail in the Appendix (Tables A through C) Table A Table B Table C .
Table 2-3 Chronic Viral Hepatitis Histologic Grading and Staging Systems SYSTEM ∗ FIBROSIS ACTIVITY Ishak K et al (1995) Portal fibrosis (0–6)
Portal inflammatory infiltrates (0–4)
Periportal inflammation (0–4)
Confluent necrosis (0–6)
Lobular necroinflammatory change (0–4) Batts KP, Ludwig J (1995) Portal fibrosis (0–4) Periportal and intralobular inflammation (0–4) METAVIR Cooperative Study Group (1994, 1996) Portal fibrosis (0–4) Piecemeal necrosis and lobular inflammation (0–3)
∗ see Expert Consult website for references.

Differential diagnosis

1. Acute viral hepatitis: Portal fibrosis is not present in acute viral hepatitis alone, with the necroinflammatory change seen in acute viral hepatitis evenly distributed from one lobule to the next. In chronic viral hepatitis, usually some degree of portal fibrosis is present, although in the very early stages of the disease, the fibrosis may be inconspicuous. In addition, in chronic viral hepatitis the degree of inflammation is most often milder than in acute hepatitis, with the inflammatory cellular component and necrosis unevenly distributed from one lobule to the next. In chronic HBV infection, ground-glass cells, seen in 1 2 to ⅔ of the cases, are indicative of chronic, and never acute, hepatitis B; however, in very early and active stages of chronic viral hepatitis, the fibrosis may not be apparent on biopsy and the lobular inflammation may be diffuse, hence mimicking acute viral hepatitis. In these instances, hepatitis serologies (e.g., presence of HBsAg in conjunction with the absence of high-titer anti-HBc IgM in chronic hepatitis B) and clinical history may be most important.
2. Autoimmune hepatitis: Autoimmune hepatitis usually has a prominent portal and lobular plasma cell component to the infiltrates and in untreated cases may also show periportal and/or perivenular confluent necrosis, features not typically seen in chronic viral hepatitis; however, chronic HBV infection can, at times, show considerable numbers of plasma cells. Therefore serologic correlation with both viral and autoimmune serologic markers is important (see “Autoimmune Hepatitis” in Chapter 12 for further discussion of the various serologic profiles of these patients).
3. Primary biliary cirrhosis (PBC): Approximately 15% of patients with PBC exhibit prominent periportal interface and intralobular inflammation, and the inflammation may mimic an active stage of chronic viral hepatitis. Nonsuppurative destructive duct lesions, duct depletion (paucity), epithelioid granulomas, Mallory bodies, and increased stainable copper-binding protein are features seen in various stages of PBC and are not present in chronic viral hepatitis. In addition, these patients have a positive antimitochondrial antibody (AMA) and often high-titer antinuclear antibodies (ANA) and are considered a PBC variant ( PBC-autoimmune hepatitis overlap syndrome; refer to Chapter 12 for a more detailed description). This serology is helpful in obtaining the correct diagnosis. Of note, although chronic HCV infection can show cytologic distortion of ducts within the lymphoid aggregates, the degree of cytologic damage is usually considerably less than that seen in PBC.
4. Primary sclerosing cholangitis (PSC): In a minority of cases of PSC, periportal interface inflammatory activity can occur. Sometimes these patients may also have high-titer ANA and/or smooth muscle antibody (SMA) ( autoimmune hepatitis-PSC overlap syndrome; refer to Chapter 12 for a more detailed description). Periductal sclerosis and obliteration, duct loss (ductopenia), Mallory bodies, and increase in stainable copper-binding protein are features seen in PSC but not present in chronic viral hepatitis. Imaging of the biliary tract that shows the characteristic “beading” appearance of the bile ducts also supports a diagnosis of PSC.
5. Drug-induced liver injury (e.g., α-methyldopa, phenylbutazone; see Table 5-13 ): The morphologic changes seen with drug-induced chronic hepatitis may be virtually indistinguishable from chronic viral hepatitis. The presence of ground-glass cells signals chronic HBV infection. Serologic serum markers and a drug history are critical for proper histologic assessment.
6. Nonspecific reactive changes: Portal lymphocytic infiltrates, mild lobular fatty change, and mild focal necroinflammatory change may be seen in certain conditions such as intra-abdominal or systemic infections and in chronic systemic inflammatory disorders (e.g., rheumatoid arthritis) and may mimic early forms of a mildly active chronic viral hepatitis on histologic grounds alone. Serologic testing and clinical correlation are necessary in these instances.
7. Wilson disease: This autosomal recessive inherited disorder associated with increased hepatic copper deposition may show all of the histologic changes seen in chronic viral hepatitis. Aiding in the correct diagnosis of Wilson disease is the presence of increased hepatic copper and copper-binding protein demonstrated by special stains on biopsy material (e.g., rubeanic acid, rhodanine stains for copper, orcein stain for copper-binding protein), the demonstration of increased hepatic copper by quantitative methods on biopsy tissue, and correlation with low serum ceruloplasmin levels and high urinary copper excretion.
8. Other causes of chronic hepatitis: A number of other liver diseases, such as α 1 -antitrypsin deficiency, sarcoidosis, and various nonviral infectious processes (e.g., salmonellosis, syphilis), may show many morphologic changes similar to the various stages in chronic viral hepatitis. Although many of these liver diseases have some morphologic characteristics distinctive from chronic viral hepatitis (e.g., granulomas in sarcoidosis), in not all instances is biopsy material adequate to arrive at the correct diagnosis. In these instances, appropriate serologic workup and clinical correlations are sometimes the only methods to help the physician arrive at the most likely diagnostic possibilities.

Clinical and biologic behavior

1. Chronic viral hepatitis involves the hepatotropic viruses B, D superinfection, and C; hepatitis A and E virus do not cause chronic disease. Hepatitis G virus is evident in chronic hepatitis but has little pathologic significance.
2. The diagnosis of hepatitis non-A through non-G refers to suspected viral hepatitis not caused by the hepatotropic viruses A, B, C, D, E, or G and is determined by negative currently available serologic and viral tests for these viruses.
3. Chronic infection with any of the hepatotropic viruses is, in part, dependent on various viral determinants such as gene products that initiate or inhibit apoptosis, with direct hepatotoxicity playing a minimal role, except in immunosuppressed patients in whom cytopathic effects are rarely seen. Abnormalities in the innate and adaptive immune response play a part in persistence of virus infection and in chronic hepatitis.
4. The liver may be enlarged, firm, and nontender, and it often becomes impalpable when cirrhosis occurs. Splenomegaly is present in about 50% of cases regardless of the cause and is almost always present when cirrhosis and portal hypertension develop.
5. Chronic HBV
a. HBV is a 3.2-kb DNA virus with complete minus strand and incomplete positive strand that replicates by reverse transcriptase; at infection peak, 10 9 virions are produced.
b. HBV genome in the hepatocyte exists in the cytoplasm as covalently closed circular DNA (cccDNA), which serves as a template for six messenger RNAs and pregenomes that maintain infection. Linear genomes recombine to produce cccDNA or recombine for integration into host DNA.
c. Replication is noncytopathic. Antiviral therapy stops new cccDNA but does not eliminate existing cccDNA, which survives mitoses. Elimination of cccDNA occurs with death of the hepatocytes, and clearance is seen with more than 70% loss of infected hepatocytes. At initial infection, HBV spreads to 95% of the hepatocytes; this declines to 30% in chronic infection.
d. An estimated 400 million persons are chronically infected with HBV worldwide, and an estimated 500,000 people die annually of cirrhosis and hepatocellular carcinoma.
e. HBV is transmitted by perinatal, percutaneous, sexual, and close person-to-person contact, the latter especially common in children and adolescents in high-endemic areas.
f. The risk of developing chronic HBV after acute exposure is approximately 2% to 4% in adults. Hepatitis B carriers are those individuals who are positive for HBsAg for more than 6 months and who have inapparent infection based on normal liver tests and low-level viral replication based on HBV DNA quantitation.
g. The clinical presentation in hepatitis B can vary, ranging from normal liver tests and minimal histologic changes in asymptomatic individuals to fatigue, vague abdominal complaints and mildly to moderately elevated serum transaminases (50 to 500 IU/L) in those who are symptomatic. Mild hepatomegaly may be the only finding. HBsAg is almost always positive, and HBV DNA may be either mildly elevated (in low-level replication, <10 2 copies/ml) or markedly elevated (>10 5 copies/ml). Serum bilirubin and hepatic synthetic function are usually normal. Mild decreases in serum albumin and prolongation of prothrombin time may be seen in early cirrhosis.
h. Three serovirologic patterns of chronic HBV infection have been observed:
i. In Asia, where perinatal transmission is common, positive HBeAg and elevated HBV DNA with normal serum transaminases persist, often into adulthood, at which time seroconversion (positive HBe antibody, negative HBeAg) may occur.
ii. In sub-Saharan Africa, where person-to-person contact occurs at an early age, HBeAg seroconversion to positive HBe antibody occurs at puberty.
iii. The third pattern occurs when HBV is acquired in adulthood, largely as a result of sexual transmission, and is characterized by detectable HBeAg, elevated serum transaminases, and measurable HBV DNA. Most patients with positive HBe antibody and low levels of HBV DNA have a benign course, but periodic reactivation may occur either spontaneously or when immunosuppression is withdrawn (as occurs after chemotherapy), leading to active severe hepatitis.
i. In approximately 0.5% to 1% of HBsAg carriers, the antigen will spontaneously clear every year. In addition, in about 4% of carriers, HBsAg will clear yearly; in other words, over a 5-year period of follow up after antiviral therapy, serovirologic conversion (negative HBe antigen, positive HBe antibody, undetectable HBV DNA) will be achieved in 20% of carriers. Most of these patients will develop immunity with the development of the HBs antibody.
j. There are seven genotypes for hepatitis B (A through G). Genotype A is more common in HBV infections in the Western world. The common genotypes in other geographic areas are as follows: Asia, B and C; West Africa, A and E; South America, A; and Central America, H. Interferon responsiveness for the different genotypes is as follows: A, 42%; B, 28%; C, 26%; and D, 20%. Genotype C has a high association with liver cancer in the Far East, whereas genotype F may be associated with HBV-related hepatocellular carcinoma in Alaskan natives.
6. Chronic HCV
a. HCV is a positive single-stranded RNA virus with a 9.6-kb genome (~3000 amino acid polyproteins) that has structural proteins (components of the mature virus) consisting of the core and two envelope proteins. The nonstructural proteins are elements that permit viral replication and consist of NS2, NS3 (protease, helicase), NS4A, NS4B, NS5A, and NS5B (polymerase).
b. Viral replication occurs by RNA-dependent RNA polymerase (NS5B polymerase), resulting in spontaneous mutations and in the development of quasispecies (population of related, slightly different, ever-changing genomes) characteristic of HCV. This provides the virus the ability to evade host antiviral processes as well as drugs. HCV infection of hepatocytes occurs when the two envelope proteins E1 and E2 bind lipoprotein ApoE1 and ApoC1, which attaches to the low-density lipoprotein (LDL) receptor on the hepatocyte cell surface and enters by endocytosis.
c. The persistence of infection within the hepatocyte is based on the ability of the virus to evade intracellular antiviral processes. Both the clearance and persistence of chronic hepatitis C infection depend on the interactions between innate immunity (complement, neutrophils, dendritic cells, macrophages, NK T cells) and adaptive immunity (dendritic cells and T and B cells). Although not clear, it is suggested that a vigorous innate immune response may be responsible for clearing acute infection.
d. Hepatitis C is the major cause of liver disease in the United States, where it is estimated that more than 4 million Americans are infected.
e. The virus is commonly transmitted by the parenteral route and less frequently (6%) through sexual and perinatal routes.
f. Chronic infection develops in about 65% of patients following acute exposure. Infection is usually asymptomatic, with fewer than 30% of patients having symptoms of acute hepatitis with jaundice, fatigue, and nausea. The risk of transfusion-acquired hepatitis C with current hepatitis C antibody (EIA-3) tests is less than 0.001% per unit transfused.
g. Chronic hepatitis is characterized by normal serum transaminase levels in about 30% of patients, modest elevations in 60% to 70%, and in some patients, marked fluctuations in serum transaminase levels, often up to 1000 IU/L in some patients. Usually the alanine transaminase (ALT) is higher than the aspartate transaminase (AST), except when cirrhosis is present. Serum bilirubin is rarely elevated, and hepatic synthetic function is preserved. Cirrhosis develops in 10% to 20% of patients over 20 to 30 years, and hepatocellular carcinoma develops in about 1% to 4% of patients per year after cirrhosis is established. Serum transaminases are lower and may even normalize when cirrhosis develops, but hepatic synthetic function is impaired. In established cirrhosis and portal hypertension, muscle wasting, ascites, and variceal bleeding may be the presenting features, and in severe cases, jaundice with pruritus may be present.
h. Elevated levels of HCV RNA indicate active viral replication. There is no correlation between the levels of HCV RNA and the severity of the hepatitis. Liver biopsy is necessary to stage and grade the severity of the disease and is useful to predict the risk of cirrhosis developing if bridging fibrosis is present. HCV RNA levels using quantitative PCR are important before initiating therapy with combination antiviral drugs and in evaluating response.
i. There are 7 genotypes (1 to 7) and more than 15 subtypes. Genotype 1 is the predominant (70%) genotype in North America.
j. Cryoglobulins are present in about 30% of patients with chronic hepatitis C, but cryoglobulinemia and vasculitis are observed in only about 2% of patients. Other extrahepatic manifestations include membranoproliferative glomerulonephritis with nephrotic syndrome and porphyria cutanea tarda. Other less well-established associations are seronegative arthritis, Sjögren syndrome, autoimmune thyroiditis, lichen planus, idiopathic pulmonary fibrosis, polyarteritis nodosa, aplastic anemia, and B-cell lymphomas.
7. Chronic HDV (δ)
a. HDV (δ agent) is an RNA defective or putative virus but is now considered a viroid. Viroids are small circular RNA pathogens that do not code for proteins but contain RNA structural elements that use the host cellular proteins to replicate, transport, evade defense mechanisms (high mutation rate), and alter its gene expression.
b. HDV is a 30- to 40-nm particle, single-stranded circular RNA genome that requires HBV for replication utilizing polymerase II. In the hepatocyte, HDV replicates in the nucleoplasm and not in the nucleoli.
c. There are a number of genotypes with 35% variation in the genotype sequence. G1 is seen mostly in Western countries; G2 and G4, in the Far East; and G3, in Africa.
d. Two modes of presentation occur: (1) coinfection (occurring in about 2% of all HDV infection cases), where HDV and HBV produce a simultaneous infection and present with a biphasic hepatitis, and (2) superinfection (occurring in >90% of HDV infections), where HDV infection occurs in an individual previously infected with HBV who developed chronic hepatitis B. The outcome of coinfection with HBV and HDV is frequently an acute severe hepatitis with a high mortality rate. If the patient survives, immunity from both viruses ensues. In superinfection, the likelihood of chronic infection with both viruses is high, with propensity to more severe histologic changes than with HBV infection alone, leading to cirrhosis in 80% over 5 to 10 years.
e. The diagnosis of HDV is made in patients who are HBsAg positive and have positive HDV antibody. In acute HDV infection, such as in coinfection, HDV IgM levels are usually higher than HDV IgG levels. In chronic HDV infection, such as occurs in superinfection, HDV IgG levels are higher than HDV IgM levels; however, in clinical practice, HDV IgG is the only test that is commercially available. HDV antigen or HDV RNA may be detected early during acute HDV and can be measured using PCR techniques.
f. In HDV/HBV chronic hepatitis, HBeAg is usually negative, HBe antibody is positive, and HBV DNA is at low levels of replication.
g. The seroprevalence of HDV was high in East Asia, occurring in more than 60% prior to 1978; however, between 1978 and 1981 the seroprevalence was 25%, which declined to 8% in 1997, likely related to the lower incidence of HBV infections and to HBV vaccination. In HBV carriers, the seroprevalence of HDV in the Middle East is 6% to 20% and in North America, 0% to 5%.

Treatment and prognosis

1. Chronic HBV
a. Studies of α-interferon therapy in a large number of HBeAg-positive patients with elevated HBV DNA have demonstrated loss of serum HBV DNA in 37% and loss of HBeAg in 33% of patients. The current recommendation is to treat (1) patients with HBV DNA greater than 2000 copies/ml who are HBeAg positive for at least 5 years and (2) those that are HBeAg negative lifelong.
b. The nucleoside analog lamivudine also results in loss of HBeAg in 17% to 32% of patients, with 47% seroconversion at 4 years. The increase in resistance mutants at 5 years for lamivudine (80%), adefovir (29%), and telbivudine (21%) at 2 years make these agents less desirable for long-term treatment. The newer drugs tenofovir (acyclic nucleoside phosphonate) and entecavir (deoxyguanosine analog) approved for treatment of chronic HBV have better seroconversion rates, with significantly lower rates of resistance mutants (0% to 2%).
c. Newer agents such as adefovir and tenofovir have been effective in the treatment of lamivudine-resistant mutants.
d. Improvement in necroinflammatory changes and fibrosis has been observed in patients who have a sustained or durable response to therapy. Liver failure can develop in patients with more advanced disease and those in whom spontaneous reactivation of hepatitis B occurs.
e. In advanced cirrhosis or acute liver failure resulting from reactivation of HBV, liver transplantation is an accepted treatment with good outcomes and low recurrence of hepatitis B when using hepatitis B immunoglobulin prophylaxis and/or lamivudine therapy.
2. Chronic HCV
a. In patients with genotype 1, chronic hepatitis C combination antiviral therapy using α-interferon and ribavirin results in sustained response in about 50% of patients, with relapses occurring in about 20% when therapy is discontinued.
b. In non-genotype 1 HCV infection, particularly in genotypes 2 and 3, response rates exceed 80%.
c. Liver biopsy is an important tool in selecting patients for therapy, particularly genotype 1 patients; the presence of bridging fibrosis predicts the development of cirrhosis over the long term.
d. Liver transplantation is recommended for patients with advanced cirrhosis and is the most common indication for transplantation in the United States, accounting for approximately 20% of all adult transplants. Recurrence of hepatitis C occurs in all patients after transplantation at variable time points, with the development of cirrhosis in about 20% to 30% of these patients over a 5-year period.
3. Chronic HDV (δ)
a. Vaccination against HBV will prevent infection from both viruses.
b. In HBV and HDV coinfections, therapy with α-interferon has been tried but the response rates are low (13% to 20%). The use of pegylated interferon has improved the response at the end of treatment in about 43% of patients. Interferon treatment combined with the nucleoside/nucleotide inhibitors in a small number of patients suggests improved outcomes.
c. In severe or fulminant hepatitis resulting from HBV and HDV, liver transplantation should be considered. It can be lifesaving and is associated with a significantly lower rate of HBV and HDV recurrence after transplantation.

Systemic Viral Infections with Hepatic Involvement

Epstein-Barr Virus
( Figs 2-53 through 2-57 )

Figure 2-53 Epstein-Barr virus . The portal tract is expanded and exhibits a prominent lymphocytic infiltrate.

Figure 2-54 Epstein-Barr virus . The sinusoids show numerous circulating lymphocytes that often have a beaded back-to-back appearance.

Figure 2-55 Epstein-Barr virus . The circulating sinusoidal lymphocytes in this example are atypical, with round to irregularly shaped nuclei and scanty to moderate eosinophilic cytoplasm.

Figure 2-56 Epstein-Barr virus . The necrosis and inflammation seen within the lobule can form irregularly shaped aggregates (“granulomatous” necrosis).

Figure 2-57 Epstein-Barr virus . Inflammation of the endothelium by lymphocytes (endothelialitis) is seen involving a portal venule (A) and a terminal hepatic vein (B).

Major morphologic features

1. Portal tracts are expanded by a marked lymphocytic infiltrate; the majority of the lymphocytes are atypical in cell size and nuclear and cytoplasmic appearance.
2. The lobular cord–sinusoid pattern is intact, without significant liver cell ballooning or hydropic change, and is associated with a mild and sometimes moderate degree of focal necrosis, apoptosis, and hepatocytolysis.
3. An increase in circulating atypical lymphocytes within the sinusoids is seen, with a tendency of these cells to line up in a beaded back-to-back pattern.

Other features

1. Areas of parenchymal necrosis may have an ill-defined “granulomatous” appearance without distinct epithelioid or multinucleated giant cells; rarely, epithelioid granulomas can be seen, but they are uncommon.
2. Portal eosinophils and plasma cells in some instances may be present.
3. Kupffer cell hyperplasia is present and is often prominent.
4. “Endothelialitis” (inflammation of the endothelial lining) by activated lymphocytes may be demonstrated occasionally and involves portal and terminal hepatic venules.
5. Some degree of macrovesicular fatty change may occur but is not prominent.
6. Cholestasis may occur but is quite uncommon.
7. Lymphocytes surrounding bile ducts and infiltrating into the duct epithelium (“nonsuppurative cholangitis”) may occasionally be seen.
8. EBV infection in immunocompromised patients may rarely initiate phagocytosis of red blood cells by Kupffer cells and macrophages. (See “Infection-Associated [Reactive] Hemophagocytic Syndrome” in Chapter 12 .)
9. Rarely, enlarged atypical lymphocytes with prominent nucleoli may be seen within portal tracts and may resemble Reed-Sternberg cells.
10. Viral inclusions are rarely identified on routine H&E stain except in rare fatal cases.
11. In biopsies taken from liver allografts in patients receiving low-dose immunosuppression, post-transplant lymphoproliferative disorders (PTLDs) may occur (see Chapter 11 for a more detailed discussion).

Immunohistochemistry

1. Epstein-Barr nuclear-associated antigens (EBNAs) and latent membrane proteins (LMPs) show positive staining of lymphocytes containing the EBV-encoded proteins.

Molecular hybridization techniques

1. In situ hybridization (PCR) on fresh frozen or fixed tissue specimens can be used in the localization and demonstration of the EBV genome (EBER) in portal lymphocytes.
Note: Both immunohistochemical and in situ methodologies are most useful in immunocompromised patients suspected of having EBV infection.

Differential diagnosis

1. Acute viral hepatitis: Mild forms of acute viral hepatitis caused by the hepatotropic viruses (most often acute HCV infection) may resemble the histologic changes seen in acute EBV, although the degrees of portal atypical lymphocytes and sinusoidal lymphocytosis are more pronounced in EBV.
2. Cytomegalovirus (CMV) hepatitis: Granulomatous necrosis tends to be somewhat more prominent in CMV infections than in EBV infection, and the degree of atypical lymphocytic infiltrates is less striking in CMV than in EBV infection. Nuclear and cytoplasmic viral inclusions may be identified in hepatocytes, biliary epithelium, endothelium, and Kupffer cells in immunocompromised patients with CMV infection.
3. Drug-induced liver cell injury (e.g., phenytoin; see Table 5-4 ): The basic morphologic features in drug-induced hepatitis may be similar to those seen in EBV infection; however, the prominence of atypical lymphocytes in EBV is not a feature seen in drug-induced hepatitis.
4. Chronic lymphocytic leukemia: Although lymphocytes within portal tracts and sinusoids may be quite prominent in EBV infection, the lymphocytes are atypical and polymorphic in type and shape, whereas in chronic lymphocytic leukemia, the infiltrates are monomorphic (confirmed on immunoperoxidase stains as well as flow cytometric techniques). In addition, granulomatous necrosis is not a feature seen in association with leukemic infiltrates.
5. Hodgkin lymphoma: The uncommon larger atypical portal lymphocytes seen in and among eosinophils and plasma cells in acute EBV infection may mimic features of Hodgkin lymphoma. The presence of numerous circulating atypical lymphocytes seen in EBV infection is not a feature of Hodgkin disease. In addition, the CD15 and CD30 immunoperoxidase markers for Reed-Sternberg cells are negative in these atypical cells associated with EBV infection.


Clinical and biologic behavior

1. EBV is a DNA lymphotropic virus of the herpesvirus group and is the recognized agent causing infectious mononucleosis, with an incidence of approximately 100,000 cases per year (twice that of acute viral hepatitis). It is also associated with a number of malignancies, including PTLDs.
2. The incubation period is approximately 5 weeks, after which fever, acute pharyngitis, splenomegaly, and lymphocytosis (atypical lymphocytes) develop; however, ½ to ⅔ of cases are subclinical.
3. The liver is involved in more than 90% of cases. Hepatomegaly is present in 10% to 15%, splenomegaly is seen in 50%, and jaundice occurs only in 5% of patients.
4. Recovery takes longer in patients who have infectious mononucleosis with liver involvement. Elevated serum transaminases are usually less than 500 IU/L, generally lower than that seen in acute viral hepatitis from the hepatotropic viruses. Alkaline phosphatase elevation may at times be pronounced (~1000 IU/L), associated with moderate hyperbilirubinemia.
5. In immunocompromised patients, chronic enzyme elevations and morphologic changes may persist for years; however, progression of the disease into a fibrotic or cirrhotic stage has not been reported.
6. Other associated conditions include Guillain-Barré syndrome, pulmonary infiltrates, pericarditis and myocarditis, and splenic rupture.
7. The “monospot” test is sensitive (80%) and specific (99%) for EBV infection, but it may be initially negative in 15% of patients. The diagnosis of EBV infection is confirmed by elevation of EBV-specific IgM antibody and absent or low-titer antibody to EBV-associated nuclear antigen (EBNA). A single high VCA (viral capsid antigen) antibody titer does not distinguish current from previous infection.
8. EBV infects B lymphocytes, with antigenic expression on the surface of the cell eliciting a response by T lymphocytes. Their interaction produces the characteristic “atypical” lymphocyte seen in the peripheral blood and in liver biopsy.
9. The technique of in situ hybridization of EBER and histochemical LMPs are methods to identify EBV in liver biopsy specimens. These techniques can be useful in the diagnosis of EBV in the post-transplant patient.
10. The pathophysiology of EBV infection has various patterns:
a. Lytic (replicative) form: The EBV genome forms a linear structure with complete gene transcription and development of full viral particles that are shed and readily infectious.
b. Latent (persistent) form: The genome forms a circular plasmid with restricted gene expression, its presence identified by the detection of EBER-1.
11. The presence of latent infection in the immunocompromised patient, especially in the post-transplant setting, may initially induce a benign polyclonal (reversible) B-cell proliferation (mononucleosis-type syndrome) that can eventually progress to a monoclonal (irreversible) B-cell population (overt malignant lymphoma) with chromosomal abnormalities and gene rearrangements.
12. Various complement receptors, such as CD21, and triggering mechanisms, such as CD95-mediated apoptosis, also play a role.

Treatment and prognosis

1. Treatment is supportive, although use of steroids has been considered by some in severe cases.
2. Antiviral therapy has a mitigating effect on the virus.

Cytomegalovirus
( Figs 2-58 through 2-63 )

Figure 2-58 Cytomegalovirus . The portal tract exhibits a prominent lymphocytic infiltrate.

Figure 2-59 Cytomegalovirus . The parenchyma demonstrates increased numbers of sinusoidal lymphocytes.

Figure 2-60 Cytomegalovirus . Higher power shows sinusoidal lymphocytosis and mild necroinflammatory change.

Figure 2-61 Cytomegalovirus . Granulomas can sometimes be seen within the lobules. In this example, epithelioid cells with scattered lymphocytes are present in the immediate periportal zone.

Figure 2-62 Cytomegalovirus (CMV) . In immunocompromised patients, CMV can often be seen as distinct viral inclusions. These low-power (A) and high-power (B) images are from an HIV-positive patient. Both nuclear and cytoplasmic inclusions can be seen within this hepatocyte. Fatty change to variable degrees may also occur in patients who have AIDS.

Figure 2-63 Cytomegalovirus . The nuclear inclusion in this HIV-positive patient most likely involves an enlarged endothelial or Kupffer cell.

Major morphologic features

1. Portal tracts exhibit a prominent lymphocytic infiltrate, with some of the lymphocytes appearing slightly atypical.
2. The lobular cord–sinusoid pattern is intact, without significant liver cell ballooning or hydropic change, and is associated with a mild and sometimes moderate degree of focal necrosis, apoptosis, and hepatocytolysis.
3. An increase in circulating lymphocytes, some atypical, within sinusoids is seen, with a tendency of these cells to line up in a beaded back-to-back pattern.
4. In immunocompromised patients, large intranuclear amphophilic viral inclusions with a surrounding halo (“owl’s eye”) can be identified in hepatocytes, Kupffer and endothelial cells, and duct epithelium. Coarsely granular cytoplasmic inclusions can also be demonstrated within the same cells.

Other features

1. Granulomas are sometimes present and are generally poorly defined ( granulomatous in type) without epithelioid or multinucleated giant cells; however, sometimes true epithelioid granulomas without caseation may occur.
2. Mild macrovesicular fatty change can sometimes be seen.
3. Cholestasis may be present in severe cases but is generally uncommon.
4. Lymphoid cells can occasionally be identified surrounding and infiltrating into interlobular bile duct epithelium, causing nonsuppurative bile duct injury.
5. Duct destruction and depletion also may be associated with periductal sclerosis (“sclerosing cholangitis”) in HIV patients (HIV-associated cholangiopathy).
6. The viral inclusions may be seen isolated, or they may elicit an inflammatory response that may be granulomatous (mixed lymphocytes, eosinophils, macrophages, neutrophils) or purely neutrophilic ( microabscess formation), the latter especially evident in liver allografts.
7. Portal fibrosis does not occur in adults; however, portal and interstitial fibrosis may be seen in neonates, often associated with multinucleated giant cell transformation, cholestasis, acute cholangitis, and duct destruction with ductopenia.

Immunohistochemistry

1. CMV: Nuclear and less commonly cytoplasmic staining of viral inclusions may be identified in hepatocytes, bile duct epithelium, and Kupffer and endothelial cells in immunocompromised patients. Most often, these inclusions are also seen on routine H&E stain; however, CMV may infect cells without accompanying nuclear inclusions or an inflammatory infiltrate, therefore making this stain clinically useful in early or latent infection.

Differential diagnosis

1. Acute viral hepatitis: Mild forms of acute viral hepatitis, more often secondary to acute HCV, may resemble the histologic changes seen in acute CMV infection, although the degree of sinusoidal lymphocytosis is more pronounced with CMV. In addition, the presence of granulomatous necrosis and epithelioid granulomas are more often seen with CMV hepatitis.
2. EBV hepatitis: Although the degree of lymphocytic infiltrates and numbers of atypical lymphocytes are more marked in EBV infection, the granulomatous response in EBV is less commonly seen than with CMV. In addition, EBV is not associated with intranuclear or intracytoplasmic inclusions on routine H&E stain.
3. Drug-induced liver cell injury (e.g., phenytoin; see Table 5-4 ): Certain drugs can elicit a histologic response similar to that seen with CMV infection, although usually a sinusoidal lymphocytosis, when present with drug-induced injury, is not prominent.
4. Chronic lymphocytic leukemia: Although numerous lymphocytes within portal tracts and sinusoids may be seen in CMV infection, the lymphocytes are sometimes atypical and polymorphous in type and shape, whereas in chronic lymphocytic leukemia, the infiltrates are monomorphic (confirmed on immunoperoxidase staining). In addition, granulomatous necrosis is not a feature seen in association with leukemic infiltrates.

Clinical and biologic behavior

1. CMV is a ubiquitous DNA virus of the herpesvirus group that is the most common etiologic agent in congenital infections. The virus commonly acquired at birth is not eradicated but becomes incorporated into the host cells as a latent infection and reactivates during immunosuppressed states (e.g., after transplantation or chemotherapy or in those with acquired immunodeficiency syndrome [AIDS]). Rarely, CMV may be acquired in adulthood from numerous blood transfusions, such as occurs after open-heart surgery.
2. CMV hepatitis is clinically mild and self-limiting and accounts for approximately 8% of cases presenting with an “infectious mononucleosis-like syndrome” with hepatic involvement. Liver tests reveal mild to moderate elevations of serum transaminases (200 to 300 IU/L), elevation of the alkaline phosphatase values, and mild hyperbilirubinemia. Atypical lymphocytes may be seen on peripheral smear.
3. The liver may be involved in congenital infection. Neonates present with hepatosplenomegaly, jaundice, thrombocytopenia, microcephaly, periventricular calcification, chorioretinitis, and other signs of intrauterine infection. Brain damage is often permanent.
4. Other associated conditions include Guillain-Barré syndrome, hemolytic anemia, meningoencephalitis, pneumonitis, myocarditis, esophagitis, and colitis presenting with diarrhea and bleeding.
5. Rare cases of fatal massive hepatic necrosis have been reported, usually in immunocompromised patients.
6. CMV can be isolated from saliva, urine, blood, and tissues, with the virus causing cytopathic change on monolayer fibroblast cultures, and can be propagated in cell culture from blood and urine samples. Antigenemia assay is the current standard for the detection of viral DNA in infected white blood cells and is used to decide preemptive antiviral therapy in patients with post-transplant infections. By using PCR techniques, both quantitative and qualitative viral DNA can be detected. Invasive CMV infection is best confirmed by histologic changes on biopsies.
7. CMV-specific antibody by solid-phase immunoassay is useful to detect primary infection; however, approximately 30% of immunosuppressed patients may produce IgM-specific antibody with recurrent infection.

Treatment and prognosis

1. Supportive therapy is offered in most cases, because the disease is almost always self-limiting in the immunocompetent patient.
2. Acyclovir is effective for prophylaxis and ganciclovir for active disease in the immunocompromised patient (e.g., status post-organ transplant, AIDS). Rarely, in ganciclovir-resistant CMV infections, foscarnet has shown benefit. The newer agent valacyclovir may hold some promise for the long-term treatment of CMV infections.
3. In patients with AIDS who are receiving highly active antiretroviral therapy (HAART), the incidence of CMV infections appears to be declining.

Herpes Simplex Virus
( Figs 2-64 through 2-66 )

Figure 2-64 Herpes simplex virus . Nuclear inclusions in hepatocytes can be seen in the middle of the field in this low-power image. The adjacent hepatocytes at the bottom of the field show extensive coagulative necrosis.

Figure 2-65 Herpes simplex virus . Higher magnification demonstrates nuclear inclusions of both Cowdry type A (large and eosinophilic, with a peripherally located “clear” space or halo) and Cowdry type B (basophilic, filling up the entire nucleus with a peripheral rim of finely granular chromatin). Some of the involved hepatocytes are multinucleated.

Figure 2-66 Herpes simplex virus . The inclusions in this example can be seen predominantly within the periportal liver cell nuclei, with some degree of cytoplasmic involvement as well. (Immunoperoxidase stain for herpes simplex virus.)

Major morphologic features

1. Coagulative-type necrosis is present, may be patchy or confluent with no particular zonal distribution pattern, and is associated with a minimal to absent inflammatory response. This infection is most often seen in immunocompromised patients.
2. Two types of intranuclear inclusions are identified in liver cells located at the interface of the necrotic and viable regions:
a. Cowdry type A: Large and eosinophilic, with a peripherally located “clear” space or halo.
b. Cowdry type B: Basophilic, filling up the entire nucleus (ground-glass appearance), with a peripheral rim of finely granular chromatin.

Other features

1. The cytoplasm of the viable liver cells containing the nuclear inclusions often has a more eosinophilic appearance.
2. The individual hepatocytes demonstrating the viral inclusions may at times be multinucleated.
3. A prominent multinucleated giant cell transformation of viable hepatocytes, particularly in the neonate, may be seen.
4. A variable, but generally sparse, portal lymphocytic inflammatory infiltrate can at times be seen.
5. Acute hemorrhage may be present in the areas of necrosis.
6. Massive hepatic necrosis has been described (in undernourished children).

Special stains

1. Feulgen reaction: Positive nuclear staining is noted when the nucleus is filled with viral DNA (Cowdry type B), but it is negative when the virus has entered the liver cell cytoplasm (Cowdry type A).

Immunohistochemistry

1. Herpes I and II antigens: Intranuclear staining of cells containing the ground-glass inclusions is seen. Occasionally, positive cytoplasmic staining of hepatocytes in and around the necrotic areas may also be present.

Differential diagnosis

1. Varicella-zoster virus infection: In rare cases, coagulative confluent necrosis can be seen with chickenpox (varicella); usually the liver injury is self-limited. Varicella infection may exhibit granulomatous necrosis as well as nuclear inclusions in bile duct epithelium and Kupffer cells, features not characteristic of herpes simplex infection.
2. Toxemia of pregnancy (eclampsia): Coagulative necrosis may be present in toxemia but is predominantly periportal in location and is associated with intrasinusoidal fibrin deposition.
3. Drug- and toxin-induced liver cell injury (e.g., acetaminophen; refer to Table 5-3 ): Certain drugs and toxins may be associated with coagulative-type necrosis without an inflammatory infiltrate. In most instances a zonal distribution pattern in this type of drug-induced injury is also seen, although when the necrosis is severe and confluent, the distinction with herpes virus infection may be difficult. The absence of viral inclusions and the history and time frame of drug use or toxin exposure are helpful clues in diagnosis.
4. Various causes of vasculitis (e.g., polyarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis) or severe vascular compromise (e.g., hyperacute humoral allograft rejection, heat stroke, left-sided heart failure with hypotension): Ischemic coagulative-type necrosis in the aforementioned disorders are due to impeded arterial blood flow and usually involve the perivenular zones (zone 3 of Rappaport) first, although confluent necrosis involving two zones or bridging necrosis involving adjacent lobules may occur in more severe cases. A pertinent clinical history and absence of viral inclusions is necessary for distinction.

Clinical and biologic behavior

1. Two variants of herpes simplex hominis that may involve the liver occur:
a. Type I: This type is present in oral secretions in 50% of the general population and clinically manifested by ulceration of the lip and buccal mucosa.
b. Type II: This type involves the genitalia and is spread by sexual contact.
2. Hepatic involvement is associated with disseminated infection and marked elevations of serum transaminases and bilirubin. Disseminated intravascular coagulopathy (DIC) is common.
3. Hepatic lesions are virtually never seen in healthy individuals, but they can be found in immunocompromised patients (patients taking steroids or receiving chemotherapy, those who are status post-transplant), malnourished children, and rarely pregnant women.

Treatment and prognosis

1. In patients with symptomatic hepatic necrosis, death usually results in more than 90% of patients 1 to 2 weeks after the beginning of symptoms.
2. Antiviral therapy with acyclovir and ganciclovir is the standard choice for treatment; however, a number of other agents, such as valacyclovir, penciclovir, and famciclovir, have been tried.
3. Liver transplantation has been offered in select patients who were diagnosed early and treated with antiviral therapy, with an overall good outcome.

Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome
( Fig. 2-67 )

Figure 2-67 Human immunodeficiency virus (HIV) . Although various viral and opportunistic infections are often associated with abnormal liver tests in HIV-positive patients (see Figs 2-62 and 2-63 ), many times no microorganisms are seen on biopsy material; however, in these instances, certain portal and lobular changes are frequent, as these two images demonstrate. A, The small portal tract is virtually normal, without an inflammatory infiltrate (portal lymphocyte depletion) despite the fact that necrosis was seen in the parenchyma. B, The parenchyma from the same biopsy shows nonspecific fatty change and mild necroinflammatory change.

Major morphologic features

1. A marked depletion of lymphocytes within portal tracts is seen in the majority of patients with clinically apparent disease.
2. Although there are no indications that a direct necroinflammatory response can occur secondary to HIV infection, superimposed secondary opportunistic infections are frequent; these infections include CMV and Mycobacterium avium-intracellulare complex ( Table 2-4 ). The morphologic changes often produce a granulomatous-type of inflammatory process.

Table 2-4 HIV-Associated Infections and Neoplasms INFECTIOUS AGENTS NEOPLASMS
Adenovirus
Aspergillus
Bartonella
Candida species
Coccidioides
Cryptococcus
Cryptosporidia
Cytomegalovirus
Epstein-Barr virus
Gram-negative bacteria
Herpesvirus
Histoplasma
Leishmania
Microsporidia
Mycobacterium: tuberculosis, avium-intracellulare complex
Pneumocystis
Toxoplasma
Varicella-zoster
Viral hepatitis, acute (A, B, C, δ, E, G)
Viral hepatitis, chronic (B, C, δ)
Kaposi sarcoma
High-grade (B-cell) lymphoma
Central nervous system lymphoma

Other features

1. The granulomas are usually ill defined and are present randomly within the lobules. Multinucleated giant cells may occasionally be seen involving the granulomas, but they are infrequent. The viable microorganisms that can be demonstrated on special stains are often abundant.
2. Some opportunistic microorganisms such as CMV can also be demonstrated within Kupffer and endothelial cells, as well as in duct epithelium.
3. Kupffer cells may exhibit erythrophagocytosis in approximately 10% of cases and have a foamy cytoplasmic appearance.
4. Mild to moderate predominantly macrovesicular fatty change may be seen in 25% to 50% of cases. In rare instances, striking macrovesicular fatty change may occur with fatal consequences.
5. Cholestasis occurs in less than 10% of cases.
6. Portal lymphocytic infiltrates, although usually sparse, can sometimes occur; at times the lymphocytic infiltrates can be prominent, particularly when associated with a coexisting viral hepatitis (particularly HCV).
7. Damage to interlobular bile ducts may occur in some cases, manifested by nuclear irregularity and pyknosis and cytoplasmic hydropic change, and are most often secondary to infiltration of the ducts by microorganisms, most notably CMV; however, considerable duct damage may be seen without demonstrable organisms or an accompanying inflammatory response orientated to the ducts.
8. Progressive duct damage, sometimes associated with portal lymphocytic and plasma cell infiltrates, periductal fibrosis and sclerosis (sclerosing cholangitis), and duct loss (HIV-associated cholangiopathy, vanishing bile duct syndrome) may occur. Cryptosporidia, although usually involving the extrahepatic biliary system, can also rarely be seen involving medium-sized interlobular and larger interlobar bile ducts and can also be associated with duct damage.
9. Peliotic lesions have been described. In addition, angioproliferative processes (bacillary angiomatosis) have also been reported secondary to infection by Bartonella (Rochalimaea) species; these organisms are demonstrated by the Warthin-Starry reaction.
10. Various neoplastic disorders such as Kaposi sarcoma, B-cell non-Hodgkin lymphomas, and high-grade lymphoma variants may also occur, with EBV infection a leading contributory factor in the development of the various lymphoproliferative processes.

Special stains

1. Identification of superinfection is usually enhanced by appropriate special stains (refer to organisms in Table 2-4 ):
a. Ziehl-Neelsen, Kinyoun’s acid-fast stain: acid-fast bacilli ( Mycobacterium tuberculosis and M. avium-intracellulare )
b. PAS: M. avium-intracellulare; fungi (Candida albicans, Cryptococcus neoformans)
c. Gomori-methenamine silver (GMS): fungi (Coccidioides immitis); protozoa (Pneumocystis carinii)
d. Warthin-Starry: bacilli (Bartonella [Rochalimaea] henselae)
2. Perl’s iron stain: Not infrequently, hemosiderin can be seen within Kupffer cells, confirmed on iron stain, due to secondary hemolysis and/or increased numbers of blood transfusions.

Immunohistochemistry

1. HBsAg, HBcAg: Coinfection with viral hepatitis, most notably HBV, is sometimes seen, with serologic markers of past and ongoing infection present in these patients with HIV infection.
2. Other viral markers (e.g., CMV, herpesvirus): Although various viral inclusions such as CMV can be seen on routine H&E stain, in some instances the inclusions can be inconspicuous, with the immunoperoxidase markers then helpful.

Differential diagnosis

1. Disorders other than AIDS that may cause portal lymphocyte depletion: Portal lymphocytic infiltrates can be minimal to absent in various liver diseases that may otherwise demonstrate lobular necroinflammatory changes. For example, this may include patients with Hodgkin lymphoma, patients who are immunocompromised secondary to chemotherapy or renal dialysis, and individuals with widespread carcinoma. In addition, elderly patients tend to have less of a portal inflammatory infiltrate in various conditions than younger patients.
2. Disorders associated with duct loss: Ductopenia may occur in patients with HIV-associated cholangiopathy, where the portal duct depletion may resemble that seen in a number of disorders, such as autoimmune cholangiopathy, primary biliary cirrhosis, and primary sclerosing cholangitis. All three listed conditions, however, show variable, but often prominent, lymphocytic portal infiltrates, as well as other morphologic changes (e.g., plasma cell infiltrates in autoimmune hepatitis and primary biliary cirrhosis, Mallory bodies in primary biliary cirrhosis and primary sclerosing cholangitis) that are not seen in HIV-associated cholangiopathy.
Note: In any case where unexpected opportunistic infections are identified in the liver, HIV infection should be considered in the differential diagnosis.

Clinical and biologic behavior

1. Approximately 34 million individuals worldwide are infected with HIV, the majority of whom live in sub-Saharan Africa and other developing countries. In the United States, the number of reported new infections is about 40,000 each year.
2. HIV is a retrovirus (specifically lentivirus) and has a propensity for mutations. There are two main types: HIV-1 and HIV-2. HIV-1 is the infection that predominates worldwide.
3. HIV has a predilection for cells that express CD4 on the surface that acts as a receptor for the HIV gp120 glycoprotein and allows viral infection. The HIV p24 antigen has also been demonstrated within Kupffer and endothelial cells, with HIV messenger RNA within liver cells themselves.
4. The virus enters cells by fusion that binds the envelope protein into cell membranes, with eventual nuclear localization. Reverse transcriptase is activated, and a DNA copy of the virus is produced, incorporating into the host cell genome and serving as the template for replication. The DNA is translated into novel proteins and packaged into virions, which are released into the extracellular space to infect other cells. Active replication within cells is highly toxic, leading to eventual cell death.
5. HIV is acquired from percutaneous and sexual transmission. The risk of transfusion-acquired HIV is about 0.0001%.
6. The primary HIV infection may be asymptomatic or present with acute retroviral syndrome (ARS) with fever, lymphadenopathy (mononucleosis-like syndrome), rash, hepatomegaly, postural hypotension, oral lesions, and meningitis or radiculopathy. Rarely, ARS can present with an AIDS-defining illness with CD4 counts of less than 400 cells/mm3. Primary HIV infection is followed by the development of HIV-specific antibodies, which occur as early as 8 days and as late as 12 months after infection. About 95% of infected persons will test positive for HIV antibody within 6 months.
7. The most common test for HIV antibody is the enzyme-linked immunosorbent assay test (ELISA) technique. If the results are negative in suspected individuals, the Western Blot is performed. Rarely, the specific viral p24 core protein or HIV RNA by PCR will be necessary to confirm the diagnosis.
8. Liver disease is secondary to associated infections or neoplasms. Chronic viral hepatitis B, HBV and HDV ( coinfection and superinfection ), HCV, and CMV have been noted in HIV-infected persons. The frequency of HBV in HIV is unknown, and HCV is estimated to occur in 9% to 40% of HIV-infected patients. Patients with HIV who are coinfected with hepatitis B and C have a more progressive liver disease and a higher risk of developing cirrhosis and hepatocellular carcinoma. Antiviral therapy is currently being offered to these patients with coinfection, with the results expecting to improve the outcomes.
9. The duct involvement (cholangiopathy) induced by HIV is frequently secondary to CMV and/or cryptosporidium infection. In addition, it is speculated that a distinct human leukocyte antigen (HLA) haplotype may be associated with duct involvement by HIV.

Treatment and prognosis

1. HAART has changed the outcome of the disease, resulting in longer survival and reduced frequency of AIDS-defining illnesses. A number of both nucleoside and non-nucleoside reverse transcriptase inhibitors and protease inhibitors are also available; however, resistance to these drugs is becoming more frequent. The cost of the treatment, the need for several drug combinations, and compliance are significant limitations in the treatment strategy.
2. In patients with Kaposi sarcoma, the median survival is 18 to 24 months. In patients with opportunistic infections, the survival is 6 to 8 months.

Rare Systemic Viral Infections with Hepatic Involvement

Lassa Fever
( Figs 2-68 and 2-69 )

Figure 2-68 Lassa fever . The portal tract exhibits a moderate lymphocytic infiltrate.

Figure 2-69 Lassa fever . The parenchyma shows focal coagulative-type necrosis with scattered lymphocytes and degenerating inflammatory cells.

Major morphologic features

1. Coagulative-type necrosis of liver cells is present and is patchy, with numerous apoptotic cells (e.g., acidophil bodies, Councilman bodies) present.
2. The degree of accompanying lobular inflammation is minimal.

Other features

1. The necrosis shows no distinct zonal distribution pattern.
2. Confluent necrosis may sometimes be seen in the more severe cases.
3. Mild fatty change can occasionally be present but is uncommon.
4. The portal tracts exhibit a mild lymphocytic infiltrate with normal bile ducts.

Electron microscopy

1. Although no viral inclusions are present on routine H&E-stained sections, arenavirus can be demonstrated on electron microscopy.


Differential diagnosis

1. Acute viral hepatitis (hepatotropic viruses): Acute viral hepatitis secondary to infection by the hepatotropic viruses usually demonstrates variable degrees of hydropic ballooning change with prominent lobular and portal lymphocytic infiltrates. These features, however, are not characteristic of Lassa fever, which instead shows coagulative necrosis with only minimal or absent lobular inflammation and only mild portal inflammatory infiltrates.
2. Other viral infections associated with numerous apoptotic cells: Certain rare viral infections (e.g., Bolivian, Korean, and Argentinian hemorrhagic fevers; Marburg and Ebola virus infections; yellow fever; dengue fever) may morphologically resemble Lassa fever. Epidemiology and isolation of the viruses are necessary for diagnosis.

Clinical and biologic behavior

1. Lassa fever is a highly contagious and multisystem disease characterized by fever, pharyngitis, cough, severe myalgia, prostration, renal failure, and the development of diffuse hemorrhage with involvement of the skin and subcutaneous tissue from a “leakage syndrome.”
2. The disease is caused by an arenavirus, a group of RNA viruses responsible for hemorrhagic fevers, and is widely present in West and Central Africa.
3. Infection is usually subclinical and transmitted by contact with rodent (reservoir) excrement.
4. Hepatomegaly, right upper quadrant pain, and tenderness are common. Serum transaminases and lactate dehydrogenase activity are elevated, but bilirubin is usually normal.
5. With use of real-time PCR, RNA levels can be detected. Viremia rises steadily before death. The marked increase in interferon-γ and tumor necrosis factor (TNF)-α shortly before death suggests that proinflammatory cytokines may play a part in the pathogenesis.
6. Specific antibodies to the Lassa virus have been detected. Antibodies appear to be directed to two proteins, 11-kDa Z and nucleoprotein (NP), which are detected in about 33% of human sera from endemic areas.

Treatment and prognosis

1. About 5000 deaths annually from Lassa virus infections occur in Western Africa, with the overall mortality from 5% to 14%; however, mortality in pregnant women is much higher.
2. Ribavirin appears to have some effect on the Lassa virus and may act through lethal mutagenesis.
3. Immunity to Lassa virus infection appears to be cell mediated, and currently vaccine development is in progress using viral glycoproteins G1 and G2.

Yellow Fever
( Figs 2-70 and 2-71 )

Figure 2-70 Yellow fever . The portal tract demonstrates a mild lymphocytic infiltrate.

Figure 2-71 Yellow fever . The parenchyma exhibits numerous apoptotic cells throughout the lobule.

Major morphologic features

1. Coagulative-type necrosis is prominent and is accentuated in the midzonal areas (zone 2 of Rappaport), with numerous apoptotic cells evident.
2. The nuclei of surviving hepatocytes may infrequently demonstrate large eosinophilic inclusions (Torres bodies) .

Other features

1. The portal tracts exhibit a moderate lymphocytic infiltrate with normal bile ducts.
2. Mild microvesicular fatty change may be present, with prominent fatty change infrequent.
3. Hepatocytes may demonstrate ballooning and rarely syncytial giant cell transformation in some cases.

Immunohistochemistry

1. Yellow fever viral antigen: The viral antigen can be demonstrated within scattered hepatocytes and Kupffer cells.

Differential diagnosis

1. Acute viral hepatitis (hepatotropic viruses): Although both acute viral hepatitis secondary to infection by the hepatotropic viruses and yellow fever demonstrate portal lymphocytic infiltrates, the lobular coagulative necrosis seen in yellow fever is quite striking and not a feature seen in acute viral hepatitis. In addition, nuclear inclusions (Torres bodies), when present, are a key in diagnosing yellow fever.
2. Other viral infections associated with numerous apoptotic cells: Certain infrequent viral infections (e.g., Bolivian, Korean, and Argentinean hemorrhagic fevers; Marburg and Ebola virus infections; yellow fever; dengue fever) usually are associated with minimal lobular and portal inflammation, whereas in yellow fever, portal and lobular inflammation is more apparent (but not as striking as that seen in acute viral hepatitis secondary to the hepatotropic viruses).

Clinical and biologic behavior

1. Yellow fever is the original viral hemorrhagic fever and is caused by a member of the Flaviviridae family.
2. The disease is transmitted to humans by the Aedes aegypti mosquito and affects 200,000 persons annually in the tropical regions of Africa and Central and South America.
3. The incubation period ranges from 3 days to 1 week, with the spectrum ranging from subclinical infection to a fulminant presentation.
4. Patients clinically present with fever, renal dysfunction (e.g., acute tubular necrosis, hemoglobinuria), gastrointestinal hemorrhage, and coagulation abnormalities. Moderate to marked elevations in serum transaminases and bilirubin are usually present.

Treatment and prognosis

1. Vaccination using the live attenuated 17D virus routinely during childhood in endemic areas and in travelers to these endemic areas is expected to decrease the incidence of this infection. The recent reports of vaccine-related yellow fever infection is a concern, although the risk is small; however, the risk of infection in nonvaccinated persons is far greater than the risk of vaccine-induced infection developing. Thus the current standard of treatment mandates vaccination based on reports of endemic activity, season, and likelihood of exposure to vector mosquitos. Research in the development of new vaccines is in progress.
2. In nonvaccinated patients, coma and death occur in 10% to 60% of patients.

Echovirus (Enterovirus)
( Fig. 2-72 )

Figure 2-72 Echovirus . Extensive confluent coagulative necrosis is seen involving the parenchyma. The small portal structure is relatively unremarkable, with occasional cholangioles present but with no inflammatory infiltrates.

Major morphologic features

1. Hemorrhagic coagulative ischemic necrosis with apoptosis may occur, is often confluent, and is usually associated with intravascular thrombosis and occlusion.
2. Massive hepatic necrosis has been described.

Other features

1. Mild portal lymphocytic infiltrates, bile duct proliferation, and portal edema may occur.

Differential diagnosis

1. Acute viral hepatitis (hepatotropic viruses): The degree of portal inflammatory infiltrates in enterovirus infection is relatively mild compared with the prominent portal lymphocytic infiltrates seen in acute viral hepatitis secondary to the hepatotropic viruses. In addition, hemorrhagic ischemic necrosis is not a feature seen in typical acute viral hepatitis.
2. Ischemia secondary to hypotension and poor hepatic perfusion: The ischemic necrosis seen in vascular compromise is similar to that present in enterovirus infection. Correlation with the clinical history and virus isolation are necessary.
3. Other viral infections associated with numerous apoptotic cells: Certain rare viral infections (e.g., Bolivian, Korean, and Argentinean hemorrhagic fevers; Marburg and Ebola virus infections; yellow fever; dengue fever), as well as enterovirus infection, are usually associated with minimal lobular and portal inflammation. In some instances hemorrhagic ischemic necrosis may also be seen in the aforementioned conditions. Correlation with the clinical presentation and viral serologies is essential.

Clinical and biologic behavior

1. Echoviruses are enteroviruses that belong to the Picornaviridae family. They have similarity to the poliovirus.
2. They comprise coxsackie virus A (serotypes 1 to 2 and 24), coxsackie B (serotypes 1 to 6), echovirus (serotypes 1 to 9, 11 to 27, and 29 to 33), and enterovirus (serotypes 68 to 71). Both echovirus 6 and 11 are considered virulent strains. Since 1967, all newly discovered viruses in this class are called enteroviruses.
3. Echoviruses are cytopathic viruses that elicit a strong humoral response. In younger children the response is homotypic (same serotype), whereas in older children and adults, the response is heterotypic (where antibodies develop against several serotypes).
4. Infections are spread by fecal-oral and respiratory routes, and they present with a nonspecific exanthematous rash, herpangina, lymphonodular pharyngitis, hemorrhagic conjunctivitis, pleurodynia, myocarditis, pericarditis, aseptic meningitis, encephalitis, myositis, and flaccid paralysis. Echovirus infections are also postulated to play a role in chronic fatigue syndrome and juvenile diabetes mellitus. Some recent evidence suggests that echovirus (coxsackie B virus) infection may cause acute liver failure in pregnancy.
5. Symptoms that generally relate to liver disease develop within approximately 4 days, with jaundice, hepatomegaly, elevated serum transaminase levels, coagulation abnormalities, and decreases in serum albumin and fibrinogen levels. Hemorrhagic complications occur in about 63% of patients, and intracranial bleeding occurs in about 30% of cases.
6. Disseminated infections develop in neonates almost exclusively, with fulminant hepatic failure resulting from hemorrhagic necrosis of the liver and adrenal glands.
7. Viral damage to the vascular and hepatic venous endothelium rather than direct damage to the hepatocytes in the early viremic phase is considered the postulated mechanism for the histologic findings.
8. The diagnosis is made by positive enterovirus antibody IgM (using radioimmunoassay or PCR-enhanced immunoassay).

Treatment and prognosis

1. Treatment centers on the patient’s presenting symptoms.
2. Mortality increases with associated myocarditis and encephalitis.
3. Although no vaccines are yet available, in one study, therapy with pleconaril (VP63843) by nasogastric tube resulted in recovery in 66% of neonatal infections and appears promising.

Other Viruses that May Cause Liver Damage
Table 2-5
Table 2-5 Other Viruses that May Cause Liver Damage DISEASE HISTOLOGY CLINICAL/LABORATORY PARAMETERS Adenovirus
• In immunocompromised patients, features are similar to those of herpes simplex virus infection, with extensive coagulative-type necrosis and little inflammation, these changes sometimes oriented to the perivenular zones.
• Intranuclear inclusions are prominent in viable liver cells.
• Adenovirus is a DNA virus related to upper and lower respiratory tract infections, lymphadenopathy, and conjunctivitis; it may also cause gastrointestinal infections and hepatitis.
• The more severe infections occur in immunocompromised patients and are associated with markedly elevated serum transaminase levels.
• Mild elevations of serum transaminases may be noted with normal bilirubin in the setting of a respiratory tract infection in the immunocompetent patient. Coronavirus
• Prominent apoptosis is seen.
• Liver cell ballooning and lobular necroinflammatory changes can occur.
• The novel coronavirus is a single-stranded RNA virus and the cause of severe respiratory distress syndrome (SARS).
• Mildly abnormal transaminase levels may be present; severe hepatitis does not occur. Dengue fever
• Focal perivenular confluent liver cell necrosis with apoptosis and dropout of hepatocytes but little inflammation is present.
• This arbovirus (RNA virus) is transmitted by the Aedes mosquito; infection is endemic in tropical countries.
• The disease is characterized by fever, severe myalgias (breakbone fever), headache, malaise, and prostration.
• The liver test results are mildly abnormal, and fulminant liver failure has not been reported. Ebola virus
• Coagulative-type necrosis without inflammation is scattered within the lobules, with numerous acidophil bodies (apoptosis) present.
• The necrosis is usually patchy but in some cases may be confluent.
• Outbreaks of infection by this RNA virus are associated with severe and often fatal hemorrhagic fever.
• Patients present with sudden onset of fever, malaise, nausea and vomiting, myalgias, maculopapular rashes, and conjunctivitis.
• Liver dysfunction develops during the second week of illness, although hyperbilirubinemia is uncommon. Group B coxsackie (enterovirus)
• Mixed portal and sinusoidal inflammatory infiltrates consisting of both mononuclear cells and neutrophils are seen.
• Perivenular cholestasis and hydropic change of hepatocytes may occur.
• Hemorrhagic necrosis may occur in the neonate.
• A member of the enteroviruses, group B coxsackie virus may be associated with respiratory tract infection, myocarditis, pericarditis, aseptic meningitis, pleurodynia, and vesicular and papular rashes; in epidemic situations it can cause hepatitis.
• Positive specific antibodies to coxsackie B virus are helpful in confirming the diagnosis. Herpes zoster
• Focal or confluent coagulative-type necrosis without inflammation (similar to that seen with herpes simplex) is present.
• A variable number of intranuclear inclusions within hepatocytes is seen.
• The predominant manifestations are the vesicular skin lesions associated with pain and neuralgia.
• Liver disease is restricted to those who are immunocompromised, in whom liver involvement may be severe. Human herpesvirus-6 (HHV)
• Mild portal lymphocytic infiltrates and mild lobular inflammation are present.
• Bile ductular proliferation with multinucleated giant cell transformation occurs.
• This member of the herpesvirus family is a cause of childhood roseola, and presents with fever, central nervous system disturbances, and a rash; bone marrow suppression may also occur.
• Two variants are known: HHV-6A, occurring later in childhood or during adulthood, and HHV-6B, the cause of roseola in childhood.
• Liver test results may be abnormal, and pancytopenia and leukopenia may be present. Marburg virus
• Coagulative-type necrosis with minimal or absent lobular inflammation is present and scattered within the lobules.
• Acidophil bodies (apoptosis) is common.
• Patchy or confluent liver cell necrosis can occur.
• This severe viral hemorrhagic febrile disorder presents with the sudden onset of fever, malaise, headache, and myalgia, with shock and disseminated intravascular coagulation.
• The mortality is high, with the liver being a major target. Parvovirus (B19 virus)
• Hydropic change of hepatocytes is present.
• Portal lymphocytic infiltrates and diffuse necroinflammatory change (in children) occur.
• Nuclear inclusions within hepatocytes may be seen.
• Giant cell hepatitis has been described in the neonate.
• Also referred to as erythrovirus, this small DNA virus is spread by infected respiratory droplets.
• Transmission through pregnancy can occur, with hydrops fetalis being a serious complication.
• Patients develop a rash with fever and malaise; arthritis can also develop in the adult, and aplastic anemia has been described.
• Abnormal liver test results indicating hyperbilirubinemia and severe coagulopathy may occur, predominantly in the neonate; acute giant cell hepatitis has also been described. Rubella
• Features of neonatal hepatitis with multinucleated giant cell transformation of liver cells is present.
• In mild cases, nonspecific focal necrosis, cholestasis, and lymphocytic infiltration are seen.
• Massive hepatic necrosis has been described but is uncommon.
• Duct loss (ductopenia) has been described but is infrequent.
• This RNA virus causes a benign, self-limited infection in humans that is manifested by mild fever, suboccipital lymphadenopathy, and skin rash.
• Congenital rubella syndrome from intrauterine infection causes growth and mental retardation, deafness, congenital heart disease, corneal opacities, cataracts, retinopathy, and meningoencephalitis; late manifestations include immunodeficiency.
• Hepatic manifestations include hepatosplenomegaly, modest increases in serum transaminase levels, and normal or mild increase in serum bilirubin.
• Serologic diagnosis is made by the presence of acute and convalescent hemagglutination inhibition antibodies. Rubeola
• Variable degrees of portal lymphocytic infiltration occur.
• Mild lobular mononuclear inflammation and focal necrosis are present.
• Fatty change to variable degrees may occur.
• Multinucleated syncytial giant cells and eosinophilic nuclear and cytoplasmic viral inclusions are rarely seen.
• This highly contagious RNA virus causes an exanthematous infection with fever, cough, coryza, and conjunctivitis developing after an incubation period of 8–12 days.
• In severe hemorrhagic measles, seizures, mucosal bleeding, and disseminated intravascular coagulation can occur.
• Transient anicteric hepatitis characterized by mild to moderate increases in serum transaminase levels may develop, with hyperbilirubinemia rare.
• Serologic tests by complement fixation, hemagglutination inhibition, and enzyme immunoassays confirm the diagnosis.

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Thomas D.L., Seeff L.B. Natural history of hepatitis C. Clin Liver Dis . 2005;9:383-398.

Fulminant hepatitis
Bernuau J., Nicand E., Durand F. Hepatitis E-associated acute liver failure in pregnancy: an Indian puzzle. Hepatology . 2008;48:1380-1383.
Farci P., Alter H.J., Shimoda A., et al. Hepatitis C virus-associated fulminant hepatic failure. N Engl J Med . 1996;335:631-634.
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Chronic viral hepatitis
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McMahon B.J. The natural history of chronic hepatitis B virus infection. Hepatology . 2009;49:S45-S55.
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Epstein-Barr virus (EBV)
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Cytomegalovirus
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Herpes simplex virus
Connor R.W., Lorts G., Gilbert D.N., et al. Lethal herpes simplex virus type 1 hepatitis in a normal adult. Gastroenterology . 1979;76:590-594.
Fahy R.J., Crouser E., Pacht E.R. Herpes simplex type 2 causing fulminant hepatic failure. South Med J . 2000;93:1212-1216.
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HIV and AIDS
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Viteri A.L., Greene J.F. Bile duct abnormalities in the acquired immune deficiency syndrome. Gastroenterology . 1987;92:2014-2018.
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Lassa fever
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Lucia H.L., Coppenhaver D.H., Harrison R.L., et al. The effect of an arenavirus infection on liver morphology and function. Am J Trop Med Hyg . 1990;43:93-98.
McCormick J.B., Fisher-Hoch S.P. Lassa fever. Curr Top Microbiol Immunol . 2002;262:75-109.
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Walker D.H., McCormick J.B., Johnson K.M., et al. Pathologic and virologic study of fatal Lassa fever in man. Am J Pathol . 1982;107:349-356.

Yellow fever
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Dias L.B., Alves V.A., Kanamura C., et al. Fulminant hepatic failure in northern Brazil: morphological, immunohistochemical and pathologic aspects of Labrea hepatitis and yellow fever. Trans R Soc Trop Med Hyg . 2007;101:831-839.
Monath T.P., Barrett A.D. Pathogenesis and pathophysiology of yellow fever. Adv Virus Res . 2003;60:343-395.
Quaresma J.A., Barros V.L., Pagliari C., et al. Hepatocyte lesions and cellular immune response in yellow fever infection. Trans R Soc Trop Hyg . 2007;101:161-168.
Quaresma J.A., Duarte M.I., Vasconcelos P.F. Midzonal lesions in yellow fever: a specific pattern of liver injury caused by direct virus action and in situ inflammatory response. Med Hypotheses . 2006;67:618-621.
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Echovirus (enterovirus)
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Chen C.A., Tsao P.N., Chou H.C., et al. Severe echovirus 30 infection in twin neonates. J Formos Med Assoc . 2003;102:59-61.
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General References
Alter M.J., Bell B.P. Epidemiology, natural history, and prevention of viral hepatitis. In: Arias I.M., Boyer J.L., Chisari F.V., et al, editors. The Liver. Biology and Pathobiology . Philadelphia: Lippincott Williams & Wilkins; 2001:783-800.
Ghany M.G., Liang T.J. Acute viral hepatitis . Yamada T., Alpers D.H., Kalloo A.N., et al, editors. Textbook of Gastroenterology, 5th ed, Vol. 2. West Sussex, UK: Wiley-Blackwell, 2009;2073-2111.
Gish R.G. Chronic hepatitis viral infection . Yamada T., Alpers D.H., Kalloo A.N., et al, editors. Textbook of Gastroenterology, 5th ed, Vol. 2. West Sussex, UK: Wiley-Blackwell, 2009;2112-2138.
Lai M.M.C., Mason W.S. Molecular biology of hepatitis viruses. In: Arias I.M., Boyer J.L., Chisari F.V., et al, editors. The Liver: Biology and Pathobiology . Philadelphia: Lippincott Williams & Wilkins; 2001:831-856.
Lucas S.B. Other viral and infectious diseases and HIV-related liver disease. In: Burt A.D., Portmann B.C., Ferrell L.D., editors. MacSween’s Pathology of the Liver . London: Churchill-Livingstone; 2007:443-491.
Schiff E.R., Sorrell M.F., Maddrey W.C., editors. Part IV: Viral hepatitis , 8th ed. Schiff’s Diseases of the Liver. Lippincott-Raven. Philadelphia. 1999;1719-905
Theise N.D., Bodenheimer H.C., Ferrell L.D. Acute and chronic viral hepatitis . Burt A.D., Portmann B.C., Ferrell L.D., editors. MacSween’s Pathology of the Liver, 5th ed. Churchill-Livingstone. London. 2007;400-441

References
The complete reference list is available online at www.expertconsult.com
Figure 3-42 Primary sclerosing cholangitis . The extrahepatic biliary system is also altered. This section from the common bile duct shows a prominent lymphocytic infiltrate.
Chapter 3 Cholestasis and Biliary Tract Disorders

EXTRAHEPATIC (MECHANICAL) BILE DUCT OBSTRUCTION 52
Early Stage 52
Early Stage to Mid-Stage 52
Late Stage 54
PRIMARY BILIARY CIRRHOSIS 58
PRIMARY SCLEROSING CHOLANGITIS 64
RECURRENT PYOGENIC CHOLANGIOHEPATITIS 68
OTHER CHOLESTATIC DISORDERS 70

Extrahepatic (Mechanical) Bile Duct Obstruction
( Figs 3-1 through 3-17 )

Figure 3-1 Extrahepatic bile duct obstruction . In the early stages, the interlobular bile ducts are dilated (ectatic), with periductal edema often evident. (Trichrome.)

Figure 3-2 Extrahepatic bile duct obstruction . The interlobular bile ducts and cholangioles show proliferation and ectasia, with neutrophils seen intermixed with the markedly dilated ductules. No overt acute cholangitis is seen in this field.

Figure 3-3 Extrahepatic bile duct obstruction . A, Neutrophils can be seen infiltrating beneath the duct basement membrane in this early stage of acute cholangitis. B, In this example of acute cholangitis, the duct is expanded and neutrophils are packed within the duct lumen. Mild periductal edema is also seen.

Figure 3-4 Extrahepatic bile duct obstruction . The interlobular duct is surrounded and infiltrated by neutrophils (acute cholangitis) . Some degree of reactive hyperplasia of the duct epithelium is also apparent.

Figure 3-5 Extrahepatic bile duct obstruction . When acute cholangitis persists, a portal abscess can occur, with partial to total destruction of the duct epithelium.

Figure 3-6 Extrahepatic bile duct obstruction . A, Perivenular (zone 3) cholestasis is common. B, Higher power shows the bile to be present both within the liver cell cytoplasm as well as within the dilated biliary canaliculi.

Figure 3-7 Extrahepatic bile duct obstruction . Mallory bodies can be seen in less than 5% of cases of long-term bile duct obstruction and are present in two hepatocytes in the center of the field. Clumped to finely granular bile is also evident within the liver cell cytoplasm in most of the hepatocytes in this example.

Figure 3-8 Extrahepatic bile duct obstruction . Feathery degeneration is seen in liver cell clusters within the periportal zone; these hepatocytes contain abundant cholesterol esters.

Figure 3-9 Extrahepatic bile duct obstruction . A, A bile lake is seen adjacent to the damaged and inflamed interlobular bile duct, with extravasation of bile into the portal tract. Numerous neutrophils are also present, encircling the damaged duct. B, This low-power example of a bile lake is associated with total destruction of the bile duct epithelium by the acute inflammatory process.

Figure 3-10 Extrahepatic bile duct obstruction . A bile infarct occurs when intracellular bile causes liver cell damage with eventual extravasation of the bile in and amongst the damaged and necrotic hepatocytes.

Figure 3-11 Extrahepatic bile duct obstruction, long term . With time, after repeated episodes of acute cholangitis, periductal fibrosis surrounding the interlobular bile ducts occurs and represents a reactive process to the acutely damaged ducts. (Trichrome.)

Figure 3-12 Extrahepatic bile duct obstruction, long term . Biliary fibrosis eventually occurs, with the fibrotic portal tracts assuming a geographic or jigsaw appearance. Note that in the early and mid-stages, the terminal hepatic venules and veins are not involved by the fibrosis.

Figure 3-13 Extrahepatic bile duct obstruction, long term . Uncommonly there may be loss of interlobular bile ducts (ductopenia) as a result of repeated bouts of duct damage. When present, this usually involves only rare portal structures within the liver, with most of the portal tracts not showing duct loss. In this example the small hepatic artery segments are seen but the interlobular bile duct, which usually parallels these small artery branches, is absent.

Figure 3-14 Extrahepatic bile duct obstruction, long term, cirrhotic stage . Secondary biliary cirrhosis eventually occurs in long-standing bile duct obstruction, with the regenerative nodules generally small and “micronodular.”

Figure 3-15 Extrahepatic bile duct obstruction, long term, cirrhotic stage . The interlobular bile ducts and cholangioles in secondary biliary cirrhosis still exhibit variable degrees of proliferation. A mild lymphocytic infiltrate is also seen.

Figure 3-16 Extrahepatic bile duct obstruction, long term, cirrhotic stage . The interlobular bile ducts often show varying degrees of periductal fibrosis in the cirrhotic stage.

Figure 3-17 Extrahepatic bile duct obstruction, long term . In long-standing bile duct obstruction, an increase in coarsely granular dark brown to black pigment representing copper-binding protein is often seen within the periportal or periseptal hepatocytes on orcein stain. This pigment is also present and often prominent in primary biliary cirrhosis and primary sclerosing cholangitis in the more advanced stages. (Orcein.)

Early Stage

(First Days to Weeks After Obstruction)

Major morphologic features

1. Portal and periductal edema is seen, with prominent proliferation and ectasia (dilation) of interlobular bile ducts.
2. Portal inflammatory infiltrates are present; they consist predominantly of neutrophils with occasional lymphocytes and histiocytes.
3. Neutrophils initially surround interlobular bile ducts (acute pericholangitis) with eventual infiltration of the neutrophils into the interlobular bile duct wall and lumen (acute cholangitis) .
4. Perivenular (zone 3 of Rappaport) cholestasis is seen; the bile is located within the dilated canaliculi and liver cell cytoplasm.

Other features

1. Proliferation of cholangioles (metaplastic ducts) is often present and is seen at the border of the portal tracts and parenchyma. The cholangioles often surround and are infiltrated by neutrophils (acute cholangiolitis); they sometimes contain bile plugs.
2. Interlobular bile ducts undergoing acute cholangitis may at times show reactive hyperplasia of the duct epithelium.
3. Variable degrees of hepatocellular necroinflammatory change are sometimes seen in the perivenular and midzones. The inflammatory component is usually mixed and composed of mononuclear cells as well as neutrophils.
4. The liver cells sometimes surround dilated canaliculi containing bile, forming small rosettes.
5. In very early-stage disease, the portal edema and inflammatory infiltrates may be quite minimal.
6. Microabscesses and less commonly larger abscesses may occur in instances of acute and persistent obstruction in untreated patients (e.g., retained gallstones within the common bile duct). Neutrophilic aggregates are seen within the portal tracts containing damaged interlobular bile ducts and within the perivenular zones of the lobules.

Early Stage to Mid-Stage

(Several Weeks to Months After Obstruction)

Major morphologic features

1. Portal, periportal, and periductal edema is present but is usually less prominent than in the early acute stage. Moderate associated mixed inflammatory infiltrates consisting of both lymphocytes and neutrophils is seen, with the neutrophils often surrounding and infiltrating into bile duct epithelium (acute cholangitis) .
2. Some degree of periductal fibrosis is usually seen.
3. Portal fibrosis may be present but is generally mild, the fibrosis assuming a biliary -type pattern (fibrous tissue laid down parallel to the adjacent parenchyma in a “jigsaw” or “geographic” pattern). Although bridging fibrosis of one portal tract to another may be seen, this feature is uncommon at this stage of the disease.

Other features

1. Morphologic features that can be seen in this stage include the following:
a. Bile lakes: accumulation of small pools of extracellular bile within portal tracts adjacent to damaged interlobular bile ducts or within the lobule, usually in the periportal zone; sometimes associated with a histiocytic and/or foreign body giant cell reaction
b. Bile infarcts: aggregates of pale-staining necrotic hepatocytes and intermixed fibrin and bile pigment with surrounding feathery degeneration of viable hepatocytes; located predominantly in the periportal zone
c. Feathery degeneration: hepatocytes with clear foamy or reticular cytoplasm; found singly or in small groups, predominantly in the periportal zone
d. Mallory bodies: amorphous irregular cytoplasmic eosinophilic inclusions within predominantly the periportal hepatocytes (seen in approximately 2% to 5% of cases)
2. Cholangiolar proliferation is present and may be prominent, often associated with a neutrophilic infiltrate (acute cholangiolitis). These cholangioles sometimes contain bile plugs and often show considerable cytologic distortion of the duct epithelium (e.g., cytoplasmic eosinophilia or vacuolization, flattening of the cytoplasm, irregularity of the nuclei with variable nuclear pyknosis).
3. Cholestasis is present predominantly within the perivenular zone and mid-zone, with rosette formation sometimes apparent.
4. Small clusters of lipid-laden histiocytes may occur within the sinusoids.
5. Lobular necroinflammatory change is often seen but is usually mild, the inflammatory cells composed of both lymphocytes and neutrophils.
6. Some degree of mild periportal interface inflammatory activity may infrequently occur.
7. The larger interlobar and hilar bile ducts may show minor changes with some degree of ectasia; however, in severe cases, bile impregnation and damage to the duct epithelium may occur. This is associated with sloughing of the duct epithelium with a resultant acute inflammatory reaction, reactive fibrosis, and periductal scar formation.
8. Microabscesses, and less frequently larger abscesses, may also be seen but are less common than in the early acute stages in untreated patients.
Note: Bile lakes and bile infarcts are often identified in wedge biopsies, autopsy material, or liver explants, when abundant tissue is present for evaluation. They are less frequently seen in core biopsies. However, when identified, these two features are virtually diagnostic of either extrahepatic bile duct obstruction or intrahepatic but large duct obstruction (e.g., hilar mass, intrahepatic biliary stones, some cases of primary sclerosing cholangitis [PSC]).

Late Stage

(Years After Obstruction)

Major morphologic features

1. Biliary fibrosis occurs, with portal-to-portal bridging and eventual secondary biliary cirrhosis. The regenerative nodules exhibit a geographic jigsaw-type pattern.
2. Periductal fibrosis is present within the fibrotic portal tracts and fibrous septa.

Other features

1. Variable degrees of bile duct and cholangiolar proliferation are seen; however, in about 2% of cases, a decrease in interlobular bile ducts in a minority of the portal tracts may also occur (ductopenia).
2. Portal inflammation is seen and is predominantly lymphocytic. Neutrophils may also be present, surrounding and infiltrating into duct epithelium (acute cholangitis), as may microabscesses, although these features are rather uncommon in this stage of the disease.
3. Interstitial edema is frequently seen involving the immediate periportal and periseptal zones, with the hepatocytes appearing swollen and often exhibiting a feathery degeneration; they sometimes contain Mallory bodies.
4. Cholestasis may be seen in periseptal hepatocytes in end-stage disease but is less frequent and usually intermittent in noncirrhotic livers.
5. Bile infarcts and bile lakes may also be seen but occur less frequently at this stage than in earlier stages of the disease.
6. Intralobular necroinflammatory change may be present but is usually mild and generally consists of mononuclear cells.
7. Thickening of hepatic arterioles within the portal tracts is often present.
8. The large interlobar and hilar bile ducts, the extrahepatic bile ducts, and the peribiliary glands exhibit variable degrees of fibrosis and both acute and chronic inflammatory infiltration.


Special stains

1. PAS after diastase digestion (DiPAS): Prominent staining of Kupffer cells and areas of necrosis in the perivenular and mid-zonal areas are frequently seen as a result of increased lysosomal activity and deposition of ceroid pigment.
2. Van Gieson: Intracellular and canalicular bile pigment stains bright green.
3. In cases of chronic long-term obstruction:
a) Orcein: Copper-binding protein (not copper) is present as dark brown to black intracytoplasmic granules in periportal and periseptal hepatocytes.
b) Rubeanic acid, rhodanine: Copper is increased within liver cell cytoplasm and stains black to black-green (rubeanic acid stain) and bright red (rhodanine stain), predominantly within the periportal and periseptal liver cells.

Differential diagnosis

1. Primary biliary cirrhosis, primary sclerosing cholangitis (PSC), and autoimmune hepatitis (autoimmune cholangitis):
a. Noncirrhotic stage: The main histologic differences in these three disease entities in the early and mid-stages with bile duct obstruction are included in Table 3-1 .
b. Cirrhotic stage: In the cirrhotic stages, all four disease entities listed show a similar type of biliary cirrhosis; however, duct loss is the rule with primary biliary cirrhosis, PSC, and autoimmune cholangitis.
2. Sepsis: Portal neutrophilic infiltrates may be seen in bacterial sepsis, the neutrophils scattered within the portal tracts and not always directly oriented to duct structures; however, sepsis can also be associated with an ascending cholangitis, which may be secondary to large duct obstruction from stones but also can occur in association with severe acute cholecystitis and acute pancreatitis. In those instances, cultures and results on ultrasound and imaging (e.g., endoscopic retrograde cholangiopancreatography [ERCP]) are helpful.
3. Toxic shock syndrome: Acute cholangitis and cholangiolitis can be seen. The dramatic clinical features of fever, severe hypotension, diffuse myalgia and/or arthralgia, and diffuse erythroderma are characteristic of this syndrome.
4. Alcoholic hepatitis: Neutrophilic infiltration is diffusely present within portal tracts and parenchyma in alcoholic hepatitis; however, the neutrophils are not directly oriented to ducts. In addition, the features of alcoholic hepatitis such as intrasinusoidal collagenosis, numerous Mallory bodies often surrounded by neutrophils, and variable but often significant fatty change are not seen in bile duct obstruction.
5. Drug-induced liver injury (e.g., allopurinol; see Table 5-11 ): Certain drugs are associated with an acute cholangitis that resembles that seen in bile duct obstruction. These ducts seldom show any significant ectasia, and periductal fibrosis and portal edema are not present.
6. Pylephlebitis: Portal neutrophilic infiltrates are seen; however, the neutrophils are oriented toward the portal venules, which are sometimes secondarily thrombosed. Bile ducts can also be involved by this infiltrate, however, as pylephlebitis is often associated with sepsis. Ultrasound and imaging (e.g., ERCP) can be helpful in the differential diagnosis.
7. Vasculitis (e.g., polyarteritis nodosa, rheumatoid arthritis): Portal mixed inflammatory infiltrates consisting of lymphocytes, eosinophils, and neutrophils can be identified in various liver diseases associated with vasculitis. The neutrophils and other inflammatory cells are oriented in these cases to the medium-sized and small arteries, with the ducts spared of inflammation or damage (an exception being duct ischemic changes if the involved small arteries are completely thrombosed).
8. Recurrent pyogenic cholangiohepatitis: Acute cholangitis with duct destruction and marked duct ectasia are characteristic findings in recurrent pyogenic cholangiohepatitis. Associated macroabscesses and microabscesses are also present. Imaging studies show strictures of the intrahepatic bile ducts with intrahepatic calculi; these features are not characteristic of extrahepatic bile duct obstruction.

Table 3-1 Differential Diagnoses of Biliary Tract Disorders

Clinical and biologic behavior

1. Common causes of extrahepatic mechanical bile duct obstruction include the following:

Acute

a. Choledocholithiasis
b. Acute pancreatitis
c. Early stages of common bile duct stricture (following hepatobiliary surgery or blunt abdominal trauma)
d. Mass lesions either directly involving ducts (e.g., cholangiocarcinoma) or compressing extrahepatic bile ducts (e.g., lymph nodes from metastases, lymphoma) or large intrahepatic bile ducts (e.g., hydatid cyst, abscess)

Chronic


a. Benign long-term stricture secondary to surgical trauma, chronic pancreatitis, and rarely choledocholithiasis
b. Extrahepatic biliary atresia
c. Parasitic infections of the biliary system (e.g., Clonorchis sinensis )
d. Tumors of the pancreas and extrahepatic bile ducts
2. Patients with acute bile duct obstruction typically present with jaundice, abdominal pain, and fever (Charcot triad) when cholangitis is present. Leukocytosis and elevations of serum bilirubin, gamma-glutamyl transpeptidase (GGTP), 5′ nucleotidase, and alkaline phosphatase values are common.
3. Bile lakes form secondary to leakage of bile directly from damaged interlobular ducts. Bile infarcts are caused by direct toxic damage of bile to the hepatocytes. Although these two changes are virtually diagnostic of large (intrahepatic or extrahepatic) bile duct obstruction, they are not commonly seen on core liver biopsies.
4. Cholestasis is predominantly perivenular (zone 3), as bile is reabsorbed and recirculated in the periportal zones.
5. In partial bile duct obstruction, the inflammatory infiltrate is usually associated with growth of bacteria in the biliary tree. If obstruction is not relieved, abscesses can occur with eventual septicemia. In total bile duct obstruction, abscess formation and cholangitis is not as common.
6. Chronic obstruction leads to a periductal fibrosis from repeated bouts of cholangitis, most of these subclinical or mild, where resolution of the acute inflammatory change leaves reactive fibrosis and scar formation encircling the involved ducts.
7. In patients with chronic pancreatitis, 8% develop strictures in the intrapancreatic segment of the common bile duct. Although asymptomatic, 79% will demonstrate features of extrahepatic obstruction on liver biopsy.
8. The length of time for the development of secondary biliary cirrhosis varies:
a. Neonates with extrahepatic biliary atresia: 6 months (critical to diagnose these cases in less than 3 months after birth for successful surgical management)
b. Common bile duct stricture: 7.1 years
c. Choledocholithiasis: 4.6 years (developing less rapidly in patients who are clinically symptomatic than in those who are asymptomatic).
9. Secondary biliary cirrhosis is associated less frequently with complications of cirrhosis (ascites and variceal bleeding) than in patients with cirrhosis of viral or alcoholic etiology.

Treatment and prognosis

1. Relief of the cause of obstruction is critical in the prevention of complications such as sepsis. When obstruction is subclinical, biliary fibrosis and eventual cirrhosis may develop.
2. Relief of obstruction will often lead to some degree of regression of portal and lobular changes in the noncirrhotic liver.
3. Unlike cirrhosis secondary to alcoholism or viral infection, hepatocellular carcinoma is not a complication.

Primary Biliary Cirrhosis
( Figs 3-18 through 3-29 )

Figure 3-18 Primary biliary cirrhosis . A, This low-power photomicrograph of a portal tract shows an interlobular bile duct infiltrated by lymphocytes (nonsuppurative destructive cholangitis) . An epithelioid granuloma is present immediately adjacent to the duct. B, This high-power image of the same duct demonstrates the characteristic duct damage seen in primary biliary cirrhosis. Note that in this example the duct epithelium is hyperplastic, with numerous lymphocytes infiltrating beneath the duct basement membrane. Lymphocytes and numerous plasma cells are also seen surrounding the duct.

Figure 3-19 Primary biliary cirrhosis . A and B. These two images demonstrate interlobular bile ducts with variable cytologic distortion of the epithelial cells. The ducts are surrounded and infiltrated by lymphocytes (nonsuppurative destructive cholangitis) . Occasional plasma cells are seen surrounding the ducts as well.

Figure 3-20 Primary biliary cirrhosis . The interlobular bile duct in the center of the field shows considerable cytologic atypia, with irregularly placed nuclei and eosinophilic cytoplasm. The duct is surrounded and focally infiltrated by lymphocytes.

Figure 3-21 Primary biliary cirrhosis . The portal tract shows an interlobular bile duct with characteristic nonsuppurative duct damage, the distorted duct in the center of the field surrounded and infiltrated by lymphocytes. Numerous plump histiocytes and epithelioid cells ( granuloma formation) are also seen surrounding the duct, with considerable numbers of plasma cells encircling the granuloma.

Figure 3-22 Primary biliary cirrhosis . Well-demarcated granulomas composed of plump eosinophilic histiocytes with scattered lymphocytes and infrequently multinucleated giant cells ( epithelioid granulomas) can be seen within portal tracts (A) as well as within the parenchyma (B) in about 25% of cases in the early stages of the disease.

Figure 3-23 Primary biliary cirrhosis . A, Periportal interface inflammatory activity (“piecemeal” necrosis) is present in this example and can be seen in up to 15% of cases of primary biliary cirrhosis. B, In some instances this feature can be marked, as in this example of primary biliary cirrhosis–autoimmune hepatitis overlap syndrome.

Figure 3-24 Primary biliary cirrhosis . Proliferation of atypical ductules along the border of the portal tracts and parenchyma are common in the early stages (usually stage 2) of the disease, as seen here in these low-power (A) and high-power (B) images, although the atypical cholangioles can at times be seen even in the cirrhotic stage in the periseptal zones.

Figure 3-25 Primary biliary cirrhosis . Mallory bodies with or without an accompanying pericellular inflammatory reaction may be present in the periportal or periseptal hepatocytes in the more advanced stages of the disease.

Figure 3-26 Primary biliary cirrhosis . With time, portal fibrosis occurs, as seen in this image, with variable lymphocytic infiltration but with interlobular bile duct loss (ductopenia) . The increase in portal venous radicals within this portal tract is a manifestation of intrahepatic portal hypertension, which can occur in the precirrhotic stage of the disease.

Figure 3-27 Primary biliary cirrhosis . Although usually interlobular bile duct loss resulting from continuing nonsuppurative duct injury begins to occur as the disease advances (stages 3 and 4), at times portal tracts with little fibrosis may also exhibit absence of ducts, as this example of a normal-sized portal tract with duct loss demonstrates.

Figure 3-28 Primary biliary cirrhosis, cirrhotic stage . A, Fibrous bands with regenerative nodules are seen. The lamellar laydown of the collagen at the border of the fibrous bands is characteristic of a biliary cirrhosis. B, Higher power of the border of a fibrous band and regenerative nodule shows the parallel lamellar nature of the collagen, with edema in between the collagen fibers. (Trichrome.)

Figure 3-29 Primary biliary cirrhosis, cirrhotic stage . The fibrous band shows a moderate degree of lymphocytic infiltrates and increase in portal venous radicals; however, there is an absence of interlobular bile ducts.


Major morphologic features
Primary biliary cirrhosis can be divided into four different stages:
Stage 1: Florid nonsuppurative destructive cholangitis is present in approximately 2 3 of cases in the early stage, primarily involving small interlobular bile ducts 40 to 80 μm in diameter, and is manifested by the following:
a. Infiltration of lymphocytes through the interlobular bile duct basement membrane into and in between the duct epithelial cells
b. Considerable cytologic duct atypia consisting of eosinophilia and vacuolization of the cytoplasm, nuclear irregularity and pyknosis, and occasionally duct epithelial hyperplasia
c. Periductal infiltration by lymphocytes and numerous plasma cells
Stage 2: Biliary fibrosis associated with prominent atypical ductular proliferation occurs, with the duct changes consisting of the following:
a. Scanty or absent lumen
b. Flattened duct epithelium with hyperchromatic nuclei
c. Irregular serpentine growth pattern of the ductules
Stage 3: Biliary fibrosis with portal-to-portal bridging is present, with a decrease in interlobular bile ducts.
Stage 4: Biliary cirrhosis eventually develops, and the regenerative nodules are arranged in an irregular, geographic or jigsaw puzzle pattern, with the following:
a. Periseptal lamellar fibrosis and edema surrounding the nodules
b. A marked decrease or absence of small to intermediate-sized interlobular bile ducts, with sparing of the larger interlobar and hilar ducts

Other features

1. Plasma cells, eosinophils, and occasional neutrophils and foamy macrophages can be seen scattered within the portal tracts, although the plasma cells can at times be more concentrated surrounding the injured bile ducts. In addition, the number of eosinophils can sometimes be quite prominent.
2. Noncaseating epithelioid granulomas are seen in up to 25% of cases in early-stage disease. These granulomas can be seen anywhere within the lobule but are more frequently present in portal tracts surrounding the injured bile ducts.
3. In many cases, some degree of periportal interface inflammatory activity can occur, but is generally mild and focal. However, in approximately 10% to 15% of the cases this feature can be prominent and involve most, if not all, of the portal tracts, often associated with moderate lobular inflammation as well (see “Autoimmune Hepatitis Overlap Variants” in Chapter 12 ).
4. Cholangioles and atypical ductules can sometimes induce a neutrophilic response, without a true acute cholangitis.
5. Focal hepatocytolysis, lymphocytic infiltrates, apoptosis, and variable degrees of Kupffer cell hyperplasia are usually present within the lobules, with no distinct zonal distribution pattern.
6. In up to 25% of more advanced cases, Mallory bodies are identified in the periportal or periseptal zones. These Mallory bodies are usually not associated with a neutrophilic infiltrate.
7. Thickening of the hepatic arterioles is often present.
8. Cholestasis in later-stage disease may be seen, predominantly within the periportal or periseptal zones. This may appear as either distinct intracanalicular bile plugs or as intracellular liver cell swelling with intracytoplasmic bile remnants (“cholate stasis”).
Note: The staging of primary biliary cirrhosis has considerable limitations, because it is not uncommon to see the morphologic features of more than one stage at the same time in a liver biopsy. The degree of fibrosis has the most impact on disease severity.

Special stains

1. In cases of more advanced disease (stages 3 and 4), the following special stains are useful:
a. Orcein: Copper-binding protein (not copper) is present as dark brown to black intracytoplasmic granules in periportal hepatocytes.
b. Rubeanic acid: Copper is increased within liver cell cytoplasm, stains black to black-green, and is seen predominantly within the periportal zones.
c. Rhodanine: The increased copper stains red.
2. Masson trichrome: This stain emphasizes the degree of fibrosis and also accentuates the loose appearance of the periportal or periseptal edema.

Differential diagnosis

1. Mechanical bile duct obstruction, PSC, and autoimmune hepatitis (autoimmune cholangitis) (see Table 3-1 ).
2. Chronic viral hepatitis: In approximately 10% to 15% of cases of primary biliary cirrhosis, significant periportal interface inflammatory activity is noted, resembling that seen in chronic viral hepatitis; however, the presence of granulomas and nonsuppurative destruction of interlobular bile ducts in the early stage and a decrease in ducts with a demonstrable increase in copper and copper-binding protein in later stages are features of primary biliary cirrhosis that are not present in chronic viral hepatitis alone. The atypical interlobular bile ducts seen in chronic hepatitis C virus infection are usually centered within a portal lymphoid aggregate and are not associated with duct loss. Assessment of hepatitis serologies is necessary in these cases.
3. Developmental causes of duct loss (e.g., paucity of duct syndrome, progressive familial intrahepatic cholestasis): Duct loss resembling that seen in primary biliary cirrhosis can be identified in a number of hereditary and developmental liver diseases. These liver diseases seldom show nonsuppurative inflammation involving ducts and are not associated with granulomas. In addition, primary biliary cirrhosis is not known to occur in the neonate or in early childhood. Finally, developmental cholestatic conditions are negative for antimitochondrial antibody (AMA), a test positive in about 95% of patients with primary biliary cirrhosis.
4. Drug-induced liver injury (e.g., chlorpromazine; see Table 5-11 ): Certain drugs may cause duct damage, with eventual duct loss that may mimic primary biliary cirrhosis. Correlation of the time frame of drug use and liver test abnormalities is recommended. Of importance is that patients with drug-induced duct damage are AMA negative.
5. Sarcoidosis: Sarcoidosis may be associated with not only epithelioid granulomas but also chronic hepatitis with biliary fibrosis and duct loss, in these instances strongly resembling features seen in primary biliary cirrhosis. The granulomas in sarcoidosis are more numerous than in primary biliary cirrhosis and are usually not directly targeted toward bile ducts, although instances of sarcoidosis with granulomatous duct damage have been described. In addition, sarcoid granulomas often tend to cluster together and segment into smaller units by fibrous septa and bands (septate division of the granulomas), and sometimes these granulomatous aggregates are large enough to be visualized on imaging. These features are not seen in primary biliary cirrhosis. Last, patients with sarcoidosis are AMA negative. Of note, however, is that very rarely both histologic and clinical features of both primary biliary cirrhosis and sarcoidosis can occur, believed by some to represent an overlap syndrome.
6. Hodgkin lymphoma: Rarely patients with Hodgkin lymphoma may demonstrate nonsuppurative duct injury and eventual duct loss. The presence of more distinctive features of Hodgkin disease (e.g., Reed-Sternberg cells) and the clinical history make the differential straightforward.
7. Idiopathic adult-onset ductopenia: This disorder occurs in the young adult population and presents as a chronic cholestatic liver disease associated with eventual biliary cirrhosis and bile duct loss. These patients are usually male and are AMA negative.


Clinical and biologic behavior

1. Primary biliary cirrhosis is a chronic progressive cholestatic liver disease typically found in middle-aged women (90%) and is responsible for approximately 0.6% to 2.0% of deaths from cirrhosis worldwide.
2. The onset is insidious, with pruritus preceding jaundice. Other clinical features include xanthomata, osteopenia, steatorrhea, hepatosplenomegaly, and in advanced disease, manifestations of portal hypertension (ascites, esophageal varices, and portal systemic encephalopathy).
3. Laboratory data include elevated serum immunoglobulin M (IgM) and cholesterol and increased alkaline phosphatase, 5′ nucleotidase, and GGTP values. Serum bilirubin becomes elevated in advanced disease (severe fibrosis or cirrhosis) and consequently is used as a prognostic indicator.
4. AMA is present in 95% of patients, and circulating immune complexes are present 60% to 90% of the time. Other autoantibodies include antinuclear (ANA), antithyroid, lymphocytotoxic, and platelet-bound antibodies.
5. Because AMA has been shown to be positive in other liver diseases (e.g., autoimmune hepatitis, PSC), depending on the mode of testing, further characterization in demonstrating the M2 fraction is most specific for primary biliary cirrhosis in some, but not all, series.
6. Autoimmune disorders are present in 84% of patients with primary biliary cirrhosis and include Sjögren syndrome, scleroderma and CRST syndrome, rheumatoid arthritis, lymphocytic interstitial pneumonia, systemic lupus erythematosus, and autoimmune thyroiditis.
7. In instance where the histology is characteristic for primary biliary cirrhosis but the AMA is repeatedly negative, with negative autoimmune serologies (ANA and smooth muscle antibody [SMA]), then a diagnosis of AMA-negative primary biliary cirrhosis is most probable; 5% of patients with primary biliary cirrhosis may be AMA negative.
8. A subgroup of patients may be entirely asymptomatic, diagnosed incidentally by increased serum alkaline phosphatase values. Biopsy shows characteristic morphologic features. It is not certain if these patients have a normal life span, because recent evidence suggests decreased survival in these cases.
9. An additional subgroup of patients who fulfill all criteria for primary biliary cirrhosis but have a normal or only slightly elevated alkaline phosphatase value is occasionally encountered.
10. Autopsy studies have shown that a healthy liver contains a mean of 1.3 to 1.5 bile ducts per portal tract. In the fibrotic stages of primary biliary cirrhosis, the ducts are decreased to 0.3 per portal tract.
11. Increased hepatic copper is due to bile retention (normal, 2.7 mg copper/100 g dry weight of liver; mechanical duct obstruction, 12.8 mg; primary biliary cirrhosis, 44.1 mg).
12. Various pathophysiologic concepts of the disease include the following:
a. Initial injury may be secondary to activated cytotoxic lymphocytes directed against bile ducts expressing histocompatibility antigens (class I human leukocyte antigen [HLA]-A, HLA-B, and HLA-C, as well as class II HLA-DR) in primary biliary cirrhosis. Immunohistochemical phenotyping shows the inflammatory cells surrounding the ducts to be a combination of CD4 and CD8 T cells, which induce cytotoxic injury to the ducts.
b. The most frequent of the antigens to which AMA is directed is the pyruvate dehydrogenase complex E2 (PDC-E2), where reacting antibodies are noted in more than 90% of patients with primary biliary cirrhosis. The primary event appears to be loss of tolerance to this complex. This autoantigen is overexpressed on biliary cells in primary biliary cirrhosis, predominantly at the luminal border, and PDC-E2-specific CD4 T cells are present in the portal inflammatory infiltrates.
c. Cytotoxic T lymphocyte antigen-4 (CTLA-4), located on the long arm of chromosome 2 (2q33), encodes a coinhibitory immunoreceptor that plays a key role in regulation of self-tolerance. Recent data suggest that single nucleotide polymorphisms in the CTLA-4 are associated with primary biliary cirrhosis, which may provide a genetic basis for the autoimmune disease process.
d. The genetic basis for autoimmunity is also supported by the fact that primary biliary cirrhosis has been noted to occur in first-degree relatives. There is a high concordance rate among monozygotic twins and an association with the HLA DRB1∗08, HLA DRB∗11, and HLA DRB∗13 alleles.
e. Environmental factors such as bacterial infection, yeast antigen, and viral infections have also been incriminated as inducing bile duct injury. The granulomas seen in early stages of primary biliary cirrhosis and directed in some instances to the duct epithelium itself may be indirectly related to infectious agents such as Mycobacterium, as sera from patients with primary biliary cirrhosis have been shown to react against two membrane polypeptides of M. gordonae, which cross-react with the two major mitochondrial autoantigens of primary biliary cirrhosis. In addition, primary biliary cirrhosis lesions have been experimentally produced in the mouse by mycoplasma-like organisms.
f. Selenium deficiency and defective sulfoxidation of certain compounds such as bile acids, estrogens, and drugs have been proposed as underlying mechanisms.

Treatment and prognosis

1. The mean survival after onset of symptoms is approximately 11 years. It is uncertain whether survival in asymptomatic patients is the same as that in the control population.
2. The presence of granulomas is found to be a good prognostic indicator.
3. Therapy with ursodeoxycholic acid has been shown to improve liver test abnormalities and may delay the progression of the disease, onset of liver failure, and time to transplantation.
4. Liver transplantation should be considered in patients progressing to hepatic failure and when complications of portal hypertension develop. Survival after transplantation is almost 85% over 4 years, but recurrence of primary biliary cirrhosis occurs in some patients.

Primary Sclerosing Cholangitis
( Figs 3-30 through 3-42

Figure 3-30 Primary sclerosing cholangitis, endoscopic retrograde cholangiopancreatography (ERCP) . Injection of radiocontrast material into the common bile duct via the ampulla of Vater demonstrates dilation and strictures (“beading” appearance) of the common bile duct, common hepatic duct, and intrahepatic ducts, characteristic of primary sclerosing cholangitis.

Figure 3-31 Primary sclerosing cholangitis . Each of these images demonstrates the prominent periductal fibrosis characteristic of primary sclerosing cholangitis. A, The large interlobar duct shows distortion of the epithelial lining with focal epithelial erosion, as well as fibrosis and scar along the duct wall. B, This medium-sized interlobular bile duct shows striking periductal fibrosis with a mild lymphocytic infiltrate surrounding the duct.

Figure 3-32 Primary sclerosing cholangitis . The smaller interlobular bile duct shows prominent periductal fibrosis. At times the small ducts may be the only ducts involved by the pathology ( small duct variant).

Figure 3-33 Primary sclerosing cholangitis . This smaller interlobular bile duct shows striking periductal fibrosis, the duct itself showing considerable irregularity of the nuclei, without ectasia of the lumen.

Figure 3-34 Primary sclerosing cholangitis . Numerous Mallory bodies are present within the periportal hepatocytes, associated with periportal edema.

Figure 3-35 Primary sclerosing cholangitis . Although usually duct loss occurs as the disease progresses, at times portal tracts may be normal in size or only minimally fibrotic and still be devoid of interlobular bile ducts, as in this example.

Figure 3-36 Primary sclerosing cholangitis, cirrhotic stage . Fibrous bands and regenerative nodules are seen in the cirrhotic stage of the disease, as these low-power (A) and medium-power (B) images demonstrate. Note that, as in primary biliary cirrhosis (see Fig. 3-28 ), the border of the fibrous bands and regenerative nodules often show lamellar collagen fibers laid down in a parallel fashion, with variable degrees of edema in between the collagen fibers, features characteristic of a biliary-type cirrhosis. (Trichrome.)

Figure 3-37 Primary sclerosing cholangitis, cirrhotic stage . The fibrous bands show a moderate lymphocytic infiltrate and numerous vascular channels, with total interlobular bile duct loss.

Figure 3-38 Primary sclerosing cholangitis, cirrhotic stage . Although interlobular bile ducts are virtually absent in the cirrhotic stage, cholangioles (metaplastic ducts) are still often seen at the border of the fibrous bands and regenerative nodules and often contain bile plugs.

Figure 3-39 Primary sclerosing cholangitis . Increased copper and copper-binding protein are present in the liver in the more advanced stages of the disease. This example of an orcein stain shows the copper-binding protein as a coarsely granular dark brown to black pigment located within the periportal hepatocytes.

Figure 3-40 Primary sclerosing cholangitis . A, A feature not uncommon in the more advances stages of the disease is prominent biliary concretions within the larger dilated hilar bile ducts, as this example from an explanted liver demonstrates. B, Microscopically these ducts are seen to contain abundant impregnated bile within the lumen. Damage to the duct epithelium is extensive, with ulceration and an accompanying acute and chronic inflammatory reaction.

Figure 3-41 Primary sclerosing cholangitis . Uncommonly the repeated damage to the large ducts with time can contribute to not only intraluminal fibrosis but also calcification and very rarely ossification. Bile pigment is also interspersed with the areas of ossification in this example.


Major morphologic features

1. Fibroobliterative “onion skin” destructive cholangitis involves medium-sized to large interlobular bile ducts, manifested by the following:
a. Prominent periductal fibrosis, focal necrosis and degeneration of duct epithelium and significant luminal narrowing with eventual obliteration of the duct lumen
b. Lymphocytic infiltration surrounding and often infiltrating into the duct wall
2. As the disease progresses, the following are seen:
a. Decreased or absent interlobular bile ducts, with an ill-defined rounded fibrous scar left in their place
b. Biliary fibrosis, with portal-to-portal bridging, and eventual biliary cirrhosis (irregular geographic or jigsaw pattern of the nodules, periseptal lamellar fibrosis and edema)

Other features

1. Often present are varying degrees of portal edema and mixed cellular infiltrates consisting predominantly of lymphocytes (sometimes forming well-delineated follicles) and occasional plasma cells, neutrophils, and some eosinophils.
2. Proliferation of cholangioles (metaplastic ducts) is often seen at the borders of the portal tracts and parenchyma. These ducts are somewhat atypical, with scanty or absent lumen and flattened duct epithelium. Neutrophils sometimes may be seen in and among these cholangioles.
3. Cholestasis is usually present and in early-stage disease is perivenular (zone 3 of Rappaport). As the disease progresses, the bile may be concentrated in the periportal and periseptal zones. In very rare instances, bile lakes and bile infarcts can occur in large tissue specimens with adequate sampling, such as explants (manifestations of obstruction to bile flow).
4. Small interlobular bile ducts may also show periductal fibrosis with eventual duct loss; at times the small ducts may be the primary ducts involved ( small duct variant).
5. Variable degrees of macrovesicular fatty change may be present and is more commonly seen in patients with ulcerative colitis.
6. Focal hepatocytolysis, apoptosis, and necroinflammatory changes are present within the lobules but are generally mild.
7. Periportal interface inflammatory activity can occur but is usually mild; however, in a small percentage of patients, the degree of both periportal and intralobular inflammatory activity can be marked (see “Autoimmune Hepatitis Overlap Variants” in Chapter 12 ).
8. The periportal and periseptal areas in more advanced stages of the disease show variable but sometimes prominent edema and Mallory body formation.
9. Segmental involvement of interlobular bile ducts may occur with only one main hepatic duct involved, resulting in focal hepatic injury (hemicirrhosis) . In addition, focal involvement of individual large interlobar ducts themselves often occurs, with uneven scarring surrounding the ducts.
10. The larger interlobar, hilar, and extrahepatic bile ducts may show the following:
a. Periductal and luminal fibrosis with scar formation
b. Varying degrees of duct damage and infiltration by inflammatory cells (neutrophils, lymphocytes, and plasma cells)
c. Focal saccular dilation of the ducts
d. Ulceration of the duct epithelium, with xanthomatous and xanthogranulomatous proliferation and bile impregnation
11. Peribiliary glands adjacent to the hilar and extrahepatic ducts can show prominent proliferation.
12. The gallbladder also exhibits fibrosis and chronic inflammatory infiltrates.

Special stains

1. In cases of more advanced disease (bridging fibrosis or cirrhosis), the following stains are helpful:
a. Orcein: Copper-binding protein (not copper) is present as dark brown to black intracytoplasmic granules in periportal and periseptal hepatocytes.
b. Rubeanic acid: Copper is increased within liver cell cytoplasm and stains black to black-green, predominantly involving the periportal and periseptal liver cells.
c. Rhodanine: Increased copper in the periportal and periseptal hepatocytes stains red.
2. Masson trichrome: The degree of fibrosis is emphasized, with periportal and periseptal edema most apparent.

Differential diagnosis

1. Mechanical bile duct obstruction, PSC, and autoimmune hepatitis (autoimmune cholangitis) (see Table 3-1 ).
2. Chronic viral hepatitis: A minority of biopsies of PSC show periportal interface inflammatory activity similar to that seen in chronic viral hepatitis. The presence of periductal sclerosis, decrease in ducts, and demonstrable copper and copper-binding protein in late-stage disease are features of PSC that are not seen in chronic viral hepatitis.
3. Developmental causes of duct loss (e.g., paucity of duct syndrome, progressive familial intrahepatic cholestasis): Duct loss resembling that seen in the advanced stages of PSC can occur in a number of hereditary and developmental liver diseases. These hepatic disorders, however, do not show periductal fibrosis and sclerosis as the disease progresses. In addition, PSC is not known to occur in the neonate or pediatric population.
4. Idiopathic adult-onset ductopenia: This disorder that occurs in the young adult population shows a chronic cholestatic liver disease associated with eventual biliary cirrhosis and bile duct loss. These patients are usually male, are AMA negative, and do not have the characteristic structural abnormalities to the biliary system characteristic of PSC demonstrable on imaging.
5. Other causes of periductal fibrosis: “Secondary sclerosing cholangitis” must also be considered in the differential diagnosis (see later discussion).

Clinical and biologic behavior

1. PSC is a chronic biliary tract disorder; 70% of cases affect middle-aged men, and it generally presents with features of bile duct obstruction, including fever, abdominal pain, intermittent and fluctuating jaundice, marked elevation of the alkaline phosphatase levels, and modest elevations of serum transaminases.
2. PSC is associated with chronic ulcerative colitis in 30% to 75% of cases, either before or after the colitis becomes clinically manifest. PSC will develop in 1% to 4% of all patients with ulcerative colitis. In addition, cholangiocarcinoma will develop in 7% of patients with both PSC and ulcerative colitis.
3. The characteristic imaging on ERCP of a “beaded” appearance of the intrahepatic and extrahepatic bile ducts, with segmental strictures and saccular dilations, is virtually diagnostic of the disease.
4. Other associated disorders include retroperitoneal and mediastinal fibrosis, Riedel thyroiditis, vasculitis, orbital pseudotumor, Sjögren syndrome, and chronic pancreatitis.
5. The entire biliary tract is generally involved, including the gallbladder; however, pure intrahepatic PSC with segmental involvement can occur, with the main hepatic and common ducts free of the disease.
6. In most cases, a liver biopsy is consistent with or suggestive of the disorder; unfortunately, the classic and virtually diagnostic fibrous obliterative duct lesion is seen in less than 1 3 of biopsy specimens, and ERCP is almost always necessary for diagnosis.
7. As the disease progresses, complications of portal hypertension develop, eventually leading to hepatic failure. In patients with ulcerative colitis and prior colectomy, varices may develop with bleeding at the ileostomy site.
8. Secondary sclerosing cholangitis: The characteristic periductal sclerosis with similar imaging findings may also be seen secondary to a number of disorders:
a. Acquired immunodeficiency syndrome (e.g., CMV, cryptosporidiosis with duct damage)
b. Status-post rupture of hydatid cysts
c. Parasitic infestation of main bile ducts (e.g., Ascaris lumbricoides, C. sinensis )
d. Drug-induced injury (e.g., floxuridine, status postchemotherapy).
9. There is evidence of a genetic predisposition, with reports of familial cases and an association of PSC with HLA-A1-B8-DR3, -DR6, and -DR2 haplotypes. The presence of DR4 is associated with poor prognosis and possibly cholangiocarcinoma. Haplotypes associated with increased PSC disease risk include B8-DRB1∗0301 and DRB1∗1501. Those with decreased risk include DRB1∗0404, DRB1∗0701, and MICA∗002.
10. Humoral immune abnormalities include the presence of hypergammaglobulinemia, circulating immune complexes, and antineutrophilic cytoplasmic antibody (ANCA), in particular atypical ANCA, which is positive in 33% to 88% of patients. Of note, atypical ANCA is distinctly different from p-ANCA and c-ANCA, the latter two being more specific for various vascular diseases, including microscopic angiitis (p-ANCA) and Wegener granulomatosis (c-ANCA). Other autoantibodies seen in PSC include ANA (7% to 77%), SMA (13% to 20%), antiendothelial cell antibody (35%), anticardiolipin antibody (4% to 66%), antithyroperoxidase antibody (7% to 16%), antithyroglobulin antibody (4%), and rheumatoid factor (15%).
11. Cellular abnormalities include lymphocyte sensitization to biliary antigens by interleukin-2 receptors on the T lymphocytes, an increase in the CD4:CD8 ratio of circulating T cells, and a predominance of T cells in the portal infiltrates.
12. Portal bacteremia associated with inflammatory bowel disease has been speculated as playing a role in the disease, because similar morphologic features have been seen in animal models associated with small bowel bacterial overgrowth.

Treatment and prognosis

1. A number of medical approaches have been tried, including the use of d -penicillamine to prevent increased copper absorption, the use of colchicine as an antifibrogenic agent, and the use of immunosuppressive therapy, with limited results. Ursodeoxycholic acid has been reported to improve liver tests but not histology, progression of disease, or time to transplantation.
2. Biliary cirrhosis develops approximately 3 to 5 years after initial presentation, although this period varies considerably.
3. Patients with advanced disease and those at high risk for the development of cholangiocarcinoma are considered for liver transplantation with 90% survival in 1 year and 84% in 2 years. Patients with established cholangiocarcinoma, however, are not candidates for transplantation because of low survival (22% to 77% in 1 year, 0% to 39% in 3 years).

Recurrent Pyogenic Cholangiohepatitis
( Figs 3-43 and 3-44 )

Figure 3-43 Recurrent pyogenic cholangiohepatitis . A, The interlobular bile duct is ectatic and contains biliary concretions. B, Higher power shows a dilated interlobular bile duct containing biliary concretions, with damage to the duct epithelium. Periductal fibrosis and edema are also seen in both images.

Figure 3-44 Recurrent pyogenic cholangiohepatitis . The interlobular bile duct is surrounded and infiltrated by numerous neutrophils (acute cholangitis), with extensive damage to the duct epithelium.


Major morphologic features

1. Dilation of large intrahepatic bile ducts is present, and the duct lumen often contains biliary calculi and biliary sludge (hepatolithiasis) , with neutrophils both focally and diffusely infiltrating into the majority of ducts (acute cholangitis) .
2. Abscesses, both microscopic and grossly apparent, occur in up to 85% of cases.

Other features

1. Cholestasis in the perivenular and midzones is common, is sometimes quite prominent, and is often associated with varying degrees of lobular infiltrates, predominantly neutrophilic infiltrates.
2. Bile duct and ductular proliferation, ectasia, and periductal fibrosis also involve smaller portal structures and resemble features seen in extrahepatic bile duct obstruction.
3. The liver distal to sites of duct involvement may undergo variable liver cell atrophy that is sometimes grossly apparent.
4. In more advanced cases, biliary fibrosis and arteriolar thickening are common.
5. Pylephlebitis of the portal vein and portal venous radicals may be present and are manifested by neutrophils hugging up against the vascular endothelium, sometimes associated with portal vein thrombosis. Rarely, infarction of the adjacent hepatic lobule may also be present.
6. Extrahepatic bile ducts may show variable degrees of dilation, fibrosis, and both acute and chronic inflammatory infiltration, with associated hyperplasia of the adjacent peribiliary glands.

Differential diagnosis

1. Extrahepatic bile duct obstruction: Various common causes of bile duct obstruction (e.g., common duct stricture, choledocholithiasis) mimic many of the features seen in recurrent pyogenic cholangiohepatitis. The degree of duct ectasia and presence of intraductal biliary concretions are quite unusual but not unheard of for bile duct obstruction, but they are characteristic for recurrent pyogenic cholangiohepatitis. In addition, abscess formation may occur but is exceptional in most cases of bile duct obstruction, whereas abscesses are the rule in recurrent pyogenic cholangiohepatitis.
2. Primary and secondary sclerosing cholangitis: Periductal fibrosis is present in recurrent pyogenic cholangiohepatitis; however, destructive fibrosing duct damage with luminal impairment and eventual duct depletion seen in sclerosing cholangitis are not characteristic features of recurrent pyogenic cholangiohepatitis.
3. Caroli disease: This disorder usually involves the entire intrahepatic biliary tree with prominent duct ectasia and strictures, without predilection for the left lobe, whereas recurrent pyogenic cholangiohepatitis is predominant in the left lobe. In addition, Caroli disease affects large and small ducts, whereas recurrent pyogenic cholangiohepatitis tends to involve mostly the large intrahepatic and hilar ducts.
4. Other causes of hepatolithiasis: Intrahepatic biliary concretions and sludge may be seen in a variety of disorders such as polycystic disease, choledochal cysts, sepsis, cystic fibrosis, and post-transplant bile duct ischemia secondary to hepatic artery thrombosis. Appropriate clinical correlation usually can point to the specific cause.

Clinical and biologic behavior

1. Also known as “Oriental cholangiohepatitis,” recurrent pyogenic cholangiohepatitis is seen most frequently in Southeast Asia, is the third most common cause of acute abdominal emergency in Hong Kong, and is the cause for biliary stones in 12% of those cases.
2. Recurrent pyogenic cholangiohepatitis is found with equal frequency in both sexes. The onset of symptoms is in the second to fourth decades, with right upper quadrant pain, fever, and jaundice, which recur with increasing frequency and severity.
3. Biliary calculi and sludge are characteristically brown-black (bilirubin), with cultures positive for enteric organisms (principally Escherichia coli ) occurring in more than 90% of cases. The gallbladder is involved in approximately 25% of cases.
4. ERCP shows characteristic features of a dilated biliary tree containing both intrahepatic and extrahepatic calculi. For reasons that are unclear, in up to 25% of cases, the majority of the intrahepatic stones are confined to the left hepatic ductal system. In some instances with left lobe involvement, the right lobe may show only minimal changes.
5. Helminth infection by C. sinensis infestation of the biliary tree is present in approximately 50% of the patients. A. lumbricoides may also be present.
6. Acute pancreatitis is a common accompaniment (12% of cases), and complications of recurrent pyogenic cholangiohepatitis include liver abscess, biliary enteric fistula, gram-negative sepsis, and portal vein thrombosis. In addition, the frequency of cholangiocarcinoma is increased in these patients.
7. The pathogenesis is uncertain. Although Clonorchis is present in only 50% of the cases, the etiology is speculated to be due in part to the deposition of eggs and intraductular parasite fragments provoking an inflammatory response, increased goblet cell secretion, and resultant stone formation. In addition, bacteria also may play some role in the formation of the intrahepatic stones as a result of bilirubin glucuronide deconjugation by bacterial E1-glucuronidase.


Treatment and prognosis

1. Treatment of any identifiable helminth infection is indicated.
2. Intrahepatic calculi involving the left lobe of the liver is often difficult to manage. Placement of a Roux-en-Y jejunal conduit is helpful for biliary drainage, although in severe symptomatic cases, left hepatic lobectomy may be necessary.

Other Cholestatic Disorders
Table 3-2 .
Table 3-2 Other Cholestatic Disorders That May Cause Liver Damage ∗ DISEASE HISTOLOGY CLINICAL/LABORATORY PARAMETERS Inspissated bile syndrome
• Perivenular cholestasis is present, with prominent bile plugs but little lobular inflammation.
• Portal tracts with mild lymphocytic and neutrophilic infiltrates may be seen.
• Hemosiderin in Kupffer cells may occur.
• This syndrome presents as obstructive jaundice in infancy and occurs in the setting of ABO- and Rh-incompatible transfusions.
• Bile duct obstruction is due to inspissated concrements of secretions and bile.
• Removal of the obstruction and concrements by washing or mucolytic agents at surgery or endoscopy is helpful.
• In some patients, spontaneous resolution may be seen. Idiopathic adulthood ductopenia
• Portal lymphocytic infiltrates with variable nonsuppurative duct damage is present.
• Small ducts may show periductal fibrosis, mimicking primary sclerosing cholangitis.
• Cholestasis associated with variable mononuclear inflammatory infiltrates may occur.
• Biliary fibrosis occurs with eventual biliary cirrhosis and ductopenia as the disease progresses.
• Increased copper and copper-binding protein in periportal and periseptal hepatocytes is present.
• A cholestatic disorder of uncertain etiology, patients present with pruritus and jaundice and are noted to have elevated serum bilirubin and alkaline phosphatase levels and mildly increased serum transaminase levels.
• Hepatic synthetic function is well preserved, although prothrombin time may be prolonged if cholestasis is long standing.
• Bile ducts are not dilated and appear normal on endoscopic retrograde cholangiopancreatography.
• Some patients improve spontaneously, but others progress to liver failure and may need a transplant.
• A careful drug history is essential to exclude drug-related vanishing bile duct syndrome.
∗ The metabolic and developmental cholestatic disorders are discussed in Chapter 8 . In addition, intrahepatic cholestasis of pregnancy is briefly discussed in Table 12-3 .

References

Extrahepatic (mechanical) bile duct obstruction
Afroudakis A., Kaplowitz N. Liver histopathology in chronic bile duct stenosis due to chronic alcoholic pancreatitis. Hepatology . 1981;1:65-72.
Bjornsson E., Gustafsson J., Borkman J., et al. Fate of patients with obstructive jaundice. J Hosp Med . 2008;3:117-123.
Demetris A.J., Lunz J.G.3d, Specht S., et al. Biliary wound healing, ductular reactions, and IL-6/gp130 signaling in the development of liver disease. World J Gastroenterol . 2006;12:3512-3522.
Geng Z.M., Yao Y.M., Liu Q.G., et al. Mechanism of benign biliary stricture: a morphological and immunohistochemical study. World J Gastroenterol . 2005;11:293-295.
Karvonen J., Kairisto V., Gronroos J.M. Stone or stricture as a cause of extrahepatic cholestasis—do liver function tests predict the diagnosis? Clin Chem Lab Med . 2006;44:1453-1456.
Rosch T., Meining A., Fruhmorgen S., et al. A prospective comparison of the diagnostic accuracy of ERCP, MRCP, CT, and EUS in biliary strictures. Gastrointest Endosc . 2002;55:870-876.
Warshaw A.L., Schapiro R.H., Ferrucci J.T.Jr., et al. Persistent obstructive jaundice, cholangitis, and biliary cirrhosis due to common bile duct stenosis in chronic pancreatitis. Gastroenterology . 1976;70:562-567.

Primary biliary cirrhosis
Bergasa N.V., Mason A., Floreani A., et al. Primary biliary cirrhosis: report of a focus study group. Hepatology . 2004;40:1013-1020.
Crosignani A., Battezzati P.M., Invernizzi P., et al. Clinical features and management of primary biliary cirrhosis. World J Gastroenterol . 2008;14:3313-3327.
Gershwin M.E., Mackay I.R. The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology . 2008;47:737-745.
Gershwin M.E., Selmi C., Worman H.J., et al. Risk factors and comorbidities in primary biliary cirrhosis: A controlled interview-based study of 1032 patients. Hepatology . 2005;42:1194-1202.
Jones D.E.J. Pathogenesis of primary biliary cirrhosis. Clin Liver Dis . 2008;12:305-321.
Kaplan M.M. Primary biliary cirrhosis. N Engl J Med . 1987;316:521-528.
Leung P.S.C., Coppel R.L., Gershwin M.E. Etiology of primary biliary cirrhosis: the search for the culprit. Semin Liver Dis . 2005;25:327-336.
Lindor K.D., Gershwin M.E., Poupon R., et al. Primary biliary cirrhosis. AASLD practice guidelines. Hepatology . 2009;50:291-308.
Ludwig J., Czaja A.J., Dickson E.R., et al. Manifestations of nonsuppurative cholangitis in chronic hepatobiliary diseases: morphologic spectrum, clinical correlations and terminology. Liver . 1984;4:105-116.
Marucci L., Ugili L., Macarri G., et al. Primary biliary cirrhosis: modalities of injury and death in biliary epithelium. Dig Liver Dis . 2001;33:576-583.
Mayo M.J., Thiele D.L., et al. Primary biliary cirrhosis. In: Yamada T., Alpers D.H., Kalloo A.N., editors. Textbook of Gastroenterology. 5th ed. Vol 2 . West Sussex, UK: Wiley-Blackwell; 2009:2193-2210.
Muratori L., Granito A., Muratori P., et al. Antimitochondrial antibodies and other antibodies in primary biliary cirrhosis: diagnostic and prognostic value. Clin Liver Dis . 2008;12:261-276.
Nakanuma Y., Tsuneyama K., Gershwin M.E., et al. Pathology and immunopathology of primary biliary cirrhosis with emphasis on bile duct lesions: Recent progress. Semin Liver Dis . 1995;15:313-328.
Portmann B., Popper H., Neuberger J., et al. Sequential and diagnostic features in primary biliary cirrhosis based on serial histologic study in 209 patients. Gastroenterology . 1985;88:1777-1790.
Reau N.S., Jensen D.M. Vanishing bile duct syndrome. Clin Liver Dis . 2008;12:203-217.

Primary sclerosing cholangitis
Casali A.M., Carbone G., Cavalli G. Intrahepatic bile duct loss in primary sclerosing cholangitis: a quantitative study. Histopathology . 1998;32:449-453.
Chapman R. Cullen S. Etiopathogenesis of primary sclerosing cholangitis. World J Gastro . 2008;14:3350-3359.
Feldstein A.E., Perrault J., El-Youssif M., et al. Primary sclerosing cholangitis in children: a long-term follow-up study. Hepatology . 2003;38:210-217.
Katabi N., Albores-Saavedra J. The extrahepatic bile duct lesions in end-stage primary sclerosing cholangitis. Am J Surg Pathol . 2003;27:349-355.
LaRusso N.F., Shneider B.L., Black D., et al. Primary sclerosing cholangitis: summary of a workshop. Hepatology . 2006;44:746-764.
Lazaridis K.N., Gores G.J. Primary sclerosing cholangitis and cholangiocarcinoma. Semin Liver Dis . 2006;26:42-51.
Levy C., Lindor K.D. Primary sclerosing cholangitis: epidemiology, natural history, and prognosis. Semin Liver Dis . 2006;26:22-30.
Ludwig J. Small-duct primary sclerosing cholangitis. Semin Liv Dis . 1991;11:11-17.
Mendes F.D., Lindor K.D. Primary sclerosing cholangitis. Clin Liver Dis . 2004;8:195-211.
Reau N.S., Jensen D.M. Vanishing bile duct syndrome. Clin Liver Dis . 2008;12:203-217.
Silveira M.G., Lindor K.D. Clinical features and management of primary sclerosing cholangitis. World J Gastroenterol . 2008;14:3338-3349.
Silveira M.G., Lindor K.D. Primary sclerosing cholangitis. Can J Gastroenterol . 2008;22:689-698.
Uchida N., Ezaki T., Fukuma H., et al. Concomitant colitis associated with primary sclerosing cholangitis. J Gastroenterol . 2003;38:482-487.

Recurrent pyogenic cholangiohepatitis
Fan S.T., Lai E.C.S., Mok F.P.T., et al. Acute cholangitis secondary to hepatolithiasis. Arch Surg . 1991;126:1027-1031.
Garcia M.J., Hermo Brion J.A., Carreira Delgado M., et al. Recurrent pyogenic cholangitis in a western patient. Gastroenterol Hepatol . 2000;23:170-173.
Honda H., Liu S.D., Nishida D.S., et al. Oriental cholangiohepatitis from outside of Asia. Hawaii Med J . 2007;66:9-11.
Kashi H., Lam F., Giles G.R. Recurrent pyogenic cholangiohepatitis. Ann Roy Coll Surg Eng . 1989;71:387-389.
Okuno W.T., Whitman G.J., Chew F.S. Recurrent pyogenic cholangiohepatitis. AJR Am J Roentgenol . 1996;167:484.
Sperling R.M., Koch J., Sandhu J.S., et al. Recurrent pyogenic cholangitis in Asian immigrants to the United States: natural history and role of therapeutic ERCP. Dig Dis Sci . 1997;42:865-871.
Wilson M.K., Stephen M.S., Mather M., et al. Recurrent pyogenic cholangitis or “oriental cholangiohepatitis” in occidentals: case reports of four patients. Aust N Z J Surg . 1996;66:649-652.

General References
Portmann B.C., Nakanuma Y. Diseases of the bile ducts. In: Burt A.D., Portmann B.C., Ferrell L.D., editors. MacSween’s Pathology of the Liver. 5th ed . London: Churchill-Livingstone; 2007:517-581.

References
The complete reference list is available online at www.expertconsult.com
Chapter 4 Alcoholic and Non-Alcoholic Fatty Liver Diseases

ALCOHOLIC LIVER DISEASE 71
Alcoholic Fatty Liver 71
Perivenular Alcoholic Fibrosis 74
Acute Alcoholic Liver Disease 76
Acute Alcoholic Fatty Liver 76
Alcoholic Hepatitis 77
Alcoholic Foamy Degeneration 81
Alcoholic Cirrhosis 83
NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) 86
Non-Alcoholic Fatty Liver (NAFL) 86
Non-Alcoholic Steatohepatitis (NASH) 87

Alcoholic Liver Disease

Alcoholic Fatty Liver
( Figs. 4-1 through 4-8 )

Figure 4-1 Metabolism of ethanol . Three of the major mechanisms for alcohol metabolism with its breakdown to acetaldehyde are highlighted in this diagram, and include the alcohol dehydrogenase (ADH) pathway, the microsomal ethanol oxidizing system (MEOS), and the catalase pathway. The alteration in normal metabolism of various proteins, carbohydrates and lipids are also noted in the diagram. NAD, nicotinamide adenine dinucleotide; NADH, reduced NAD; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced NADP; GSH, glutathione; GSSG, glutathione disulfide.
(Adapted from Hall P de la M. Alcoholic liver disease. In: Burt AD, Portmann BC, Ferrell LD, eds. MacSween’s Pathology of the Liver, 5th ed, London: Churchill-Livingstone, 2007, p. 329.)

Figure 4-2 Alcoholic fatty liver . This liver is markedly enlarged (3300 g) and is yellow and greasy on external examination and cut section due to virtually all of the hepatocytes containing macrovesicular fat.

Figure 4-3 Alcoholic fatty liver . Macrovesicular fatty change is seen. The terminal hepatic (central) venule in the center of the field is unremarkable.

Figure 4-4 Alcoholic fatty liver . The terminal hepatic (central) venule shows no evidence of perivenular or intraluminal fibrosis. Macrovesicular fatty change is abundant (trichrome).

Figure 4-5 Alcoholic fatty liver . A, Two lipogranulomas are seen amongst the hepatocytes that contain macrovesicular fat. B, High power shows a lipogranuloma to be composed of lymphocytes and histiocytes, many of the latter containing small fat vacuoles.

Figure 4-6 Alcoholic fatty liver, enlarged mitochondria . A and B . Megamitochondria are seen within many of the hepatocytes in these low and high power fields. These mitochondria are the same size or larger than the liver cell nucleus and are distinctly round and eosinophilic.

Figure 4-7 Alcoholic fatty liver, enlarged mitochondria . The megamitochondria stain intensely dark red on Masson trichrome stain.

Figure 4-8 Alcoholic fatty liver, enlarged mitochondria . Less commonly the enlarged mitochondria may also be irregular to spindle-shaped.

Major morphologic feature

1. Macrovesicular fat (fat droplets equal to or greater than the size of a liver cell nucleus) is present within hepatocytes, first seen in the perivenular zone (zone 3 of Rappaport) in the early stages, but may diffusely involve all zones.

Other features

1. Hepatocytes may at times also exhibit small foci of microvesicular fat (fat droplets less than the diameter of the liver cell nucleus) as well.
2. Focal necroinflammatory change in the vast majority of patients is absent. When seen, it is mild and usually perivenular in location.
3. Lipogranulomas may occur and are usually more prominent in the perivenular zone. These lipogranulomas are a response to rupture of liver cells distended with fat, and consist of coalescent extracellular fat droplets eliciting a mild lymphocytic and histiocytic reaction. Multinucleated giant cells are uncommon.
4. Discrete usually round but occasionally spindle-shaped intracytoplasmic eosinophilic inclusions are seen in the perivenular hepatocytes in a minority of cases (estimated at approximately 15%), and represent enlarged mitochondria (megamitochondria). Most often the hepatocytes contain one or two inclusions per cell. The round inclusions are characteristic of alcoholic liver disease, while the spindle-shaped inclusions may be seen in both alcoholic and non-alcoholic fatty liver disease.
5. Portal tracts show no fibrosis or inflammatory infiltrates in simple alcoholic fatty liver, and intrasinusoidal collagen deposition on routine stains is absent. Of note, however, is that thin bands of perisinusoidal collagen are often seen under electron microscopic evaluation.
6. With abstinence, the fat usually disappears with 3 to 6 weeks.

Special stains

1. Masson trichrome: The presence of sinusoidal collagen deposition is indicative of not simply a fatty liver induced by alcohol but of some degree of alcoholic liver disease. In addition, this stain is helpful in identifying the enlarged mitochondria, which stain bright red.

Differential diagnosis

1. Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatits (NASH) (refer to discussion at the end of this chapter) These conditions, seen more often in diabetic and/or obese individuals, are associated with prominent fatty change. The fat is usually diffuse without a zonal distribution pattern, while alcoholic fatty liver tends to involve first the perivenular zone. In addition, NASH is associated with variable degrees of sinusoidal collagen deposition, necroinflammatory change, and sometimes Mallory body formation, these features not present in simple alcoholic fatty liver.
2. Severe malnutrition: Macrovesicular fat in severely malnourished infants and children (kwashiorkor) is common and may diffusely involve all zones. Clinical correlation is necessary for distinction.
3. Chronic debilitating infections: Certain conditions such as acquired immunodeficiency syndrome and disseminated tuberculosis may exhibit an associated usually mild to moderate fatty change, which is often periportal but may at times be scattered throughout the lobules. Periportal fat distribution is not a feature of alcoholic fatty liver.
4. Drug-induced liver injury (e.g., corticosteroids; refer to Table 5-6 , Fatty Change ): Many drugs are associated with variable degrees of fatty change. Some are also associated with variable necroinflammatory change as well (e.g., amiodarone). Usually but not always the drugs do not have a zonal accentuation to the fat. Clinical correlation with the time frame of drug usage and history of alcohol intake is necessary for differentiation.
5. Sepsis: Bacterial sepsis is often associated with some degree of fatty change. Usually lobular mixed inflammatory infiltrates are also seen, with portal neutrophils common, these features not characteristic of simple alcoholic fatty liver.


Clinical and biologic behavior

1. Fatty change is the most common hepatic morphologic feature in an alcoholic and is seen in over 90% of biopsy and autopsy specimens in these patients.
2. There are three important pathways in alcohol metabolism (refer to Fig. 4-1 ):

This is a major pathway, and results in a shift of the NAD + /NADH redox potential, resulting in increased fatty acid synthesis and decreased fatty acid oxidation (“fatty liver”).

The MEOS is cytochrome P450-dependent, with its enhancement contributing to alterations of the metabolism of certain drugs. For example, significant liver cell injury can occur with the ingestion of as little as 2 g of acetaminophen (as opposed to approximately 10 g in the non-alcoholic).

This process occurs in the peroxisomes. Acetaldehyde is further metabolized in the mitochondria to acetate and then secreted. The acetaldehyde itself is toxic and causes variable degrees of mitochondrial distortion as well as impairment in microtubular function, contributing in part to the enlargement of the mitochondria (megamitochondria) as well as the hydropic ballooning change of the hepatocytes seen in alcoholic liver disease.
3. The degree of fat approximately varies with the amount of alcohol intake and to some extent the quantity of protein in the diet.
4. Alcohol stimulates collagen formation. Although stains for collagen may not demonstrate sinusoidal collagen in simple fatty change, chemical analysis of these livers shows moderate increases in hydroxyproline, a major amino acid found in collagen fibers.
5. Fat is generally graded as 1+, involving up to 25% of hepatocytes; 2+, 25% to 50% of hepatocytes; 3+, 50% to 75% of hepatocytes, and 4+, greater than 75% of hepatocytes.
6. Hepatomegaly is usually the only abnormality on physical examination and most often resolves over several weeks with abstinence of alcohol intake. Mild elevations in serum aminotransferases are frequently noted but hepatic synthetic function is normal.
7. Increased fat in the liver is noted on ultrasound examination, where an increased echotexture is seen. On computed tomography (CT) scans, decreased density of the liver is characteristic of fatty change, which sometimes can be focal in nature.

Treatment and prognosis

1. Simple fatty change is asymptomatic. The fat will disappear in a severely fatty liver within 8 weeks of abstinence of alcohol.

Perivenular Alcoholic Fibrosis
( Figs. 4-9 and 4-10 )

Figure 4-9 Perivenular alcoholic fibrosis . Both the portal tract (right) and the terminal hepatic venule (left) are fibrotic, with collagen fibers extending in an arachnoid-type pattern into the adjacent sinusoids (trichrome).

Figure 4-10 Perivenular alcoholic fibrosis . These two terminal hepatic venules from the same specimen show extensive perivenular as well as intraluminal fibrosis, with total occlusion of the lumen on the (A) trichrome and (B) H&E stains.

Major morphologic feature

1. Thickening of the fibrous rim surrounding the terminal hepatic (central) venules is present, with extension into the perivenular sinusoids often occurring to variable degrees.
2. Thin intraluminal fibrosis of these vessels is also seen.

Other features

1. Variable degrees of macrovesicular fatty change are seen predominantly within the perivenular zone.
2. Enlarged mitochondria ( megamitochondria , refer to earlier discussion under Alcoholic Fatty Liver ) may be present in the perivenular zone in a minority of cases.
3. Necroinflammatory change, the inflammatory cells chiefly mononuclear, is seen but is usually mild.
4. Mallory bodies may be present but are few in number, and when seen are more often present in the perivenular zone. If abundant, superimposed acute alcoholic liver injury (refer to discussion under Alcoholic Hepatitis ) is also present.
5. The portal tracts exhibit only a mild lymphocytic infiltrate.
6. Interlobular bile ducts are normal to only slightly increased in number; however, proliferating bile ductules (metaplastic ducts ) may also be seen at the border of the portal tracts and parenchyma.
7. Variable degrees of portal fibrosis are often present, manifested by widening of the portal tracts with variable periportal intrasinusoidal collagen deposition.
8. The degree of perivenular collagen deposition may in some instances be striking, with marked intraluminal sclerosis and vascular occlusion of the small outflow vessels (“phlebosclerosis” and “veno-occlusive” changes) as well as variable degrees of lymphocytic infiltrates involving the intima and wall (“lymphocytic phlebitis”). The fibrosis also extends to and involves the larger terminal hepatic veins and sublobular veins.
Note: Virtually all of the morphologic features described above are also seen in alcoholic fibrosis and cirrhosis and in biopsies from patients having bouts of alcoholic hepatitis.

Special stains

1. Masson trichrome, Sirius Red: The perivenular and periportal intrasinusoidal collagen stains bright blue and red, respectively. In addition, the Masson trichrome stain is helpful in identifying the enlarged mitochondria, which stain bright red.
2. Reticulin: The perivenular and periportal intrasinusoidal collagen deposition can be appreciated by the reticulin condensation.
3. Verhoef-van Gieson: The sclerosis of the terminal hepatic venules can be highlighted by this elastic tissue stain.

Differential diagnosis

1. Non-alcoholic steatohepatitis: This liver disease exhibits fat and perivenular sinusoidal collagen deposition and may be indistinguishable from alcoholic perivenular fibrosis on histologic grounds alone. Clinical correlation is necessary for distinction.
2. Drug-induced liver cell injury (e.g., amiodarone; refer to Table 5-6 , Fatty change): Certain drugs may elicit not only fatty change but also intrasinusoidal collagenosis. Clinical correlation with examination of the time frame of drug usage and the onset of abnormal liver tests is important in diagnosis.
3. Long-standing right-sided heart failure: Perivenular fibrosis may be seen in this condition due to prolonged perivenular ischemia. Variable but often prominent perivenular sinusoidal dilatation and congestion with liver cell atrophy also are seen in right-sided heart failure. Fatty change and megamitochondria are not features associated with heart failure.
4. Veno-occlusive disease (VOD): The intraluminal fibrosis of the terminal hepatic venules seen in VOD is morphologically similar to the intraluminal sclerosis seen in chronic alcoholic liver disease (termed “veno-occlusive changes”); however, in true veno-occlusive disease (refer to discussion in Chapter 6 ) there is considerable endothelial damage of the terminal hepatic venules, with sloughing and loss of the endothelial cells, features not present in the perivenular damage seen in chronic alcoholic liver disease.

Clinical and biologic behavior

1. The importance of this lesion, as opposed to simple alcoholic fatty liver, is that its presence in the early stages signals almost certain progression to cirrhosis if the patient does not abstain from drinking.
2. This lesion has also experimentally been induced in baboons fed alcohol.
3. The fibrosis occurs as a result of activation and conversion of the mesenchymal stellate cells (Ito cells, fat-storing cells) seen in the perisinusoidal space to transitional cells and eventually fibroblasts and myofibroblasts in the perivenular zone. This then results in the synthesis of type III collagen in the perivenular extracellular matrix in the space of Disse.
4. Patients are usually asymptomatic at the early stage of the disease, with only mild abnormalities in the aminotranferase activities, the AST value only slightly elevated with the ALT value usually normal.

Treatment and prognosis

1. Abstinence of alcohol prevents progression of the disease. In addition, partial and sometimes complete resolution of the fibrosis also may occur.


Acute Alcoholic Liver Disease

Acute Alcoholic Fatty Liver (Steatosis) With or Without Cholestasis
( Figs. 4-11 through 4-13 )

Figure 4-11 Acute alcoholic fatty liver . This low power image shows a portal tract with periportal arachnoid fibrosis. The parenchyma shows 100% of the hepatocytes filled with macrovesicular fat.

Figure 4-12 Acute alcoholic fatty liver with cholestasis . Abundant macrovesicular fat is seen. Cholestasis is also evident with bile plug formation.

Figure 4-13 Acute alcoholic fatty liver with cholestasis . Bile both within liver cell cytoplasm as well as within dilated biliary canaliculi is evident on this iron stain, which uses the eosin counterstain to enable the bile to stand out better than on the routine H&E stain.

Major morphologic features

1. Prominent macrovesicular fatty change is present and involves all zones, with greater than 75% of the hepatocytes involved.
2. Cholestasis may be present, with accentuation in the perivenular zone (zone 3 of Rappaport).

Other features

1. Sinusoidal collagen deposition is minimal to absent.
2. Focal necrosis and hepatocytolysis may be present but are usually mild.
3. Lipogranulomas may be seen in the perivenular zone as a response to rupture of liver cells distended with fat, and consist of coalescent extracellular fat droplets eliciting a mild lymphocytic and histiocytic reaction. Multinucleated giant cells are uncommon.
4. Some degree of microvesicular fat may also be present at times but is less common.
5. Usually round but occasionally spindle-shaped inclusions may be seen within the liver cell cytoplasm in a minority of cases, are most prominent in the perivenular zone, and represent enlarged mitochondria ( megamitochondria, refer to discussion under Alcoholic Fatty Liver ).
6. Portal tracts may be normal in size or exhibit a mild periportal fibrosis.
7. Only a mild lymphocytic infiltrate with occasional neutrophils is seen within the portal tracts, with interlobular bile ducts normal to only minimally increased in number.
8. Occasionally proliferating ductules (metaplastic ducts) may be present at the border of the portal tracts and parenchyma.

Special stains

1. PAS after diastase digestion (DiPAS): This stain highlights areas of necroinflammatory change by demonstrating increase in lysosomal activity and ceroid pigment within Kupffer cells and macrophages within the areas of injury.
2. Masson trichrome: Thin blue strands of perivenular sinusoidal collagen are more readily identifiable, although the degree of this type of collagen laydown is generally mild. In addition, megamitochondria stain bright red.

Differential diagnosis

1. Non-alcoholic steatohepatitis (NASH) : NASH contains abundant fat, variable necroinflammatory change, and both portal, periportal and perivenular fibrosis, and may mimic to some degree acute alcoholic fatty liver disease. Perivenular collagen deposition is quite uncommon in acute alcoholic fatty liver, while cholestasis is quite unusual in NASH. In addition, NASH often contains numerous glycogenated nuclei, a feature that is not commonly seen in acute alcoholic fatty liver.
2. Drug-induced liver cell injury (e.g., ibuprofen; refer to Table 5-6 , Fatty Change ): Usually, but not always, drug induced fatty livers do not have as much fat as that seen in acute alcoholic fatty liver. In addition, megamitochondria are not features typically seen in drug-induced fatty change.
3. Other conditions associated with marked fatty change: Numerous other conditions besides alcoholic liver disease, non-alcoholic steatohepatitis and drug-induced injury (e.g., acute fatty liver of pregnancy, kwashiorkor, Reye syndrome) can be associated with marked fatty change. Other co-existing morphologic features characteristic of the particular disease as well as clinical correlation help distinguish between the different disorders.

Clinical and biologic behavior

1. Heavy drinking (>80 g of alcohol per day) must occur for at least 3 to 5 years before acute alcoholic liver disease will develop.
2. These patients usually present with nonspecific complaints of nausea, vomiting, and malaise. Occasionally jaundice may be present.
3. Marked hepatomegaly is present, with liver weights at autopsy exceeding 3000 g.
4. Laboratory tests show mildly elevated AST values, with ALT often normal. Serum bilirubin may be normal or slightly elevated. Hepatic synthetic function is normal.
5. The fat will disappear 6 to 12 weeks upon cessation of drinking, with hepatomegaly resolving over a longer period (usually over several months).

Treatment and prognosis

1. Cessation of drinking is essential.
2. Complications of acute alcoholic liver disease, such as infections and acute and/or chronic pancreatitis, may affect outcome.

Alcoholic Hepatitis
( Figs. 4-14 through 4-25 )

Figure 4-14 Alcoholic hepatitis . A, The terminal hepatic venule shows extensive perivenular and pericellular arachnoid fibrosis. B, High-power shows extensive intrasinusoidal collagen laydown. The adjacent hepatocytes show hydropic ballooning change (trichrome).

Figure 4-15 Alcoholic hepatitis . The perivenular zone shows extensive intrasinusoidal collagen deposition with almost total sclerosis and occlusion of the terminal hepatic venule. Some of the adjacent hepatocytes are hydropic and contain Mallory bodies ( upper right corner of the field ).

Figure 4-16 Alcoholic hepatitis . A and B . These medium and high power fields both show hydropic hepatocytes containing an eosinophilic ropey intracytoplasmic material representing Mallory bodies.

Figure 4-17 Alcoholic hepatitis . Numerous Mallory bodies are seen within enlarged hydropic hepatocytes. Neutrophils are present surrounding and focally infiltrating into the hepatocytes containing the Mallory bodies. Prominent macrovesicular fat is also present.

Figure 4-18 Alcoholic hepatitis . A, Numerous Mallory bodies are seen. In addition, a prominent neutrophilic infiltrate is present, many of these neutrophils surrounding the hepatocytes containing Mallory bodies (“satellitosis”). B, Immunoperoxidase stain for Mallory bodies. The Mallory bodies stain strongly positive with ubiquitin , as seen in this example.

Figure 4-19 Alcoholic hepatitis . Mallory bodies can either stain brightly red or blue, depending in part on the age and type of the intermediate filaments that comprise the Mallory bodies (trichrome).

Figure 4-20 Alcoholic hepatitis (Mallory bodies) . This high-power image highlights the ropey eosinophilic nature of the Mallory bodies.

Figure 4-21 Mallory body (electron microscopy) . The Mallory bodies appear as randomly oriented filaments varying from 5 to 20 μm. The type II Mallory body, seen in this field and in greater detail within the inset, is the most common type present in patients with active alcoholic liver disease.
(From Hall P de la M: Alcoholic liver disease. In: MacSween RNM, et al, eds. Pathology of the Liver, 3rd ed. Edinburgh: Churchill Livingstone, 1994, p. 332.)

Figure 4-22 Alcoholic hepatitis . A, A prominent lobular neutrophilic infiltrate is present. Often the neutrophils can be seen surrounding hepatocytes containing Mallory bodies. B, The neutrophilic infiltrates within the lobules can at times be quite prominent, usually associated with a marked leukocytosis.

Figure 4-23 Alcoholic hepatitis . Cholestasis is present. Occasional hepatocytes contain Mallory bodies. Neutrophils are also present within the lobule.

Figure 4-24 Alcoholic hepatitis . In severe forms of alcoholic hepatitis, the hydropic hepatocytes can undergo severe ballooning with lytic change, this feature most often seen in autopsy specimens. Some of the hepatocytes also contain Mallory bodies.

Figure 4-25 Alcoholic hepatitis . The portal tract is fibrotic and exhibits a prominent mixed inflammatory infiltrate consisting of lymphocytes and numerous neutrophils. Bile duct and cholangiolar proliferation are also seen.

Major morphologic features

1. Extensive perivenular intrasinusoidal collagen deposition is present, often with extension into the midzones, with partial to total obliteration of the terminal hepatic venules.
2. Hydropic ballooning change of the perivenular liver cells is seen, many of these cells containing ropey eosinophilic cytoplasmic inclusions (Mallory bodies) that are often surrounded by neutrophils (“satellitosis”).
3. Macrovesicular fatty change is usually present to variable degrees.

Other changes

1. Portal tracts show variable degrees of fibrosis, with prominent periportal “arachnoid” fibrosis (periportal intrasinusoidal collagen deposition) occurring.
2. Portal mixed inflammatory infiltrates consisting of lymphocytes and numerous neutrophils are seen, these inflammatory cells not directly oriented to any particular portal structures.
3. Bile duct proliferation is present, with proliferating cholangioles (metaplastic ducts ) often prominent.
4. Perivenular cholestasis may be seen.
5. Megamitochondria (enlarged mitochondria) are sometimes identified within the hydropic perivenular hepatocytes.
6. Mixed lobular necroinflammatory change is present, the inflammatory cells consisting predominantly of neutrophils.
7. Sinusoidal leukocytosis is often seen, associated with elevated white blood cell counts in the majority of patients.
8. A variant of this disorder that is severe and seen mostly in autopsy specimens shows marked perivenular hydropic ballooning change of the hepatocytes with lysis of the cell membranes, the cytoplasm usually also containing Mallory bodies (lytic necrosis) .
9. The degree of periportal and perivenular fibrosis varies, with eventual bridging fibrosis and a micronodular cirrhosis eventually occurring in the patient who continues to drink (refer to discussion under Alcoholic Cirrhosis ).

Special stains

1. Masson trichrome: Sinusoidal collagen fibers and sclerosis of the terminal hepatic venules are accentuated by the blue staining pattern. Mallory bodies also stain either bright red or blue, dependent on the age of the Mallory bodies. Megamitochondria stain red.
2. Mallory’s phloxine: Mallory bodies in their early stage stain intensely red, while older Mallory bodies stain pink or are colorless.

Immunohistochemistry

1. Ubiquitin, pancytokeratin: The intermediate filaments that are an important component of Mallory bodies stain intensely.
2. Horseradish peroxidase (PAP): Mallory bodies nonspecifically are bound by the peroxidase anti-peroxidase (PAP) reaction.

Differential diagnosis

1. Non-alcoholic steatohepatitis (NASH): Fatty change, perivenular sinusoidal collagenosis, and Mallory bodies are seen in both alcoholic hepatitis and the more severe cases of NASH. The numbers of Mallory bodies in NASH are usually, but not always, less than the number seen in alcoholic hepatitis. Mallory bodies surrounded by neutrophils (satellitosis) are often present in alcoholic hepatitis but less commonly seen in NASH. Glycogenated nuclei are more often present in NASH than in alcoholic hepatitis. In addition, portal neutrophils, portal ductular proliferation, and cholestasis are not characteristic of NASH but are frequent in alcoholic hepatitis. Finally, a useful biochemical marker is the serum AST:ALT ratio, which is usually greater than 2:1 in alcoholic hepatitis but is equal to or less than 1 in NASH. Table 4-2 , under the discussion of Non-Alcoholic Fatty Liver Disease at the end of this chapter, compares the two disorders.
2. Other conditions where fat, Mallory bodies and lobular inflammation (steatohepatitis) may be present: Wilson disease, Indian childhood cirrhosis, chronic cholestatic disorders (primary biliary cirrhosis, primary sclerosing cholangitis), certain drugs (amiodarone), and hepatocellular carcinoma are just a few of the disorders that may exhibit Mallory bodies (refer to Table 4-3 , Liver disorders morphologically resembling alcoholic and non-alcoholic fatty liver disease , at the end of this chapter). Usually these disorders do not contain the same degree of sinusoidal collagen deposition and numbers of Mallory bodies as that seen in alcoholic hepatitis. Other morphologic features as well as clinical and laboratory correlation will usually make the distinctions more apparent.
Table 4-2 Morphologic Comparison of Alcoholic Liver Diseases versus Non-Alcoholic Steatohepatitis   ALCOHOLIC LIVER DISEASE NON-ALCOHOLIC STEATOHEPATITIS Mallory bodies Abundant Present but less common Lobular inflammation Usually neutrophils Neutrophils, or mixed neutrophils and lymphocytes Portal inflammation Mixed lymphocytes and neutrophils Predominantly lymphocytes Periportal interface inflammation Usually absent Usually present to variable degrees Glycogenated nuclei Infrequent Present, often numerous Ductular (cholangiolar) reaction Present, sometimes prominent Infrequent Megamitochondria Round, usually perivenular Round to spindly, perivenular or random Fat Usually abundant, with perivenular zonal predilection; macrovesicular or microvesicular Usually abundant, perivenular or scattered with no zonal predominance; usually macrovesicular, can be microvesicular Cholestasis Often seen in active disease Uncommon Perivenular sinusoidal fibrosis Common Present to a lesser extent Veno-occlusive changes Common Infrequent

Table 4-3 Liver Disorders Morphologically Resembling Alcoholic and Non-Alcoholic Fatty Liver Disease

Clinical and biologic behavior

1. A subset of patients with alcoholic liver disease develop an acute or subacute and virulent form of inflammatory injury (“alcoholic hepatitis”) with a substantially worse prognosis and outcome.
2. Patients with alcoholic hepatitis present with a broad range of clinical and biochemical abnormalities. In mild disease, patients are asymptomatic, but in severe cases, jaundice, ascites, and hepatic encephalopathy are present leading to increased mortality. Hepatomegaly, hepatic pain and tenderness, leukocytosis (rarely as high as 100,000/cm 3 ), fever, and hepatic systolic bruits are frequently present.
3. Serum total and direct bilirubin are elevated, serum albumin values are depressed, and prothrombin time is prolonged, markedly so in severe cases. Alkaline phosphatase elevation is variable. AST is elevated, usually in the 100 to 300 IU/L range, but ALT is substantially lower and in some cases is normal.
4. Technetium sulfur colloid liver-spleen scan demonstrates marked redistribution of the isotope to the spleen and bone marrow, with little if any uptake within the liver. Isotope flow scan shows increased hepatic arterial flow in a large proportion of cases.
5. For unclear reasons, a worsening of the clinical and laboratory parameters 2 to 4 weeks after cessation of alcohol may be seen.
6. Mallory bodies are a principal morphologic feature seen in hepatocytes. Although present in over 20 liver disorders, it is seen most commonly and abundantly in alcoholic hepatitis. Mallory bodies are filamentous randomly oriented intracytoplasmic processes composed of various polypeptides and cytokeratins. Its origin is secondary to damage of the intermediate filaments by alcohol, and can be divided into three ultrastructural variants:
a. Type I: Parallel array of the filaments
b. Type II: Randomly oriented filaments
c. Type III: Amorphous and granular, few filaments seen
7. Different staining patterns of Mallory bodies are seen on trichrome stain (red or blue) and may be related to different subtypes or age of the Mallory bodies. The Mallory bodies themselves can nicely be demonstrated by the ubiquitin immunoperoxidase stain.
8. The dense deposition of collagen fibers (predominantly type III) that are most marked in the perivenular sinusoids causes partial or complete obliteration of the terminal hepatic venules, with obstruction to hepatic venous outflow and consequent post-sinusoidal portal hypertension.
9. With abstinence, the new collagen fibers may be broken down by collagenase and ultimately resorbed; however, continued deposition of periportal and perivenular collagen in the active alcoholic leads to portal portal and portal perivenular bridging fibrosis and eventual cirrhosis.
10. Some of the pathophysiologic process

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