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Valeer J. Desmet Department of Morphology and Molecular Pathology, University of Leuven, Belgium


Histopathological study of the liver biopsy in viral hepatitis B allows to diagnose acute hepatitis, its severity and stage of evolution. Prediction of chronicity is feasible after two months. In chronic disease, histopathology allows to diagnose chronic hepatitis, its aetiology, grade of severity and stage of progression. Interface hepatitis and bridging confluent necrosis are important prognostic features.

Severity is graded according to extent of necro-inflammatory lesions, which include portal inflammation, interface hepatitis, intralobular liver cell damage and death, and confluent (bridging) necrosis. Staging of progression is based on extent of fibrosis and lobular architectural changes (cirrhosis).

Semiquantitative scoring of grade and stage is useful in trials of new drugs, in clinical research, and for comparison of pre- and post-treatment biopsies. It is not recommendable in routine diagnostic practice.

In situ hybridization and (immuno-)electron microscopy are less practical and mostly used in research.

Immunohistochemical staining for HBV antigens, especially for HBcAg and HBsAg, is useful for specifying the aetiology and the viral phase of the disease.

The viral replicative phase is characterized by mild activity, nuclear localization of HBcAg, cytoplasmic HBeAg and membranous expression of HBsAg; the viral clearance phase features more severe inflammation and necrosis, possibly including the bridging type, whereas immunostaining reveals nuclear, cytoplasmic and membranous HBcAg; HBsAg stains in the cytoplasm of some cells, and in cellular membranes; the residual integration phase reveals no or only mild activity and cytoplasmic HBsAg, without demonstrable HBcAg.

Attention for and reporting of premalignant lesions is important in improving adequate patient surveillance for possible development of hepatocellular carcinoma. Recognizable lesions include large cell and small cell liver cell dysplasia in dysplastic foci and nodules.

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Examination of liver tissue from living patients is performed on surgical and needle biopsies. It comprises mainly histopathological study, and may serve diagnostic and/or research purposes. Diagnostic investigations require close collaboration with the clinician to assure optimal reliability. Of paramount importance are adequate biopsies (1) and impeccable histopathological and histochemical techniques.(2)

I. Diagnostic Investigations

1. Histopathological study

Histopathology of the liver biopsy allows diagnosis of acute hepatitis, its degree of severity, and in most cases differentiation from chronic hepatitis.

Since histopathologically acute viral hepatitis B appears essentially similar to other forms of acute hepatitis, an aetiological diagnosis is less reliable. Acute viral hepatitis B may show different patterns; shortly described below.(3-5)

Acute hepatitis with spotty necrosis is the classical picture of self-limiting acute hepatitis. Cell damage tends to predominate in the centrolobular areas.(6)

Distinction can be made between an early, fully developed, late, and residual stage.(7)

Acute hepatitis with bridging necrosis represents more severe hepatitis with confluent areas of necrosis of the lytic type. The necrosis may link afferent and efferent vascular landmarks (portal-central bridging necrosis).(8)

Extensive confluent necrosis is often followed by collapse of the denuded reticulin framework, resulting in scarring fibrous septa. Older scars can be identified by their elastin content. (9, 10)

Acute hepatitis with panlobular or multilobular necrosis is more severe, seen in fulminant hepatitis.

Acute hepatitis with periportal necrosis features periportal interface hepatitis (piecemeal necrosis). The occurrence of this lesion in acute hepatitis B was considered an indicator of possible transition to chronicity (11); as was also bridging hepatic necrosis.(8) It appears that in the later stage of acute hepatitis (after 2 months) both lesions are unfavorable prognostic signs.(12, 13) The most reliable predictor of chronicity is the demonstrable presence of HBV antigens in scattered hepatocytes. (14)

The histological differentiation of acute hepatitis B from viral-like drug-induced and auto-immune hepatitis may sometimes be difficult. Chronic hepatitis is recognizable by predominance of portal and periportal changes, possible presence of elastin-containing septa, and detectable viral antigens (HBsAg, HBcAg) on immunostaining. Differentiation from bile duct obstruction and acute alcoholic hepatitis is feasable.

The histopathology of chronic viral hepatitis B comprises the elementary lesions of any form of chronic hepatitis; and some specific features. (15)

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Common features in chronic hepatitis.

Portal infiltration. Most portal tracts are infiltrated by inflammatory cells, predominantly lymphocytes. (16)

Interface hepatitis (previously termed piecemeal necrosis) is typical of more active disease. It corresponds to lymphocytic infiltration at the interface between connective tissue (portal tracts and septa) and parenchyma, associated with apoptotic death of local hepatocytes. (15, 17) The lesion may be minimal, mild or severe.

True interface hepatitis must be differentiated from periportal necro-inflammation in hepatitis A, from “biliary piecemeal necrosis” in chronic biliary diseases, and from spill-over of inflammatory cells unassociated with liver cell damage. (16)

Intralobular focal necro-inflammation (spotty necrosis) varies in extent with the severity of disease. Confluent lytic necrosis (bridging, panlobular, multilobular) characterizes severe disease, and clinical exacerbations of chronic disease.(18)

Hepatitic rosettes correspond to clusters of surviving hepatocytes in areas of extensive necro-inflammation.(5)

Most authors consider bridging necrosis an ominous prognostic finding (19, 20) although the lesion may also heal. (21) Apparently bridging necrosis carries a sinister long-term prognosis when associated with interface hepatitis, whereas the cirrhogenic evolution of chronic disease marked by interface hepatitis (“chronic active hepatitis”) is accelerated by bridging hepatic necrosis. (7)

Hepatic fibrosis in chronic hepatitis B occurs mostly in a septal pattern, comprising so-called active and passive septa. (11) Active septa are rich in cells; they represent extensive interface hepatitis eventually leading to portal-portal septal fibrosis. (7) Passive septa carry few or no inflammatory cells, are sharply delineated, and derive from postnecrotic collapse after confluent necrosis.

The mesenchymal cells responsable for fibrosis comprise portal/septal myofibroblasts, interface myofibroblasts and activated intralobular hepatic stellate cells. (22)

Parenchymal regeneration is evidenced by thickening of liver cell plates (2-3 cells wide), and increased numbers of bi- and tri-nucleated hepatocytes.(15) Activation of liver progenitor cells also participates in regeneration in chronic hepatitis.(23, 24)

Parenchymal regeneration in between a restructuring fibrous scaffold, leads to progressive disturbance of the lobular architecture and results in cirrhosis, usually of the macronodular type. (25)

Necro-inflammation may continue in the cirrhotic stage (active cirrhosis) or burn out (inactive cirrhosis). (25)

The common elementary lesions of chronic hepatitis constitute the base for grading and staging in chronic liver disease (see below).

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Specific features of chronic hepatitis B

The most distinctive histological feature for identifying HBV aetiology is the “ground-glass hepatocyte”.(26) It has a finely granular, and faintly eosinophilic cytoplasm due to proliferation of the smooth endoplasmic reticulum containing accumulated Hepatitis B surface Antigen (HBsAg). (27, 28) Ground-glass cells are highlighted by special stains, including Shikata’s orcein or aldehyde fuchsin (29) and Victoria blue.(30)

Orcein staining needs to be critically performed. (31) Ground-glass hepatocytes can be specifically stained by more sensitive immunohistochemistry (32) (see below).

Ground-glass cells must be differentiated from oncocytic change, due to densely packed mitochondria (mitochondriosis) of unclear significance. (33, 34) The differential diagnosis of HBsAg positive ground-glass cells further includes a similar appearance due to drug-induction, to cyanamide toxicity, to Lafora’s disease, and to fibrinogen storage disease. (35)

Ground-glass inclusions from several causes may co-exist in the same patient and in the same hepatocyte. (36)

“Sanded nuclei” are another, though not obvious change in some cases of chronic hepatitis B. These are pale finely granular inclusions in nuclei containing huge amounts of HBcAg particles (37), staining reddish violet with chromotrope aniline blue.(38)

A study on the frequency of chracteristic features for chronic hepatitis B, C, autoimmune and cryptogenic hepatitis concluded that the respective histological patterns have low sensitivity, but high specificity and predictability. (39)

Chronic hepatitis B can be distinguished from acute hepatitis by older fibrosis (positive elastin stain) and presence of orcein positive (HBsAg positive) ground-glass cells or inclusions. (5) Bilirubinostasis is rare in chronic and frequent in acute hepatitis.

Chronic biliary diseases (e.g. PBC, PSC) are differentiated by their features of ductopenia, cholate stasis, cholestatic liver cell rosettes and biliary type fibrosis. Chronic alcoholic liver disease has its own characteristics of steatosis, pericellular fibrosis, Mallory bodies, satellitosis and micronocular pattern of cirrhosis.

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2. Immunohistochemistry, in situ hybridization, electron and immuno-electron microscopy

Immunohistochemical staining with specific antibodies for HBV antigens allows to specify the HBV aetiology of chronic hepatitis and the viral phase in the disease. (3, 40)

In situ hybridization (ISH) of viral DNA is helpful in detecting HBV infection and its topography in the infected cells.

Various direct and indirect immunofluorescence and immunoperoxidase procedures can be applied on fresh frozen and paraffin embedded tissue. The sensitivity of immunoperoxidase methods can be enhanced by techniques of antigen retrieval and signal amplification like the Immunomax (41) and the EnvisionTM+ system.(42)

In acute hepatitis B, very little or no viral antigens are demonstrable (4, 43, 44), except in the very early phase (45, 46) and according to one study in patients infected with a mutant HBV (“silent HBV”). (47)

In chronic hepatitis B, antigen localization patterns vary. The course of chronic hepatitis B comprises three successive phases: virus tolerance (viral replication) phase, virus clearance and residual integration phase. (48-50)

During the immunotolerant, viral replicative phase there is only mild hepatocellular damage and inflammation. Immunostaining reveals predominant nuclear localization of HBcAg. (51, 52) HBcAg and HBeAg generally have a coincident cellular expression (53-55), but the ratio of HBcAg to HBeAg may differ in subcellular locations. Strong cytoplasmic HBeAg is a marker of high viral replication. (52, 54) HBsAg is found in the cytoplasm of some hepatocytes and in the membrane of numerous cells in a honeycomb-like pattern. (56, 57)

The viral clearance phase is characterized by immune elimination of virus-infected hepatocytes, seroconversion from HBeAg to HBe antibody, and reduction of viral replication. (58) Liver histopathology consists of more severe lesions, including confluent necrosis of variable extent. (59) Immunostaining reveals nuclear, cytoplasmic and membranous HBcAg. Cytoplasmic HBcAg correlates predominantly with liver damage (51, 52, 60) and proliferation (61) HBsAg shows weak cytoplasmic positivity in some hepatocytes and a membranous staining pattern. (49, 57, 62, 63) HBeAg has been found localized in nucleus and cytoplasm of hepatocytes. (52, 54, 64, 65) and in liver cell membranes (66)

Some virus-infected hepatocytes apparently escape immune elimination, resulting in persistence of viral infection and integration of viral DNA into the host genome (viral integration phase). (67, 68) If damage during the virus clearance phase was not extensive, the liver may recover to only minimal abnormalities.(69) In case several exacerbations occurred (70) the liver may have developed cirrhosis.(49)

Active replication of HBV has ceased, but HBsAg is produced by hepatocytes that contain integrated HBV-DNA. (71) HBsAg accumulates in clusters of hepatocytes. HBcAg is usually undetectable. (72) Mild inflammation may persist for some time, but substantial necro-inflammation should alert for a possible superinfection with another virus. (73)

Some patients show ongoing active disease after HBeAg seroconversion, due to persistence of a precore stop mutant HBV with deficient HBeAg synthesis (74, 75) or other mutations. (76) Immunostaining in such cases reveals cytoplasmic HBcAg (75, 77, 78) and precore peptide.(79)

HBxAg has been visualized in the nucleus and cytoplasm of hepatocytes, more widely present than HBsAg or HBcAg, perhaps representing a more sensitive immunohistochemical test for HBV infection. (80) Its presence in hepatocellular carcinoma cells in HBV+ patients supports its involvement in hepatocarcinogenesis. (81)

In situ hybridization (ISH) for detection of HBV sequences has been performed with radioactively and with chemically labeled probes, the former yielding higher sensitivity, the latter better resolution. ISH identified the hepatocyte cytoplasm as the site of HBV replication. (82-86) Combination of ISH with immunostains for HBV antigens revealed that HBV DNA is present in numerous antigen negative cells, but co-localizes mainly with cytoplasmic and less with nuclear HBcAg. (85, 87, 88) Hepatocytes with cytoplasmic HBsAg accumulation are not virus replicating. (89)

HBV specific sequences were also found in bile duct epithelium, endothelial and vascular smooth muscle cells. (84) In hepatitis B, immunohistochemistry is more sensistive than ISH. (90)

Electron and immuno-electron microscopy allow to visualize and identify structural components of HBV in liver cells.

HBc particles appear as spherical structures, 24-27nm in diameter, in the nucleoplasm, and in the hyaloplasm between hepatocellular organelles. (89, 91) The finding that cells with nuclear HBcAg are mostly free from HBV-DNA by ISH (87, 88) suggests an accumulation of empty or non-replicating core particles. (89)

Encapsulation of core particles within the endoplasmic reticulum (Dane particle formation) has been documented. (92-94) Membrane localization of HBcAg in the hepatocellular plasmalemma was confirmed by immuno-electron microscopy. (95)

HBsAg appears as filaments within the cisternae of the endoplasmic reticulum. (96-98) Ground-glass hepatocytes exhibit a marked hyperplasia of the endoplasmic reticulum which dislocates the cytoplasmic organelles to the cell periphery. Within the cisternae, there are typical filaments giving a positive reaction for HBsAg and pre-S by immuno-electron microscopy. (27, 28, 89, 98)

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3. Grading and staging of chronic viral hepatitis B. Semiquantitative scoring

The old classification of chronic hepatitis (99) was essentially a rough grading system, distinguishing milder from more severe variants of disease.

Progress in aetiological insight and treatment options necessitated a revised classification.

The new classification of chronic hepatitis is based on aetiology (viral, autoimmune, drug-induced and cryptogenic), also taking into account the histological grade of disease activity and the stage of evolution in terms of fibrosis and architectural derangement (cirrhosis).(100, 101)

Grading and staging is done in (preferably standardized) verbal descriptions, for instance: mild, moderate and severe chronic hepatitis as grades; and mild, moderate, severe fibrosis and cirrhosis as stages.(100)

Several semiquantitative scoring systems have been proposed, in which numerical scores are assigned to different grades and stages of chronic hepatitis. These methods are primarily indicated in the context of therapeutic trials or research projects; they are not intended to replace verbal reports in routine diagnostic practice. (100, 102-107)

The first successful scoring system specifically designed for chronic hepatitis is widely known as the Knodell Histological Activity Index (HAI).(108) Scores for the individual lesion categories are added to obtain an overall “histological activity index”. This broadly used system is subject to a number of criticisms, the most important being that scores for necro-inflammation (grading) are added to those for fibrosis (staging). (100, 109)

Subsequent scoring systems have taken these deficiencies into account and comprise more simple and more complex prescriptions. Several simple and easily applicable systems are available. (110-112) The French METAVIR group devised a simple algorithm for standardized grading (113), and an assessment of fibrosis (staging) in five categories. (114) Simpler scoring systems provide less information but tend to be more reproducible than complex ones. (115)

An updated version of the Knodell HAI116 separates grading from staging and is more detailed to provide more information. It assures adequate inter-observer reliability. (117)

Several problems are inherent to all scoring systems available: use of arbitrary scores that are not mathematically valid, observer variation, sampling variability and aetiological diversity. (103)

Accuracy and consistency of scoring procedures can be improved by previous planning and agreement between clinician(s) and pathologist(s), by excluding biopsy specimens of inadequate size and quality, by agreement on definition of histological criteria at the start of the study, by preferable use of dual observers, by avoiding long time intervals between scoring of biopsies, and by checking intra- and inter-observer variation. (116)

In general, staging of fibrosis and architectural changes has proved to be more reproducible than grading of necro-inflammatory lesions. (115, 118)

Semiquantitative scoring of liver biopsies has been extensively applied in clinical trials for new treatments of chronic hepatitis B, C and D.(119)

Morphometry has been used as well for quantitation, mostly for assessment of fibrosis. (120, 121) Image analysis based automated quantification of liver fibrosis was claimed to be a sensitive, precise, objective and reproducible method for quantification, thus supplementing scoring systems that are more based on distribution patterns of fibrosis. (122)

The potential usefulness of a mathematical scoring system based on fractal geometry for quantifying irregular patterns of fibrosis as observed in chronic hepatitis was recently addressed. (123)

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4. Precancerous lesions

Both HBV and HCV infections may lead to chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). (124, 125) Some cellular changes and nodular lesions are considered premalignant or precursors of HCC. Recognition and reporting of such lesions is important for adequate patient surveillance. Liver cell dysplasia (LCD), which may be of the large cell type (126) or of the small cell type (127) belongs to this type of change.

Large cell LCD in biopsies of patients with chronic hepatitis B (or C) is an independent risk factor for the development of HCC. (128, 129) Small cell LCD might originate from hepatic progenitor cells (130) and may represent an early step in carcinogenesis.(129)

Clusters of LCD measuring less than 1mm in diameter are termed “dysplastic foci”. Lesions measuring more than 1mm in diameter are designated as nodules. (131)

A macroregenerative nodule (measuring 0,8cm or more) is particularly common in macronodular cirrhosis. Histologically it shows hyperplastic liver parenchyma but no cellular atypia nor disorder in muralia arrangement. Dysplastic nodules do display atypical features, but not severe enough to qualify for frank HCC. Dysplastic nodules are subclassified as low or high grade, and considered distinct stages in the multistep process of hepatocarcinogenesis. (132) Foci and nodules should be carefully identified and reported. (5, 133)

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5. Special cases of chronic viral hepatitis B

Short reference is made to those conditions in which liver tissue examination may be contributory.

5.1. Coinfection with Hepatitis D virus

Coinfection with Hepatitis D virus (HDV, delta agent) alters the course of acute hepatitis B, favours chronic evolution and enhances severity of disease. (110, 134, 135) Microvesicular steatosis of hepatocytes (morula cells) was a notable feature in an outbreak of HDV infection in Venezuelan Indians. (136-138)

Specific immunostaining allows to confirm HDV aetiology. HDAg is detected in hepatocyte nuclei (139, 140) and in the cytoplasm and plasmalemma of hepatocytes. (141) Large amounts of nuclear HDAg may cause a “sanded nuclei” appearance. (142, 143)

Double immunostaining reveals separate expression of HDAg versus HBsAg and HBcAg; co-expression in the same cell is found though rarely with HBcAg. (141, 144)

ISH for HDV RNA may be more sensitive than immunostaining for HDAg. (84, 145, 146)

HDV RNA localizes in nuclei, usually together with HDAg, but occasionally alone. (146)

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5.2. Recurrent HBV infection post transplantation

Recurrent HBV infection post transplantation may either show the typical features observed in non-transplanted liver, or, more rarely, atypical patterns of liver damage.

Atypical patterns include hepatocyte ballooning, fatty change and a distinctive cholestatic syndrome, which also may occur in combination. (147)

Hepatocyte ballooning typically occurs without significant inflammation, but shows high level of viral replication reflected in diffuse nuclear and cytoplasmic immunostaining for HBcAg and HBeAg. (148) Ballooning associated with steatosis may explain the term “steatoviral hepatitis”. (149)

The terms “fibrosing cholestatic hepatitis” (fibrosing cytolytic hepatitis, fibroviral hepatitis) refer to a distinctive pattern of injury associated with rapidly progressive graft failure. (147-153) The histological pattern comprises periportal fibrosis surrounding ductular structures, prominent hepatocyte ballooning, bilirubinostasis, and mild or absent inflammation. Immunostaining reveals markedly positive cytoplasmic HBcAg. This stage may be followed by extensive postnecrotic collapse, fibrosis and ductular reaction.

This lesional pattern was also reported in other immunodeficiency states, including HIV infection (154) and following renal transplantation.(155)

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5.3. Association of HBV with other viral infection

Dual and triple infections with HBV, HCV and HDV occur. Histopathologically, there are no specific findings to suggest the possibility of multiple infections. (156) Immunohistochemical analysis may reveal suppression of HBsAg and HBcAg by simultaneous HCV infection. (157)

HCV infection is suspected on the base of characteristic histological features158 and positive immunostaining with specific antibody. (159)

Co-infection of HBV with cytomegalovirus (CMV) infection can be identified by typical nuclear inclusions, abnormal basophilic granular cytoplasm, microabcesses, and immunohistochemical staining for CMV antigen. (5)

Co-infection of HBV with HIV usually results in diminished histological activity (160), although more severe activity was also reported. (161) Immunostaining revealed more diffuse staining for HBV and HDV antigens in tissue specimens of HIV coinfected patients.(160)

5.4. Association of HBV with concomitant liver disease

Histopathological study often reveals clinically unsuspected concomitant liver disease. Examples include: alpha-1-antitrypsin dificiency, alcoholic liver disease, primary sclerosing cholangitis, haemochromatosis, amongst others.(2)

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II. Special Studies (Research)

Inventive investigations in different ways of tissue examination are applied to broaden the insight in pathophysiology. Examples include: semiquantitative evaluation of activated hepatic stellate cells (162-164); immunohistochemical studies on lymphocyte subsets, antigen presenting cells, adhesion molecules and apoptosis markers (165, 166); study of cytokines (167); elution of liver infiltrating lymphocytes (168); microdissection of sublobular regions of high and low degree of liver damage and their relationship to HBV variants (169); and cDNA microarray based analysis of differences in gene expression between chronic hepatitis B and C. (170)

To meet future requirements, pathology evaluates appropriate techniques of tissue preparation for high throughput molecular analysis.(171)

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  1. Schlichting P, Holund B, Poulsen H. Liver biopsy in chronic aggressive hepatitis. Diagnostic reproducibility in relation to size of specimen. Scand J Gastroenterol 1983;18:27-32.
  2. Desmet V, Fevery J: Liver Biopsy. In: Hayes PC, ed. Baillieres Clinical Gastroenterology. International Practice and Research. Investigations in Hepatology. Vol. 9 (nr. 4). London: Baillière Tindall, 1995; 811-828.
  3. Ferrell LD, Theise ND, Scheuer PJ: Acute and chronic viral hepatitis. In: MacSween RNM, Burt AD, Portmann BC, Ishak KG, Scheuer PJ, Anthony PP, eds. Pathology of the Liver. 4th ed. London: Churchill Livingstone, 2002; 313-362.
  4. Bianchi L, Spichtin HP: Histopathological studies of hepatitis B. In: Gerety RJ, ed. Hepatitis B. Orlando: Academic Press, 1985; 269-302.
  5. Scheuer PJ, Lefkowitch JH, eds. Liver Biopsy Interpretation. 6th ed. London: WB Saunders, 2000.
  6. Kobayashi K, Hashimoto E, Ludwig J, Hisamitsu T, Obata H. Liver biopsy features of acute hepatitis C compared with hepatitis A, B and non-A, non-B, non-C. Liver 1993;13:69-73.
  7. Bianchi L, De Groote J, Desmet VJ, Gedigk P, Korb G, Popper H, Poulsen H, et al. Acute and chronic hepatitis revisited. Lancet 1977;II:914-919.
  8. Boyer JL, Klatskin G. Pattern of necrosis in acute viral hepatitis. Prognostic value of bridging (subacute hepatic necrosis). N Engl J Med 1970;283:1063-1071.
  9. Scheuer PJ, Maggi G. Hepatic fibrosis and collapse: histological distinction by orcein staining. Histopathology 1980;4:487-490.
  10. Thung SN, Gerber MA. The formation of elastic fibers in livers with massive hepatic necrosis. Arch Pathol Lab Med 1982;106:468-469.
  11. Bianchi L, De Groote J, Desmet V, Gedigk P, Korb G, Popper H, Poulsen H, et al. Morphological criteria in viral hepatitis. Lancet 1971;I:333-337.
  12. Desmet VJ: Acute viral hepatitis: Hepatitis B. In: Gitnick G, ed. Modern Concepts of Acute and Chronic Hepatitis. New York: Plenum Publishing Corporation, 1989; 87-111.
  13. Vanstapel MJ, Van Steenbergen W, De Wolf-Peeters C, Desmyter J, Fevery J, De Groote J, Desmet VJ. Prognostic significance of piecemeal necrosis in acute viral hepatitis. Liver 1983;3:46-57.
  14. Houthoff HJ, Niermeijer P, Gips CH, Arends A, Hofstee N. Hepatic morphologic findings and viral antigens in acute hepatitis B. A longitudinal study. Virchows Arch (A) 1980;389:153-166.
  15. Ishak KG. Pathologic features of chronic hepatitis: a review and update. Am J Clin Pathol 2000;113:40-55.
  16. Baptista A, Bianchi L, De Groote J, Desmet VJ, Ishak KG, Korb G, MacSween RNM, et al. The diagnostic significance of periportal hepatic necrosis and inflammation. Histopathology 1988;12:569-579.
  17. Lau JY, Xie X, Lai MM, Wu PC. Apoptosis and viral hepatitis. Semin Liver Dis 1998;18:169-176.
  18. Villari D, Raimondo G, Brancatelli S, Longo G, Rodino G, Smedile V. Histological features in liver biopsy specimens of patients with acute reactivation of chronic type B hepatitis. Histopathology 1991;18:73-77.
  19. Cooksley WGE, Bradbear RA, Robinson W, Harrison M, Halliday JW, Powell LW, Ng HS, et al. The prognosis of chronic active hepatitis without cirrhosis in relation to bridging necrosis. Hepatology 1986;6:345-348.
  20. Combes B. The initial morphologic lesion in chronic hepatitis, important or unimportant ? Hepatology 1986;6:518-522.
  21. Chen T, Liaw YF. The prognostic significance of bridging hepatic necrosis in chronic type B hepatitis: a histopathologic study. Liver 1988;8:10-16.
  22. Cassiman D, Libbrecht L, Desmet V, Aertsen P, Denef C, Roskams T. Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol 2002;36:200-209.
  23. Hsia CC, Evarts RP, Nakatsukasa H, Marsden ER, Thorgeirsson S. Occurrence of oval-type cells in hepatitis B virus-associated human hepatocarcinogenesis. Hepatology 1992;16:1327-1333.
  24. Libbrecht L, Desmet V, Van Damme B, Roskams T. Deep intralobular extension of human hepatic "progenitor cells" correlates with parenchymal inflammation in chronic viral hepatitis: can "progenitor cells" migrate ? J Pathol 2000;192:373-378.
  25. Desmet V. Liver lesions in hepatitis B viral infection. Yale J Biol Med 1988;61:61-83.
  26. Hadziyannis S, Gerber MA, Vissoulis C, Popper H. Cytoplasmic hepatitis B antigen in "ground-glass" hepatocytes of carriers. Arch Pathol 1973;96:327-330.
  27. Gerber MA, Hadziyannis S, Vissoulis C, Schaffner F, Paronetto F, Popper H. Electron microscopy and immuno-electronmicroscopy of cytoplasmic hepatitis B antigen in hepatocytes. Am J Pathol 1974;75:489-502.
  28. Yamada G, Nakane PK. Hepatitis B core and surface antigens in liver tissue. Light and electron microscopic localization by the peroxidase-labelled antibody method. Lab Invest 1977;26:649-659.
  29. Shikata T, Uzawa T, Yoshiwara N, Akatsuka T, Yamazaki S. Staining methods of Australia antigen in paraffin section - detection of cytoplasmic inclusion bodies. Jpn J Exp Med 1974;44:25-36.
  30. Tanaka K, Mori W, Suwa K. Victoria blue-nuclear fast red stain for HBs antigen detection in paraffin sections. Acta Pathol Jpn 1981;31:93-98.
  31. Kerr R, Hall P. An evaluation of orcein methods for demonstrating hepatitis B surface antigen and copper-associated protein in human liver. Stain Technology 1986;61:243-247.
  32. Camilleri JP, Amat C, Chousterman M, Petite JP, Duboust A, Boddaert A, Paraf A. Immunohistochemical patterns of hepatitis B surface antigen (HBsAg) in patients with hepatitis, renal homograft recipients and normal carriers. Virchows Arch A Pathol Anat Histol 1977;376:329-341.
  33. Lefkowitch JH, Arborgh BA, Scheuer PJ. Oxyphilic granular hepatocytes. Mitochondrion-rich liver cells in hepatic disease. Am J Clin Pathol 1980;74:432-441.
  34. Gerber MA, Thung SN. Hepatic oncocytes. Incidence, staining characteristics and ultrastructural features. Am J Clin Pathol 1981;75:498-503.
  35. Callea F, De Vos R, Togni R, Tardanico R, Vanstapel MJ, Desmet VJ. Fibrinogen inclusions in liver cells: a new type of ground-glass hepatocyte. Immune light and electron microscopic characterization. Histopathology 1986;10:65-73.
  36. Alonso-Marti C, Moreno A, Barat A, Solera JC, Oliva H. Co-existence of hepatocyte ground-glass inclusions from several causes. Histopathology 1990;16:304-307.
  37. Bianchi L, Gudat F. Sanded nuclei in hepatitis B. Eosinophilic inclusions in liver cell nuclei due to excess in hepatitis B core antigen formation. Lab Invest 1976;35:1-5.
  38. Ozeki T, Mizuno O, Sanefuzi H, et al. Localization of hepatitis B core antigens in chronic active hepatitis using immuno-peroxidase and chromotrope aniline blue staining. Br J Exp Pathol 1987;68:605-612.
  39. Czaja AJ, Carpenter HA. Sensitivity, specificity, and predictability of biopsy interpretations in chronic hepatitis. Gastroenterology 1993;105:1824-1832.
  40. Gerber MA, Thung SN. The diagnostic value of immunohistochemical demonstration of hepatitis viral antigens in liver. Hum Pathol 1987;18:771-774.
  41. Merz H, Malisius R, Mannweiler S, Zhou R, Hartmann W, Orscheschek K, Moubayed P, et al. ImmunoMax: a maximized immunohistochemical method for retrieval and enhancement of hidden antigens. Lab Invest 1995;73:149-156.
  42. Sabattini E, Bisgaard K, Ascani S, Poggi S, Piccioli M, Cessarelli C, Pieri F, et al. The EnVisionTM + system: a new immunohistochemical method for diagnostics and research. Critical comparison with the APAAP, ChemMateTM, SCA, LABL and SABC techniques. J Clin Pathol 1998;51:506-511.
  43. Gudat F, Bianchi L, Sonnabend W, Thiel W, Aenishaenslin W, Stalder GA. Pattern of core and surface expression in liver tissue reflects state of specific immune response in hepatitis B. Lab Invest 1975;32:1-9.
  44. Bianchi L, Gudat F: Immunopathology of hepatitis B. In: Popper H, Schaffner F, eds. Progress in Liver Diseases. Vol. VI. New York: Grune and Stratton, 1979; 371-392.
  45. Edgington TS, Chisari FV. Immunological aspects of hepatitis B virus infection. Am J Med Sci 1975;270:213-227.
  46. Arnold W, Meyer zum Büschenfelde KH, Hess G, Knolle J. The diagnostic significance of intrahepatocellular hepatitis-B-surface-antigen (HBsAg), hepatitis-B-core-antigen (HBcAg) and IgG for the classification of inflammatory liver diseases. Klin Wochenschr 1975;53:1069-1074.
  47. Uchida T, Shimojima S, Gotoh K, Shikata T, Mima S. Pathology of livers infected with "silent" hepatitis B virus mutant. Liver 1994;14:251-256.
  48. Chu CM, Karayiannis P, Fowler MJF, Monjardino J, Liaw YF, Thomas HC. Natural history of chronic hepatitis B virus infection in Taiwan. Studies of hepatitis B virus DNA in serum. Hepatology 1985;5:431-434.
  49. Chen DS. Natural history of chronic hepatitis B virus infection: new light on an old story. J Gastroenterol Hepatol 1993;8:470-475.
  50. Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology 2001;34:1225-1241.
  51. Hsu HC, Su IJ, Lai MY, Chen DS, Chang MH, Chuang SM, Sung JL. Biologic and prognostic significance of hepatocyte hepatitis B core antigen expressions in the natural course of chronic hepatitis B virus infection. J Hepatol 1987;5:45-50.
  52. Naoumov NV, Portmann BC, Tedder RS, Ferns B, Eddleston ALWF, Williams R. Detection of hepatitis B virus antigens in liver tissue. A relation to viral replication and histology in chronic hepatitis B infection. Gastroenterology 1990;99:1248-1253.
  53. Chu CM, Liaw YF. Immunohistological study of intrahepatic expression of hepatitis B core and E antigens in chronic type B hepatitis. J Clin Pathol 1992;45:791-795.
  54. Lindh M, Savage K, Rees J, Garwood L, Horal P, Norkrans G, Dhillon AP. HBeAg immunostaining of liver tissue in various stages of chronic hepatitis B. Liver 1999;19:294-298.
  55. Mondelli M, Tedder RS, Ferns B, Pontisso P, Realdi G, Alberti A. Differential distribution of hepatitis B core and e antigens in hepatocytes: analysis by monoclonal antibodies. Hepatology 1988;6:199-204.
  56. Chu CM, Liaw YF. Membrane staining for hepatitis B surface antigen in hepatocytes: a sensitive and specific marker of active viral replication in hepatitis B. J Clin Pathol 1995;48:470-473.
  57. Hsu HC, Lai MY, Su IJ, Chen DS, Chang MH, Yang PM, Wu CY, et al. Correlation of hepatocyte HBsAg expression with virus replication and liver pathology. Hepatology 1988;8:749-754.
  58. Loriot MA, Marcellin P, Bismuth E, Martinot-Peignoux M, Boyer N, Degott C, Erlinger S, et al. Demonstration of hepatitis B virus DNA by polymerase chain reaction in the serum and the liver after spontaneous or therapeutically induced HBeAg to anti-HBe or HBsAg to anti-HBs seroconversion in patients with chronic hepatitis B. Hepatology 1992;15:32-36.
  59. Liaw YF, Yang SS, Chen TJ, Chu CM. Acute exacerbation in hepatitis B e antigen - positive chronic type B hepatitis - a clinico-pathological study. J Hepatol 1985;1:227-233.
  60. Chu CM, Liaw YF. Intrahepatic distribution of hepatitis B surface and core antigens in chronic hepatitis B virus infection. Hepatocyte with cytoplasmic/membranous hepatitis B core antigen as a possible target for immune hepatocytolysis. Gastroenterology 1987;92:220.
  61. Chu CM, Yeh CT, Sheen IS, Liaw YF. Subcellular localization of Hepatitis B core antigen in relation to hepatocyte regeneration in chronic hepatitis B. Gastroenterology 1995;109:1926-1932.
  62. Desmet VJ. Immunopathology of chronic viral hepatitis. Hepatogastroenterology 1991;38:14-21.
  63. Ray MB, Desmet VJ, Fevery J, Ge Groote J, Bradburne AF, Desmyter J. Distribution patterns of hepatitis B surface antigen (HBsAg) in the liver of hepatitis patients. J Clin Pathol 1976;29:94-100.
  64. Ballare M, Lavarini C, Brunetto MR, Petruzzelli E, Dovis M, Molino G, Bonino F. Relationship between the intrahepatic expression of e and c epitopes of the nucleocapsid protein of hepatitis B virus and viraemia. Clin Exp Immunol 1989;75:64-69.
  65. Villari D, Pollicino T, Spinella S, Russo F, Campo S, Rodino G, Squadrito G, et al. Hepatitis Be antigen detection in formalin fixed liver biopsy specimens. A tool to investigate wild-type and e-minus variant HBV infection. Am J Clin Pathol 1995;103:136-140.
  66. Yamada G, Takaguchi K, Matsueda K, Nishimoto H, Takahashi M, Fujiki S, Mizuno M, et al. Immunoelectron microscopic observation of intrahepatic HBeAg in patients with chronic hepatitis B. Hepatology 1990;12:133-140.
  67. Hadziyannis SJ, Lieberman HM, Karvountzis GG, Shafritz DA. Analysis of liver disease, nuclear HBcAg, viral replication, and hepatitis B virus DNA in liver and serum of HBeAg vs anti-HBe positive carriers of hepatitis B virus. Hepatology 1983;3:656-662.
  68. Shafritz DA, Shouval D, Sherman H, Hadziyannis S, Kew M. Integration of hepatitis B virus DNA into the genome of liver cells in chronic liver disease and hepatocellular carcinoma. N Engl J Med 1981;305:1067-1073.
  69. Su IJ, Lai MY, Hsu HC, Chen DS, Yang PM, Chuang SM, Sung JL. Diverse virological, histopathological and prognostic implications of seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection. J Hepatol 1986;3:182-189.
  70. Davis GL, Hoofnagle JH. Reactivation of chronic type B hepatitis presenting as acute viral hepatitis. Ann Int Med 1985;102:762-765.
  71. Shafritz DA, Hadziyannis SJ: Molecular pathobiology of persistent hepatitis B virus infection in relation to chronic liver disease and primary hepatocellular carcinoma. In: Farber E, Phillips MJ, Kaufman N, eds. Pathogenesis of liver diseases. Baltimore: Williams and Wilkins, 1987; 136-152.
  72. Martinot-Peignoux M, Boyer N, Colombat M, Akremi R, Pham BN, Ollivier S, Castelnau C, et al. Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers. J Hepatol 2002;36:543-546.
  73. Perillo RP, Brunt EM. Hepatic histologic and immunohistochemical changes in chronic hepatitis B after prolonged clearance of HBeAg and hepatitis B surface antigen. Ann Int Med 1991;115:113-115.
  74. Brunetto MR, Stemler M, Schödel F, Will H, Ottobrelli A, Rizetto M, Verme G, et al. Identification of HBV variants which cannot produce precore derived HBeAg and may be responsible for severe hepatitis. Ital J Gastroenterol 1989;21:151-154.
  75. Naoumov NV, Schneider R, Grötzinger T, et al. Precore mutant hepatitis B virus infection and liver disease. Gastroenterology 1992;102:538-543.
  76. Naoumov NV, Eddleston ALWF. Host immune response and variations in the virus genome: pathogenesis of liver damage caused by hepatitis B virus. Gut 1994;35:1013-1017.
  77. Park YN, Han KH, Kim KS, Chung JP, Kim S, Park C. Cytoplasmic expression of hepatitis B core antigen in chronic hepatitis B virus infection: role of precore stop mutants. Liver 1999;19:199-205.
  78. Bonino F, Rosina F, Rizzetto M, Rizzi R, Chiaberge E, Tardanico R, Callea F, et al. Chronic hepatitis in HBsAg carriers with serum HBV-DNA and anti-HBe. Gastroenterology 1986;90:1268-1273.
  79. Dienes HP, Gerken G, Goergen B, Heermann K, Gerlich W, Meyer zum Büschenfelde KH. Analysis of the precore DNA sequence and detection of precore antigen in liver specimens from patients with anti-hepatitis-B-e positive chronic hepatitis. Hepatology 1995;21:1-7.
  80. Wang WL, London WT, Lega L, Feitelson MA. HBxAg in the liver from carrier patients with chronic hepatitis and cirrhosis. Hepatology 1991;14:29-37.
  81. Wang WL, London WT, Feitelson MA. Hepatitits B x antigen in hepatitis B virus carrier patients with liver cancer. Cancer Res 1991;51:4971-4977.
  82. Gowans EJ, Burrell CJ, Jilbert AJ, Marmion BP. Cytoplasmic (but not nuclear) hepatitis B virus (HBV) core antigen reflects HBV-DNA synthesis at the level of the infected hepatocyte. Intervirology 1985;24:220-225.
  83. Gowans EJ, Burrell CJ, Jilbert AR, Marmion BP. Patterns of single- and double-stranded hepatitis B virus DNA and viral antigen accumulation in infected liver cells. J Gen Virol 1983;64:1229-1239.
  84. Negro F, Pacchioni D, Monardini A, Bussolati G, Bonino F. In situ hybridization in viral hepatitis. Liver 1992;(Spec. issue) 12:217-226.
  85. Naoumov NV, Daniels HM, Davison F, Eddleston ALWF, Alexander GJM, Williams R. Identification of hepatitis B virus-DNA in the liver by in situ hybridization using a biotinylated probe. Relation to HBcAg expression and histology. J Hepatol 1993;19:204-210.
  86. Caballero T, Caballero MA, Ruiz-Extremera A, Barrios-del-Pino Y, O'Valle F, Salmeron FJ, Sanchez-Salgado G. Detection of hepatitis B virus in liver by in situ hybridization (ISH) in HBsAg seropositive and seronegative patients. Histol Histopathol 1995;10:265-270.
  87. Infantolino D, Pinarelly A, Ceccato R, Barbazza R. HBV-DNA by in situ hybridization. A method to improve sensitivity on formalin-fixed, paraffin embedded liver biopsies. Liver 1989;9:360-366.
  88. Lau JYN, Naoumov NV, Alexander GJM, Williams R. Rapid detection of hepatitis B virus DNA in liver tissue by in situ hybridization and its combination with immunohistochemistry for simultaneous detection of HBV antigens. J Clin Pathol 1991;44:905-908.
  89. Bianchi L, Gudat F: Chronic hepatitis. In: MacSween RNM, Anthony PP, Scheuer PJ, Portmann B, Burt AD, eds. Pathology of the Liver. 3rd ed. Edinburgh: Churchill Livingstone, 1994; 349-395.
  90. Nuovo GJ. Histologic distribution of hepatitis A, B, C, D, E and G with concomitant cytokine response in liver tissues. Diagn Mol Pathol 1998;7:265-275.
  91. De Vos R, Ray MB, Desmet VJ. Electron microscopy of hepatitis B virus components in chronic active liver disease. J Clin Pathol 1979;32:590-600.
  92. Kamimura T, Yoshikawa A, Ichida F, Sasaki H. Electron microscopic studies of Dane particles in hepatocytes with special reference to intracellular development of Dane particles and their relation with HBeAg in serum. Hepatology 1981;1:392-397.
  93. Yamada G, Sakamoto Y, Mizuno M, Nishihara T, Kobayashi T, Takahashi T, Nagashima H. Electron and immuno-electron microscopic study of Dane particle formation in chronic hepatitis B virus infection. Gastroenterology 1982;83:348-356.
  94. Huang SN, Neurath AR. Immunohistologic demonstration of hepatitis B viral antigens in liver with reference to its significance in liver injury. Lab Invest 1979;40:1-17.
  95. Kojima T, Bloemen J, Desmet VJ. Immune electron microscopic demonstration of hepatitis B core antigen (HBcAg) in liver plasma membranes. Liver 1987;7:191-200.
  96. Stein O, Fainaru M, Stein Y. Visualization of virus-like particles in endoplasmatic reticulum of hepatocytes of Australia antigen carriers. Lab Invest 1972;26:262-269.
  97. Huang SN, Groh V, Beaudoin JG, Dauphinee WD, Guttmann RD, Morehouse DD, Aronoff A, et al. A study of the relationship of virus-like particles and Australia antigen in liver. Hum Pathol 1974;5:209-222.
  98. Cabral GA, Gyorkey F, Gyorkey P, Melnick JL, Dreesman GR. Immunohistochemical and electron microscopic detection of hepatitis B surface and core antigens. Exp Mol Pathol 1978;29:156-169.
  99. De Groote J, Desmet VJ, Gedigk P, Korb G, Popper H, Poulsen H, Scheuer P, et al. A classification of chronic hepatitis. Lancet 1968;II:626-628.
  100. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis : diagnosis, grading and staging. Hepatology 1994;19:1513-1520.
  101. International Working Party. Terminology of chronic hepatitis, hepatic allograft rejection, and nodular lesions of the liver: summary of recommendations developed by an international working partly supported by the World Congresses of Gastroenterology Los Angeles, 1994. Am J Gastroenterol 1994;89:S177-S181.
  102. Desmet VJ. Histological classification of chronic hepatitis. Acta Gastroenterol Belg 1997;60:259-267.
  103. Hübscher SG. Histological grading and staging in chronic hepatitis: clinical applications and problems. J Hepatol 1998;29:1015-1022.
  104. Hall Pdl. Broadsheet number 47: Chronic hepatitis: an update with guidelines for histopathological assessment of liver biopsies. Pathology 1998;30:369-380.
  105. Scheuer PJ. Chronic hepatitis: what is activity and how should it be assessed ? Histopathology 1997;30:103-105.
  106. Brunt EM. Grading and staging the histopathological lesions of chronic hepatitis: the Knodell Histology Activity Index and beyond. Hepatology 2000;31:241-246.
  107. Scheuer PJ. Scoring of liver biopsies: are we doing it right ? Eur J Gastroenterol Hepatol 1996;8:1141-1143.
  108. Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431-435.
  109. French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 1994;20:15-20.
  110. Lok ASF, Lindsay I, Scheuer PJ, Thomas HC. Clinical and histological features of delta infection in chronic hepatitis B virus carriers. J Clin Pathol 1985;38:530-533.
  111. Scheuer PJ. Classification of chronic viral hepatitis: a need for reassessment. J Hepatol 1991;13:372-374.
  112. Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol 1995;19:1409-1417.
  113. Bedossa P, Poynard T, METAVIR Cooperative Study Group. An algorithm for the grading of activity in chronic hepatitis C. Hepatology 1996;24:289-293.
  114. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997;349:825-832.
  115. Goldin RD, Goldin JG, Burt AD, Dhillon PA, Hubscher S, Wyatt J, Patel N. Intra-observer and inter-observer variation in the histopathological assessment of chronic viral hepatitis. J Hepatol 1996;25:649-654.
  116. Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696-699.
  117. Westin J, Lagging LM, Westjal R, Norkrans G, Dhillon P. Interobserver study of liver histopathology using the Ishak score in patients with chronic hepatitis C virus infection. Liver 1999;19:183-187.
  118. Bedossa P, Bioulac-Sage P, Callard P, Chevallier M, Degott C, Deugnier Y, Fabre M, et al. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 1994;20:15-20.
  119. Dusheiko GM. New treatments for chronic viral hepatitis B and C. Baillière's Clin Gastroenterol 1996;10:299-333.
  120. Chevallier M, Guerret S, Chossegros P, Gerard F, Grimaud JA. A histological semiquantitative scoring system for evaluation of hepatic fibrosis in needle liver biopsy specimens: comparison with morphometric studies. Hepatology 1994;20:349-355.
  121. Pilette C, Rousselet MC, Bedossa P, Chappard D, Oberti F, Rifflet H, Maiga MY, et al. Histopathological evaluation of liver fibrosis: quantitative image analysis versus semi-quantitative scores. Comparison with serum markers. J Hepatol 1998;28:439-446.
  122. Masseroli M, Caballero T, O'Valle F, Del Moral RMG, Perez-Milena A, Del Moral RG. Automatic quantification of liver fibrosis: design and validation of a new image analysis method: comparison with semiquantitative indexes of fibrosis. J Hepatol 2000;32:453-464.
  123. Dioguardi N, Grizi F, Bossi P, Roncalli M. Fractal and spectral dimension analysis of liver fibrosis in needle biopsy specimens. Anal Quant Cytol Histol 1999;21:262-266.
  124. Okuda K. Hepatocellular carcinoma. J Hepatol 2000;32 (Suppl 1):225-237.
  125. Chisari FV. Viruses, immunity and cancer: lessons from hepatitis B. Am J Pathol 2000;156:1118-1132.
  126. Anthony PP, Vogel CL, Barker LF. Liver cell dysplasia: a premalignant condition. J Clin Pathol 1973;26:217-223.
  127. Watanabe S, Okita K, Harada T, Kodama T, Numa Y, Takemoto T, Takahashi T. Morphologic studies of the liver cell dysplasia. Cancer 1983;51:2197-2205.
  128. Ganne-Carrié N, Chastang C, Chapel F, Munz C, Pateron D, Sibony M, Deny P, et al. Predictive score for the development of hepatocellular carcinoma and additional value of liver large cell dysplasia in Western patients with cirrhosis. Hepatology 1996;23:1112-1118.
  129. Libbrecht L, Craninx M, Nevens F, Desmet V, Roskams T. Predictive value of liver cell dysplasia for development of hepatocellular carcinoma in patients with non-cirrhotic and cirrhotic chronic viral hepatitis. Histopathology 2001;39:66-73.
  130. Libbrecht L, Desmet V, Van Damme B, Roskams T. The immunohistochemical phenotype of dysplastic foci in human liver: correlation with putative progenitor cells. J Hepatol 2000;33:76-84.
  131. International Working Party. Terminology of nodular hepatocellular lesions. Hepatology 1995;22:983-993.
  132. Kojiro M. Premalignant lesions of hepatocellular carcinoma: pathologic viewpoint. J Hepatobiliary Pancreatic Surg 2000;7:535-541.
  133. Le Bail B, Bernard PH, Carles J, Balabaud C, Bioulac-Sage P. Prevalence of liver cell dysplasia and association with HCC in a series of 100 cirrhotic liver explants. J Hepatol 1997;27:835-842.
  134. Verme G, Amoroso P, Lettieri G, Pierri P, David E, Sessa F, Rizzi R, et al. A histologic study of hepatitis delta virus liver disease. Hepatology 1986;6:1303-1307.
  135. Craig JR, Govindarajan S, DeCock KM. Delta viral hepatitis. Histopathology and course. Pathol Annu 1986;21(Pt2):1-21.
  136. Popper H, Thung SN, Gerber MA, Hadler SC, de Monzon M, Ponzetto A, Anzola E, et al. Histologic studies of severe delta agent infection in Venezuelan Indians. Hepatology 1983;3:906-912.
  137. Buitrago B, Popper H, Hadler SC, Thung SN, Gerber MA, Purcell RH, Maynard JE. Specific histologic features of Santa Marta hepatitis . A severe form of hepatitis delta-virus infection in northern South America. Hepatology 1986;6:1285-1291.
  138. Lefkowitch JH, Goldstein H, Yatto R, Gerber MA. Cytopathic liver injury in acute delta virus hepatitis. Gastroenterology 1987;92:1262-1266.
  139. Recchia S, Rizzi R, Acquaviva F, Rizzetto M, Tison V, Bonino F, Verme G. Immunoperoxidase staining of the HBV-associated delta antigens in paraffinated liver specimens. Pathologica 1981;73:773-777.
  140. Di Bisceglie AM, Negro F. Diagnosis of hepatitis delta virus infection. Hepatology 1989;10:1014-1016.
  141. Kojima T, Callea F, Desmyter J, Sakurai I, Desmet VJ. Immuno-light and electron microscopic features of chronic hepatitis D. Liver 1990;10:17-27.
  142. Moreno A, Ramon Y Cajal S, Marazuela M, Carreno V, Milicua JM, Cerezo E, Ciesta C, et al. Sanded nuclei in delta patients. Liver 1989;9:367-371.
  143. Moreno A, Martinez CJ, Carreno V. Liver biopsy and the etiologic diagnosis of chronic hepatitis. J Hepatol 1993;17:S112-S115.
  144. Ryley NG, Heryet AR, Goldin R, Monjardino J, Saldanha J, Fleming KA. Co-expression of markers for hepatitis delta and hepatitis B viruses in human liver. Histopathology 1992;20:331-337.
  145. Negro F, Bonino F, Di Bisceglie A, Hoofnagle JH, Gerin JL. Intrahepatic markers of hepatitis delta virus infection. A study by in situ hybridization. Hepatology 1989;10:916-920.
  146. Pacchioni D, Negro F, Chiaberge E, Rizzetto M, Bonino F, Bussolati G. Detection of hepatitis Delta virus RNA by a nonradioactive in situ hybridization procedure. Hum Pathol 1992;23:557-561.
  147. Davies SE, Portmann BC, O'Grady JG, Aldis PM, Chaggar K, Alexander GJM, Williams R. Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis. Hepatology 1991;13:150-157.
  148. Harrison RF, Davies MH, Goldin RD, Hübscher SG. Recurrent hepatitis B in allografts: a distinctive form of rapidly developing cirrhosis. Histopathology 1993;23:21-28.
  149. Phillips MJ, Cameron R, Flowers MA, Blendis LM, Greig PD, Wanless I. Post transplant recurrent hepatitis B viral liver disease. Am J Pathol 1992;140:1295-1308.
  150. Demetris AJ, Todo S, Van Thiel DH, Fung JJ, Iwaki Y, Sysyn G, Ming W, et al. Evolution of hepatitis B virus liver disease after hepatic replacement. Am J Pathol 1990;137:667-676.
  151. Todo S, Demetris A, Van Thiel D, Teperman L, Fung JJ, Starzl TE. Orthotopic liver transplantation for patients with hepatitis B virus related liver disease. Hepatology 1991;13:619-626.
  152. Benner KG, Lee RG, Keeffe EB, Lopez RR, Sasaki AW, Pinson CW. Fibrosing cytolitic liver failure secondary to recurrent hepatitis B after liver transplantation. Gastroenterology 1992;103:1307-1312.
  153. Hübscher SG, Portmann BC: Transplantation pathology. In: MacSween RNM, Burt AD, Portmann BC, Ishak KG, Scheuer PJ, Anthony PP, eds. Pathology of the Liver. 4th ed. London: Churchill Livingstone, 2002; 228-941.
  154. Fang J, Wright T, Lau J. Fibrosing cholestatic hepatitis in a patient with HIV and hepatitis B. Lancet 1993;342:1175.
  155. Booth JCL, Goldin RD, Brown JL, Karayiannis P, Thomas HC. Fibrosing cholestatic hepatitis in a renal transplant recipient associated with the hepatitis B virus precore mutant. J Hepatol 1995;22:500-503.
  156. Colombari R, Dhillon AP, Piazzola E, Tomezzoli AA, Angelini GP, Capra F, Tomba A, et al. Chronic hepatitis in multiple virus infection: histopathological evaluation. Histopathology 1993;22:319-325.
  157. Guido M, Thung SN, Fattovich G, Cusinato R, Leandro G, Cecchetto A, Cesaro S, et al. Intrahepatic expression of hepatitis B virus antigens: effect of hepatitis C virus infection. Mod Pathol 1999;12:599-603.
  158. Goodman ZD, Ishak KG. Histopathology of hepatitis C virus infection. Semin Liver Dis 1995;15:70-81.
  159. Verslype C, Nevens F, Depla E, Maertens G, van Pelt J, Fevery J, Roskams T. Validation of immunohistochemical staining with the monoclonal antibody 17H10 (IGH222) in liver biopsies for the diagnosis of chronic hepatitis C [Abstract]. Hepatology 2000;32 (no. 4, pt. 2):213A.
  160. Goldin RD, Fish DE, Hay A, Waters JA, McGarvey MJ, Main J, Thomas HC. Histological and immunohistochemical study of hepatitis B virus in human immunodeficiency virus infection. J Clin Pathol 1990;43:203-205.
  161. Housset C, Pol S, Carnot F, Dubois F, Nalpas B, Housset B, Berthelot P, et al. Interactions between human immunodeficiency virus-1, hepatitis delta virus and hepatitis B virus infections in 260 chronic carriers of hepatitis B virus. Hepatology 1992;15:578-583.
  162. Guido M, Rugge M, Chemello L, Leandro G, Fattovich G, Giustina G, Cassaro M, et al. Liver stellate cells in chronic viral hepatitis: the effect of interferon therapy. J Hepatol 1996;24:301-307.
  163. Sakaida I, Nagatomi A, Hironaka K, Uchida K, Okita K. Quantitative analysis of liver fibrosis and stellate cell changes in patients with chronic hepatitis C after interferon therapy. Am J Gastroenterol 1999;94:489-496.
  164. Kweon YO, Goodman ZD, Dienstag JL, Schiff ER, Brown RA, Burkhardt E, Schoonhoven R, et al. Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B. J Hepatol 2001;35:749-755.
  165. Huang SN, C CT, Tsai SL, Liaw YF. Histopathology and pathobiology of hepatotropic virus-induced liver injury. J Gastroenterol Hepatol 1997;12 (Suppl):S195-S217.
  166. Moreno-Otero R, Gracia-Buey L, Mateos F, Garcia-Monzon C. Pathogenesis of chronic viral hepatitis: lessons from immunohistochemistry. Viral Hepatitis Reviews 1996;2:61-79.
  167. Maher JH. Cytokines : overview. Semin Liver Dis 1999;19:109-115.
  168. Koziel MJ. Cytokines in viral hepatitis. Semin Liver Dis 1999;19:157-169.
  169. Kojima N, Horiike N, Michitaka K, Onji M. In situ detection of mutated hepatitis B virus in microdissected, formalin-fixed liver tissue from patients with chronic hepatitis B. J Hepatol 1999;30:359-365.
  170. Honda M, Kaneko S, Kawai H, Shirota Y, Kobayashi K. Differential gene expression between chronic hepatitis B and C hepatic lesion. Gastroenterology 2001;120:955-966.
  171. Gillespie JW, Best CJ, Bichsel VE, Cole KA, Greenhut SF, Hewitt SM, Ahram M, et al. Technical advance. Evaluation of non-formalin tissue fixation for molecular profiling studies. Am J Pathol 2002;160:449-457.

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