Anatomic Pathology / PATHOLOGIC FEATURES OF CHRONIC HEPATITIS

The general histopathologic changes of chronic hepatitis and those related to the various causes are reviewed. Consideration also is given to underlying or associated diseases and to mixed infections in chronic viral hepatitis. Changes occurring in exacerbations or relapses are described. Selected histopathologic changes are illustrated. The nomenclature is reviewed briefly, with emphasis on separation of activity from stage of disease. The generally accepted definition of chronic hepatitis is necroinflammatory disease of the liver lasting more than 6 months. Histopathologic aspects of chronic hepatitis are herein reviewed and updated, with clinicopathologic correlations. Chronic hepatitis in the liver allograft is not included. General Histopathologic Changes of Chronic Hepatitis Chronic hepatitis, regardless of cause, is characterized by several lesions, the most important of which is “interface hepatitis” (piecemeal necrosis) ❚Image 1❚. This necroinflammatory change, sometimes referred to as “lymphocytic” piecemeal necrosis, initially destroys the limiting plate of liver cells (ie, is periportal). In the untreated patient, there is continuous erosion of the hepatic parenchyma with closer and closer approximation of expanded portal areas. The necroinflammatory changes are succeeded by fibrosis. Interface hepatitis may not involve all portal areas equally in a given case and can affect a segment or the entire perimeter of a portal area. It can continue unabated in the cirrhotic liver, complicating chronic hepatitis and, thus, contributing to the activity of the cirrhotic process. Degenerative changes affecting liver cells in areas of interface hepatitis include “cytoplasmic dissociation” (a change characterized by swelling of liver cells with cytoplasmic rarefaction, coarse clumping of cytoplasmic organelles, and, eventually, lysis of nuclei and cell membranes), and apoptosis ❚Image 2❚. The latter change results in the formation of variably sized, often rounded, fragments of liver cells that are located in the liver plates or sinusoids (Image 1). The larger apoptotic bodies, sometimes Anatomic Pathology / REVIEW ARTICLE containing nuclear fragments, often are referred to as acidophilic bodies. Within the sinusoids, the apoptotic bodies are phagocytosed and ultimately digested by Kupffer cells. For further information on apoptosis in viral hepatitis, see the review by Lau et al.1 There is an intimate relationship between lymphocytes or plasma cells and liver cells in chronic hepatitis. The degenerating hepatocytes and inflammatory cells are closely apposed, and the lymphocytes or plasma cells often are located in spaces of Disse, with indentation of the cytoplasm of liver cells (peripolesis). Sometimes the hepatocyte completely encircles a lymphocyte or plasma cell (emperipolesis). There is loss of microvilli of the plasma membrane of the liver cell facing the lymphocyte or plasma cell. Hassan et al2 found that plasma cells in areas of interface hepatitis in chronic hepatitis produce interleukin-1. They suggested that interleukin-1 with other mediators might stimulate the production of collagen by hepatocytes in these areas. In another study, transforming growth factor-beta1 was found to be activated in chronic hepatitis C, and was considered to contribute to hepatic fibrogenesis.3 Zylberberg et al4 found that histologic fibrosis and activity in chronic hepatitis C correlated with levels of soluble tumor necrosis factor receptors, particularly R75. The tumor necrosis factor alpha–tumor necrosis factor receptor system also is activated in the liver in chronic hepatitis B virus (HBV) infection and is thought to have an important role in the pathogenesis of liver damage and viral clearance.5,6 Portal inflammation often is variable in intensity and includes infiltration by lymphocytes and plasma cells. Lymphoid aggregates or follicles with reactive centers may be present. They are considered typical, although not pathognomonic, of chronic hepatitis C ❚Image 3❚. Immunohistochemical studies of these aggregates have been performed by several groups of investigators; they are regarded as true functional lymphoid follicles. Mosnier et al7 found that they contained activated B cells in germinal centers surrounded by a follicular dendritic cell network. A mantle zone of B cells surrounds the activated B cells. The B-cell follicle in turn is surrounded by a T-cell zone. Talc crystals may be seen in portal macrophages of abusers of intravenous drugs. The crystals are a specific but © American Society of Clinical Pathologists Am J Clin Pathol 2000;113:40–55 41 ❚Image 2❚ Interface hepatitis. Separated liver cells are swollen and exhibit cytoplasmic clumping (dissociation) (H&E, ×440). ❚Image 3❚ Lymphoid follicle in portal area in chronic hepatitis C. Note the circumferential interface hepatitis (H&E, ×160). ❚Image 1❚ Interface hepatitis. The junction of the markedly inflamed portal area with the hepatic parenchyma is ill-defined or eroded. Note the apoptotic body (arrow) (H&E, ×450). Ishak / PATHOLOGIC FEATURES OF CHRONIC HEPATITIS not a sensitive marker of previous intravenous drug abuse.8,9 Such crystals are best visualized by polarizing microscopy and show a characteristic “pastry flake” appearance on scanning electron microscopy. In some addicts, the talc may be intermingled with black birefringent granules containing titanium ❚Image 4❚. The elements silicon, magnesium in the talc, and titanium can be identified by x-ray microanalysis10 ❚Figure 1❚. It is recommended that all liver biopsy sections with chronic hepatitis be examined routinely by polarizing microscopy inasmuch as the patient’s physician may be unaware of previous intravenous drug abuse, or because the patient may deny such abuse when asked. A histopathologic feature that is highly characteristic, if not pathognomonic of chronic hepatitis, is the isolation and entrapment of single or groups of liver cells in the expanded portal areas (Image 2).10 Bile duct lesions, long assumed to be degenerative, are believed to represent diverticula; they are considered most characteristic, although not pathognomonic, of chronic hepatitis C ❚Image 5❚. They were found in one third of cases of 1 series of chronic hepatitis C and were not associated with loss of bile ducts.11 Vyberg12 identified 3 types of hepatitis-associated bile duct lesions. The type 2 lesion is the one most frequently recognized in chronic hepatitis. It involves bile ducts with an outer diameter of 15 to 40 μm. The abnormal ducts frequently are surrounded by a lymphoid aggregate or follicle. Some represent preexisting ducts undergoing degeneration with swelling, cytoplasmic vacuolization, nuclear pyknosis or karyorrhexis, and infiltration by inflammatory cells, typically mononuclear. Kaji et al13 found that the dendritic cells involved in the bile duct damage in primary biliary cirrhosis differed from those in chronic hepatitis C. Thus, interdigitating dendritic cells frequently are seen in the early stages of primary biliary cirrhosis, while follicular dendritic cells are observed more frequently in chronic hepatitis C. Bile duct inflammation has been noted to improve after interferon therapy.14 Most instances of chronic hepatitis reveal intra-acinar necroinflammatory changes of variable severity, in addition to periportal interface hepatitis. In the typical case, they are focal (“spotty”) and consist mainly of apoptotic bodies of varied size, as well as foci of necrosis with aggregates of lymphocytes and plasma cells ❚Image 6❚. Hypertrophied Kupffer cells that have scavenged the apoptotic bodies and other granular debris also are present in the foci of necrosis. Steatosis, mild to moderate, and generally macrovesicular, is considered typical of chronic hepatitis C, as will be noted later. More severe intra-acinar injury generally is seen in exacerbations and relapses of chronic hepatitis. In chronic hepatitis B, these may be spontaneous, secondary to withdrawal of cytotoxic or immunosuppressive therapy, or associated with delta virus or HIV infection. Other than the clinical and biochemical findings, acute exacerbations of chronic hepatitis B are characterized by increases in serum HBVDNA and IgM anti–hepatitis B core antigen titers. In addition to spontaneous exacerbations15 and relapses after interferon therapy, there are reports of reactivation of chronic hepatitis C after withdrawal of immunosuppressive therapy.16 Spontaneous flare-ups of chronic hepatitis C may be related to heterologous (mixed) infections of hepatitis C virus (HCV).17 In 1 study, spontaneous acute exacerbations of chronic hepatitis C occurred in 40% of patients.15 They were less severe than exacerbations of chronic hepatitis B biochemically and histologically, although interface hepatitis was observed more frequently. Exacerbations with marked elevations of aminotransferase levels have been reported in © American Society of Clinical Pathologists 42 Am J Clin Pathol 2000;113:40–55 ❚Image 4❚ A, Birefringent talc particles in portal area of an intravenous drug abuser (×440). B, Granular black pigment in portal area of an intravenous abuser of drugs is composed of titanium (H&E, ×450). A B Anatomic Pathology / REVIEW ARTICLE several cases of ibuprofen-induced hepatotoxic effects in chronic hepatitis C.18 Relapses of chronic autoimmune hepatitis have been reported after treatment withdrawal,19 but relapses also can be spontaneous. In my experience, 1 or more of the following histopathologic changes can be observed in exacerbations or relapses of chronic hepatitis: (1) an increase in the degree of spotty necrosis; (2) ballooning degeneration, often most severe in zone 3, with dropout of hepatocytes and central-to-central and central-to-portal bridging necrosis that is subsequently followed by fibrosis ❚Image 7❚; ballooning degeneration may be associated with variable cholestasis; in such cases there is significant periportal cholangiolar proliferation, with infiltration of the cholangioles by neutrophils (acute cholangiolitis); (3) multiacinar necrosis, followed eventually by the formation of irregularly shaped, multiacinar scars. It is important to emphasize that those changes are superimposed on the chronic portal or periportal changes that characterize chronic hepatitis. Regeneration in chronic hepatitis typically is seen in the form of 2-cell–thick plates (periportal or periseptal) and an increased number of binucleated and trinucleated cells. © American Society of Clinical Pathologists Am J Clin Pathol 2000;113:40–55 43 ❚Image 5❚ Bile duct degeneration in chronic hepatitis C. The bile duct is infiltrated by 2 lymphocytes (large arrow), and at least 2 degenerating cells have lost their nuclei (small arrow) (H&E, ×880). ❚Image 6❚ Intra-acinar focal necrosis and an apoptotic body (arrow) in chronic hepatitis C (H&E, ×350). ❚Image 7❚ Zone 3 necrosis with bridging in patient with autoimmune hepatitis who had a relapse (H&E, ×120). 0.0 5.0 10.0 15.0 Ti Si