Features of specific types of CAH Autoimmune hepatitis

Diagnostic criteria are currently being developed for autoimmune hepatitis. Characteristics that provide a 'disease profile' are: seronegativity for viral markers; female sex; northern Caucasian ethnic origin; multisystem disease expression (arthritis, rashes, thyroiditis, hemolytic anemia, ulcerative colitis); histologically large areas of periportal necrosis and prominence of plasma cells; pronounced hypergammaglobulinemia, >30gl~'; serum autoantibodies; HLA-B8, -DR3 and -DR4; rapid response to, and dependency on, corticosteroid drugs; and 'resistance' to hepatocellular carcinoma compared with other types of chronic hepatitis or cirrhosis. Most weight attaches to the autoantibody markers, which are predominantly to antigens of nuclei and smooth muscle

(Figure 3). The multiple nuclear antigenic reactants include DNA (rarely), histones and lamins, and the smooth muscle reactant is the cytoskeletal filament, F-actin. Autoantibody to neutrophil cytoplasmic antigen (ANCA) is also seen. In a variant now called autoimmune hepatitis type 2, the marker antigen is enriched in liver and kidney microsomes (LKM). The LKM antigen has been identified as a particular cytochrome P450 isoform, CYP450 2D6. There is suspected to be a liver-specific autoantigen, perhaps membrane-associated, and one candidate is the asialoglycoprotein receptor (ASGP-R); however this to a degree lacks fine disease specificity for association with autoimmune hepatitis. Long-term treatment with prednisolone, combined with azathioprine, is highly effective.

Figure 3 Serological reactions in type 1 autoimmune hepatitis. Top left, lupus erythematosus (LE) cell as the former marker of antinuclear antibody (ANA); top right, homogeneously reactive ANA by immunofluorescence on Hep2 cells; bottom left, smooth muscle antibody (SMA) by immunofluorescence on mouse stomach; bottom right, F-actin specificity of SMA on cultured fibroblast showing staining of cytoplasmic microfilaments.

Figure 3 Serological reactions in type 1 autoimmune hepatitis. Top left, lupus erythematosus (LE) cell as the former marker of antinuclear antibody (ANA); top right, homogeneously reactive ANA by immunofluorescence on Hep2 cells; bottom left, smooth muscle antibody (SMA) by immunofluorescence on mouse stomach; bottom right, F-actin specificity of SMA on cultured fibroblast showing staining of cytoplasmic microfilaments.

HBV-associated CAH (CAH-B)

HBV is a DNA virus that is parenterally transmitted. The frequency of chronic infection is higher in males and in localities in which HBV infection is endemic. Infection with HBV is acquired neonatally from infected mothers in high endemicity regions, and sporadically as a parenteral infection in low endemicity regions. The diagnosis of HBV-associated CAH (CAH-B) depends on detecting antigens of HBV in serum, the surface's' antigen (HBsAg), and in early cases the 'e' antigen (HBeAg). In liver cells, HBV as the core antigen (HBcAg) is demonstrable immuno-histochemically or by nucleic acid hybridization. CAH-B has a variable clinical expression and, although often indolent, undergoes progression to cirrhosis, and there is a clear predisposition to supervening hepatocellular carcinoma. Treatment with type 1 interferons may eliminate the virus and arrest the disease.

HCV-associated CAH (CAH-C)

HCV-associated CAH, which accounts for most examples of previously called non-A, non-B viral hepatitis, is due to an RNA virus which is transmitted parenterally. Formerly transmission was mainly by blood transfusion or treatment of hemophilia by blood products; currently the main routes are contaminated equipment of intravenous drug abusers, or close intrafamilial contact. Persisting infection with HCV is frequent after an acute infection. HCV-associated CAH (CAH-C) usually progresses silently to cirrhosis, and primary hepatocellular carcinoma is a risk in the later stages. Cirrhosis and hepatocellular carcinoma appear to be potentiated by coexisting alcoholic liver disease. Many cases formerly specified as cryptogenic CAH

(see below) will probably be attributable to infection with HCV. The diagnosis depends on serologic demonstration of antibody to antigens of HCV, or amplification of viral sequences in blood or liver tissue by the polymerase chain reaction. Treatment with type 1 interferons arrests infection in a proportion of cases. Some instances of CAH-C are associated with low-titer anti-LKM reactions, but this reactivity is not regarded as signifying that autoimmunity plays any role in their pathogenesis.

Drug-associated CAH

Various drugs, of which well-known examples include halothane and chlorpromazine, induce (infrequently) acute idiosyncratic hypersensitivity reactions affecting the liver, with hepatitic or cholestatic expressions. As an accompaniment of these reactions, there may be demonstrable serum autoantibodies of the type usually seen in autoimmune liver diseases, directed to antigens of nuclei (ANA), smooth muscle (SMA), mitochondria (AMA) or liver microsomes (anti-CYP450 2D6). In cases with a protracted course, the histopathology of the liver resembles that of autoimmune CAH. However, characteristically, the disease resolves when the offending drug is withdrawn, and cirrhosis seldom eventuates. The immunopathogenesis of drug-induced CAH is uncertain.

'Toxic-metabolic' CAH

Histologically evident CAH may be seen in cases of chronic liver disease with a defined metabolic cause including alcohol abuse, or effects of inborn genetic errors including a,-antitrypsin deficiency, Wilson's disease or hemochromatosis. This category is relatively unimportant in terms of immunology, and features of the associated disease are dominant.

Cryptogenic CAH

This term is used for cases of CAH that are negative for markers of autoimmunity or infection with HBV or HCV and for which no other cause is ascertainable. Some cases may be attributable to infection with hepatitis viruses of which markers are absent from serum, to infection with as yet unidentified hepatitis viruses, or to autoimmunity wherein autoantibodies are no longer demonstrable.

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