DEFINITION OF AUTOIMMUNE HEPATITIS
Autoimmune hepatitis is a chronic disorder characterized by continuing hepatocellular necrosis and inflammation, usually with fibrosis, which can progress to cirrhosis and liver failure. When fulfilling criteria of severity, this type of chronic hepatitis, when untreated, may have a 6-month mortality of as high as 40%. Based on contemporary estimates of the natural history of autoimmune hepatitis, the 10-year survival is 80−98% for treated and 67% for untreated patients. The prominence of extrahepatic features of autoimmunity and seroimmunologic abnormalities in this disorder supports an autoimmune process in its pathogenesis; this concept is reflected in the prior labels lupoid and plasma cell hepatitis. Autoantibodies and other typical features of autoimmunity, however, do not occur in all cases; among the broader categories of “idiopathic” or cryptogenic chronic hepatitis, many, perhaps the majority, are probably autoimmune in origin. Cases in which hepatotropic viruses, metabolic/genetic derangements (including nonalcoholic fatty liver disease), and hepatotoxic drugs have been excluded represent a spectrum of heterogeneous liver disorders of unknown cause, a proportion of which are most likely autoimmune hepatitis.
IMMUNOPATHOGENESIS OF AUTOIMMUNE PATHOGENESIS
The weight of evidence suggests that the progressive liver injury in patients with autoimmune hepatitis is the result of a cell-mediated immunologic attack directed against liver cells in the setting of a loss of, or failed, immunologic tolerance for self liver antigens. In all likelihood, predisposition to autoimmunity is inherited, whereas the liver specificity of this injury is triggered by environmental (e.g., chemical, drug [e.g., minocycline], or viral) factors. For example, patients have been described in whom apparently self-limited cases of acute hepatitis A, B, or C led to autoimmune hepatitis, presumably because of genetic susceptibility or predisposition. Evidence to support an autoimmune pathogenesis in this type of hepatitis includes the following: (1) in the liver, the histopathologic lesions are composed predominantly of cytotoxic T cells and plasma cells; (2) circulating autoantibodies (nuclear, smooth muscle, thyroid, etc.; see below), rheumatoid factor, and hyperglobulinemia are common; (3) other autoimmune disorders—such as autoimmune thyroiditis, rheumatoid arthritis, autoimmune hemolytic anemia, ulcerative colitis, membranoproliferative glomerulonephritis, juvenile diabetes mellitus, vitiligo, celiac disease, and Sjögren’s syndrome—occur with increased frequency in patients and in their relatives who have autoimmune hepatitis; (4) histocompatibility haplotypes associated with autoimmune diseases, such as HLA-B1, B8, DR3, and DR4 as well as extended haplotype DRB1*0301 and DRB1*0401 alleles, are common in patients with autoimmune hepatitis; and (5) this type of chronic hepatitis is responsive to glucocorticoid/immunosuppressive therapy, effective in a variety of autoimmune disorders.
Cellular immune mechanisms appear to be important in the pathogenesis of autoimmune hepatitis. In vitro studies have suggested that in patients with this disorder, CD4+ T lymphocytes are capable of becoming sensitized to hepatocyte membrane proteins and of destroying liver cells. Molecular mimicry by cross-reacting antigens that contain epitopes similar to liver antigens is postulated to activate these T cells, which infiltrate, and result in injury to, ...