Advances in the Diagnosis, Pathogenesis, and Management of Autoimmune Hepatitis

Flow chart of therapy for AIH. Patients are given only corticosteroids or a lower dose of corticosteroids in combination with azathioprine (preferred initial regimen). The outcomes of initial therapy dictate changes in the treatment strategy.

Putative pathogenic pathways of AIH. The antigenic peptide (a self-antigen or foreign antigen that resembles a self-antigen) is displayed in the antigen-binding groove of a class II molecule of the MHC. Genetic factors, especially DRB1*0301 and DRB1*0401 in white North American and northern European adults, encode the structure of the antigen-binding groove and affect the nature of the antigen that can be accommodated. Recognition of the antigen display on the surface of the antigen-presenting cell (APC) by the CD4⁺ T-cell completes the first costimulatory signal necessary for immunocyte activation (1^st signal). Ligation of a B7 molecule on the surface of the APC with the CD28 molecule on the surface of the CD4⁺ T cell completes the second costimulatory signal necessary for immunocyte activation (2^nd signal). The activated CD4⁺ T cells produce signature cytokines that facilitate the clonal expansion of liver-infiltrating cytotoxic T cells (type 1 cytokine response) or plasma cells that produce Ig (type 2 cytokine response). Deficiencies in the number and function of the Treg cells and NK cells and genetic polymorphisms in TNFA*2 and TNFRSF6 increase the type 1 cytokine response and proliferation of liver-infiltrating cytotoxic T cells. Hepatocyte apoptosis is accomplished by binding of the Fas ligand of the cytotoxic T cell to the Fas molecule on the hepatocyte surface (cell-mediated cytotoxicity). The Igs produced by the expanded clone of plasma cells, possibly as a consequence of deficient Treg and NKT cell function, bind to normal constituents of the hepatocyte membrane and attract NK cells with Fc receptors. The hepatocytes undergo cytolysis (antibody-mediated cellular cytotoxicity). IgG4 staining can be used to characterize some of the plasma cells.