Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) affects primarily middle-aged women and is characterized by chronic cholestasis and the presence in serum of high-titer antimitochondrial autoantibodies (AMA). The disease leads to the destruction of the intrahepatic bile ducts and progressive fibrosis. The diagnosis is made when two out of three criteria are met, i.e., positive serum AMA, alkaline phosphatase elevation, and compatible liver histology. Like other autoimmune diseases, the onset of PBC seems to depend on the cumulative effects of some susceptibility genes and the effects of environmental agents, infectious or chemical. Genome-wide association studies strongly point to the genes of the IL-12 pathway, among others. The association of AMA, identified as autoantibody directed against the E2 subunit of the mitochondrial pyruvate complex (PDC-E2), with biliary ductular lesions, is enigmatic, but it is suspected that PDC-E2 during degradation undergoes faulty apoptosis with production of a disease-inducing apotope. The presence in nearly 50% of cases of atypical PBC-related antinuclear antibodies remains a mystery. Treatment with the now-approved ursodeoxycholic acid is surprisingly effective. Several informative transgene-based mouse models have been developed and confirm the nexus between AMA reactivity and cholangiocyte destruction, and experimental models are available supporting the participation in pathogenesis of environmental xenobiotics. Possible tracks towards an understanding of the “cause” of PBC can be visualized.