Etiology of primary biliary cirrhosis: The search for the culprit

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease characterized by the presence of high titer antimitochondrial autoantibodies (AMAs) and destruction of intrahepatic small bile ducts. Despite vigorous efforts in the characterization of autoantibodies and bile duct histopathology, the etiology of this disease is unclear. Although there is no correlation between the titer of AMAs and disease severity, the presence of AMAs usually occurs before symptoms of liver abnormalities. We believe that the production of AMAs is not an epiphenomenon, and an understanding of the mechanism of AMA induction will shed light on the etiology of PBC. Recent studies have suggested that the induction of PBC is multifactorial, in which the primary player involves the xenobiotics modification of mitochondrial proteins or exposure to xenobiotic modified bacterial mitochondrial protein homologs, leading to breaking of tolerance to the human mitochondrial autoantigens and eventually liver pathology in genetic susceptible individuals. We discuss the immunophysiological characteristics of biliary epithelial cells, biochemistry of the 2-oxo-acid dehydrogenase complex, and environmental and genetic factors relevant to PBC.