Primary biliary cirrhosis (PBC) is the inflammatory, primarily T cell-mediated, chronic destruction of intrahepatic microscopic bile ducts of unknown etiology. In 90% of cases it affects women who exhibit elevated immunoglobulin M, anti-mitochondrial antibodies (AMAs) directed against the E2 subunit of pyruvate dehydrogenase (PDH-E2), and a cholestatic liver enzyme profile leading to cirrhosis over the course of years or decades. A prominent feature is the presence of extrahepatic immune-mediated disease associations, including autoimmune thyroid disease, Sjogren's syndrome, rheumatoid arthritis, inflammatory bowel disease, and, less frequently, celiac disease and CREST syndrome. Extra-hepatic syndromes frequently precede hepatic disease manifestation [64-66].
Anti-mitochondrial antibodies are found in approximately 95% of patients with PBC and are considered a serological hallmark of this disease. The targets of AMAs in PBC sera are members of an enzyme family, the 2-oxo acid dehydrogenase complexes (2-OADC), which are located on the inner membrane of the mitochondria and catalyze the oxidative decarboxylation of various alpha-keto acid substrates. Components of 2-OADC include the E2 subunit of PDC (PDC-E2), the E2 subunit of the 2-oxoglutarate dehydrogenase complex (OGDC-E2), the E2 subunit of the branched-chain 2-oxo acid dehydrogenase complex (BCOADC-E2), and the dihydrolipoamide dehydrogenase-binding protein (E3BP). The most predominant reactivity of AMAs in sera from PBC patients is directed against PDC-E2. Reactivity against OGDC-E2 and BCOADC-E2 is lower, around 50-70%. Antibodies to PDC-El-alpha are present in lower titers. Approximately 10% of patients react only to OGDC-E2 or BCOADC-E2, or to both [67-69].
Antinuclear antibodies (ANAs) have been identified in more than 50% of patients with PBC. These include antibodies against the nuclear pore protein, gp120, which are found in 25% of patients with AMA-positive PBC and in up to 50% of patients with AMA-negative PBC. The disease specificity for the detection of such antibodies by immunoblotting is more than 90% . Other autoantigens include the nuclear pore protein p62, which is recognized by PBC sera in 32% of cases . In about 20-30% of PBC patients, autoantibodies are directed against the nucleoprotein Sp100, which appears to have a high specificity for PBC . Less than 1% of PBC patients present antibodies to the lamin B receptor (LBR), an inner nuclear membrane protein that also has a high disease specificity for PBC . In summary, the presence of PBC-associated ANAs in AMA-negative patients may be the only seroimmunological clue for establishing the diagnosis of PBC.
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