Aetiology
PBC is thought to be an autoimmune disease. There is a very high incidence of autoantibodies, most characteristically directed against mitochondrial antigens (antimitochondrial antibody). These antibodies, which are present in over 95% of patients, are principally directed against pyruvate dehydrogenase complex E2 subunit (PDC-E2), although reactivity is also seen, to a lesser degree, against other PDC components and the E2 subunits of related enzyme complexes.[16] Patients with PBC also have a higher incidence of autoantibodies directed at disease-specific nuclear antigens (ANA).[17] The most common ANA antibodies seen in PBC are anti-sp100 and anti-gp210.[14]
There is a genetic predisposition to developing PBC; an affected first-degree relative increases the risk almost tenfold, and concordance between monozygotic twins is 63%.[18] Certain HLA antigens have also been associated with the development of PBC; they are thought to modulate the individual’s reaction to environmental stimuli and the biological processes involved in disease pathogenesis.[18][19] Loss of tolerance to PDC-E2 and the development of PBC is thought to be triggered by an environmental exposure in genetically-susceptible individuals. Putative environmental triggers include smoking, exposure to volatile compounds, hair dye, nail polish, use of hormone replacement therapies, shingles, and urinary tract infections.[13][20][21][22]
Pathophysiology
The pathophysiological process in PBC is damage to, and progressive destruction of, the biliary epithelial cells lining the small intrahepatic bile ducts. There is loss of immune tolerance to biliary epithelial cells, leading to inflammation, cholestasis, and progressive fibrosis.[18] In the end stages of the disease there can be a complete loss of small intrahepatic ducts. Loss of bile duct cross-sectional area within the liver leads to cholestasis with variable and progressive bile acid retention. The predominantly hydrophobic bile acid pool can, when retained in this way, cause secondary damage within the liver, further contributing to progressive bile duct loss. There is therefore a self-sustaining element to the damage process.
Fibrosis occurs within the liver as a consequence of progressive damage, and this can lead to cirrhosis over a variable time period. The factors that dictate the rate of fibrosis development and the risk of cirrhosis (which both appear to vary significantly between patients) are at present unclear. This means that it is difficult, in practice, to predict the risk of developing advanced liver disease in any patient in the early stages of disease.
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