Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disorder that can progress to cirrhosis, shortening life expectancy. PBC patients are often asymptomatic, present with biochemical cholestasis, and test positive (>90%) for antimitochondrial antibodies (AMAs) in serum. Although AMA positivity without biochemical cholestasis may indicate increased risk of future PBC development, the contribution of these antibodies to pathogenesis remains enigmatic. Environmental risks and genetic determinants are likely implicated in PBC etiology. Given the familial aggregation of PBC, we hypothesized that AMAs also aggregate among relatives of PBC probands. We investigated the prevalence of AMAs in first-degree relatives (FDRs) of PBC probands to examine whether AMAs aggregate in such pedigrees. Using a PBC family registry, we prospectively screened for AMAs in the serum of 306 FDRs in 145 pedigrees, 350 PBC probands, and 196 controls who were age-matched, sex-matched, race-matched, and residence-matched to probands. The prevalence of AMA in FDRs and controls was 13.1% and 1%, respectively. Greater prevalence of AMA was found in female FDRs of PBC probands [sisters (20.7%), mothers (15.1%), and daughters (9.8%)] than in male FDRs [brothers (7.8%), fathers (3.7%), and sons (0%)]. Conclusions: AMAs aggregate among FDRs of PBC probands. Our data have clinical implications for FDRs of PBC probands because AMA positivity may suggest susceptibility to PBC. Thus, the identification and follow-up of these relatives may lead to earlier disease diagnosis and treatment. Furthermore, if AMA development is heritable, this trait will provide a basis to dissect the genetic predisposition to PBC. (HEPATOLOGY 2007;46:785-792.)
P rimary biliary cirrhosis (PBC) is a progressive cholestatic liver disease primarily affecting women and characterized by immune-mediated destruction of the intrahepatic bile ducts, gradually leading to cholestasis and cirrhosis. 1 Interestingly, about 50% of PBC patients have no symptoms and are incidentally diagnosed following abnormal results in routine liver tests. The early detection of PBC is important because timely treatment with ursodeoxycholic acid before the development of latestage disease appears to normalize life expectancy. The pathogenesis of PBC is considered to be complex, the result of interplay between environmental exposure and unknown genetic susceptibility alleles. Nongenetic risk factors associated with PBC thus far include past smoking, 6,7 a history of urinary tract infection, 7 and hormone replacement therapy. In addition, a number of microorganisms, such as Novosphingobium aromaticivorans, Chlamydia pneumoniae, and betaretrovirus, have been proposed to have a role in PBC development. The genetic contribution to PBC pathogenesis is also