Immunopathogenesis of primary biliary cirrhosis: an old wives' tale

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of autoimmune origin, characterised by inflammatory destruction of the small intrahepatic bile ducts, and fibrosis which can progress to cirrhosis and subsequent liver failure [1-3]. Symptoms include fatigue, insomnia, pruritus, Sicca symptoms, and arthralgias. More severe symptoms relate to portal hypertension and hepatic decompensation [1-3]. PBC shows a high female preponderance, mainly affecting middle aged women [1-4]. The female to male ratio ranges from 9:1 to 20:1, which is relatively higher than other autoimmune diseases [2]. Diagnosis requires the presence of at least two out of three of the following: antimitochondrial antibodies (AMA) in serum, biochemical markers of cholestasis, and characteristic histopathological features [2,5-7]. AMA and disease-specific anti-nuclear antibodies (ANA) are usually present at high titres [2,5,6,8]. Many 'non-autoimmune' liver disorders such as viral hepatitides and acute liver failure are characterised by the presence of autoantibodies, however, when AMA are present they are often suggestive of co-existing PBC [6,9-18]. In these non-autoimmune driven liver pathologies, it is not clear whether AMA or other autoantibodies just indicate immune dysregulation or are pathologically relevant [19-25].AMA are present in 95% of PBC patients, with a specificity of nearly 100% [6,7,20,21,26,27], therefore true AMA-negative PBC can exist but is extremely rare [28]. AMA is primarily of the IgG isotype, however, IgA and IgM are also detected [5]. As the presence of AMA is so strongly associated with PBC, it is generally viewed that asymptomatic patients who are AMA positive will eventually develop PBC [29,30]. Patients with PBC exhibit a multi-lineage response to the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), which involves AMA as well as autoreactive CD4 and CD8 responses [6,31-33]. Histological features typical for PBC include: destruction of bili