Primary biliary cirrhosis (PBC) is characterized by a T-lymphocyte-mediated attack on small intralobular bile ducts (picture 1A-B). A continuous assault on the bile duct epithelial cells leads to their gradual destruction and eventual disappearance (picture 2). The sustained loss of intralobular bile ducts causes the signs and symptoms of cholestasis, and eventually results in cirrhosis and liver failure [1-3]. (See "Clinical manifestations, diagnosis, and natural history of primary biliary cirrhosis".)
This topic review will focus on the pathogenesis of PBC while its diagnosis and management are presented separately. (See appropriate topic reviews).
CLUES ABOUT ETIOLOGY BASED ON THE EPIDEMIOLOGY OF PBC
The precise cause of PBC is unknown but, as with other autoimmune diseases, is related to genetic susceptibility and environmental factors [4-6]. A number of environmental causes have been implicated, including several bacteria, viruses, toxins, and drugs, which are described below [7-11]. Some of the most compelling evidence for an environmental factor has been derived from epidemiologic studies, which have demonstrated geographic clustering, clustering of cases across time, and seasonal variation in the diagnosis of PBC [9,10].
As examples, the incidence of PBC has been estimated to be 200 to 251 per million in South Wales and Northeast England, less than 25 per million in Canada and Australia, and almost zero in Sub-Saharan Africa and India [12-16]. A limitation of these studies is that the varying incidence rates may in part be due to genetic differences in the populations and to differences in study methodology. However, that an environmental factor may be involved was strongly implicated in a study from a well-defined geographical population cohort in Northern England  and around toxic waste sites in New York City . Analysis of cases demonstrated unequivocal clustering in well-demarcated geographic regions.
The unanswered question in PBC is what causes or triggers the T-cell attack on small bile duct epithelial cells? Current data suggest that PBC is an autoimmune disease [18,19]. Like other better characterized autoimmune diseases, there appear to be at least two distinct requirements for PBC to develop: genetic susceptibility; and a triggering event that initiates the autoimmune attack on bile duct cells.