PBC is a classical autoimmune disease. Although it is predominantly a disease of middle-aged woman, with a median age of diagnosis of approximately 50 years, 5–10% of patients are men, and the reported age range is 22–93. It is reported throughout the world, but with varying geographic incidence and prevalence; the highest reported incidence and prevalence is in northern Europe and the northern United States. Studies have suggested the incidence and prevalence are increasing worldwide. Antimitochondrial autoantibodies (AMAs) are found in 95% of patients with PBC. The targets of the autoantibodies are members of the family of the 2-oxo-acid dehydrogenase complexes, most particularly the E2 subunits of the pyruvate dehydrogenase complex (PDC-E2). The immunologic injury is marked by a T-cell–mediated destruction of the intrahepatic bile ducts. The only proven therapy for PBC is ursodeoxycholic acid (UDCA). Despite early diagnosis and treatment, many patients have an inexorable disease progression leading ultimately to cirrhosis and end-stage liver disease.

A. Genetic Factors

There have been several studies indicating the role of genetics in determining the susceptibility to PBC. Particularly important observations include the following (Figure 52–1):

1. 
   

   First-degree relatives of patients with PBC have a 100-fold higher prevalence of disease than the general population.

   
   
2. 
   

   PBC has the highest reported concordance rate (62.5%) in monozygotic twins of any autoimmune disease.

   
   
3. 
   

   The prevalence of AMAs in first-degree relatives of patients with PBC was 13.1% compared with 1% of controls.

A number of candidate genes have been implicated in PBC including CTLA4 and IL12A. The interleukine-12 (IL-12) pathway is involved in Th1 immune responses and has been implicated in autoimmunity.

B. Environmental Factors

As with other autoimmune conditions, molecular mimicry is felt to be the mechanism for the initiation of autoimmunity. Several candidate environmental triggers have been suggested, including infectious agents (viruses and bacteria) and chemicals. These potential triggers have significant homology to human mitochondrial proteins, particularly PDC-E2. The role of transient environmental agents in the pathogenesis of PBC was supported by a recent study that demonstrated highly statistically significant space-time clustering in 1015 cases of PBC in northeast England. Further study among this population suggested a seasonally varying environmental agent as there was a marked peak for diagnoses in the month of June.

C. Immunologic Factors

The T cells infiltrating the portal triads are specific for the PDC-E2 autoepitope. However, it is not clear why the immune attack has such specificity for the biliary epithelium when the target mitochondrial proteins are present in all nucleated cells. Studies have suggested that the mechanism of the metabolic processing of PDC-E2 in biliary epithelium results in the autoantigen remaining immunologically intact and available for presentation to antigen-presenting cells. In all other cell types the autoepitope is destroyed during apoptosis.