Primary biliary cholangitis develops when the immune system attacks the small intrahepatic bile ducts.
Pathogenesis
The exact cause of PBC remains unknown, but different lines of evidence point to an autoimmune basis. Immune-mediated mechanisms directed, possibly, at the bile duct cells destroy them mainly through T cells and eventually produce biliary cirrhosis. When the immune cells that gather around the bile ducts are studied, CD4+ T cells, CD8+ T cells, NK cells and B cells are all found there. The disease is centred on the small intrahepatic biliary ducts, whose epithelial cells are destroyed and lost.
The main autoantibody in PBC, and one that is both highly sensitive and specific for it, is anti-mitochondrial antibody (AMA). AMA are directed against the E2 part of the pyruvate dehydrogenase complex (PDC-E2), a protein on the inner mitochondrial membrane. AMA are found in 90–95% of patients, so their absence does not exclude the disease.
AMA themselves are not thought to cause the duct damage. Three observations support this: they persist after liver transplantation without evidence of disease progression, disease severity is unrelated to the antibody titre, and they are not always present.
Other autoantibodies are common alongside AMA. ANA is present in about half of all patients with PBC and in nearly 85% of those who are AMA-negative. ANA is a general term for antibodies against different nuclear antigens; in PBC the important targets are anti-multi-nuclear-dot antibodies (anti-MND), whose antigen is Sp100, anticentromere antibodies (ACA), and antinuclear envelope antibodies against GP210, P62 and the lamin B receptor, which give a rim-like immunofluorescence pattern. An anti-MND or rim-like ANA is strongly suggestive of PBC in an AMA-negative patient, and the specificity of anti-GP210 for PBC is above 99%. Patients who are positive for antibodies in addition to AMA have a worse prognosis.
One hypothesis for how the autoantibodies arise is mimicry between an exogenous antigen and an endogenous one. PDC-E2 is highly conserved between bacteria and mammals, which supports a mimicry basis for the immune response, and several studies point to a relation between E. coli and the progression of PBC.
What keeps the disease confined to the liver is a property of cholangiocytes. Unlike other epithelial cells, cholangiocytes translocate PDC-E2 intact into the apoptotic bodies formed during apoptosis. The combination of AMA, macrophages and cholangiocyte apoptotic bodies carrying PDC-E2 activates the inflammatory response and drives further apoptosis. Because this translocation happens only in cholangiocytes, the process keeps the disease restricted to the liver.
Family history matters in PBC, and genetic studies built on it have identified risk variants. HLA-DRB1*08 carries a higher risk of PBC, while HLA-DRB1*11 and DRB1*13 are protective, although these associations differ between populations. More than 80–90% of patients with PBC do not carry a susceptible allele at all, which points to the importance of the non-HLA genes, which are mostly immune-related.