Figure 1. Pathogenesis, Clinical Subtypes, and Outcomes of Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis is caused by the interaction of predisposing genetic factors and environmental exposures in local biologic processes that occur at the level of the gut (i.e., gut lymphocyte homing to liver and chronic mucosal inflammation) and the liver (i.e., activation of cholangiocytes and the bile milieu). This condition is influenced by the intestinal microbiome and other dynamic elements, including the epigenome and metabolome. The stochastic effect of environmental factors on germline and somatic biologic events leads to a variety of clinical subtypes of primary sclerosing cholangitis. The persistence and progressive nature of biologic dysfunction result in multifaceted, often interrelated, outcomes of primary sclerosing cholangitis. These outcomes range from chronic liver cholestasis and inflammation to malignant transformation of the liver and gut and to metabolic bone disease, and they may necessitate liver transplantation.