Etiology and natural history of primary sclerosing cholangitis.

The etiology of primary sclerosing cholangitis remains unknown. Bacteria, toxins, viral infections, and immunological and genetic factors have all been proposed as etiological agents. Portal bacteremia, toxins absorbed from the diseased colon in inflammatory bowel disease, and cytomegalovirus and reovirus infections have been implicated by various investigators but there is little evidence to support these hypotheses. The close association between primary sclerosing cholangitis and various human leukocyte antigen haplotypes is now well established and lends support to the theory that immunologic and genetic mechanisms may be involved in its pathogenesis. Patients with primary sclerosing cholangitis may have elevated levels of circulating immune complexes, immunoglobulins, and non-organ specific autoantibodies. The association between ulcerative colitis and primary sclerosing cholangitis remains unexplained and both groups of patients have a high prevalence of antibodies to the perinuclear cytoplasmic antigen. The long-term prognosis in primary sclerosing cholangitis is tempered by the development of cholangiocarcinoma in 6%-30% of patients when followed over long periods of time. Detecting cholangiocarcinoma early in a patient with primary sclerosing cholangitis is one of the most frustrating problems faced by a clinician while caring for these patients. The long-term outlook for patients with primary sclerosing cholangitis and cholangiocarcinoma remains dismal, whatever the treatment modality employed. However, the development of a multivariate statistical survival model from long-term survival data from the Mayo Clinic and other centers has been a major step in identifying individual primary sclerosing cholangitis patients at low, moderate, and high risk of dying. Such models have been useful for stratifying patients in therapeutic trials, for in patient counseling, and in patient selection and timing of liver transplantation.