Primary sclerosing cholangitis

To discuss exhaustively: clinical, serological and pathologic aspects of primary sclerosing cholangitis (PSC); recent advantages in the knowledge of the disease's pathogenesis, therapeutic approaches that still appear today less preferable than liver transplantation. We have reviewed the most important researches on PSC of recent years. PSC is characterized by chronic inflammation of the main bile ducts, except for the gallbladder. HLA-B8 and HLA-DR3 haplotypes have been associated with PSC. It is probable that PSC is an organ-specific disease. Some studies have shown the presence of antibodies against the cytoplasm of neutrophils (ANCA) in the serum of more than 50% of patients, and the presence of anticatalase antibodies in 60% of patients. ANCAs induce leukocyte metabolic activation, that forms H2O2 and the anion superoxide O-2, which in turn impair components of both cell and cellular matrix. Catalase is mainly found in the liver; it is active in the "antioxidative defense system" against toxic O2 metabolites. Anticatalase antibodies are directed against an essential region of catalases, by inhibiting their enzymatic functions. In these conditions, a state of oxidative stress is determined by imbalanced ratio of oxidative to antioxidative factors, due to effective production of radical species as well as to simultaneous failure of antiradical defenses. Radical stress results in irreversible impairment of tissues. In PSC, primary lesions seem to be secondary to the production of radicals by ANCAs, deposited immunocomplex, complementary proteins and bacterial toxins. The subsequent lysis of bile epithelial cells seems to release catalases, that are thought to act as "nonself" once recognized by the immunocompetent system. Since the neoantigen catalase seems to be highly expressed in PSC patients, it may easily associate itself with MHC molecules for presentation to the immune system. Thus, in turn, B lymphocytes would be forced to produce anticatalase antibodies. Since anticatalase antibodies inhibit catalases, it can be hypothesized that they play a role in the pathogenesis of PSC. From a therapeutic viewpoint, the only effective cure is transplantation.