Primary Sclerosing Cholangitis

Primary sclerosing cholangitis is a chronic liver disease of unknown etiology, whose features suggest an autoimmune pathogenesis, characterized by irregular damage to the extrahepatic and/or medium to large intrahepatic bile ducts &. Association with chronic inflammatory bowel disease or other disorders is common, and the risk of malignant transformation is high &. In children, the disorder often resembles autoimmune hepatitis &. The onset is typically marked by hepatomegaly and cholestasis without icterus; fifty per cent of the patients have normal serum alkaline phosphatase, whereas gamma-glutamyltranspeptidase levels are 5- to 10-fold above the upper normal limits. Isolated splenomegaly and signs of portal hypertension without other symptoms are less common. Hypergammaglobulinemia and positivity for antinuclear (ANA) or anti-smooth muscle (ASMA) autoantibodies, with normal C3 and C4 levels, are frequently observed.
Secondary sclerosing cholangitis may occur with other diseases, such as Langerhans’ cell histiocytosis,  immune deficiencies, and infections. The mechanism of bile duct lesions in Langerhans’ cell histiocytosis is unknown, but it is likely to reflect periductal fibrosis following infiltration of the portal tracts by histiocytes.
Both primary and acquired immune deficiencies may associate with sclerosing cholangitis. Interestingly, these conditions share defective expression of CD40 ligand, an activation-dependent, T-cell surface molecule, that plays a key role in protecting against intracellular pathogens. Indeed, infection of the bile ducts epithelium by cytomegalovirus, cryptosporidium, or microsporidium has been considered to be crucial in determining the  biliary lesions &.
Sclerosing cholangitis with neonatal onset (10% of all cases) is characterized by cholestatic jaundice during the first 3-6 months of age, that resolve spontaneously but tend to relapse after 2-10 years, with recurrent episodes of jaundice and/or hepatosplenomegaly; high levels of serum alkaline phosphatase and gamma glutamiltranspeptidase. 
Diagnosis of sclerosing cholangitis is based upon clinical, biochemical and histological observations $. Treatment, including chemotherapy (as for cases associated with Langherans’ cell histiocytosis) and immune suppression (autoimmune sclerosing cholangitis), is usually not effective. Improvement may be achieved with high doses of ursodeoxycholic acid &. There are no reliable prognostic indicators, but multivariate statistical survival models may be of help in identifying patients at high risk of dying &. Liver transplantation is usually required, and combined liver and bone marrow transplantation may be needed in patients with primary immune deficiency &.