Primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disorder of the biliary system that results in progressive fibrosis and strictures of the intrahepatic and extrahepatic bile ducts. Typical radiological changes on retrograde cholangiography are shown in Figure 1. These strictures cause cholestatic liver disease that may progress to end-stage cirrhosis. The disorder has a strong association with inflammatory bowel disease, particularly ulcerative colitis. Although only 5% of patients with ulcerative colitis develop PSC, at least 70% of patients with PSC will either have inflammatory bowel disease or will subsequently develop inflammatory bowel disease. However, despite these associations, the development and outcome of PSC appears to be independent of the activity of colitis and may even occur after proctocolectomy. Although there are equal numbers of men and women with ulcerative colitis, primary sclerosing cholangitis appears to be more common in men (70%). The pathogenesis of PSC continues to be unclear. There is only limited support for hypotheses that attribute biliary inflammation to portal bacteremia, toxic bile acids, biliary infections and ischemic damage. More recently, most of the attention has focussed on disorders of immune regulation that may be common to both PSC and ulcerative colitis. In PSC, markers of altered immunity include elevated serum levels of IgM and the presence in serum of smooth muscle antibodies, antinuclear antibodies and antineutrophil cytoplasmic antibodies (p-ANCA). The latter appear to be directed against a nuclear envelope protein and can be detected in 80–100% of patients with PSC. However, it can also be detected in unaffected family members with PSC as well as patients with ulcerative colitis and other chronic inflammatory disorders. One interesting possibility is that PSC is mediated by long-lived memory T cells that were originally activated in the gut. Recruitment to the liver may be mediated by aberrant expression of chemokines and adhesion molecules on endothelial cells with the subsequent development of biliary inflammation. There is only limited information on susceptibility genes for PSC. No twin studies have been reported. In family studies, one report indicates that the prevalence of PSC in siblings and firstdegree relatives is low at 1.5% and 0.7%, respectively. There are similar risks for inflammatory bowel disease in first-degree relatives of patients with ulcerative colitis. In relation to HLA antigens, patients with PSC have a higher than expected frequency of HLA-B8 and -DR3 and perhaps -DR52a. However, these associations are not specific for PSC since similar associations have been observed in other autoimmune diseases including autoimmune hepatitis. There is also the possibility that accelerated progression of PSC is associated with the heterozygous genotype corresponding to HLA-DR3, -DQ2. Other polymorphisms that have been reported to influence susceptibility to PSC involve the tumor necrosis factor–alpha gene (TNFA), the major histocompatibility class 1 chain-related gene family (MIC), the stromelysin gene (MMP) and the intercellular adhesion molecule -1 gene (ICAM-1). Two of these genes, TNFA and MIC, map closely to the HLA region on chromosome 6. However, corroborative studies are required before these non-HLA genotypes are accepted as established susceptibility genes for PSC.