Chronic cholestatic diseases

Chronic cholestatic diseases, whether occurring in infancy, childhood or adulthood, are characterized by defective bile acid transport from the liver to the intestine, which is caused by primary damage to the biliary epithelium in most cases. In this article, approaches to diagnosis and management of the main specific disorders are provided and some of the recent developments in this field are discussed. Major advances in the understanding of the cellular and molecular physiology of bile secretion have led to identification of genetic defects responsible for the different types of progressive familial intrahepatic cholestasis (PFIC). The potential role of the genes involved in PFIC in some adult cholestatic disorders remains to be determined. The majority of adult patients with chronic cholestasis have primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). Recently, variant forms of PBC have been described. The term autoimmune cholangitis is used to describe patients having chronic non-suppurative cholangitis with negative antimitochondrial antibodies (AMA) but positive antinuclear and/or antismooth muscle antibodies. Autoimmune cholangitis and AMA-positive PBC are quite similar in terms of clinical presentation, survival and response to ursodeoxycholic acid (UDCA) therapy. In contrast, autoimmune cholangitis must be distinguished from PBC-autoimmune hepatitis (AIH) overlap syndrome in which biochemical and histological characteristics of both PBC and AIH coexist. Combination of UDCA and corticosteroids is required in most patients with overlap syndrome to obtain a complete clinical and biochemical response. Long-term UDCA treatment improves survival without liver transplantation in PBC patients. Among the putative mechanisms of the beneficial effects of UDCA, description of anti-apoptotic properties and effect on endotoxin disposal in biliary cells have provided new insights. In patients with incomplete response to UDCA, combination of UDCA with antiinflammatory or immunosuppressive drugs is under evaluation. Variant forms of PSC have also been described, including PSC-AIH overlap syndrome, especially in children or young adults, and small-duct PSC, which is characterized by normal cholangiogram in patients having chronic cholestasis, histologic features compatible with PSC and inflammatory bowel disease. Development of cholangiocarcinoma (CC) is a major feature of PSC, occurring in 10-15% of patients. Early diagnosis of CC is a difficult challenge, although positron emission tomography seems a promising tool. Unlike PBC, effective medical therapy is not yet available in PSC, reflecting the lack of knowledge about the exact pathogenesis of the disease. Currently, liver transplantation is the only effective therapy for patients with advanced disease, although recurrence of PSC in the graft may occur.