Drug-induced cholestasis

Abstract

Drugs may cause several overlapping syndromes of cholestasis, the pathophysiological syndrome resulting from impaired bile flow. These reactions comprise approximately 17% of all hepatic adverse drug reactions (ADRs) and they may be severe. Causes of 'pure' (bland) cholestasis include oestrogens and anabolic steroids; rarer associations are with antimicrobials and NSAIDs. 'Cholestatic hepatitis' is a common drug reaction in which liver injury and inflammation cause significant elevation of serum alanine aminotransferase (ALT) as well as cholestasis. Chlorpromazine and ketoconazole are classic examples, but it is now exemplified by amoxycillin-clavulanate and other oxy-penicillins. Chronic cholestasis results from small bile duct injury leading to the vanishing bile duct syndrome (VBDS), a disorder mimicking primary biliary cirrhosis, or from injury to larger bile ducts causing secondary sclerosing cholangitis. Whilst there is increasing evidence of a genetic predisposition to cholestatic drug reactions, there are currently no pretreatment tests to predict drug safety. Prevention of severe reactions therefore relies on early detection of liver injury and prompt drug withdrawal. Symptomatic management includes relief of pruritus and correction of fat-soluble vitamin deficiency. In small cohort studies, ursodeoxycholic acid (UDCA) arrested progressive cholestasis in two-thirds of cases, but evidence for use of corticosteroids is anecdotal. This review considers diagnosis, pathogenesis, prevention and management of drug-induced cholestasis, with particular reference to frequently- and newly-described causes.