Drug-Induced Cholangiopathies

Since it plays a central role in the metabolism of xenobiotics, including drugs, the liver is one of the main targets of drug toxicity, often due to active metabolites. Liver toxicity is a challenging issue and a frequent cause of failure during drug development. In particular, drug-induced bile duct injury is a side effect of several drugs and dietary supplements, that can be either easy to manage and characterized by a good outcome, or mostly unpredictable, difficult to treat, and even potentially fatal. In fact, drug-induced bile duct injury could display a wide range of pathological features, ranging from asymptomatic patients that exhibit only isolated elevations in biochemical markers and mild bile duct disorder or “ductopenia,” to progressive forms of vanishing bile duct syndrome. In the majority of patients, drug-induced bile duct injury affects the biliary epithelium of interlobular ducts, as happens in other cholangiopathies, such as primary biliary cholangitis or small duct primary sclerosing cholangitis. A precise characterization of the molecular pathophysiological mechanisms of drug-induced cholangiopathies, and the gene profiling of susceptible patients may help the prediction of biliary drug-induced liver injury still during the preclinical phase of drug development, leading to the identification of subsets of patients who are at risk of this adverse drug reaction, which remains difficult to treat and with an uncertain outcome.