Drug-induced cholestatic liver diseases

Cholestatic DILI is an important and frequently challenging differential diagnosis in patients presenting with elevated liver tests with predominant elevation in alkaline phosphatase. A number of competing etiologies need to be ruled out, such as hepatobiliary malignancy, choledocholithiasis, cholestatic forms of viral hepatitis, cholestasis of sepsis, primary and secondary cholangitis, and right-sided cardiac failure to name a few. Important advances have occurred in the understanding and knowledge of the clinical phenotypes, new etiological agents, risk factors, pathophysiology, and genetic determinants of drug-induced cholestasis since the last review on drug-induced cholestasis was published in Hepatology in 2011. Secondary sclerosing cholangitis (SSC) due to drugs has been well documented for several different drugs. Checkpoint inhibitors are one of the types of drugs shown to lead to secondary sclerosing cholangitis. Several new herbal and dietary supplements have recently been shown to lead to cholestatic liver injury. A number of genetic risk factors for cholestasis due to drugs have been identified in the last decade, and the pathogenesis behind cholestatic injury is better defined. In this review, the focus is on diagnostic approach and description of new clinical phenotypes such as secondary sclerosing cholangitis and vanishing bile duct syndrome. Furthermore, the review provides an overview of the risk factors, genetic determinants, and the pathophysiology of hepatobiliary transporters leading to cholestasis. Management, areas of uncertainty, and future direction are also presented.