Drug-induced cholestasis

Abstract

Recent progress in understanding the molecular mechanisms of bile formation and cholestasis have led to new insights into the pathogenesis of drug-induced cholestasis. This review summarizes their variable clinical presentations, examines the role of transport proteins in hepatic drug clearance and toxicity, and addresses the increasing importance of genetic determinants, as well as practical aspects of diagnosis and management.

Fig 1

Hepatocyte couplet illustrating location of major transporters that determine bile production and hepatic drug transport. The major drug transporters are indicated in red. ATP dependent transporters are the dark circles. See Table 4 for their definition and function. (Na⁺ = sodium; BA^- = bile acid; OA^- = organic anion; OC⁺ = organic cation; PC= phosphatidylcholine; BA-G = bile acid glucuronides; BA-S = bile acid sulfates);GSH = glutathione;

Fig 2

Drug induced cholestasis from interaction of cyclosporine and verapamil in a 46 y WM 5 days post Liver transplant. Note rise in alkaline phosphatase (AP),alanine aminotransferase (ALT) and plasma cyclosposrin levels (CSA) during simultaneous administration of verapamil and cyclosporine, two MDR1 substrates. Drug induced cholestasis resolved quickly after discontinuing the verapamil.