药物性胆汁淤积发生机制与防治研究进展

Mechanism, prevention, and treatment of drug-induced cholestasis

药物性胆汁淤积(drug-induced cholestasis,DIC)是指由各类处方或非处方的化学药物,生物制剂,传统中药,天然药及其代谢产物等所引发的胆汁分泌或排泄障碍而导致胆酸在肝组织或循环系统内的蓄积.近年来,随着人口老龄化与临床用药种类及联合用药的比例增加,作为药物性肝损伤(drug-induced liver injury,DILI)常见表现形式的DIC的发病率逐年上升,已引起包括临床药师在内的医务工作者的广泛关注.DIC所致的肝损伤是一个复杂的过程,主要被两类生物反应所触发:胆酸蓄积所导致的损害性反应,以及机体旨在清除蓄积胆酸的适应性反应.DIC涉及的机制涉及转运蛋白,肝细胞,胆小管等功能或微观结构的改变.DIC目前仍然缺乏特效的治疗方法,发现可疑导致DIC药物时,及时停用,根据DIC的临床症状选用合适的药物缓解,极少数进展至肝衰竭的重症患者者可考虑肝移植以挽救生命.对DIC发生机制的准确理解有助于新药开发与上市后体内DILI预测与预警模型的优化,推动防治方案的完善与相关干预药物的研发.本文综述DIC的病理发生机制与防治研究进展,以期为DIC后续的深入研究提供参考.

Drug-induced cholestasis(DIC)refers to the accumulation of bile acid in the liver or systemic circulation due to the obstruction of intrahepatic and extrahepatic bile flow caused by various prescription or non-prescription chemicals,biological agents,traditional Chinese medicines,natural drugs,and their metabolites.In recent years,the incidence of DIC,a common manifestation of drug-induced liver injury(DILI),has been increasing with the aging of the population,the increase of the variety of clinical medications,and the more common use of combined drugs.Therefore,DIC has attracted wide attention from medical professionals,including clinical pharmacists.Hepatic injury induced by DIC is a complex process,which is triggered by two types of biological reactions:the deteriorative response,caused by bile acid accumulation,and the adaptive response aiming at removing the accumulated bile acids.Current studies have shown that several factors can trigger DIC,including changes of functions or microstructures of membrane transporters,hepatocytes,and bile ducts.There is still a lack of specific effective treatment for DIC.Timely withdrawal of suspected liver-injuring drugs is the most important strategy for DIC,and appropriate drugs should be then chosen to relieve the condition based on the clinical type of DIC and symptoms such as itching.For very few patients with severe liver failure,liver transplantation should be considered to save their lives.As such,in-depth knowledge of the mechanism of DIC can help to optimize the prediction and pharmacovigillance model of DILI in vivo during drug development and afterwards marketing,and promote the improvement of prevention and treatment strategies and the development of related interventions.This article reviews the progress in the understanding of the pathogenesis,prevention,and treatment of DIC,with an aim to provide reference for further studies.