Published online Apr 7, 2018. doi: 10.3748/wjg.v24.i13.1373
Peer-review started: January 28, 2018
First decision: February 10, 2018
Revised: February 16, 2018
Accepted: February 26, 2018
Article in press: February 26, 2018
Published online: April 7, 2018
Drug-induced liver injury (DILI) has become a major topic in the field of Hepatology and Gastroenterology. DILI can be clinically divided into three phenotypes: hepatocytic, cholestatic and mixed. Although the clinical manifestations of DILI are variable and the pathogenesis complicated, recent insights using improved preclinical models, have allowed a better understanding of the mechanisms that trigger liver damage. In this review, we will discuss the pathophysiological mechanisms underlying DILI. The toxicity of the drug eventually induces hepatocellular damage through multiple molecular pathways, including direct hepatic toxicity and innate and adaptive immune responses. Drugs or their metabolites, such as the common analgesic, acetaminophen, can cause direct hepatic toxicity through accumulation of reactive oxygen species and mitochondrial dysfunction. The innate and adaptive immune responses play also a very important role in the occurrence of idiosyncratic DILI. Furthermore, we examine common forms of hepatocyte death and their association with the activation of specific signaling pathways.
Core tip: Drug-induced liver injury (DILI) represents a broad spectrum of clinical manifestations, and is generally divided into two subtypes: intrinsic and idiosyncratic hepatotoxicity. Drugs and their reactive metabolites covalently bind to mitochondria and cause direct hepatic toxicity through accumulation of oxidative stress (ROS and RNS), endoplasmic reticulum stress and mitochondrial dysfunction, ultimately leading to cell death. The innate and adaptive immune responses also play an important role in the occurrence of idiosyncratic immunological reactions towards the drugs. In this review, we discuss the pathophysiological mechanisms underlying DILI, specific signaling pathways and the common forms of hepatocyte death.