Dissecting the molecular pathophysiology of drug-induced liver injury

Abstract

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.

Clinical Characteristics of 162 Patients with Drug-Induced Liver and/or Kidney Injury

“…ere are more than 1,000 drugs known to cause liver injury. e pathogenesis of drug-induced liver injury can be summarized as follows [12]: (1) direct toxicity of the drug or metabolite for the liver or (2) a specific heterogeneous response [13]: mediated by the immune response or the metabolic response, including oxidative stress, mitochondrial damage [14], and the adaptive immune response.…”

Meropenem-induced liver injury and beta-lactam cross-reactivity

“…The mechanism of iDILI involves activation of both the innate and adaptive immune system, leading to hepatocyte death via apoptosis and necrosis 14. Notably, our patient exhibited greater peak levels of liver enzymes after the second exposure to meropenem, consistent with an adaptive immune response.…”

Clozapine‐induced hepatitis confirmed by rechallenge

“…For example, a lower level of drug-metabolising enzymes is a genetic risk factor. 13 Pertinent in this case is that South Asians have been reported as having lower levels of CYPA12. 14 This is the main metabolising enzyme for clozapine.…”