Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

Abstract

Background: Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD.

Aim: The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward.

Relevance for patients: Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening.

Keywords: DILI; NAFLD; acetaminophen; cytochrome P450; drug; halothane; hepatotoxicity; isoflurane; liver; methotrexate; mitochondria; obesity; pentoxifylline; rosiglitazone; stavudine; tamoxifen; toxicity.

Figure 1. Mechanisms whereby NASH could increase the susceptibility of drug-induced acute liver injury. NASH is associated with increased CYP2E1 expression and activity, reduced MRC activity and inflammation. These events lead to ROS overproduction, reduced ATP synthesis and increased production of pro-inflammatory cytokines such as TNFα, which can favor the occurrence of drug-induced acute liver injury.

Figure 2. Increased hepatotoxicity induced by acetaminophen and halothane in obesity and NAFLD. Obesity and NAFLD are associated with higher hepatic cytochrome P450 2E1 (CYP2E1) activity, which is responsible for a greater biotransformation of acetaminophen and halothane to the highly reactive metabolites N-acetyl-p-benzoquinone imine and trifluoroacetyl chloride, respectively. These reactive metabolites bind to glutathione (GSH) and key cellular targets, in particular at the mitochondrial level. These deleterious events induce mitochondrial dysfunction, reduced ATP synthesis and oxidative stress, thus triggering hepatic cytolysis.

Figure 3. Mechanisms whereby some drugs could aggravate fatty liver and promote its progression to NASH in obese patients. Drug-induced worsening of fatty liver could be secondary to reduced VLDL secretion, increased lipogenesis and impaired mitochondrial FAO. The progression of fatty liver to NASH could be triggered by lower ATP production, higher mitochondrial ROS production, ER stress and inflammation. Notably, drug-induced inhibition of MRC could be a common mechanism leading to impaired FAO, reduced ATP levels and higher ROS production.