Obesity has become a worldwide pandemic, mainly attributed to sedentary life style and calorie over consumption, which creates a major health burden. It has also known to increase the risk of various illnesses such as type 2 diabetes, coronary heart disease, some cancers and nonalcoholic fatty liver disease (NAFLD). This results subsequently in the consumption of more drugs, on average in obese individuals as compared to non-obese individuals, which in turn give rise to another major issue, in particular for hepatologists, as many drugs have the potential to induce liver injury. Several studies also corroborated these findings, suggesting obesity and NAFLD can increase the risk of drug-induced liver injury (DILI). 

This drug-induced hepatotoxicity in obese patients with NAFLD could occur as two distinct clinical settings, some drugs can worsen pre-existing NAFLD while others could induce an acute hepatitis. Drugs that can deteriorate NAFLD in obese patients include tamoxifen, irinotecan, methotrexate and nucleoside reverse transcriptase inhibitors (NRTIs) such as stavudine and didanosine. Drugs that can cause acute liver injury more frequently in obese individuals are the volatile halogenated anesthetic halothane and isoflurane, acetaminophen (APAP), and other drugs such as losartan, ticlopidine and omeprazole. 

Several potential mechanisms are implicated by which drugs can become more hepatotoxic in obese individuals. Certain can trigger lipogenesis in steatotic or fatty liver, by activating lipogenic transcription factors such as peroxisome proliferator-activated receptor-c (PPARc) (e.g. rosiglitazone), pregnane X receptor (e.g. tamoxifen) and carbohydrate response element-binding protein (e.g. pentoxifylline). Additionally, few drugs are known to impair mitochondrial function, leading to increased oxidation, which in turn can aggravate fatty liver. Increased fatty acid oxidation during

NAFLD is a key adaptive mechanism in inhibiting fat accretion, and any alteration to this adaptation can remarkably exacerbate fatty liver. Besides, researches also suggest that several drugs interfere with VLDL synthesis by obstructing microsomal triglyceride transfer protein (MTP) activity (e.g. amiodarone, tianeptine) or apolipoprotein B-100 synthesis (e.g. mipomersen). Furthermore, numerous drugs can cause progression of NAFLD into non-alcoholic steatohepatitis (NASH), attributed to the induced oxidative stress. This in turn, can generate glutathione (GSH) depletion and inhibition of the mitochondrial respiratory chain (MRC) that can accelerate the progression of fatty liver to NASH.

Source: Fromenty B. Drug-induced liver injury in obesity. Journal of Hepatology. 2013; 58: 824–826.