Fernando Bessone1, Melisa Dirchwolf2, María Agustina Rodil1, María Valeria Razori3, Marcelo G Roma3. 1. Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina. 2. Unidad de Transplante Hepático, Servicio de Hepatología, Hospital Privado de Rosario, Rosario, Argentina. 3. Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
Abstract
BACKGROUND: Nonalcoholic fatty disease (NAFLD) is the most common liver disease, since it is strongly associated with obesity and metabolic syndrome pandemics. NAFLD may affect drug disposal and has common pathophysiological mechanisms with drug-induced liver injury (DILI); this may predispose to hepatoxicity induced by certain drugs that share these pathophysiological mechanisms. In addition, drugs may trigger fatty liver and inflammation per se by mimicking NAFLD pathophysiological mechanisms. AIMS: To provide a comprehensive update on (a) potential mechanisms whereby certain drugs can be more hepatotoxic in NAFLD patients, (b) the steatogenic effects of drugs, and (c) the mechanism involved in drug-induced steatohepatitis (DISH). METHODS: A language- and date-unrestricted Medline literature search was conducted to identify pertinent basic and clinical studies on the topic. RESULTS: Drugs can induce macrovesicular steatosis by mimicking NAFLD pathogenic factors, including insulin resistance and imbalance between fat gain and loss. Other forms of hepatic fat accumulation exist, such as microvesicular steatosis and phospholipidosis, and are mostly associated with acute mitochondrial dysfunction and defective lipophagy, respectively. Drug-induced mitochondrial dysfunction is also commonly involved in DISH. Patients with pre-existing NAFLD may be at higher risk of DILI induced by certain drugs, and polypharmacy in obese individuals to treat their comorbidities may be a contributing factor. CONCLUSIONS: The relationship between DILI and NAFLD may be reciprocal: drugs can cause NAFLD by acting as steatogenic factors, and pre-existing NAFLD could be a predisposing condition for certain drugs to cause DILI. Polypharmacy associated with obesity might potentiate the association between this condition and DILI.
BACKGROUND:Nonalcoholic fatty disease (NAFLD) is the most common liver disease, since it is strongly associated with obesity and metabolic syndrome pandemics. NAFLD may affect drug disposal and has common pathophysiological mechanisms with drug-induced liver injury (DILI); this may predispose to hepatoxicity induced by certain drugs that share these pathophysiological mechanisms. In addition, drugs may trigger fatty liver and inflammation per se by mimicking NAFLD pathophysiological mechanisms. AIMS: To provide a comprehensive update on (a) potential mechanisms whereby certain drugs can be more hepatotoxic in NAFLD patients, (b) the steatogenic effects of drugs, and (c) the mechanism involved in drug-induced steatohepatitis (DISH). METHODS: A language- and date-unrestricted Medline literature search was conducted to identify pertinent basic and clinical studies on the topic. RESULTS: Drugs can induce macrovesicular steatosis by mimicking NAFLD pathogenic factors, including insulin resistance and imbalance between fat gain and loss. Other forms of hepatic fat accumulation exist, such as microvesicular steatosis and phospholipidosis, and are mostly associated with acute mitochondrial dysfunction and defective lipophagy, respectively. Drug-induced mitochondrial dysfunction is also commonly involved in DISH. Patients with pre-existing NAFLD may be at higher risk of DILI induced by certain drugs, and polypharmacy in obese individuals to treat their comorbidities may be a contributing factor. CONCLUSIONS: The relationship between DILI and NAFLD may be reciprocal: drugs can cause NAFLD by acting as steatogenic factors, and pre-existing NAFLD could be a predisposing condition for certain drugs to cause DILI. Polypharmacy associated with obesity might potentiate the association between this condition and DILI.
Authors: Robin H Isaacson; Juliane I Beier; Nicholas Kh Khoo; Bruce A Freeman; Zachary Freyberg; Gavin E Arteel Journal: J Nutr Biochem Date: 2020-04-08 Impact factor: 6.048
Authors: Dahea You; Lascelles E Lyn-Cook; Daniel M Gatti; Natalie Bell; Philip R Mayeux; Laura P James; William B Mattes; Gary J Larson; Alison H Harrill Journal: Toxicol Sci Date: 2020-06-01 Impact factor: 4.849