Drugs and steatohepatitis.
In addition to the usual associations with insulin resistance, type 2 diabetes, central obesity, and hypertriglyceridemia, nonalcoholic steatohepatitis (NASH) has been associated with several drugs and toxins. However, drug-induced liver disease is a relatively uncommon cause of steatohepatitis. The term drug-induced steatohepatitis is preferred when the association appears to result from a direct toxic effect of the drug on the liver. For some agents implicated as causing cirrhosis or fatty liver disorders, the association may be coincidental because NASH is a common component of the insulin resistance (or metabolic) syndrome. In other instances, corticosteroids, tamoxifen, and estrogens may precipitate NASH in predisposed persons by exacerbating insulin resistance, central obesity, diabetes, and hypertriglyceridemia, and methotrexate may worsen hepatic fibrosis in NASH. Drug-induced steatohepatitis is associated with prolonged therapy (more than 6 months) and possibly drug accumulation, which in the case of perhexiline maleate is favored by a genetic polymorphism of CYP2D6 that leads to slow perhexiline oxidation. The toxic mechanism appears to involve mitochondrial injury, which causes steatosis because of impaired beta-oxidation of fatty acids, and leads to generation of reactive oxygen species and ATP depletion. Thus, drug-induced steatohepatitis may provide clues to injurious events in the more common metabolic forms of NASH. A clinical feature of some types of drug-induced steatohepatitis is progression after discontinuation of the causative agent. It follows that early recognition of hepatotoxicity is crucial to prevent the development of severer forms of liver disease and improve the clinical outcome.
Farrell
Geoffrey C
GC
Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW, Australia. geoff_farrell@wmi.usyd.edu.au
D000255:Adenosine Triphosphate / Q000378:metabolism; D000305:Adrenal Cortex Hormones / Q000009:adverse effects; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology*; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects / Q000494:pharmacology; D004967:Estrogens / Q000009:adverse effects; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced* / Q000503:physiopathology; D006801:Humans; D007333:Insulin Resistance; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D010084:Oxidation-Reduction; D011110:Polymorphism, Genetic; D017382:Reactive Oxygen Species; D013629:Tamoxifen / Q000009:adverse effects
D000305:Adrenal Cortex Hormones; D018931:Antineoplastic Agents, Hormonal; D004967:Estrogens; D005227:Fatty Acids; D017382:Reactive Oxygen Species; D013629:Tamoxifen; D000255:Adenosine Triphosphate; D019389:Cytochrome P-450 CYP2D6