ABSTRACT
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 β-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.
KEYWORDS
Nonalcoholic steatohepatitis - insulin resistance syndrome - drugs - perhexiline maleate
- amiodarone - tamoxifen - estrogens - corticosteroids - methotrexate - calcium channel
blockers - industrial hepatotoxicity - hepatic fibrosis
