Farrell Geoffrey C
Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW, Australia.
Semin Liver Dis. 2002;22(2):185-94. doi: 10.1055/s-2002-30106.
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.
除了通常与胰岛素抵抗、2型糖尿病、中心性肥胖和高甘油三酯血症相关外，非酒精性脂肪性肝炎（NASH）还与多种药物和毒素有关。然而，药物性肝病是脂肪性肝炎相对少见的病因。当这种关联似乎是由药物对肝脏的直接毒性作用导致时，使用“药物性脂肪性肝炎”这一术语更为合适。对于一些被认为可导致肝硬化或脂肪性肝病的药物，这种关联可能是巧合，因为NASH是胰岛素抵抗（或代谢）综合征的常见组成部分。在其他情况下，皮质类固醇、他莫昔芬和雌激素可能会通过加剧胰岛素抵抗、中心性肥胖、糖尿病和高甘油三酯血症，促使易感人群发生NASH，而甲氨蝶呤可能会使NASH患者的肝纤维化加重。药物性脂肪性肝炎与长期治疗（超过6个月）以及可能的药物蓄积有关，就马来酸哌克昔林而言，CYP2D6的基因多态性导致哌克昔林氧化缓慢，从而有利于药物蓄积。其毒性机制似乎涉及线粒体损伤，线粒体损伤会因脂肪酸β氧化受损而导致脂肪变性，并导致活性氧的产生和ATP耗竭。因此，药物性脂肪性肝炎可能为更常见的代谢型NASH中的损伤事件提供线索。某些类型的药物性脂肪性肝炎的一个临床特征是停用致病药物后病情仍会进展。因此，早期识别肝毒性对于预防更严重形式的肝病发展和改善临床结局至关重要。
