Julie N L, Julie I M, Kende A I, Wilson G L
Department of Pathology, Shady Grove Adventist Hospital, Rockville, MD, USA.
Diabetologia. 2008 Nov;51(11):2108-16. doi: 10.1007/s00125-008-1133-6. Epub 2008 Aug 23.
AIMS/HYPOTHESIS: Troglitazone was approved for treatment of type 2 diabetes mellitus, but by 2000 it had been removed from all world markets due to severe drug-induced liver injury. Even today, we still do not know how many patients sustained a long-term liver injury. No system is in place to acquire that knowledge. Regarding toxicity mechanisms, controversy persists as to which ones are class effects of thiazolidinediones (TZDs) and which are unique to troglitazone. This study aims to provide long-term outcome data and new insights on mechanisms of troglitazone-induced liver injury.
This case series reports the liver injuries sustained by eleven type 2 diabetic patients treated with troglitazone between 1997 and 2000. Exhaustive review of medical records was performed for all patients. Long-term outcomes were available for all the non-fatal cases. A comprehensive literature review was also performed.
Long-term liver injury progressing to cirrhosis was identified in seven patients. All eleven cases had liver injury patterns consistent with troglitazone toxicity. Analysis of these cases and of the experimental troglitazone toxicity data points to mitochondrial toxicity as a central factor. The general clinical patterns of mitochondrial hepatotoxic events are reviewed, as are the implications for other members of the TZD family.
CONCLUSIONS/INTERPRETATION: This analysis enables the liver injury induced by troglitazone to be better understood. In future cases of delayed drug-induced liver injury that progresses after discontinuation, the possibility of mitochondrial toxicity should be considered. When appropriate, this can then be evaluated experimentally. Such proactive investigation may anticipate clinical risk before a large-scale therapeutic misadventure occurs. Drug-induced liver injury due to mitochondrial hepatotoxins may be less unpredictable than has previously been surmised.
目的/假设：曲格列酮曾被批准用于治疗2型糖尿病，但到2000年，由于严重的药物性肝损伤，它已从全球所有市场撤下。即使在今天，我们仍然不知道有多少患者遭受了长期肝损伤。目前尚无获取这一信息的系统。关于毒性机制，噻唑烷二酮类（TZDs）的哪些毒性是类效应，哪些是曲格列酮所特有的，仍存在争议。本研究旨在提供曲格列酮所致肝损伤的长期结局数据，并对其机制提供新的见解。
本病例系列报告了1997年至2000年间接受曲格列酮治疗的11例2型糖尿病患者所遭受的肝损伤。对所有患者的病历进行了详尽审查。所有非致命病例均有长期结局数据。还进行了全面的文献综述。
7例患者出现了进展为肝硬化的长期肝损伤。所有11例病例的肝损伤模式均与曲格列酮毒性一致。对这些病例以及曲格列酮实验毒性数据的分析表明，线粒体毒性是一个核心因素。本文综述了线粒体肝毒性事件的一般临床模式，以及对TZDs家族其他成员的影响。
结论/解读：该分析有助于更好地理解曲格列酮所致的肝损伤。在未来出现停药后仍进展的迟发性药物性肝损伤病例中，应考虑线粒体毒性的可能性。在适当的时候，可以通过实验进行评估。这种前瞻性研究可能在大规模治疗失误发生之前预测临床风险。由线粒体肝毒素引起的药物性肝损伤可能比之前推测的更具可预测性。
