Shi Qiang, Yang Xi, Greenhaw James J, Salminen Alec Thomas, Russotti Gary M, Salminen William F
1 Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, USA.
2 Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA.
Int J Toxicol. 2017 Sep/Oct;36(5):365-379. doi: 10.1177/1091581817721675. Epub 2017 Aug 18.
Drug-induced liver injury in children (cDILI) accounts for about 1% of all reported adverse drug reactions throughout all age groups, less than 10% of all clinical DILI cases, and around 20% of all acute liver failure cases in children. The overall DILI susceptibility in children has been assumed to be lower than in adults. Nevertheless, controversial evidence is emerging about children's sensitivity to DILI, with children's relative susceptibility to DILI appearing to be highly drug-specific. The culprit drugs in cDILI are similar but not identical to DILI in adults (aDILI). This is demonstrated by recent findings that a drug frequently associated with aDILI (amoxicillin/clavulanate) was rarely associated with cDILI and that the drug basiliximab caused only cDILI but not aDILI. The fatality in reported cDILI studies ranged from 4% to 31%. According to the US Food and Drug Administration-approved drugs labels, valproic acid, dactinomycin, and ampicillin appear more likely to cause cDILI. In contrast, deferasirox, isoniazid, dantrolene, and levofloxacin appear more likely to cause aDILI. Animal models have been explored to mimic children's increased susceptibility to valproic acid hepatotoxicity or decreased susceptibility to acetaminophen or halothane hepatotoxicity. However, for most drugs, animal models are not readily available, and the underlying mechanisms for the differential reactions to DILI between children and adults remain highly hypothetical. Diagnosis tools for cDILI are not yet available. A critical need exists to fill the knowledge gaps in cDILI. This review article provides an overview of cDILI and specific drugs associated with cDILI.
儿童药物性肝损伤（cDILI）约占各年龄组报告的所有药物不良反应的1%，占所有临床药物性肝损伤病例的不到10%，占儿童所有急性肝衰竭病例的约20%。儿童对药物性肝损伤的总体易感性被认为低于成人。然而，关于儿童对药物性肝损伤的敏感性，有争议的证据正在出现，儿童对药物性肝损伤的相对易感性似乎具有高度药物特异性。cDILI中的罪魁祸首药物与成人药物性肝损伤（aDILI）中的药物相似但不完全相同。最近的研究结果表明，一种经常与aDILI相关的药物（阿莫西林/克拉维酸）很少与cDILI相关，而巴利昔单抗仅导致cDILI而非aDILI，这证明了这一点。报告的cDILI研究中的死亡率在4%至31%之间。根据美国食品药品监督管理局批准的药物标签，丙戊酸、放线菌素和氨苄西林似乎更有可能导致cDILI。相比之下，地拉罗司、异烟肼、丹曲林和左氧氟沙星似乎更有可能导致aDILI。已经探索了动物模型来模拟儿童对丙戊酸肝毒性易感性增加或对乙酰氨基酚或氟烷肝毒性易感性降低的情况。然而，对于大多数药物来说，动物模型并不容易获得，儿童和成人对药物性肝损伤反应差异的潜在机制仍然高度假设性。cDILI的诊断工具尚不存在。填补cDILI知识空白的迫切需求存在。这篇综述文章概述了cDILI以及与cDILI相关的特定药物。
