基于文献回顾分析癫痫患者使用丙戊酸致肝毒性的特点及影响因素

Literature review of valproic acid-induced hepatotoxicity in patients with epilepsy

目的探讨癫痫患者使用丙戊酸致肝毒性的特点、风险因素及临床转归,为临床丙戊酸安全用药提供参考。方法通过检索中英文数据库收集丙戊酸致肝毒性病例,提取患者年龄、性别、丙戊酸日剂量、发生肝毒性的用药时间、血药浓度、生化指标、临床表现、合并用药、处置与转归等信息并进行统计分析。结果共纳入文献34篇,涉及病例数41例。男性和女性患者例数相当(1∶1.05),以儿童患者居多(共28例,占68.29%)。丙戊酸单独用药21例,合并用药20例,以合并其他抗癫痫药物为主。肝毒性最早出现在用药后4 d,最晚出现在用药后3年,30例患者在用药3个月内发生肝毒性,占73.17%。90%的患者在肝毒性初期症状表现为嗜睡、乏力、厌食、恶心、呕吐,进展至全身症状为发热、出血、黄疸、腹水。肝毒性的处置包括药物减量或停药、肉碱解救、保肝药物治疗、透析或肝移植。最终,29例患者经治疗后肝功能恢复正常,12例患者经对症治疗无效后死亡。结论丙戊酸致肝毒性与患者原患疾病、年龄、联合用药等相关;伴遗传代谢障碍的难治性癫痫、婴幼儿患者及联合其他抗癫痫药应用丙戊酸治疗时,肝毒性发生的风险将升高。临床应加强丙戊酸的用药监护,重点关注以上风险因素,提高丙戊酸的用药安全性。

Objective To determine the characteristics,risk factors and clinical outcomes of valproic acid-induced hepatotoxicity,and to provide references for the safe use of valproic acid.Methods We searched the Chinese and English databases for valproic acid-induced liver adverse reactions,patients’age,gender,daily dose of valproic acid,medication time for liver toxicity,blood drug concentration,biochemical indicators,clinical manifestations,medication combination and prognosis were analyzed.Results Totally of 34 studies were included,involving 41 patient cases.20 males and 21 females(1∶1.05),and 28(68.29%)were children.Valproic acid was used alone in 21 patient,in combanation use in antother 20 patient.Hepatotoxicity first appeared 4 days after the medication,and the latest appeared 3 years after the medication.Tatally 30(73.17%)patients developed liver toxicity within 3 months of medication.In 90%of the patients,initial symptoms of hepatotoxicity included drowsiness,fatigue,anorexia,nausea,and vomiting,and the systemic symptoms were fever,bleeding,jaundice,and ascites.Treatment of liver toxicity included drug reduction or discontinuation,carnitine rescue,hepatoprotective drug treatment,dialysis or liver transplantation.Tatally 29 patients regained to normal liver function after the treatment,but 12 patients died despite the symptomatic treatment Conclusion The liver toxicity caused by valproic acid is related to patients’original disease,age,and combination medication.For people with intractable epilepsy with genetic metabolic disorders,infants and young children,valproic acid in combination with other antiepileptic drugs,the risk of liver toxicity will increase.Clinical monitoring of valproic acid medication should be strengthened to improve the safe use of valproic acid.