丙戊酸诱发癫痫患儿高血氨的影响因素研究

Influencing factors of hyperammonemia in epileptic children treated with volproic acid

目的:研究影响丙戊酸诱发高血氨的遗传及非遗传因素。方法:将260例服用丙戊酸的癫痫患儿(年龄<16岁)按血氨水平分为高血氨组130例、对照组130例。记录各组患儿人口学信息(包括性别、身高、体质量、年龄)、肝功能指标和用药信息(日剂量、合并用药等),同时测定相关代谢酶CYP2C9,UGT1A6,UGT2B7,UGT1A4,转录因子AhR及尿素循环酶CPS1基因多态性,通过多因素Logistic回归分析遗传及非遗传因素对丙戊酸诱发高血氨的影响。结果:高血氨组肝功能指标GGT、丙戊酸的剂量、合并托吡酯的比例及合并服用其他抗癫痫药的数量均明显高于对照组。2组间CPS1,AhR和UGT2B7的基因型分布存在差异。CPS1 rs1047891 CA和AA型(P<0.001)以及AhR rs2066853 AG和AA型(P<0.001)是丙戊酸导致血氨升高的危险因素。结论:丙戊酸诱发的高血氨与多种遗传和非遗传风险因素相关,在癫痫儿童应用丙戊酸进行治疗时,建议定期监测体内血氨浓度,避免高血氨的发生。

OBJECTIVE To explore the genetic and non-genetic factors influencing hyperammonemia in epileptic children(age<16 years)treated with valproic acid(VPA).METHODS A total of 260 cases of epileptic children taking VPA were divided into hyperammonemia group(n=130)and control group(n=130)based upon ammonia level.Demographic profiles(gender,height,weight&age),liver function parameters and medication information(daily dosage,drug combination,etc)were recorded.The candidate gene polymorphism of related metabolic enzymes CYP2C9,UGT1A6,UGT2B7,UGT1A4,transcription factor AhR,urea cycle enzyme CPS1 were determined.And the effects of the above factors on VPA inducing hyperammonemia were analyzed by multivariate Logistic regression.RESULTS The level of liver function parameter gamma-glutamyltransferase(GGT),the dose of VPA,the proportion of topiramate and the number of other antiepileptic agents were significantly higher in hyperammonemia group than those in control group.The genotypic distribution of CPS1,AhR and UGT2B7 was different between two groups.CPS1 rs1047891 CA/AA(P<0.001)and AhR rs2066853 AG/AA(P<0.001)were potential risk factors for hyperammonemia induced by VPA.CONCLUSION Hyperammonemia induced by VPA is associated with a variety of genetic and non-genetic risk factors.Regular monitoring of blood ammonia concentration is recommended for preventing the occurrence of hyperammonemia in epileptic children.