Department of Clinical Laboratory, Yantai Yuhuangding Hospital, Yantai, Shandong, China.
School of life science, Jilin University, Changchun, Jilin, China.
Clin Toxicol (Phila). 2024 Feb;62(2):101-106. doi: 10.1080/15563650.2024.2316144. Epub 2024 Mar 4.
Valproic acid has been widely used as an antiepileptic drug for several decades. Long-term valproic acid treatment is usually accompanied by liver injury. Although both men and women are susceptible to valproic acid-associated liver injury, hepatotoxicity differs between the sexes. However, the mechanisms underlying sex differences in valproic acid-associated liver injury remain unclear.
To explore potential risk factors for the susceptibility to valproic acid-associated liver injury, 231 pediatric patients with epilepsy (119 males, 112 females) were enrolled for laboratory and genetic analysis.
Heterozygous genotype of C-262T ( = 0.045) and the concentrations of glutathione ( = 0.002) and thiobarbituric acid-reactive substances ( = 0.011) were associated with the sex-specific susceptibility to valproic acid-associated liver injury. Meanwhile, logistic regression analysis revealed that carriers of heterozygous genotype of C-262T ( = 0.010, odds ratio: 4.163; 95 percent confidence interval 1.400 - 7.378), glutathione concentration ( = 0.001, odds ratio: 2.421; 95 percent confidence interval 2.262 - 2.591) and male patients ( = 0.005, odds ratio: 1.344; 95% confidence interval 0.782 - 2.309) had a higher risk for valproic acid-associated liver injury.
The mechanism underlying valproic acid-induced hepatotoxicity remains unclear. Additionally, factors that may contribute to the observed differences in the incidence of hepatotoxicity between males and females have yet to be defined. This study identifies several genetic factors that may predispose patients to valproic acid-associated hepatotoxicity.
This relatively small sample size of children with one ethnicity some of whom were taking other antiepileptics that are potentially hepatotoxic.
C-262T genotype, glutathione concentration and gender (male) are potential risk factors for the susceptibility to valproic acid-associated liver injury.
丙戊酸作为一种抗癫痫药物已被广泛应用数十年。长期丙戊酸治疗通常伴随着肝损伤。虽然男性和女性都易患丙戊酸相关性肝损伤，但性别之间的肝毒性存在差异。然而，丙戊酸相关性肝损伤性别差异的机制尚不清楚。
为了探讨易患丙戊酸相关性肝损伤的潜在危险因素，纳入了 231 名癫痫患儿（男 119 例，女 112 例）进行实验室和基因分析。
C-262T（ = 0.045）杂合基因型和谷胱甘肽（ = 0.002）及硫代巴比妥酸反应物质（ = 0.011）浓度与丙戊酸相关性肝损伤的性别特异性易感性相关。同时，logistic 回归分析显示，C-262T（ = 0.010，比值比：4.163；95%置信区间 1.400 - 7.378）杂合基因型、谷胱甘肽浓度（ = 0.001，比值比：2.421；95%置信区间 2.262 - 2.591）和男性患者（ = 0.005，比值比：1.344；95%置信区间 0.782 - 2.309）发生丙戊酸相关性肝损伤的风险更高。
丙戊酸诱导肝毒性的机制尚不清楚。此外，导致男性和女性肝毒性发生率差异的因素尚未确定。本研究确定了一些可能使患者易患丙戊酸相关性肝毒性的遗传因素。
本研究的样本量相对较小，仅包括一个种族的儿童，其中一些儿童还服用其他可能具有肝毒性的抗癫痫药物。
C-262T 基因型、谷胱甘肽浓度和性别（男性）是易患丙戊酸相关性肝损伤的潜在危险因素。
