Association between serum trace element concentrations and valproic acid-induced hepatotoxicity in pediatric patients with epilepsy

Valproic acid (VPA), a commonly used antiepileptic drug, may cause hepatotoxicity during its clinical use. However, the mechanisms underlying VPA-associated hepatotoxicity remain unclear. In this study, 137 age-matched epileptic patients receiving long-term VPA treatment were enrolled, and the blood samples were collected for liver function, trace element concentrations and oxidative stress tests. The results revealed that patients with VPA-induced hepatotoxicity had higher concentrations of iron (Fe, P ? 0.001), and lower concentrations of cobalt (Co) and selenium (Se) than those in the control group (P = 0.036 and P ? 0.001, respectively). In addition, multiple regression analysis indicated that the Fe concentration was positively associated with transferase activities and oxidative stress parameters (glutathione and thiobarbituric acid-reactive substances, P ? 0.05), while the concentrations of Co and Se were negatively correlated with transferase activities and oxidative stress parameters (P ? 0.05). Moreover, logistic regression analysis indicated that the Fe concentration was correlated with a greater risk for hepatotoxicity (P = 0.001, OR: 2.387), whereas the concentrations of Co (P = 0.038, OR: 0.889) and Se (P = 0.001, OR: 0.813) were negatively correlated with VPA-associated hepatotoxicity. These results clarified that certain trace elements (Fe, Co and Se) may contribute to the pathogenesis of VPA-associated hepatotoxicity via the oxidative stress pathway.