Sex differences in the susceptibility to valproic acid-associated liver injury in epileptic patients

Abstract

Background

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.

Methods

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.

Results

Heterozygous genotype of catalase C-262T (P = 0.045) and the concentrations of glutathione (P = 0.002) and thiobarbituric acid-reactive substances (P = 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 catalase C-262T (P = 0.010, odds ratio: 4.163; 95 percent confidence interval 1.400 − 7.378), glutathione concentration (P = 0.001, odds ratio: 2.421; 95 percent confidence interval 2.262 − 2.591) and male patients (P = 0.005, odds ratio: 1.344; 95% confidence interval 0.782 − 2.309) had a higher risk for valproic acid-associated liver injury.

Discussion

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.

Limitations

This relatively small sample size of children with one ethnicity some of whom were taking other antiepileptics that are potentially hepatotoxic.

Conclusion

Catalase C-262T genotype, glutathione concentration and gender (male) are potential risk factors for the susceptibility to valproic acid-associated liver injury.

Keywords:

• Valproic acid
• sex differences
• glutathione
• catalase C-262T
• liver injury

Acknowledgements

We are grateful to Dr. Jianlei Zhao from the Wayne State University, for revising this manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Additional information

Funding

This study was supported by the Natural Science Foundation of Shandong province grant (No. ZR2023QH039).