Valproic Acid-Induced Liver Injury: A Case-Control Study from a Prospective Pharmacovigilance Program in a Tertiary Hospital

Abstract

Introduction: Valproic acid (VPA) is an antiepileptic drug extensively used for treating partial and generalised seizures, acute mania and as prophylaxis for bipolar disorder. Drug-induced liver injury (DILI) persists as a significant issue related to fatal outcomes by VPA. The aim of this study was to increase our knowledge about this condition and to better identify patients affected. Methods: We conducted an observational retrospective case-control study that identified cases of DILI by VPA from the Pharmacovigilance Programme from our Laboratory Signals at La Paz University Hospital from January 2007 to December 2019. From the Therapeutic VPA Monitoring program, two control groups were assigned, VPA-tolerant patients and the other with patients who developed mild VPA-related liver injury but who did not meet the DILI criteria, matched for date, age and sex. Results: A total of 60 patients were included in the study: 15 cases of DILI, 30 VPA-tolerant controls and 15 controls with mild liver injury. Mean age for the cases was 45.7 years, 4 (26.7%) were women and 5 (33.34%) were children under 18 years, of them 3 (20%) were fatal. Polytherapy with other antiepileptic drugs (p = 0.047) and alcohol consumption (p < 0.001) were associated with a greater risk of developing DILI by VPA. A diagnosis of epileptic seizure was more frequently related to DILI when compared with the VPA-tolerant controls (p < 0.001). The cases developed hepatocellular liver injury (p < 0.001), while the mild hepatic damage controls had a higher rate of cholestatic liver injury (p < 0.001). The laboratory lactate dehydrogenase values were statistically higher (even at baseline) in patients with DILI than in both control groups (p = 0.033 and p = 0.039). Conclusions: VPA hepatotoxicity remains a considerable problem. This study offers interesting findings for characterising VPA-induced liver injury and at-risk patients.

Valproic acid for children below 2 years of age with epilepsy

“…10,11 Reports of acute drug reaction and hepatotoxicity were more common below the age of two years. 12,13,14 In our study, no reported death related to VPA. Multiple studies showed the safety of valproic acid as monotherapy in younger patients and less side effects were reported.…”

A Physiologically-Based Pharmacokinetic Model for Cannabidiol in Healthy Adults, Hepatically-Impaired Adults, and Children

“…The widespread use of CBD raises concern for potential clinically significant CBD-drug interactions, especially because CBD (750 mg orally twice daily) can be hepatotoxic, as evidenced by elevated serum alanine aminotransferase (ALT) (Watkins et al, 2021). This ALT elevation is dose-dependent (10-20 mg/kg/day; Epidiolex® Package Insert) and is more pronounced in adult and pediatric patients who also take valproic acid, another hepatotoxin (Devinsky, Patel, Cross, et al, 2018;Meseguer et al, 2021). The United States Food and Drug Administration (FDA) recommends monitoring serum ALT and bilirubin before initiating Epidiolex® in patients taking valproic acid (Epidiolex® Package Insert).…”

Correlation between Level of Serum Transaminases and Duration of Antiepileptic Drugs in Epilepsy Children in Sanglah Hospital

“…Young children have prolonged elimination (17-40 h). Valproic acid is recommended to be initiated at dosages 15-20 mg/kg/day in children and titrated at weekly intervals by 5-10 mg/kg/day until seizures are controlled or adverse effects become intolerable [17], [18]. The maximum recommended dosage is 60 mg/kg/day; however, some children with refractory seizures may require higher dosages to achieve the desired degree of seizure control.…”