Hepatic adverse effects of valproic acid: what action to take?

Introduction: Valproic acid is an older-generation antiepileptic drug. It has been implicated in liver-related adverse effects. Methods: This is a retrospective study carried out by collecting non-cutaneous reactions linked to Antiepileptic drugs notified to the pharmacovigilance center of Sfax over 9 years. A pharmacovigilance survey was performed according to the French Begaud imputability method. The plasma determination was carried out by an immune-enzymatic method using an INDIKO device in the pharmacology laboratory of the Faculty of Medicine. Results: We collected 8 cases of hepatic cytolysis with varying severity: 1 case of moderately severe cytolysis (case 1), 1 case of fatal cytolysis (case 8) and 6 cases of benign cytolysis (case 2-7). We stopped the administration of this antiepileptic drug in cases 1, 2 and 8 in the face of high transaminase levels ≥ 5 times the upper limit of normal with a favorable outcome for cases 1 and 2 and fatal for case 8. A dosage was requested in the other cases. For cases 3, 4 and 5, the dosage result was within the therapeutic range with associated digestive intolerance. The approach was to avoid this antiepileptic drug with a good outcome. For cases 6 and 7, the result was close to the upper limit of normal, hence a reduction in the dose of valproic acid was recommended with good progress. Conclusion: The management of valproic acid-related hepatic cytolysis depends on their severity, the results of the plasma valproic acid assay and the results of the etiological assessment. Hepatic adverse effects of valproic acid: what action to take? Imen Bouaziz 1 (MD), Rim Atheymen 1 (MD), Rym Sahnoun 1 (MD), Kamilia Ksouda 1 (MD), Hanen Affes 1 (MD), Serria Hammami 1 (MD), Khaled Zghal 1 (MD) 1 : Regional Pharmacovigilance Service of Sfax, Pharmacology Laboratory, Faculty of Medicine of Sfax; 3029 Sfax, Tunisia. Corresponding author Imen Bouaziz Regional Pharmacovigilance Service of Sfax, Pharmacology Laboratory, Faculty of Medicine of Sfax; 3029 Sfax, Tunisia. E-mail : [email protected] What is already known about this subject: Valproic acid is a widely prescribed older-generation antiepileptic drug. It has been implicated in causing liver-related adverse effects. What this study adds: Our article could provide a better understanding of hepatic antiepileptic drugs under valproic acid with clear explanations of the therapeutic management according to the case. The data availability statement: The datasets analyzed during the current study are available from the corresponding author on reasonable request. Principal Investigator statement: ”The authors confirm that the Principal Investigator for this paper is Imen Bouaziz and she had direct clinical responsibility for patients.”

Valproic acid is an older-generation antiepileptic drug. It has been implicated in liver-related adverse effects.

This is a retrospective study carried out by collecting non-cutaneous reactions linked to Antiepileptic drugs notified to the pharmacovigilance center of Sfax over 9 years. A pharmacovigilance survey was performed according to the French Begaud imputability method. The plasma determination was carried out by an immune-enzymatic method using an INDIKO device in the pharmacology laboratory of the Faculty of Medicine.

We collected 8 cases of hepatic cytolysis with varying severity: 1 case of moderately severe cytolysis (case 1), 1 case of fatal cytolysis (case 8) and 6 cases of benign cytolysis (case 2-7). We stopped the administration of this antiepileptic drug in cases 1, 2 and 8 in the face of high transaminase levels ≥ 5 times the upper limit of normal with a favorable outcome for cases 1 and 2 and fatal for case 8. A dosage was requested in the other cases. For cases 3, 4 and 5, the dosage result was within the therapeutic range with associated digestive intolerance. The approach was to avoid this antiepileptic drug with a good outcome. For cases 6 and 7, the result was close to the upper limit of normal, hence a reduction in the dose of valproic acid was recommended with good progress.

The management of valproic acid-related hepatic cytolysis depends on their severity, the results of the plasma valproic acid assay and the results of the etiological assessment.

Valproic acid; hepatic adverse effects; imputability; severity; management Abbreviations: • AED : Antiepileptic drug • AEs : Adverse effects • ALAT : Alanine aminotransferase • PTM : Pharmacological Therapeutic monitoring • RCPV : Regional Center of Pharmacovigilance • ROS : Reactive oxygen species • ULS : Upper limit of normal • VPA :Valproic acid

Valproic acid (VPA) is an older generation antiepileptic drug (AED). It’s widely prescribed in the treatment of epilepsy and some psychiatric disorders (1). However, this drug can induced multiple adverse effects (AEs), including gastrointestinal, neurological, hematological and hepatic (1,2). Elevated serum aminotransferase levels are the most common type of hepatotoxicity with this AED (3). However, severe life-threatening hepatitis is possible (4). Reporting of hepatic AEs to the pharmacovigilance center is necessary to establish the imputability of the VPA and to adapt the appropriate therapeutic management. The objectives of our study were to investigate hepatic AEs of VPA reported within the regional pharmacovigilance center (RCPV) of Sfax, to explain the underlying mechanisms and to recommend appropriate actions in these situations, based on evidence from the literature.

2-1- Type and population of the study: This is a retrospective descriptive study, based on collecting hepatic AEs related to VPA and reported to the RCPV of Sfax over a nine‑year period from January 2015 to June 2023. We included cases with at least doubtful imputability score (I ≥ 1). We excluded patients whose pharmacovigilance investigation concluded to a non-drug origin. 2-2- Causality study: A pharmacovigilance Investigation was carried out on all patients according to the French imputability method of Begaud and al. (5,6) . The Roussel Uclaf Causality Assessment Method (RUCAM) score (7) was also calculated for patients. 2-3-Classification of the severity of liver injury: The severity of reported liver cytolysis was classified according to the recommendations of the US Drug‑Induced Liver Injury Network (8). 2-4- Plasma Valproic Acid Monitoring: Plasma VPA dosage was performed in patients with suspected hepatic cytolysis‑related overdose to confirm the diagnosis. These dosages were performed using an immune-enzymatic method using an INDIKO (Thermo scientific) device in the pharmacology laboratory of the Faculty of Medicine of Sfax (Tunisia). Samples were collected at least 5 halves‑lives after treatment initiation or any dose change, and 12 hours after the last dose. Plasma VPA concentrations were set at between 40 and 100 mg/ml.

The mean age of the patients was 46.62 ± 11.71 years ranging from 24 to 62 years. A male predominance was observed, with 6 men and 2 women, resulting in a sex-ratio of 3. During the study period, we collected 8 cases of hepatic cytolysis with varying severity: one case of moderately severe cytolysis (case 1), one case of fatal cytolysis (fulminant hepatitis, case 8) and 6 cases of benign cytolysis (case 27). Among these mild cases, only case 2 presented transaminase levels ≥ 5 times the upper limit of normal (ULN). The time to onset of cytolysis was highly suggestive in 2 cases and compatible in 6 cases. The different times to onset are summarized in Table 2. A search for the association with other hepatotoxic drugs, in order to exclude their involvement, was carried out in all patients. It found only paracetamol, administered at therapeutic doses, in case 7. The other associated drugs, known to be non-hepatotoxic, were continued in all cases at the same doses. Administration of VPA was discontinued in cases 1, 2, and 8 following detection of serum transaminase levels ≥ 5 times ULN. Following VPA withdrawal, liver function in cases 1 and 2 improved notably. Whereas that of case 8 deteriorated rapidly with fatal outcome. The different times to disappearance of these hepatic cytolysis are summarized in Table 2. A plasma dosage of VPA was recommended in 5 cases of benign cytolysis with an Alanine aminotransferase (ALAT) level varying from 2 times ULN to 3 times ULN. For cases 3, 4 and 5, the plasma concentration of VPA was within the therapeutic range with the appearance of associated signs of digestive intolerance (vomiting, nausea). The VPA discontinuation was recommended, as a precaution, in these cases with good progress. In cases 6 and 7, the result was near the ULN. A reduction in the dose of VPA, which in these two patients went from 500 mg*3/day to 500 mg*2/day, was recommended with good evolution. A subsequent plasma VPA dosage in these patients showed results within the therapeutic range but close to its lower limit. In five cases, further investigations were conducted to exclude non-drug causes. Abdominal ultrasound was normal in Cases 2 and 7, but revealed diffuse hepatic steatosis in Cases 3 and 4. Viral hepatitis serology was performed in four cases (2, 3, 7, and 8) and returned negative results. Autoimmune hepatitis serology, including tests for anti-LKM1 antibodies, anti-mitochondrial antibodies (AMA), anti-smooth muscle antibodies (SMA), and anti-nuclear antibodies (ANA), was conducted in three cases (2, 3, and 7), all of which were negative. These findings are summarized in table 1. The imputability and RUCAM scores were calculated in the different cases. They allowed us to suspect the responsibility of the VPA in all cases. The imputability score of this AED remained doubtful in the case of fulminant hepatitis given a rapidly fatal evolution and the RUCAM score of this case was 2. Detailed scores and management strategies for each case are presented in table 2.

VPA is associated with multiple AEs including liver injury which can range from asymptomatic elevation of transaminases to liver failure or even fatal fulminant hepatitis. (9–11). VPA was implicated in only 8 cases of hepatic cytolysis. This may be related to under-reporting of these AEs. In fact, increased transaminase levels have been reported in approximately 5 to 10% of patients on VPA (12,13). Their severity was calculated, in our study, according to the US Drug-Induced Liver Injury Network classification (8). We noted a predominance of benign cytolysis (6 cases), among them only one case presented transaminase levels ≥ 5 times ULN and required the withdrawal of VPA. Indeed, several studies have recommended this threshold for discontinuing the suspect drug (14). In the study by Meseguer ES et al (15), this enzyme elevation was employed as a diagnostic criterion for drug‑induced liver injury (DILI). In the event of an increase, the therapeutic approach involved immediate discontinuation of VPA, especially in the presence of symptoms or other abnormal laboratory signs. In cases of more moderate elevations (case 37), several approaches have been adopted including a dose reduction (16). In our patients, plasma VPA concentration measurement was recommended in cases of benign cytolysis with ALAT levels ≤ 3 times ULN. Dose reduction was necessary in 2 patients (cases 6 and 7) with values near to ULN with a subsequent good evolution. Plasma dosage of VPA and dose adjustment are essential, especially in cases of elevated transaminases, even if the results remain within the therapeutic range (17,18). However, avoidance of this AED was recommended in the other 3 patients (cases 3, 4 and 5) in front of a result within the therapeutic range and a symptomatic high ALAT level. Indeed, some recommend stopping this medication or adjusting its dosage if changes in liver function are clinically symptomatic (19). Other studies have reported that VPA can be continued in cases of moderate elevations up to 2 to 3 times ULN in liver enzymes and when the patient remains asymptomatic (2,20). A search for an association with other hepatotoxic drugs identified only paracetamol, administered at therapeutic doses, in case 7. Consequently, the involvement of these drugs was excluded in our cases. Further investigations were conducted to exclude non-drug causes. Abdominal ultrasound was performed in case 4 and case 3, showing diffuse hepatic steatosis. In these cases, steatosis may result either from VPA induced inhibition of mitochondrial beta‑oxidation of fatty acids or from an alternate etiology, notably metabolic overload (21). This type of VPA-induced toxicity can occur after a delayed delay of weeks to months, and in some cases even years (22). Case 7 had an abdominal ultrasound which was normal. Autoimmune hepatitis and viral hepatitis B and C were ruled out in cases 3 and 7. In the literature, it is emphasized that, for suspected drug‑induced liver injury (DILI), further investigations are essential to exclude other etiologies such as viral hepatitis and autoimmune disease (21). We suspected the role of VPA in the genesis of these 5 cases of benign cytolysis given the improvement in liver function when it was stopped or its dose was reduced, with a plausible imputability score in all cases and probable RUCAM scores for cases 3 and 7 and possible in the other cases. On the other hand, we recommended discontinuation and contraindication of further use of VPA in 3 patients: one case with moderately severe hepatic cytolysis (case 1), one case with benign cytolysis (case 2) with transaminase levels ≥ 5 times the ULN and one case with fatal cytolysis (case 8). We retained the responsibility of the VPA in the genesis of case 1 in view of a positive re-administration, a likely imputability score and a RUCAM score calculated at 9. For case 2, the role of VPA was retained in view of suggestive onset and disappearance times and a negative etiological assessment (eliminating autoimmune hepatitis or hepatitis B and C with a normal liver ultrasound). In this case, the imputability score was plausible and the RUCAM score was 7. In case 8, the 10‑year latency aligns with a compatible time to onset, but the course remained inconclusive due to the patient’s death. In the literature, although cases of VPA-induced fulminant hepatitis generally occur within the first few months following treatment initiation (12,23), rare cases with a delay of years have been reported (24,25). In our case, the hepatitis C serology was negative but the rest of the etiological assessment was not completed given the patient’s death. The role of VPA in the genesis of this case was doubtful and the RUCAM score was calculated at 2. The mechanism of VPA-induced hepatotoxicity is complex, it can be dose-dependent, reversible, or idiosyncratic, leading to severe liver failure (26). It is linked to its metabolism in the liver. Indeed, there are three pathways of VPA metabolism : glucuronidation, β-oxidation in mitochondria (considered the major pathways) and cytochrome P450 (CYP)-mediated oxidation (minor pathway: metabolism of 10% of the administered dose) (27). Perturbations of these 3 pathways is thought to be the cause of the hepatotoxicity of this AED. VPA can induce hepatic oxidative stress via increased metabolism by cytochrome P450, which generates a reactive metabolite (4-ene-valproate). This derivative alters mitochondrial functioning leading to the accumulation of reactive oxygen species (ROS). VPA-induced oxidative stress may also be related to the inhibition of mitochondrial β-oxidation of fatty acids (4,15,28–30). In addition, VPA, by inhibiting L-carnitine, block mitochondrial transport of fatty acids and leading to microvesicular steatosis (31). In L-carnitine deficient patients, VPA metabolism shifts to microsomal oxidation, producing reactive hepatotoxic dicarboxylic metabolites (2-n-propylpentanoic acid, 4-ene-valproate). Theses metabolites inhibit the conversion of ammonia to urea, which can cause hyperammonemic encephalopathy, a rare and idiosyncratic but serious complication of VPA (32). Patients with L-carnitine, β-oxidation, or urea cycle enzyme deficiencies are particularly at risk. In these patients, VPA is contraindicated. In cases of severe hepatitis induced by VPA, some authors recommend intravenous administration of L-carnitine (50–100 mg/kg/day), associated with discontinuation of treatment (19,33). An immunoallergic mechanism in the context of antiepileptic hypersensitivity syndrome is rarely described with VPA and the liver damage linked to this syndrome can range from a mild elevation of transaminases to fulminant hepatitis (4,34,35). This mechanism is unlikely in our study given the absence of other signs of hypersensitivity syndrome (visceral and/or allergic cutaneous signs). We found that pharmacological therapeutic monitoring (PTM) of VPA is interested in the management of patients treated with this AED. Indeed, this drug is characterized by interindividual variability in its pharmacokinetics, a narrow therapeutic index and a risk of toxicity, particularly hepatic, in the event of overdose. PTM allows dose adjustments, improving efficacy and reducing AEs. This monitoring is particularly important in children, patients taking multiple medications or those with liver failure (36) . In the literature, most studies mainly contribute to the description and analysis of hepatic AEs caused by VPA or are limited to case reports (4,15,32,37–40) . Our article could provide a better understanding of hepatic AEs under VPA with clear explanations of the therapeutic management according to the case. However, we have a limited number of patients, hence the interest in collaborating with the pharmacovigilance center. Furthers works on larger series, particularly involving pharmacogenetic studies are crucials to explore and prevent VPA hepatotoxity.

In our study, VPA was associated with cytolytic liver damage that was essentially benign, but one case had a fatal outcome. The actions taken in these situations were varied and depended on the severity of the liver damage, the results of the plasma VPA assay, the etiological assessment to eliminate another etiology and the possible presence of associated symptoms.

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Hepatology (Baltimore, Md). 1 sept 2007;2:591‑7. 40. Shahbaz O, Majumder S. Valproic Acid-Induced Acute Liver Failure: 473. Official journal of the American College of Gastroenterology | ACG. oct 2012;107:S197. Table captions: Table 1: Results of further investigations requested in cases of liver adverse effects. Table 2: Characteristics of valproic acid hepatic cytolysis. Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Metrics & Citations Metrics Article Usage 427views 136downloads Citations Download citation Imen Bouaziz, Rim Athimen, Rym Sahnoun, et al. Hepatic adverse effects of valproic acid: what action to take?. Authorea. 25 September 2025. DOI: https://doi.org/10.22541/au.175879451.11901021/v1 DOI: https://doi.org/10.22541/au.175879451.11901021/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. 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