What is the risk of hepatotoxicity associated with Valproate (Valprol), an anticonvulsant medication?

From the Guidelines

Valproic acid (Valprol, Depakote) and soltus (sodium valproate) can cause hepatotoxicity, a serious potential side effect requiring monitoring, with the highest risk in children under 2 years of age, patients with metabolic disorders, severe seizure disorders, or those taking multiple anticonvulsants 1. The liver damage typically occurs within the first 6 months of treatment and presents with symptoms like fatigue, weakness, lethargy, facial edema, anorexia, vomiting, and jaundice. Some key points to consider when prescribing valproic acid or soltus include:

• Regular liver function tests should be performed before starting therapy and periodically during treatment, especially during the first 6 months 1.
• If a patient shows signs of liver dysfunction (elevated liver enzymes, particularly ALT and AST), the medication should be discontinued immediately.
• The mechanism of hepatotoxicity involves the formation of toxic metabolites that can damage hepatocytes.
• Patients and caregivers should be educated about the warning signs of liver problems and instructed to seek immediate medical attention if these symptoms develop.
• Alternative anticonvulsants should be considered for patients with pre-existing liver disease or those at high risk for hepatotoxicity, as use of valproic acid has been associated with complications such as thrombocytopenia and hepatotoxicity 1. Given the potential risks, it is essential to carefully weigh the benefits and risks of valproic acid or soltus therapy, particularly in high-risk patients, and to closely monitor liver function to minimize the risk of hepatotoxicity 1.

From the FDA Drug Label

WARNINGS Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting Caution should be observed when administering valproic acid to patients with a prior history of hepatic disease The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent.

Valproate Hepatotoxicity: Valproate can cause hepatotoxicity, which may be fatal. The risk is higher in patients with a prior history of hepatic disease, and the drug should be used with caution in these patients.

• Risk Factors: Patients with a history of hepatic disease, children under 2 years old, and those with congenital metabolic disorders are at higher risk of developing hepatotoxicity.
• Monitoring: Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months.
• Discontinuation: The drug should be discontinued immediately if significant hepatic dysfunction is suspected or apparent. 2 2

From the Research

Valproate-Associated Hepatotoxicity

• Valproate, also known as valproic acid, has been associated with severe and sometimes fatal hepatotoxicity, with approximately 80 cases reported worldwide 3.
• The syndrome typically affects children, especially those receiving more than one anticonvulsant, and usually develops in the early weeks or months of therapy 3.
• The liver damage can manifest as hepatocyte necrosis, microvesicular steatosis, or cholestatic changes, consistent with a drug toxicity reaction 3.

Biochemical Mechanisms

• Increased amounts of unsaturated metabolites of valproate, such as 4-en-valproate, have been found in blood and urine during hepatotoxicity, which may contribute to the liver damage 3.
• Impaired beta-oxidation of valproate and accumulation of toxic metabolites may also play a role in the hepatotoxicity 3, 4.
• Valproate has been shown to inhibit beta-oxidation and synthesis of fatty acids, gluconeogenesis, urea synthesis, oxidative phosphorylation, and the glycine cleavage system in the liver 4.

Mitochondrial Dysfunction

• Sodium valproate has been shown to induce mitochondrial respiration dysfunction in HepG2 cells, leading to decreased oxygen consumption rates, mitochondrial membrane potential, and ATP production 5.
• Valproate exposure also increased mitochondrial reactive oxygen species (ROS) and decreased protein levels of mitochondrial superoxide dismutase SOD2, suggesting oxidative stress and impaired elimination of mitochondrial ROS 5.
• Mitochondrial diseases, particularly those with POLG1 gene mutations, may be at increased risk of valproate-induced hepatotoxicity due to impaired mitochondrial function 6.

Diagnostic Tools

• The [13C]methionine breath test may be a useful non-invasive tool to assess liver mitochondrial function in patients with valproate-associated microvesicular steatosis 7.
• This test may provide a way to monitor liver function and detect potential hepatotoxicity early on, allowing for prompt intervention and prevention of severe liver damage 7.