What is the risk of liver failure associated with Depakote (valproate)?

Valproate (Depakote) Liver Failure Risk

Valproate therapy carries a significant risk of hepatotoxicity that can progress to fatal liver failure, particularly in children under 2 years of age, patients with congenital metabolic disorders, severe seizure disorders with mental retardation, and those with organic brain disease. 1

Risk Factors and Incidence

• Hepatic failure resulting in fatalities typically occurs within the first six months of treatment, though approximately one-third of cases may occur after this period 2

• Children under 2 years of age are at considerably increased risk of developing fatal hepatotoxicity 1

• Other high-risk groups include:

  • Patients on multiple anticonvulsants 1
  • Patients with congenital metabolic disorders 1
  • Patients with severe seizure disorders accompanied by mental retardation 1
  • Patients with organic brain disease 1
  • Patients with mitochondrial disorders, particularly those with POLG-1 gene mutations 3, 4

• The risk of fatal hepatotoxicity decreases considerably in progressively older patient groups 1

• Worldwide, approximately 132 patients have died of valproate-associated liver failure and/or pancreatitis 2

• About 35% of patients with fatal liver failure were normally developed, 23.5% were receiving valproate monotherapy, and 35.3% were aged ≤2 years 2

Warning Signs and Monitoring

• Serious or fatal hepatotoxicity is often preceded by non-specific symptoms such as:

  • Malaise, weakness, lethargy 1
  • Facial edema 1
  • Anorexia and vomiting 1, 2
  • Apathy or coma 2
  • Increased seizure frequency 2
  • Symptoms often appear in combination with febrile infections 2

• Liver function tests should be performed:

  • Prior to initiating therapy 1
  • At frequent intervals thereafter, especially during the first six months 1
  • Healthcare providers should not rely solely on serum biochemistry as these tests may not be abnormal in all instances 1

Pathogenesis

• The exact pathogenesis of valproate-induced liver failure remains unknown 5, 2
• Proposed mechanisms include:
  • Depletion of beta-oxidation and change of biotransformation to other pathways with increased synthesis of toxic unsaturated valproate derivatives 6
  • Possible valproate-induced depression of free radical scavenging enzyme activities 6
  • Formation of abnormal metabolites like 4-ene-VPA, which was detected in all examined patients with fatal outcomes 5
  • Mitochondrial dysfunction, particularly in patients with underlying mitochondrial cytopathies 3

Management Recommendations

• Valproate should be used with extreme caution in high-risk groups and only as a sole agent when necessary 1
• The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent 1
• Early or immediate withdrawal of valproate after the first signs of hepatotoxicity may increase the chance of recovery 2
• N-acetylcysteine has been used successfully in treating children with severe hepatotoxicity 6
• In cases of fulminant liver failure, liver transplantation may be considered, though many experts consider valproate-induced acute liver failure in patients with mitochondrial disorders to be a contraindication to liver transplant 4

Prevention

• Careful clinical and laboratory monitoring with special focus on vomiting, apathy, liver enzymes, and coagulation tests are mandatory during the first 6 months after introduction of valproate 5
• Patients and their families must be made aware of the clinical symptoms of hepatotoxicity 2
• Valproate should be avoided in the presence of certain risk factors, particularly known mitochondrial diseases 6, 3
• Benefits of therapy must be carefully weighed against the risks, especially in high-risk populations 1