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[Irreversible valproate-associated liver failure]
Insights
Valproate treatment in an infant with Dandy-Walker malformation led to fatal hepatotoxicity, indicated by high levels of a specific metabolite. Supportive therapies were ineffective in preventing the severe liver injury.
Area of Science:
- Pediatric Neurology
- Clinical Pharmacology
- Toxicology
Background:
- Infantile spasms are a severe epilepsy syndrome in infants.
- Dandy-Walker malformation is a congenital brain abnormality.
- Valproate is a common antiepileptic drug used in infants.
Observation:
- A severely impaired infant with Dandy-Walker malformation received valproate for infantile spasms.
- Despite valproate discontinuation, the infant developed fulminant hepatotoxicity and died.
- Elevated levels of the E,E-2,3'-dien-valproate metabolite were detected during liver failure.
Findings:
- Valproate-associated hepatotoxicity can be fatal in infants, even after drug cessation.
- Specific valproate metabolites, like E,E-2,3'-dien-valproate, may play a role in its toxicity.
- Standard liver enzyme monitoring may not predict acute, severe hepatotoxicity.
Implications:
- This case highlights the critical risk of valproate-induced liver injury in infants.
- Further research into valproate metabolism and toxicity is warranted.
- Close monitoring and consideration of alternative treatments may be necessary for infants with complex neurological conditions.
Abstract:
A very severely retarded infant with a Dandy-Walker malformation was treated with valproate since the age of 6 months on account of infantile spasms. Three weeks after start of therapy dexamethasone was applied additionally because valproate was ineffective. Seventy-six days after initiation of valproate therapy the infant died with the clinical signs of fulminant valproate-associated hepatotoxicity despite the discontinuation of valproate. In combination with a febrile otitis media the child had been periodically restless and lethargic during the last week prior to liver coma. Activity of liver enzymes remained within normal limits up to two days before coma occurred. Analysis of valproate metabolites by gas chromatography/mass spectrometry yielded unusually high concentrations of the di-unsaturated metabolite E,E-2,3'-dien-valproate before and during liver failure. The concentrations of the main metabolites E-2-en-valproate und 3-keto-valproate remained within the usual range found during valproate therapy at steady state. The oxydation products 4-en-valproate and E-2,4-dien-valproate which are formed by alternative pathways and are considered to be hepatotoxic were detected in very low concentrations only. The application of carnitine, of antioxidants thought to improve the capacity of the free radical scavenger system (selen, vitamin E), and of N-acetylcysteine which can detoxify reactive drug metabolites could not prevent the fatal outcome.