To the Editor:
Dr. Sztajnkrycer provided an excellent review of valproic acid (VPA) toxicity Citation[1], detailing the complex clinical spectrum of adverse effects and metabolic pathways seen with valproate therapy and overdose. Although he stated that hepatotoxicity has only been rarely reported with VPA overdose, it is rarer still that the definitive histology of microvesicular steatosis be documented. Given the typically prolonged coma, variable hyperammonemia, problems with VPA immunoassay reliability Citation[2], and suggestive carnitine‐modified metabolic pathways that may contribute in these abnormalities, we believe that carnitine therapy should play a more prominent role in treatment.
Dr. Sztajnkrycer states that there is no evidence that L‐carnitine supplementation changes the clinical outcome in VPA‐induced hyperammonemia and acute overdose, but also notes that when assayed, this supplement has improved the pathways responsible for urea metabolism.
Bohan et al. analyzed the association of L‐carnitine treatment with hepatic survival in 92 patients with severe, symptomatic, VPA‐induced hepatotoxicity Citation[3]. Isolated hyperammonia was not considered a laboratory sign of hepatic dysfunction, and the majority of these patients had histologic evaluation revealing microvesicular steatosis or mitochondrial abnormalities. The early intravenous administration of L‐carnitine was associated with a survival rate of 50% compared with 10% in the untreated group, quite a significant difference. Furthermore, because early treatment in these chronic VPA cases was associated with improved outcome and L‐carnitine itself is a safe therapy, all patients with significant VPA intoxication should be considered candidates for L‐carnitine therapy.
We agree with the author that L‐carnitine remains a reasonable intervention in acute VPA intoxication and hyperammonemia, given the potential for secondary cerebral edema. We recommend that intravenous L‐carnitine be used in any patient with coma, despite falling VPA concentration, and climbing ammonia levels and, pending further study, in all patients with VPA concentrations greater than 450 µg/L Citation[4].
References
- Sztajnkrycer M. D. Valproic acid toxicity: overview and management. J Tox Clin Tox 2002; 40(6)789–801
- Benton D. C., McKay C. A., Wu A. H.B. Serum vaplroate immunoassay variablility following overdose. J Tox Clin Tox 2001; 39(5)498
- Bohan T. P., et al. Effect of L‐carnitine treatment for valproate‐induced hepatotoxicity. Neurology 2001; 56: 1405–1409
- Beauchamp J., Olson K. Valproic acid overdoses: a retrospective study comparing serum drug levels and the incidence of adverse outcomes. J Tox Clin Tox 1999; 37(5)637