valproic acid associated hyperammonemia

Valproic acid-associated hyperammonemia is common and seen in acute overdose as well as with chronic therapy. Propionic acid, a metabolite of valproic acid, inhibits carbamoyl phosphate synthetase, a mitochondrial enzyme in the urea cycle (necessary for ammonia [NH3] elimination). Carbamoyl phosphate synthetase is especially inhibited in states of relative carnitine deficiency, such as due to dietary deficiency, severe liver disease, mitochondrial disorders, and certain renal tubular abnormalities. Some patients experiencing very high NH3 levels due to valproic acid may have underlying urea cycle disorders.

Modest hyperammonemia consequent to valproic acid is rather common; even high levels may not produce clinical findings. When levels are severely elevated, as in this case of acute overdose, coma is common, and lethal cerebral edema can follow.

Treatment of valproic acid toxicity with hyperammonemia includes usual supportive measures (activated charcoal), lactulose, and sodium phenylacetate/sodium benzoate. Hemodialysis and infusion of L-carnitine have been used in severe intoxications. The indication for hemodialysis, the most rapid means to lower NH3 levels, is severe encephalopathy in the setting of threefold or fourfold elevations in serum NH3 levels. L-carnitine lowers NH3 levels and has even been proposed as a prophylactic supplement for some patients taking valproic acid. Whole-bowel irrigation and forced diuresis are not effective.1234

Footnotes

  1. SEEK Questionnaires ↩

  2. Clay AS, Hainline BE. Hyperammonemia in the ICU. Chest. 2007;132(4):1368-1378. PubMed ↩

  3. Mathias RS, Kostiner D, Packman S. Hyperammonemia in urea cycle disorders: role of the nephrologist. Am J Kidney Dis. 2001;37(5):1069-1080. PubMed ↩

  4. Nicholson C, Fowler M, Mullen C, et al. Evaluation of levocarnitine, lactulose, and combination therapy for the treatment of valproic acid-induced hyperammonemia in critically ill patients. Epilepsy Res. 2021;178:106806. PubMed ↩