Valproate is a commonly prescribed
anticonvulsant drug that may cause potentially fatal hepatotoxicity, bone-marrow toxicity, and
pancreatitis. Toxicity usually resolves, though, after discontinuation of the medication. We report a 9-year-old boy who had
Down's syndrome and who developed
valproate-associated bone marrow toxicity, and hepatotoxicity that persisted greater than 2 years after discontinuation of
valproate therapy. Three years after starting
valproate, he developed
erythrocyte aplasia with a severe, normochromic,
macrocytic anemia requiring several
blood transfusions. Several months later while still receiving
valproate, he developed progressive
hyperammonemia and decreased hepatic synthetic function. The
macrocytic anemia resolved and hepatic synthetic function improved after discontinuation of
valproate therapy. However,
hyperammonemia, steatosis, mitochondrial injury, and marked hepatic
iron accumulation persisted greater than 2 years after the
valproate was discontinued. The persistent
hyperammonemia was responsive to
lactulose therapy. A decrease in hepatic
iron content by serial phlebotomies did not result in any improvement in the
hyperammonemia or hepatic synthetic function. This is the first report of persistent
hyperammonemia and hepatic mitochondrial injury after
valproic acid therapy.