HEPATOTOXICITY ASSOCIATED WITH ANTIEPILEPTIC DRUG-THERAPY - AVOIDANCE, IDENTIFICATION AND MANAGEMENT

Idiosyncratic hepatotoxicity is a rare adverse effect associated with antiepileptic drug (AED) therapy. Carbamazepine, phenytoin, phenobarbi tal (phenobarbitone) and structurally related compounds may produce he patic injury as part of a more widespread hypersensitivity reaction. R eactive compounds, the arene oxides, are generated by the cytochrome P 450 enzyme system during the metabolism of these drugs. Arene oxides b ind to cellular molecules and appear to trigger an immune response. La boratory monitoring of asymptomatic effects may allow for the early de tection of hepatotoxicity, but is complicated by the incidence of dose -related increases in serum transaminase levels associated with the ad ministration of some AEDs. Signs such as fever, rash and eosinophilia typically accompany the hepatic injury associated with these agents. T reatment is supportive, and prompt withdrawal of medication may improv e the prognosis. Valproic acid (sodium valproate) is associated with r are idiosyncratic hepatotoxicity without concomitant signs of hypersen sitivity. The effects of valproic acid on fatty acid metabolism appear to be a factor in the aetiology of hepatotoxicity. A febrile illness often precedes the onset of this condition, and anorexia, vomiting, se izure exacerbation and lethargy are also common presenting signs. Chil dren less than 2 years of age receiving valproic acid as polytherapy c onstitute the highest risk group for the development of hepatotoxicity . Asymptomatic monitoring has been recommended in patients receiving v alproic acid, but this is also limited by dose-related changes in labo ratory values. Specific treatment regimens have been recommended, but not prospectively studied. Of the drugs recently introduced into the U S, felbamate has been linked to cases of hepatotoxicity, while gabapen tin and lamotrigine have not.