[Valproate-associated hepatotoxicity--pathogenesis, clinical aspects, therapy and prevention].
The potential hepatotoxicity resulting in fatal liver failure is of major concern in treating patients with valproate (VPA). Until now there is no relevant laboratory parameter allowing early detection of impending liver failure. The major routes of VPA biotransformation are glucuronidation and beta-oxidation. There are several other pathways of degradation with formation of mono- und di-unsaturated derivates. VPA dose, patients age, co-medication (anticonvulsants, aspirin), fasting and glucose supply influence the VPA metabolism. The clinical spectrum of VPA-associated hepatotoxicity reaches from slight increases of liver enzymes without clinical manifestations over reversible slight to severe liver dysfunction to fatal liver failure. With respect to pathogenesis attention has focused on depletion of beta-oxidation and change of biotransformation to other pathways with increased synthesis of toxic unsaturated VPA derivates. Several inborn errors of metabolism, acute infections and status epilepticus seem to predispose to liver failure. Another hypothesis lies in the possible VPA-induced depression of free radical scavenging enzyme activities. On this basis N-acetylcysteine has been used successfully in treating children with severe hepatotoxicity. In the presence of certain risk factors VPA should be avoided.
Siemes
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Rittberg-Kinderklinik, Berlin.
Nau
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D000641:Ammonia / Q000097:blood; D001711:Biotransformation; D002331:Carnitine / Q000172:deficiency; D056486:Chemical and Drug Induced Liver Injury / Q000145:classification / Q000209:etiology* / Q000628:therapy; D002648:Child; D005609:Free Radicals; D006501:Hepatic Encephalopathy / Q000139:chemically induced; D006801:Humans; D008099:Liver / Q000187:drug effects; D008661:Metabolism, Inborn Errors / Q000378:metabolism; D010084:Oxidation-Reduction; D014635:Valproic Acid / Q000009:adverse effects* / Q000378:metabolism
D005609:Free Radicals; D014635:Valproic Acid; D000641:Ammonia; D002331:Carnitine
Valproat-assoziierte Hepatotoxizität--Pathogenese, klinisches Spektrum, Therapie und Prophylaxe.