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Valproate (VPA) Metabolites in Various Clinical Conditions of Probable VPA‐Associated Hepatotoxicity
Author(s) -
Siemes Hartmut,
Nau H.,
Schultze K.,
Wittfoht W.,
Drews E.,
Penzien J.,
Seidel U.
Publication year - 1993
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1157.1993.tb02419.x
Subject(s) - metabolite , medicine , valproic acid , fulminant hepatic failure , gastroenterology , lactic acidosis , hepatotoxin , toxicity , pharmacology , epilepsy , liver transplantation , transplantation , psychiatry
Summary: Of a cohort of 470 epileptic patients in whom valproate (VPA) serum metabolites had been measured, 170 subjects without symptoms or signs of hepatic side effects were chosen as a reference group to establish the usual metabolic pattern. A wide interindividual variation of VPA metabolite concentrations was noted. Infants receiving VPA monotherapy and comedication with other antiepileptic drugs (AEDs) showed lower concentrations of the potential hepatotoxin 4‐ene‐VPA than did older children. In 11 patients with early symptoms and signs of possible fatal VPA‐associated hepatotoxicity, the following spectrum of benign clinical conditions was observed: unusually severe side effect during initiation of VPA therapy (1 patient), high VPA dosage (2 patients), reversible impairment of coagulation with bleeding manifestations in association with a slight increase in transaminase levels (1 child), and reversible liver dysfunction associated with febrile illness (7 patients). Reversible or irreversible fulminant liver failure had occurred in 5 children. Three of the 4 children with a fatal outcome had massive lactic acidosis. In all patients with probable VPA‐associated hepatotoxicity, some aspects of VPA metabolism differed distinctly from that of the reference group, but the interindividual profile of metabolites varied considerably, even in the subgroup of 4 children who died. Impairment of VPA β‐oxidation and increase of metabolites of alternative metabolic pathways (ω‐ and ω1‐hydroxylation, dehydrogenation reactions) were the most frequent findings. Increased values of 2‐ n ‐propyl‐4‐pentenoic acid metabolite of VPA (4‐ene‐VPA), could be detected only in 1 of the 5 patients with fulminant liver failure and in one other child with a slight hepatic dysfunction, indicating that this VPA metabolite is not the decisive hepatotoxin or indicator of hepatotoxicity. Because we cannot distinguish between benign and life‐threatening hepatic adverse reactions on the basis of VPA metabolites, all identified changes are considered secondary to an as‐yet‐unknown primary metabolic event. The most toxic compound could be VPA itself, which may unmask an inborn or an acquired metabolic defect in the processing of fatty acids.