Pharmaceutisch Weekblad

, Volume 14, Issue 3, pp 118–121 | Cite as

Valproate hepatotoxicity syndrome: Hypotheses of pathogenesis

  • Jeffrey R. Stephens
  • René H. Levy
Recent Developments on Valproate and its Metabolites


Therapeutic use of the anticonvulsant valproate (VPA) has been associated with a rare, but severe and often fatal hepatotoxicity. Cases usually present with lethargy, anorexia, and vomiting with rapid progression to coma. Liver histopathology is characterized by steatosis with and without necrosis. In some instances only necrosis was present. Several hypotheses of pathogenesis have been postulated. These deal mainly with biochemical systems that are known to be affected by VPA, or with the possible idiosyncratic production of toxic VPA metabolites, especially Δ4-VPA. At present, no hypothesis entirely explains the diverse characteristics of the disorder.


Biotransformation Carnitine Hyperammonemia Liver disease Metabolites Necrosis Pathology Steatosis Valproic acid 


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Copyright information

© Royal Dutch Association for Advancement of Pharmacy 1992

Authors and Affiliations

  • Jeffrey R. Stephens
    • 1
  • René H. Levy
    • 1
  1. 1.Department of Pharmaceutics, School of Pharmacy, BG-20University of WashingtonSeattleUSA

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