Advertisement

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

Abstract

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.

Keywords

Biotransformation Carnitine Hyperammonemia Liver disease Metabolites Necrosis Pathology Steatosis Valproic acid 
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Gerber N, Dickinson RG, Harlan RC, Lynn RK, Houghton D, Antonias JI, et al. Reye-like syndrome associated with valproic acid therapy. J Pediatr 1979;95:142–4.PubMedGoogle Scholar
  2. 2.
    Suchy FJ, Balistreri WF, Buchino JJ, Sondheimer JM, Bates SR, Kearns GL, et al. Acute hepatic failure associated with the use of sodium valproate. N Engl J Med 1979;300:962–6.PubMedGoogle Scholar
  3. 3.
    Zimmerman H, Ishak HJ. Valproate-induced hepatic injury: analysis of 23 fatal cases. Hepatology 1982;2:591–7.PubMedGoogle Scholar
  4. 4.
    Zafrani ES, Berthelot P. Sodium valproate in the induction of unusual hepatotoxicity. Hepatology 1982;2:648–9.PubMedGoogle Scholar
  5. 5.
    Willmore LJ, Wilder B J, Bruni J, Villarreal HJ. Effect of valproic acid on hepatic function. Neurology 1978; 28:961–4.PubMedGoogle Scholar
  6. 6.
    Sussman NM, McLain LW. A direct hepatotoxic effect of valproic acid. JAMA 1979;242:1173–4.CrossRefPubMedGoogle Scholar
  7. 7.
    Jeavons PM. Non-dose-related side effects of valproate. Epilepsia 1984;25 Suppl 1:S50–5.PubMedGoogle Scholar
  8. 8.
    Dreifuss FE, Santilli N, Langer DH, Sweeney KP, Moline KA, Menander KB. Valproic acid hepatic fatalities: a retrospective review. Neurology 1987;37:379–85.PubMedGoogle Scholar
  9. 9.
    Sheffner D. Fatal liver failure in children on valproate. Lancet 1986;2:511.CrossRefGoogle Scholar
  10. 10.
    Dickinson RG, Bassett ML, Searle J, Tyrer JH, Eadie MJ. Valproate hepatotoxicity: a review and report of two instances in adults. Clin Exp Neurol 1985;21:79–91.PubMedGoogle Scholar
  11. 11.
    Gram L. Hepatic toxicity of valproate: reflection on the pathogenesis and proposal for an international collaborative registration. In: Oxley J, Janz D, Meinardi H, eds. Chronic toxicity of antiepileptic drugs. New York: Raven Press, 1983:67–78.Google Scholar
  12. 12.
    Eadie MJ, Hooper WD, Dickinson RG. Valproateassociated hepatotoxicity and its biochemical mechanisms. Med Toxicol 1988;3:85–106.Google Scholar
  13. 13.
    Coulter DL, Allen RJ. Secondary hyperammonemia: a possible mechanism for valproate encephalopathy. Lancet 1980;1:1310–1.CrossRefPubMedGoogle Scholar
  14. 14.
    Lewis JH, Zimmerman HJ, Garrett CT, Rosenberg E. Valproate-induced hepatic steatogenesis in rats. Hepatology 1982;2:870–3.PubMedGoogle Scholar
  15. 15.
    Kesterson JW, Granneman GR, Machinist JM. The hepatotoxicity of valproic acid and its metabolites in rats. I. Toxicologic, biochemical and histopathologic studies. Hepatology 1984;4:1143–52.Google Scholar
  16. 16.
    Sugimoto T, Araki A, Nishida N, Sakane Y, Woo M, Takeuchi T, et al. Hepatotoxicity in rat following administration of valproic acid: effect of L-carnitine supplementation. Epilepsia 1987;28:373–7.PubMedGoogle Scholar
  17. 17.
    Becker C-M, Harris RA. Influence of valproic acid on hepatic carbohydrate and lipid metabolism. Arch Biochem Biophys 1983;223:381–92.CrossRefPubMedGoogle Scholar
  18. 18.
    Bjorge SM, Baillie TA. Inhibition of medium-chain fatty acidβ-oxidationin vitro by valproic acid and its unsaturated metabolite, 2-n-propyl-4-pentenoic acid. Biochem Biophys Res Commun 1985;132:245–52.CrossRefPubMedGoogle Scholar
  19. 19.
    Coude FX, Grimber G, Pelet A, Benoit Y. Action of the antiepileptic drug, valproic acid, on fatty acid oxidation in isolated rat hepatocytes. Biochem Biophys Res Commun 1983;115:730–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Turnbull DM, Dick DJ, Wilson L, Sherratt HSA, Alberti KGMM. Valproate causes metabolic disturbances in normal man. J Neurol Neurosurg Psychiatr 1986;49:405–10.PubMedGoogle Scholar
  21. 21.
    Moore KH, Decker BP, Schreefel FP. Hepatic hydrolysis of octanoyl-CoA and valproyl-CoA in control and valproate-treated animals. Int J Biochem 1988;20:175–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Stumpf DA, Parker D, Angelini C. Carnitine deficiency, organic acidemias, and Reye's syndrome. Neurology 1985;35:1041–5.PubMedGoogle Scholar
  23. 23.
    Bohles H, Richter K, Wagne-Thiessen E, Schafer H. Decreased serum carnitine in valproate induced Reye syndrome. Eur J Pediatr 1982;139:185–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Coulter DL. Carnitine deficiency: a possible mechanism for valproate hepatotoxicity. Lancet 1984;1:689.CrossRefGoogle Scholar
  25. 25.
    Ohtani Y, Endo F, Matsuda I. Carnitine deficiency and hyperammonemia associated with valproic acid therapy. J Pediatr 1982;101:782–5.PubMedGoogle Scholar
  26. 26.
    Laub MC, Paltzke-Brunner I, Jaeger G. Serum carnitine during valproic acid therapy. Epilepsia 1986;27:559–62.PubMedGoogle Scholar
  27. 27.
    Murphy JV, Marquardt KM, Shug AL. Valproic acid associated abnormalities of carnitine metabolism. Lancet 1985;1:820–1.CrossRefGoogle Scholar
  28. 28.
    Beghi E, Bizzi A, Codegoni AM, Trevisan D, Torri W, Collaborative Group for the Study of Epilepsy. Valproate, carnitine metabolism and biochemical indicators of liver function. Epilepsia 1990;31(3):346–52.PubMedGoogle Scholar
  29. 29.
    Melegh B, Kerner J, Acsadi G, Lakatos J, Sandor A.l-Carnitine replacement therapy in chronic valproate treatment. Neuropediatrics 1990;21:40–3.PubMedGoogle Scholar
  30. 30.
    Melegh B, Kerner J, Kispal G, Acsadi G, Dani M. Effect of chronic valproic acid treatment on plasma and urine carnitine levels in children: decreased urinary excretion. Acta Paed Hungar 1987;28(2):137–42.Google Scholar
  31. 31.
    Coulter DL, Allen RJ. Hyperammonemia with valproic acid therapy. J Pediatr 1981;99:317–9.PubMedGoogle Scholar
  32. 32.
    Laub MC. Nutritional influence of serum ammonia in young patients receiving sodium valproate. Epilepsia 1986;27:55–9.PubMedGoogle Scholar
  33. 33.
    Rawat S, Borkowski WJ, Swick HM. Valproic acid and secondary hyperammonemia. Neurology 1981;31:1173–4.PubMedGoogle Scholar
  34. 34.
    Williams CA, Tiefenback S, McReynolds JW. Valproic acid-induced hyperammonemia in mentally retarded adults. Neurology 1984;34:550–3.PubMedGoogle Scholar
  35. 35.
    Zaccara G, Campostrini R, Paganini M, Moroni F, Valenza T, Targioni G, et al. Acute changes of blood ammonia may predict short-term adverse effects of valproic acid. Neurology 1984;34:1519–21.PubMedGoogle Scholar
  36. 36.
    Zaccara G, Paganini M, Campostrini R, Moroni F, Valenza T, Messori A, et al. Effect of associated antiepileptic treatment on valproate-induced hyperammonemia. Ther Drug Monitor 1985;7:185–90.Google Scholar
  37. 37.
    Ratnaike RN, Schapel GJ, Purdie G, Rischbieth RHC, Hoffman S. Hyperammonemia and hepatotoxicity during chronic valproate therapy: enhancement by combination with other antiepileptic drugs. Br J Clin Pharmacol 1986;22:100–3.PubMedGoogle Scholar
  38. 38.
    Warter JM, Brandt C, Marescaux C, Rumbach L, Micheletti G, Chabrier G, et al. The renal origin of sodium valproate-induced hyperammonemia in fasting humans. Neurology 1983;33:1136–40.PubMedGoogle Scholar
  39. 39.
    Warter J, Imler M, Marescaux C, Chabrier G, Rumbach L, Micheletti G, et al. Sodium valproateinduced hyperammonemia in the rat: role of the kidney. Eur J Pharmacol 1983;87:177–82.CrossRefPubMedGoogle Scholar
  40. 40.
    Hjelm M, De Silva LVK, Seakins JWT, Oberholzer VG, Rolles C J. Evidence of inherited urea cycle defect in a case of fatal valproate toxicity. BMJ 1986;292: 23–4.PubMedGoogle Scholar
  41. 41.
    Tripp JH, Hargreaves T, Anthony PP, Searle JF, Miller P, Leonard JV, et al. Sodium valproate and ornithine carboxyl transferase deficiency. Lancet 1981;1: 1165–6.CrossRefGoogle Scholar
  42. 42.
    Sherratt HSA, Osmundsen H. On the mechanisms of some pharmacological actions of the hypoglycemic toxins hypoglycin and pent-4-enoic acid: a way out of the confusion. Biochem Pharmacol 1976;25:743–50.CrossRefPubMedGoogle Scholar
  43. 43.
    Baillie TA. Metabolism of valproate to hepatotoxic intermediates. Pharm Weekbl [Sci] 1992;14(3A):122–5.Google Scholar
  44. 44.
    Levy RH, Lin JMH, Acheampong AA, Russell RG. Dose effect of L-carnitine on Δ4-VPA associated hepatotoxicity. In: Levy RH, Penry JK, eds. Idiosyncratic reactions to valproate: clinical risk patterns and mechanisms of toxicity. New York: Raven Press, 1991: 25–9.Google Scholar
  45. 45.
    Levy RH, Rettenmeier AW, Anderson GD, Wilensky AJ, Friel PN, Baillie TA, et al. Effects of polytherapy with phenytoin, carbamazepine, and stiripentol of 4-ene-valproate, a hepatotoxic metabolite of valproic acid. Clin Pharmacol Ther 1990;48:225–35.PubMedGoogle Scholar
  46. 46.
    Farrell K, Abbott FS, Junker AK, Waddell JS, Pippenger CE. Successful treatment of valproate hepatotoxicity withN-acetylcysteine. Epilepsia 1989;30(5):700.Google Scholar
  47. 47.
    Appleton RE, Farrell K, Applegrath DA, Dimmick JE, Wong LTK, Davidson AGF. The high incidence of valproate hepatotoxicity in infants may relate to familial metabolic defects. Can J Neurol Sci 1990;17:145–8.PubMedGoogle Scholar
  48. 48.
    Lenn NJ, Ellis WG, Washburn ER, Ruebner B. Fatal hepatocerebral syndrome in siblings discordant for exposure to valproate. Epilepsia 1990;31(5):578–93.PubMedGoogle Scholar

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

Personalised recommendations

Cite article

Buy options