Valproate-Associated Hepatotoxicity and its Biochemical Mechanisms

Abstract

Intake of the anticonvulsant drug valproic acid, or its sodium salt, has been associated with occasional instances of severe and sometimes fatal hepatotoxicity. Probably at least 80 cases have occurred worldwide. The syndrome affects perhaps 1 in 10,000 persons taking the drug, and usually develops in the early weeks or months of therapy. Most instances have involved children, usually those receiving more than 1 anticonvulsant. Multiple cases have occurred in 2 families. The typical presentation is of worsening epilepsy, increasing depression of consciousness, and progressive clinical and biochemical evidence of liver failure. The liver has sometimes shown hepatocyte necrosis, and on other occasions widespread microvesicular steatosis, while cholestatic changes have also occurred. The appearances are interpreted as consistent with a drug toxicity reaction. During the hepatotoxicity increased amounts of unsaturated metabolites of valproate, notably 4-en-valproate, have been found in blood and urine. In 4 cases there has been evidence of impaired beta-oxidation of valproate with, in 1 case, accumulation of isomers of valproate glucuronide caused by intramolecular rearrangement of the conjugate. There are molecular structural similarities between 4-en-valproate and 2 known hepatotoxins (4-en-pentanoate and methylenecyclopropylacetic acid, the latter being responsible for hypoglycin poisoning). There are also clinical and histopathological similarities between valproate hepatotoxicity and both hypoglycin poisoning and certain spontaneous disorders of isoleucine metabolism (one pathway of valproate metabolism is analogous to oxidative degradation of isoleucine). Unsaturated metabolites of valproate, in particular 4-en-valproate, may contribute to the hepatotoxicity of the drug. However, since the hepatotoxicity appears to involve an element of idiosyncrasy, the primary defect in some cases may be an inherited or acquired deficiency in the drug's beta-oxidation. This defect may divert valproate metabolism towards omega-oxidation, with increased formation of the toxin 4-en-valproate, but may also allow increased formation of a toxic metabolite derived from isoleucine, since beta-oxidation of isoleucine derivatives will also be impaired.

Effects of Sodium Valproate on Corticotropin-Releasing Factor Systems in Rat Brain

“…First, valproate administration was rapidly fatal in rats at a dose of 1424 mg/kg/day that was expected to yield significantly lower serum concentrations than observed based upon the prior experiments (Figure 2). A literature search failed to locate a known, pathologic basis of acute valproate toxicity in rats; a rare incidence of fulminant heptatoxicity in humans has been reported (Eadie et al 1988). A second challenge is that the relationship between dose and serum concentration is nonlinear; an abrupt increase in serum concentration was observed between the highest two doses in the pilot study (Figure 2).…”

Amino Acid Conjugates: Metabolites of 2-Propylpentanoic Acid (Valproic Acid) in Epileptic Patients

“…A large body of evidence has emerged to link the hepatotoxicity of VPA to its metabolism and has been reviewed over the years (Eadie et al, 1988;Abbott and Anari, 1999;Radatz and Nau, 1999). Moreover, a review of mass-balance studies indicated that the total recovery of a VPA dose cannot be completely accounted for in humans (Baillie and Sheffels, 1995), suggesting the existence of yet unknown metabolites.…”

“…Concerns over its teratogenicity and hepatotoxicity side effect have encouraged the need to develop analogs of VPA devoid of the adverse effects. However, this task is complicated by the fact that the mechanism of action of the drug itself remains to be understood.A large body of evidence has emerged to link the hepatotoxicity of VPA to its metabolism and has been reviewed over the years (Eadie et al, 1988;Abbott and Anari, 1999;Radatz and Nau, 1999). Moreover, a review of mass-balance studies indicated that the total recovery of a VPA dose cannot be completely accounted for in humans (Baillie and Sheffels, 1995), suggesting the existence of yet unknown metabolites.…”

Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats

“…All the rats were raised for 8 consecutive weeks. The duration of the experiment was based on two major factors: 1) VPA-induced microvesicular steatosis was developed in the early weeks of therapy, and 2) the rats treated with an HFD for 8 weeks showed initial evidence of NAFLD [5,27] . Two dose levels of VPA, a therapeutic level (100 mg/kg) and a subtoxic level (500 mg/kg), were selected [28,29] .…”

“…VPA has broad applications. For this reason, the side effects associated with VPA, especially hepatotoxicity, have aroused widespread global concern [5,6] . Abdominal ultrasound studies showed the presence of non-alcoholic fatty liver disease (NAFLD) in 61% of VPA-treated patients [7] , which suggested a high frequency of changes in asymptomatic hepatic steatosis induced by VPA.…”