A patient on valproate for epilepsy develops tremor, weight gain, and elevated liver enzymes. Which mechanism explains valproate's hepatotoxicity?

• A Induction of CYP2E1, converting valproate to reactive quinone metabolites
• B Formation of valproate-glucuronide conjugates that directly damage hepatocyte membranes
• C Valproate-induced hyperammonaemia causing direct hepatocellular necrosis
• D Inhibition of mitochondrial beta-oxidation by valproate and its metabolite 4-en-valproate, leading to microvesicular steatosis ✓

Explanation

Valproate undergoes omega-oxidation to 4-en-valproic acid, which inhibits mitochondrial beta-oxidation and the respiratory chain, leading to accumulation of long-chain fatty acids and microvesicular steatosis. This is idiosyncratic and most severe in children under 2 years on polytherapy. Hyperammonaemia is a separate metabolic complication (CPSI inhibition) distinct from hepatotoxicity.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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