Valproate induced carnitine deficiency and hyperammonaemia

Editor – I read with interest the article by Yu-E et al,¹ and the earlier case by Camilleri et al.² Hyperammonemia is a recognised complication of treatment with valproic acid (VPA) or its sodium salt (sodium valproate) and although the mechanism is not fully understood, secondary carnitine deficiency is believed to play a significant role.

Primary carnitine deficiency is an autosomal recessive inherited metabolic disorder (IMD) affecting the SLC22A5 gene and OCTN2 transporter. Secondary deficiencies are also seen in other IMDs (eg organic acidurias and primary disorders of fatty acid oxidation) or acquired through inadequate dietary intake, renal failure, malabsorption states or are drug induced (eg VPA).

VPA (and sodium valproate) is a widely used anti-epileptic drug (AED) and depletes carnitine stores, especially during long-term or high-dose therapy, through various synergistic mechanisms (including impaired renal tubular reabsorption).³ It has three pathways for metabolism: primarily glucuronidation, β-oxidation and, to a lesser extent, ω-oxidation. Carnitine is essential for β-oxidation and in the depleted state, ω-oxidation of VPA is favoured leading to elevated levels of 4-en-VPA, which can inhibit carbamoyl phosphate synthetase (CPS) and impair the urea cycle with resultant hyperammonaemia.⁴

Risks factors for carnitine depletion include age <24 months, the presence of concomitant neurologic or metabolic disorders, and receipt of multiple AEDs (including VPA and sodium valproate).³ Measurement of carnitine levels is indicated in patients who are at risk for deficiency in order to identify those who would benefit from supplementation. In the acute setting, measurement of carnitine levels may not be useful (due to availability and turnaround time) and treatment should be initiated promptly where acquired carnitine deficiency is suspected, particularly in the presence of life threatening hyperammonaemia (e.g. valproate-induced hyperammonemic encephalopathy).

The British Inherited Metabolic Disease Group (BIMDG) formulary⁵ recommends levocarnitine (L-carnitine) 100–200 mg/kg/day, orally, in two to four divided doses, maximum of 3 grams a day for the treatment of adults with secondary carnitine deficiency. Furthermore, the development of life-threatening hyperammonaemia should raise concerns about the potential unmasking of an undiagnosed IMD (eg ornithine transcarbamylase OTC deficiency (particularly heterozygote female carriers) or another UCD).