Hyperammonemia and hepatic status during valproate therapy

Abstract

The present study was conducted to assess correlation of ammonia levels with valproate levels in epileptic patients presenting with valproate toxicity and also whether liver enzymes and ammonia levels could serve as biochemical marker of valproate toxicity. 100 patients with epilepsy who had received valproate therapy for more than 12 months and had presented with valproate toxicity and 100 controls were included in the study. The serum valproate, ammonia and liver enzymes were measured in these subjects. In patients with valproate toxicity, the mean level of serum valproate was 110.91 ± 28.68 mg/dL (therapeutic range 50-100 mg/dL). Serum ammonia was higher (86.37 ± 39.90 µg/dL) in patients with valproate toxicity compared to controls (68.73 ± 30.07 µg/dL). Out of 100 patients, only 37 patients had serum valproate level > 120 mg/dL and 22 patients had raised levels of valproate as well as ammonia. Age < 30 years and serum ammonia > 69 μg/dL is risk factors for valproate toxicity. Serum ammonia, liver enzymes should be regularly investigated in patients on valproate therapy for early diagnosis of valproate toxicity.

High Blood Ammonia Levels Associated with Long-term Valproic Acids Therapy in Epileptic Children

“…They reported that blood ammonia concentrations in children with epilepsy were 46.5 mmol/L and 50.9 mmol/L, respectively. 8,9 Their results were lower than those found in the present study. It may be related with the aged of the subjects.…”

“…In the present study, the subject's mean aged were 6.2 years while in the other two studies cited above, they were 7.1 years and 9.2 years, respectively. 8,9 Thus, the lower mean aged in the subjects of the present study means that they were likely to exhibit higher concentrations of blood ammonia. 9 The blood ammonia concentrations of the subjects who receiving VPA therapy for two years or more were significantly higher than those of subjects who receiving VPA therapy for less than two years.…”

“…8,9 The blood ammonia concentrations of children with epilepsy who received VPA therapy with doses of <10 mg/kg, 10-20 mg/kg, 20-30 mg/kg and >30 mg/kg were 46.8 mg/dL, 60.4 mg/dL 85.7 mg/dL and 92.6 mg/dL, respectively. 8 The dose of VPA apparently appeared to be correlated with blood ammonia concentration in children with epilepsy was 30.4 mg/kg or more. 9 Studies in adults also reported that VPA dose was an independent risk factor of blood ammonia concentration.…”

“…However, although VPA is highly effective in controlling seizure in children, it also has several adverse effects such as fatigue, gastrointestinal disturbances, weight gain, muscle tremors, hair loss, thrombocytopenia, and an increase in hepatic enzymes. 1,2 Other than that, VPA also increases blood ammonia concentrations (hyperammonemia) in adults [3][4][5][6][7] and children [8][9][10][11][12][13][14][15] . The actual increases in blood ammonia concentrations depend on the dose of VPA 4,8 and the use of long-term therapy with VPA 5 .…”

“…The increase of blood ammonia concentrations is depend on the dose and duration of VPA and combination therapy with phenytoin, phenobarbital or topiramate, as well as with female gender. 4,8 The mechanism of hyperammonemia directly inhibits carbamoyl phosphate synthetase (CPS), an enzyme that cause imbalances between the synthesis and degradation of ammonia in the liver and indirectly inhibits the fatty acid beta-oxidation pathway. 4 Ammonia is toxic, especially to the central nervous system.…”