Carnitine deficiency and hyperammonemia associated with valproic acid therapy

doi:10.1016/S0022-3476(82)80320-X

The Journal of Pediatrics

Volume 101, Issue 5, November 1982, Pages 782-785

https://doi.org/10.1016/S0022-3476(82)80320-X Get rights and content

Plasma carnitine and blood ammonia concentrations were measured in 25 severely handicapped patients, ages 3 to 21 years, and 27 age-matched control subjects. Fourteen of the handicapped patients were treated with anticonvulsant drugs including valproic acid; the remaining 11 patients were treated with drugs excluding valproic acid. Plasma carnitine concentrations were lower and blood ammonia values were higher in patients treated with valproic acid than in the untreated patients and control subjects. A significant inverse relationship was found between plasma carnitine concentrations and the dosage of valproic acid, and between plasma carnitine and blood amonia values. After oral administration of d,l-carnitine (50 mg/kg/day) for four weeks, both carnitine deficiency and hyperammonemia were corrected.

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Cited by (252)

Valproic Acid Overdose: Case Report and Literature Review
2022, Journal of Emergency Medicine
Valproic acid (VPA) is a common antiepileptic drug that is also used routinely for various psychiatric disorders. VPA toxicity typically manifests as central nervous system depression, while hyperammonemic encephalopathy and hepatotoxicity are potentially life-threatening complications.
We describe the case of a 56-year-old man who presented to the emergency department after an intentional VPA overdose, was found to have hyperammonemia, and was treated with L-carnitine exclusively. He was subsequently admitted to the hospital for monitoring and serial laboratory testing.
Although VPA toxicity has conventionally been managed by gastric decontamination, L-carnitine, and, in severe and refractory cases, extracorporeal removal, recent literature supports the use of carbapenem antibiotics, particularly meropenem. Thus, we report the details of current treatment modalities for VPA toxicity by reviewing current literature.
The Roles of Antidotes in Emergency Situations
2022, Emergency Medicine Clinics of North America
Citation Excerpt :
During the process of mitochondrial β-oxidation, VPA depletes carnitine stores. Carnitine supplementation is well tolerated and may be beneficial in acute and chronic valproate exposure.100–104 Additionally, the supplementation of levocarnitine may be beneficial in high-risk patients.99
Evaluation of levocarnitine, lactulose, and combination therapy for the treatment of valproic acid-induced hyperammonemia in critically ill patients
2021, Epilepsy Research
Citation Excerpt :
In patients receiving valproic acid, carnitine concentrations were found to be significantly reduced and ammonia levels significantly elevated compared to those who were not receiving valproic acid. Those who were given oral supplementation of carnitine had significant reductions in ammonia levels by approximately 50% (Ohtani et al., 1982). Lactulose is commonly used in practice to treat hepatic encephalopathy in patients with elevated ammonia, but has also been used in case reports either alone or in combination with levocarnitine for valproic acid-induced hyperammonemia (Aiyer et al., 2016; Sousa, 2013).
Critically ill patients treated with valproic acid are at risk for hyperammonemic encephalopathy. Both levocarnitine and lactulose, either alone or in combination, have been used for the treatment of hyperammonemia associated with valproic acid, however they have not been directly compared in the literature. The aim of this study was to compare the effect of levocarnitine, lactulose, and combination therapy for the treatment of valproic acid-induced hyperammonemia in critically ill patients.
This was a retrospective, system-wide, cohort study of critically ill patients who received valproic acid and levocarnitine, lactulose, or combination therapy from January 1, 2012 to October 31, 2019. The primary outcome of the study was the change in ammonia level from baseline to the lowest point within the first 48 h of treatment. Secondary outcomes included the change in ammonia levels within the first 7 days, the incidence of a clinically significant reduction, ICU length of stay, hospital length of stay, and hospital mortality.
A total of 371 charts were reviewed and 114 patients (levocarnitine [n = 15], lactulose [n = 72], and combination [n = 27]) were included. No difference in the primary outcome was observed (levocarnitine [11umol/L] vs. lactulose [20 umol/L] vs. combination [23 umol/L], p = 0.605). The incidence of a clinically significant reduction in ammonia levels at 48 h did not differ between groups, nor did mortality.
In critically ill patients with valproic acid-induced hyperammonemia, there was no significant difference in the reduction in ammonia levels in the first 48 h of treatment between levocarnitine, lactulose, and combination therapy.
Effects of L-carnitine supplementation in patients with childhood-onset epilepsy prescribed valproate
2021, Epilepsy and Behavior
Citation Excerpt :
Secondary carnitine deficiency has been reported following treatment with valproate (VPA), a widely used, broad-spectrum antiepileptic. Valproate depletes carnitine stores via various mechanisms [1–3]. Valproate combines with carnitine to form valproylcarnitine, which is excreted in urine.
The benefits of carnitine supplementation in patients treated with valproate (VPA) are not clear. Therefore, we retrospectively explored the benefits of carnitine supplementation by analyzing laboratory data.
We measured the serum-free carnitine (FC), VPA, aspartate aminotransferase, alanine aminotransferase, amylase, and ammonia levels, and the platelet count, in 69 patients with childhood-onset epilepsy treated with VPA. Eight patients had received carnitine supplementation. The serum FC and acylcarnitine levels were measured using an enzyme cycling method. We compared laboratory values between patients with and without carnitine supplementation and analyzed the correlations between serum FC levels and laboratory values.
The serum FC levels were normal (median, 48.8 μmol/L; range: 41.9–68.3 μmol/L) in all eight patients with carnitine supplementation, but below normal in 32 of 61 patients without supplementation. The median serum amylase levels were lower in the patients with carnitine supplementation (median, 48 U/L; range: 27–149 U/L) than in those without (median, 7 U/L; range: 14–234 U/L). The platelet count and serum ammonia levels did not differ significantly between patients with and without supplementation. There was no significant correlation between the serum FC level and the platelet count, serum amylase level, or ammonia level.
Carnitine supplementation helps maintain serum FC levels in patients treated with VPA. The lower serum amylase levels in patients with carnitine supplementation may reflect protective effects of carnitine against latent pancreatic injury.
EASL Clinical Practice Guidelines: Drug-induced liver injury
2019, Journal of Hepatology
Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver disorders faced by hepatologists, because of the myriad of drugs used in clinical practice, available herbs and dietary supplements with hepatotoxic potential, the ability of the condition to present with a variety of clinical and pathological phenotypes and the current absence of specific biomarkers. This makes the diagnosis of drug-induced liver injury an uncertain process, requiring a high degree of awareness of the condition and the careful exclusion of alternative aetiologies of liver disease. Idiosyncratic hepatotoxicity can be severe, leading to a particularly serious variety of acute liver failure for which no effective therapy has yet been developed. These Clinical Practice Guidelines summarize the available evidence on risk factors, diagnosis, management and risk minimization strategies for drug-induced liver jury.
Evaluation ofserum free carnitine/acylcarnitine levels and left ventricular systolic functions in children with idiopathic epilepsy receiving valproic acid
2018, Clinical Neurology and Neurosurgery
In the study, the effect of valproic acid on serum free/acylcarnitine levels and left ventricular systolic function in pediatric patients with idiopathic epilepsy receiving valproic acid was investigated.
Patients receiving valproic acid treatment for six months between January 2012 and December 2012 were evaluated. Blood samples were obtained from the participants twice (pretreatment and the sixth month of treatment) and serum-free and acylcarnitine levels (from C2 to C18:1-OH) were measured using tandem mass spectrometry. Cardiac functions (ejection fraction, shortening fraction, cardiac output, left ventricular systolic and diastolic diameters, left atrial diameter, aortic diameter, cardiac output, and myocardial performance index) were evaluated by echocardiography simultaneously.
A total of fourty patients, 23 female (57.5%) and 17 male (42.5%), with the diagnosis of idiopathic epilepsy and receiving valproic acid monotherapy were studied. Comparison of serum-free and acylcarnitine levels measured pretreatment and sixth month of treatment revealed a decrease in average C0 and C5:1 (respectively p < 0.001, p = 0.013) and an increase in C2, C3, C5-OH, C8:1 and C4-DC levels (respectively p < 0.001, p < 0.001, p = 0.019, p = 0.013, p < 0.001). Other serum acylcarnitine levels did not change significantly (p > 0.05). No difference was observed in concurrent echocardiographic measurements of left ventricular systolic function (p > 0.05).
The study demonstrated that valproic acid treatment results in low levels of free carnitine and changes in some acylcarnitine subgroups but has no influence on left ventricular systolic function.

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^*: Supported by a grant from the Ministry of Health and Welfare, Japan.

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Carnitine deficiency and hyperammonemia associated with valproic acid therapy*

J Pediatr

J Pediatr

Clin Chim Acta

Clin Chim Acta

Lancet

Valproic acid therapy in childhood epilepsy

JAMA

Pancreatitis associated with valproic acid therapy for epilepsy

Ann Neurol