• Users Online: 24
  • Print this page
  • Email this page


 
 
Table of Contents
LETTER TO EDITOR
Year : 2023  |  Volume : 6  |  Issue : 1  |  Page : 1-2

A pathophysiological mechanism for valproate-induced hyperammonemia


Department of Medicine, Federal University of Santa Maria, Santa Maria, Brazil

Date of Submission11-Feb-2022
Date of Acceptance11-Sep-2022
Date of Web Publication3-Jan-2023

Correspondence Address:
Jamir Pitton Rissardo
Av. Roraima, 1000 - Camobi, Santa Maria - RS, 97105-900
Brazil
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jnsm.jnsm_19_22

Rights and Permissions

How to cite this article:
Rissardo JP, Fornari Caprara AL. A pathophysiological mechanism for valproate-induced hyperammonemia. J Nat Sci Med 2023;6:1-2

How to cite this URL:
Rissardo JP, Fornari Caprara AL. A pathophysiological mechanism for valproate-induced hyperammonemia. J Nat Sci Med [serial online] 2023 [cited 2023 Jan 30];6:1-2. Available from: https://www.jnsmonline.org/text.asp?2023/6/1/1/366996



Dear Editor,

We read the article entitled "Valproic Acid-Induced Hepatotoxicity in Rats: Protective Effect of Selenium" on the esteemed "Journal of Nature and Science of Medicine" with great interest. Adikwu and Liverpool assessed the protective effect of selenium against valproic acid (VPA)-associated hepatotoxicity in rat models. Hepatocyte necrosis and fatty change were observed in VPA-administered Wistar rats. But, selenium supplementation significantly improved liver injury.[1]

VPA is one of the most frequently used anticonvulsant drugs. Furthermore, it is approved for the management of migraine and bipolar mania due to its broad spectrum. The mechanism of this medication is not clearly understood, but probably involves an increased level of the inhibitory neurotransmitter gamma-aminobutyric acid.[2] In this context, VPA is associated with multiple adverse events such as influences in metabolic pathways causing hyperammonemia.

Herein, we would like to discuss more the mechanism of VPA-associated hyperammonemia. The hypotheses in the literature for this association are based on rat models. In hepatocytes, after entering the cell VPA receives the group coenzyme A (CoA) from acetyl CoA synthetase. VPA enters into the mitochondria by the carnitine shuttle. Inside the mitochondria, the valproyl-CoA inhibits the N-acetylglutamate (NAG) synthase. This decreases the production of NAG, which is an essential allosteric cofactor of carbamoyl phosphate synthetase 1 (CPS1). Therefore, the reduced activity of CPS1 leads to increased levels of ammonia, bicarbonate, and phosphate [Figure 1].[3]
Figure 1: Schematic diagram of valproate associated with hyperammonemia. CoA: Coenzyme A, CPS1: Carbamoyl phosphate synthetase 1, NAG: N-acetylglutamate, NAGS: N-acetylglutamate synthase, VPA: Valproic acid

Click here to view


The description of this pathway for the development of high levels of ammonia following VPA use is important since could partly explain commonly reported adverse events like abnormal movements.[2] It is believed that blood–brain barrier permeability may increase with ammonia, and other toxins can permeate more easily and deposit in the basal ganglia. The accumulation of these substances may affect cellular metabolism and the concentration of other neurotransmitters.[3]

Alhagamhmad et al. reported a healthy toddler aged 20 months who accidentally ingested 1500 mg of VPA. The individual showed hyperammonemic encephalopathy with preserved liver function. He was managed conservatively and gradually improved his level of consciousness. Their report was interesting because there was no sign of liver function abnormality.[4] Thus, this finding supports the hypothesis presented in [Figure 1], in which there is a metabolic pathway related to the liver that does not directly damage this organ.

In a recent Austrian study, two psychiatric inpatients with regular VPA intake who showed severe cognitive impairment were assessed. After further analysis, one of the patients had ornithine transcarbamylase deficiency and the other was in the use of multiple medications. Thus, Mitschek et al. conclude that urea cycle deficiencies and potential drug interactions should be considered in patients receiving VPA to avoid potential life-threatening events.[5]

In sum, VPA can be associated with hyperammonemia, which could be or not be related to liver function abnormalities. Valproyl-CoA may inhibit the NAG synthase leading to reduced activity of CPS1. There are many clinical manifestations including abnormal movements and cognitive impairment. Clinicians prescribing VPA should be aware of urea cycle disorders and polypharmacy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Adikwu E, Liverpool E. Valproic acid-induced hepatotoxicity in rats: Protective effect of selenium. J Nat Sci Med 2021;4:118-23.  Back to cited text no. 1
  [Full text]  
2.
Rissardo JP, Caprara AL, Durante Í Valproate-associated movement disorder: A literature review. Prague Med Rep 2021;122:140-80.  Back to cited text no. 2
    
3.
Wu J, Li J, Jing W, Tian X, Wang X. Valproic acid-induced encephalopathy: A review of clinical features, risk factors, diagnosis, and treatment. Epilepsy Behav 2021;120:107967.  Back to cited text no. 3
    
4.
Alhagamhmad M, Elarwah A, Alhassony A, Alougly S, Milad H, Dehoam A, et al. Valproate-induced hyperammonemic encephalopathy following accidental ingestion in a toddler. J Pediatr Pharmacol Ther 2021;26:210-2.  Back to cited text no. 4
    
5.
Mitschek MM, Vanicek T, Unterholzner J, Kraus C, Weidenauer A, Naderi-Heiden A, et al. How to prevent and manage hyperammonemic encephalopathies in valproate therapy. J Affect Disord Rep 2021;5:100186.  Back to cited text no. 5
    


    Figures

  [Figure 1]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
References
Article Figures

 Article Access Statistics
    Viewed408    
    Printed0    
    Emailed0    
    PDF Downloaded56    
    Comments [Add]    

Recommend this journal