The measurement of ammonia blood levels in patients taking valproic acid: Looking for problems where they do not exist?
Introduction
Valproic acid (VPA) is an antiepileptic drug (AED) commonly used in the treatment of generalized as well as focal epilepsy. Hepatic insufficiency associated with hyperammonemia (HA) and hyperammonemic encephalopathy are among the most serious adverse effects. Not surprisingly, the development of HA in VPA-treated patients often raises concern among clinicians over the potential risk of hepatic failure or encephalopathy, even in the absence of any clinical symptoms. In fact, the most recent Physicians’ Desk Reference recommends close monitoring of plasma ammonia (NH3) levels in patients with asymptomatic HA and consideration of the discontinuation of VPA if the elevation persists [1]. This leads in many cases to the unnecessary discontinuation of the drug. In fact, there is a large body of literature that indicates the relatively high prevalence of HA in asymptomatic patients whose liver function is intact.
Ammonia, the product of degradation of amino acids and other nitrogenated compounds, is a normal constituent of all body fluids. Its elimination is promoted by the urea cycle, which consists of a series of metabolic reactions in which the liver plays a fundamental role. Any disturbance in the urea cycle can result in an increase in intracellular and plasmatic NH3 and suggest hepatic dysfunction.
The mechanism by which VPA causes HA is not well understood. Some hypotheses have implicated the liver, whereas others have implicated the kidneys. In isolated rat hepatocytes, accumulation of valproyl-CoA (esterified valproic acid) has been demonstrated. Valproyl-CoA has been shown to reduce hepatocyte N-acetyl glutamate which is required for carbamyl phosphate synthetase I activity and seems to play an important role in the short-term regulation of the synthesis of urea. Therefore, a VPA-induced decrease in N-acetyl glutamate could reduce the synthesis of urea and produce a rise in NH3[2].
Two studies, one carried out in humans and the other in rats, suggested a pathogenic role for the kidneys in the development of VPA-induced HA [3]. The investigators measured NH3 plasma concentrations in the femoral artery and femoral, internal jugular, renal, and hepatic veins following intravenous administration of VPA in two patient groups: a group of patients who were already on chronic VPA therapy and a control group naive to VPA. Both chronic and acute administration of VPA increased the concentrations of NH3 released by the kidney into the circulation. In the study performed in rats, the renal origin of HA induced by VPA was confirmed by its absence after bilateral nephrectomy [4].
The main purpose of this study was to review the literature in an attempt to estimate the prevalence and magnitude of VPA-related HA. Our secondary objectives were to analyze the association of HA with clinical symptomatology and to determine the existence of risk factors for the development of HA.
Section snippets
Methods
We performed a systematic review of articles available on Pubmed and Cochrane between 1980 and December 2005 and identified all articles that included the terms valproate or valproic acid and ammonia or hyperammonemia, and reviewed all the related studies cited. Subsequently, we selected the articles that met the following criteria:
- (1)
Articles that reported on the prevalence and clinical significance of HA in VPA-treated patients,
- (2)
studies in humans,
- (3)
studies with more than 10 patients,
- (4)
prospective and
Results
Among the 24 studies included, 7 were prospective [5], [6], [7], [8], [9], [10], [11] and 17 cross-sectional [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]. Two studies have prospective and cross-sectional components [5], [11]. Seven studies were performed in adults [5], [6], [7], [8], [17], [20], [27], 12 in pediatric patients [11], [12], [13], [14], [15], [16], [18], [19], [22], [23], [24], [25], and the other 5 in both age groups [9], [10]
Discussion
Review of these studies demonstrates that HA is a very common occurrence in VPA-treated patients and is unlikely to be a risk factor for the development of liver failure. It can be detected during the first few hours after the start of VPA and persists throughout its administration.
With respect to the magnitude of the increase in NH3, one of the limitations of our findings stems from the difficulty in comparing data from different series, as the methods used to measure NH3 levels varied among
Conclusion
Review of these studies clearly demonstrates that measurement of NH3 blood levels in asymptomatic patients taking VPA is unnecessary and can only lead to diagnostic confusion. Furthermore, VPA should not be discontinued solely on the basis of HA. Ammonia blood levels should be measured only in patients taking VPA exhibiting signs of an acute encephalopathic process. It should, however, be emphasized that such occurrences need not be the expression of HA-related encephalopathy, but may result
Acknowledgment
The authors thank Dr. Tudor Iacob for his assistance in the preparation of this article.
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