Why does valproic acid cause elevated ammonia?
Ah, serum ammonia. A lab that is often sent and often a head-scratcher. Sometimes an altered patient with cirrhosis and the most textbook asterixis will have a normal serum ammonia. And other times a patient has a sky-high ammonia and you have no idea why. Have you ever stopped and checked if they’re on valproic acid?
Valproic acid (VPA) is a commonly-prescribed anti-seizure medication. It was first synthesized in 1881 by the American Chemist Beverly Burton, but only found clinical use nearly a century later, and by accident. In Grenoble, France, a researcher named Pierre Eymard was studying the anti-convulsant properties of various herbal compounds and he used VPA as a solvent. He found that all of the herbal compounds prevented seizures in his animal subjects, so he then tested VPA on them and realized that VPA itself was the therapeutic agent. Within a few years, the same group that had made the initial observations also reported the effect in patients with epilepsy and VPA quickly became a wisely-used anti-epileptic drug (AED) in Europe. It wasn’t approved for use in the USA until 1978 (possibly because the anti-emetic thalidomide, which we discussed in Episode 83, had also seemed safe in animal models and ended up causing birth defects in thousands of babies).
To be clear, VPA is also well-known to cause neural and cardiac defects in fetuses and is mostly contraindicated in pregnancy. But some early studies on VPA occasionally noted some strange side-effects in adults. A 1974 study published in The British Medical Journal noted that “drowsiness occurred in eight patients, two becoming so drowsy as to be nearly stuporous.” All the patients were receiving other anticonvulsants, so the thought was that combining AEDS was the cause. However BMJ published the first randomized controlled trial of VPA the following and none of the 20 patients had severe side effects. In 1979, a case series of several patients again reported “stupor,” like a 37-year-old on 1,750 mg per day of VPA. However, they were also given phenytoin, carbamazepine, and primidone. After stopping VPA, the patient returned to baseline, only to become altered when they resumed VPA. All of these studies seemed to indicate that combining AEDs (especially with VPA) was the cause of altered mental status. A very reasonable theory, as polypharmacy is widely known to cause cognitive impairment, especially in our older patients.
In the above-mentioned case series, the authors wrote that “it is unlikely that stupor was caused by metabolic disturbances, since in each case the serum glucose, blood urea nitrogen, [AST], LDH, and alkaline phosphatase were normal.” Who did they neglect to check amongst the usual rogues gallery of altered mental status (AMS)? Ammonia.
Around that time, David Coulter and Richard Allen from the University of Michigan Medical Center observed increased plasma glycine and propionic acid concentrations in patients with valproic acid toxicity. Elevations in these compounds are rare and usually a sign of a inherited metabolic disorder. Coulter and Allen noted that the levels weren’t nearly as high as one would expect in those diseases. However, they’d also recently seen a patient on VPA with altered mental status who had hyperammonemia without any history of liver disease (the usual suspect as the liver is the main clearer of ammonia in the body). They wondered if there was a connection between these four compounds: VPA, ammonia, glycine and propionic acid. The next time a patient on VPA presented with AMS and hyperammonemia, they stopped the VPA and the ammonia levels and mental status improved. After giving the same patient a load of VPA, he glycine, propionic acid, and ammonia concentrations all increased and they became altered yet again.
We’re hinting (if that) at a connection between VPA and ammonia. But why does that happen? Dust off your biochemistry textbooks because we’re going to talk about the urea cycle (don’t worry, we’ve put a diagram below so you can follow along).
The primary role of the urea cycle is to convert toxic ammonia (which is produced both by cells and also bacteria in the gut) into urea, a non-toxic compound excreted in urine. One of the metabolites of VPA inhibits N-acetyl-glutamate synthase, also known as NAGS. As its name implies, NAGS is essential for synthesizing N-acetyl-glutamate, a required activator of carbamoyl phosphate synthetase I, the first and rate-limiting enzyme of the urea cycle. With NAGS inhibited, the urea cycle is impaired and toxic ammonia builds up. Elevated glycine ( a precursor molecule to ammonia) and propionic acid are signs of an impaired urea cycle. On an interesting side note, propionic acidemia, a rare inborn error of metabolism, can similarly cause hyperammonemia because one of the precursors of propionic acid is also a NAGS inhibitor!
To make matters worse, VPA depletes carnitine, which alters valproic acid metabolism, generating toxic metabolites that further inhibit ammonia elimination. In fact, carnitine supplementation is one of the mainstays of VPA-induced hyperammonemia treatment, as multiple studies have shown it to help reduce ammonia levels and improve mental status. Other things that researchers have shown to be effective include carbapenem antibiotics, which work by irreversible inhibition of acylpeptide hydrolase, a compound that helps convert VPA metabolites back to the active form.
VPA-induced hyperammonemia is not the most common of diagnoses. But it’s not as rare as you might think. Between 17% and 28% of patients on VPA have hyperammonemia. And since symptomatic encephalopathy occurs in about 3-5% of patients with hyperammonemia, it’s always good to pause when you see VPA on a med list and wonder if it’s wandered into unintended biochemical territories
Take Home Points
- Valproic acid can lead to an increase in serum ammonia levels in approximately a quarter of patients, although most remain asymptomatic.
- The primary mechanism is through inhibition of the urea cycle
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Credits & Suggested Citation
◾️Episode written by Tony Breu
◾️Show notes written by Tony Breu and Giancarlo Buonomo
◾️Audio edited by Clair Morgan of nodderly.com
Breu AC, Abrams HR, Cooper AZ Buonomo G, Manna, M. Ammonia Rising. The Curious Clinicians Podcast. October 8th, 2025.
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