Ammonium and Hyperammonemia

Ammonium is a product of nitrogen metabolism, is highly toxic and consists of nitrogen and hydrogen. Under physiological conditions its production and elimination rate is stable and closely regulated. Ammonium measurement is used in clinical practice for the diagnosis, monitoring and prognosis of hyperammonemia-related diseases. The accuracy of ammonium determination is highly dependent on both pre-analytical factors and the methodology used.

Among the pre-analytical factors linked to the patient we have the following: age (ammonium concentrations are four to eight times higher in neonates, and two to three times higher in children under three years of age), smoking (ammonium concentrations have been found to rise 10 μmol/L after a cigarette), exercise (physiological ammonium values increase more than three times after exercise), and certain drugs such as barbiturates and diuretics also increase ammonium levels. As for the sample to be used for ammonium determination, EDTA plasma is recommended.

What is the etiology of hyperammonemia?

Hyperammonemia is secondary to:

1. Increased ammonium production

a) Gastrointestinal bleeding.

b) Use of corticosteroids.

c) Trauma.

d) Total parenteral nutrition.

e) Infections due to urease degrading microorganisms.

f) Multiple myeloma.

2. Decrease in ammonium elimination

a) Fulminant hepatic failure

b) Porto-systemic short circuits

c) Drugs: among which salicylates, glycine, valproate, carbamazepine, ribavirin and pyrimethamine stand out.

d) Inborn errors of metabolism: including ornithine transcarbamylase deficiency, carbamyl synthesis deficiency, organic acidurias, alterations in fatty acid oxidation.

What is the relationship between ammonium and brain pathophysiology?

Under physiological conditions astrocytes supply adjacent neurons with adenosine-5-triphosphate, glutamine and cholesterol. Neurons metabolize glutamine to glutamate, a neurotransmitter that activates N-methyl D-aspartate receptors. After synaptic release, glutamate is recycled by astrocytes to glutamine. When ammonium levels are acutely elevated in the brain, the conduction of astrocytes and neurons is affected. Astrocytes metabolize ammonium to glutamine, resulting in elevated intracellular osmolarity causing edema and loss of astrocytes releasing inflammatory cytokines such as tumor necrosis factor alpha (TNFα), Interleukin-1 and 6 and interferon. In the remaining astrocytes there is ammonium-mediated inhibition of alpha-ketoglutarate dehydrogenase and depletion of the carboxylic acid necessary for glutamine synthesis, thus causing paralysis of the Krebs cycle. Decreased expression of glutamate receptors in astrocytes induces increased glutamate concentrations and seizures, increased cerebral blood flow, loss of effective cerebral autoregulation and development of cerebral edema and intracranial hypertension may occur.

Cerebral edema and herniation usually occur when arterial ammonium levels are greater than 200 μmol/liter. In patients with chronic hyperammonemia, ammonium is efficiently metabolized in the muscle and splanchnic bed, with less deleterious effect on the brain because there is no acute increase in osmolarity, which is associated with down-regulation of N-methyl-D-aspartate receptors and less glutamate neurotoxicity.


The initial evaluation of patients with suspected hyperammonemia consists of serum ammonium determination. Once hyperammonemia is confirmed, studies should be performed to determine its etiology, including: liver function tests, coagulation tests, liver ultrasound, abdominal computed axial tomography.

If these studies are not sufficient to determine the etiology, inborn errors of metabolism should be suspected and the following determinations should be performed in serum and urine: Citrulline, Glutamine, and Arginosuccinic acid.

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