Excerpt from Hyperammonemia

Synonyms, Key Words, and Related Terms: urea cycle disorders, urea cycle enzyme deficiencies, hepatic encephalopathies, Reye syndrome, toxic encephalopathies, metabolic disorders, ornithine transcarbamoylase deficiency, OTC deficiency, N-acetylglutamate synthetase deficiency, NAGS deficiency, carbamoyl phosphate synthetase I deficiency, carbamyl phosphate synthetase I deficiency, CPS I deficiency, argininosuccinic acid synthetase deficiency, AS deficiency, argininosuccinic lyase deficiency, AL deficiency, arginase deficiency, isovaleric acidemia, propionic acidemia, methylmalonic acidemia, glutaric acidemia type II, multiple carboxylase deficiency, beta-ketothiolase deficiency, congenital lactic acidosis, pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, mitochondrial disorders, acyl CoA dehydrogenase deficiency, systemic carnitine deficiency, hyperammonemia-hyperornithinemia-homocitrullinuria, HHH

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Background

Ammonia is a normal constituent of all body fluids. At physiologic pH, it exists mainly as ammonium ion. Reference serum levels are less than 35 µmol/L. Excess ammonia is excreted as urea, which is synthesized in the liver through the urea cycle. Sources of ammonia include bacterial hydrolysis of urea and other nitrogenous compounds in the intestine, the purine-nucleotide cycle and amino acid transamination in skeletal muscle, and other metabolic processes in the kidneys and liver.

Increased entry of ammonia to the brain is a primary cause of neurological disorders associated with hyperammonemia, such as congenital deficiencies of urea cycle enzymes, hepatic encephalopathies, Reye syndrome, several other metabolic disorders, and some toxic encephalopathies.

Pathophysiology

Ammonia is a product of the metabolism of proteins and other compounds, and it is required for the synthesis of essential cellular compounds. However, a 5- to 10-fold increase in ammonia in the blood induces toxic effects in most animal species, with alterations in the function of the central nervous system.

On the basis of animal study findings, the mechanism of ammonia neurotoxicity at the molecular level has been proposed. Acute ammonia intoxication in an animal model leads to increased extracellular concentration of glutamate in the brain and results in activation of the N-methyl D-aspartate (NMDA) receptor. Activation of this receptor mediates ATP depletion and ammonia toxicity; blocking the NMDA receptor with dizocilpine (MK-801) prevents both phenomena. The ATP depletion is due to activation of Na⁺/K⁺-ATPase, which, in turn, is a consequence of decreased phosphorylation by protein kinase C. Activation of the NMDA receptor is probably the cause of seizures in acute hyperammonemia.

High levels of ammonia also induce other metabolic changes that are not mediated by activation of the NMDA receptor and thus are not involved directly in ammonia-induced ATP depletion or neurotoxicity. These include increases in brain levels of lactate, pyruvate, glutamine, and free glucose, and decreases in brain levels of glycogen, ketone bodies, and glutamate.

Chronic hyperammonemia is associated with an increase in inhibitory neurotransmission as a consequence of two factors. The first is down-regulation of glutamate receptors secondary to excessive extrasynaptic accumulation of glutamate. The second is an increased GABAergic tone resulting from benzodiazepine receptor overstimulation by endogenous benzodiazepines and neurosteroids. These changes probably contribute to deterioration of intellectual function, decreased consciousness, and coma.

Ammonia also increases the transport of aromatic amino acids (eg, tryptophan) across the blood-brain barrier. This leads to an increase in the level of serotonin, which is the basis for anorexia in hyperammonemia.

Frequency

United States

Collecting accurate data on the frequency of metabolic disorders is difficult, because the information collected is representative of the particular area or the population group; however, the prevalence of urea cycle disorders is estimated at 1 case per 30,000 live births.

International

In a recently published study, the incidence of urea cycle disorders in British Columbia was shown to be 1 case per 53,717 persons, which is approximately 1.9 cases per 100,000 live births.

Mortality/Morbidity

Coma and cerebral edema are the major causes of death; the survivors of coma have a high incidence of intellectual impairment.

Race

These disorders have been observed in all races.

Sex

All the urea cycle disorders are inherited in an autosomal recessive pattern, except ornithine transcarbamoylase (OTC) deficiency, which is inherited as an X-linked trait; however, female carriers of the OTC gene can become symptomatic.

Age

Early-onset hyperammonemia presents in the neonatal period. Urea cycle disorders can present later in life (see History).

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