Ammonia and Hyperammonemia

Ammonia is a small molecule that is produced as a part of normal tissue metabolism. Its formation results from the breakdown of compounds containing nitrogen, such as the amino groups in proteins and the nitrogenous bases in nucleic acids. In the tissues, ammonia is stored mainly in the form of amino acids, specifically the amino acid glutamine which has three amino groups. Normally, the body can remove excess ammonia easily via the liver pathway known as the urea cycle. This short, 4-step cyclical pathway converts two ammonia molecules into a small, water soluble urea molecule, making it able to be easily excreted in the urine. Without a functional urea cycle however, the body has no other adequate mechanism for getting rid of the ammonia that is constantly being produced by metabolism.

Liver damage or disease can disrupt the urea cycle, causing blood ammonia levels to rise. This is the most common cause of elevated ammonia in the adult population. In a pediatric patient, elevated ammonia is frequently seen as a consequence of an inborn error of metabolism (IEM). Many IEM, especially those in the urea cycle pathway, will result in elevated blood ammonia levels. In addition, in IEM causes, the ammonia concentrations may be well over 1000 µmol/L, when the normal range of ammonia is generally in the 30 – 50 µmol/L range. Elevated blood ammonia concentrations are serious because ammonia is toxic to the brain. The higher the ammonia concentration is, and the longer it stays high, the more brain damage that will occur.

Interestingly, the concentration of ammonia in the blood may not correlate with the neurological symptoms that are seen. Usually if the ammonia concentration is <100 µmol/L, the person will show no symptoms at all. Concentrations of ammonia in the 100 – 500 µmol/L range are associated with a wide variety of symptoms including: loss of appetite, vomiting, ataxia, irritability, lethargy, combativeness, sleep disorders, delusions and hallucinations. These patients may present with an initial diagnosis of altered mental status, and if there is no reason to suspect an elevated ammonia, the symptoms may lead to drug or alcohol testing. When ammonia concentrations are >500 µmol/L, cerebral edema and coma may be seen, with cytotoxic changes in the brain. Ammonia concentrations in the 1000+ µmol/L range are extremely critical and are treated aggressively with dialysis to pull the ammonia out of the system. In particular, urea cycle defects require close monitoring of ammonia and glutamine concentrations, with immediate response when they rise.

Laboratory testing for ammonia is often problematic as contamination can occur from a number of sources including atmospheric ammonia, smoking and poor venipuncture technique. In addition if the sample is not centrifuged and analyzed promptly, ammonia is formed by the continuous deamination of amino acids and the concentration increases by 20% in the first hour and up to 100% by 2 hours. Consequently samples to be tested for ammonia should be placed on ice immediately after being collected and transported to the lab for analysis as soon as possible. Many minimally elevated ammonia results are a consequence of poor sample handling. However, a truly elevated ammonia is a critical lab finding that should be addressed immediately.

-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.

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