Ammonia & Urea Metabolism
A schematic representation of ammonia production is illustrated below.
Ammonia is produced from dietary amino acids and by catabolism of amino acids, amines, nucleic acids, glutamine and glutamate (nitrogenous wastes) in peripheral tissues (especially skeletal muscle). Gastrointestinal micro-organisms (primarily coliforms and anaerobes in the colon and cecum) convert dietary amino acids and urea into ammonia in the gastrointestinal system. The ammonia is absorbed into the portal circulation, taken up by the liver and converted in the liver, via the urea cycle, into urea. Urea is then excreted into the gastrointestinal system (producing a futile cycle) and into the urine.
Of the total ammonia produced, 80-90% is shunted into the urea cycle, with the remaining 10-20% metabolised by peripheral tissues, including the kidney, heart, and brain.

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Assay

Measurement of ammonia is problematic as it is very unstable. Arterial blood samples are preferable to venous blood samples as results are more consistent. Heparinized plasma samples are preferable to serum. Due to the instability of ammonia and leakage of ammonia from erythrocytes, samples need to be assayed for ammonia as soon as possible after sample collection and maintained at 4 C (or on ice) until assay (stable for a maximum of 3 hours under these conditions). The sample must be separated from cells as soon as possible as leakage of ammonia from erythrocytes occurs within 30 minutes, resulting in artifactually high values. This is not easy to accomplish under most situations, therefore ammonia assays are not routinely performed. Furthermore, any ammonia in the environment (air, water supply) can contribute to the ammonia in the patient sample. Control samples (from a clinically healthy animal) should always be run in conjunction with patient samples, to ensure that sample collection and handling are not responsible for elevations in ammonia.

Increased ammonia

Ammonia is toxic to the CNS and is one of the causes of hepatic encephalopathy.
  • Artifact: Delayed sample submission, delayed plasma separation and hemolysis. This is the most common cause for an elevated ammonia concentration.
  • Physiologic High protein meals, extreme exercise.
  • Disease:
    1) Inherited disorders in the urea cycle: These have been reported rarely in dogs and in cats. Persistent hyperammonemia has been reported in 2 related Morgan weanlings and was thought to be due to defective mitochondrial transport of ornithine, a required intermediate in the urea cycle.
    2) Hepatic insufficiency: Ammonia increases when >60% hepatic function is lost. Ammonia will increase in portosystemic shunts because ammonia taken up by the portal system bypasses the liver. Ammonia is less sensitive than bile acids for the diagnosis of shunts in dogs (resting ammonia levels may be normal). Ammonia tolerance tests may be performed in animals with suspected shunts, but are a risk to the animal (hepatic encephalopathy) and have been supplanted by measurement of bile acids.
    3) Toxicosis: Urea toxicosis in ruminants.
    4) Miscellaneous: Lack of urea cycle intermediates (arginine deficiency in cats), renal shutdown. There have been reports of hyperammonemia in adult horses. These horses had concurrent gastrointestinal disease (e.g. colic) and signs of encephalopathy (head pressing, blindness and maniacal behavior). An underlying cause was not identified (they did not have concurrent liver disease).

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