Ammonia from deamination is converted to urea in the liver
Mnemonic
“Ordinarily, Careless Crappers Are Also Frivolous About Urination”:
- O - Ornithine
- C - Carbamoyl phosphate
- C - Citrulline
- A - Aspartate
- A - Argininosuccinate
- F - Fumarate
- A - Arginine
- U - Urea
The cycle spans two compartments: the first two steps are mitochondrial, the rest cytosolic, and ornithine and citrulline are shuttled across.
The rate limiting enzyme is carbamoyl phosphate synthetase I, activated by N-acetylglutamate. Ornithine transcarbamylase deficiency is the commonest defect, X-linked, and produces hyperammonaemia with a raised orotic acid and a low urea, distinguishing it from other causes.
Expansion
- Transamination transfers amino groups to glutamate, using vitamin B6 dependent aminotransferases (ALT and AST)
- Oxidative deamination of glutamate releases ammonia
- Muscle exports nitrogen safely as glutamine and alanine (the glucose-alanine cycle)
- The urea cycle in periportal hepatocytes converts ammonia to urea, which is excreted renally
Ammonia is highly toxic to the brain, being converted to glutamine in astrocytes, causing swelling and cerebral oedema.
Causes of hyperammonaemia
- Liver failure and portosystemic shunting
- Urea cycle defects, of which ornithine transcarbamylase deficiency is the commonest and is X-linked
- Sodium valproate, and organic acidaemias
Urea cycle disorders classically present in a neonate after a protein feed, with vomiting, lethargy and coma, and the biochemical signature of hyperammonaemia with respiratory alkalosis (ammonia stimulates the respiratory centre) and a normal anion gap, which separates them from the organic acidaemias.
Treatment is protein restriction, calories to prevent catabolism, and nitrogen scavengers.