1. Basic Concepts - Hyperammonaemia

Hyperammonaemia can either be due to increased production or decreased detoxification of ammonia, and there are many underlying causes for both of these groups.

Hyperammonaemia is life-threatening because of potential neuro-toxicity. Untreated, it can cause death, and, even when treated, patients may suffer significant neurological consequences.

Hyperammonaemia can be either primary (i.e. a defect within the urea cycle) or secondary (i.e. a defect outside the urea cycle leading to a decrease in normal urea cycle function).

Causes of increased ammonia production:

  • Infections
  • Fever of any cause
  • Vomiting
  • Gastrointestinal or internal bleeding (increased protein load)
  • Decreased energy and/or protein intake (e.g. fasting before surgery; major weight loss in neonates)
  • Catabolism and involution of the uterus during the postpartum period (OTC females)
  • Chemotherapy, high dose steroids
  • Prolonged or intense physical exercise
  • Surgery under general anesthesia
  • Urinary tract infection with urease producing bacteria & abnormal urethelium e.g. prune belly disease

Causes of decreased ammonia detoxification:

  • Primary defects of the urea cycle.
  • Secondary hyperammonaemia caused by inhibition of the urea cycle.
  • Secondary hyperammonaemia caused by urea cycle substrate deficiency.
  • Liver shunting.
  • Any cause of liver failure.
  • Transient hyperammonaemia of the newborn (THAN).

Causes of secondary hyperammonaemia:

  • Organic acidurias.
  • Fatty acid oxidation defects.
  • Carnitine cycle defects.
  • Pyruvate carboxylase deficiency.
  • Hyperinsulinism-Hyperammonaemia (HIHA) syndrome (rare in neonates).
  • Mitochondrial OXPHOS defects.
  • Lysinuric protein intolerance.
  • Ornithine aminotransferase (OAT) deficiency (mostly in neonates).
  • Pyruvate dehydrogenase complex disorders.
  • Pyrroline 5-carboxylate synthetase deficiency.
  • Carbonic anhydrase Va deficiency.

Fig 5 below illustrates the mechanisms by which various metabolites influence urea cycle function.

Legend: Figure showing sites of action of various compounds on urea cycle function by either leading to inhibition of enzymes (NAGS or CPS1) or to a decrease in intermediate substrates (both forms of inhibition are depicted as (-).
HIHA: Hyperinsulinism-hyperammonaemia syndrome; FAOD: Fatty acid oxidation defects; PDHCD: Pyruvate dehydrogenase complex disorders; OA: Organic acidemias; HHH: Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome; PC: Pyruvate carboxylase defect; Citrin: Citrullinaemia type 2; LPI: Lysinuric protein intolerance; P5CS: Pyrroline-5-carboxylate synthetase defect. The site of action of valproate has also been added. (+) Depicts the stimulatory effect of NAG on CPS1.

See Ref. 3 and 4 for further information.

You will learn more about hyperammonaemic disorders at a later stage of this course.