Ammonia and hyperammonaemia

OVERVIEW

• Hyperammonaemia is easily forgotten as a potential cause of metabolic encephalopathy
• Ammonia is produced by the hepatic metabolism of amino acids and is primarily degraded via the urea cycle
• In the absence of obvious liver dysfunction or a drug cause, metabolic errors should be considered — some metabolic errors can go undiagnosed until adulthood

AMMONIA

• NH3
• colourless pungent-smelling gas
• highly water soluble
• produced from protein, amino acid and glutamine break down
• toxic to human cells
• normal range (varies between laboratories: 10 to 65 umol/L or 17-110 mg/L

Produced by:

1. GI tract – action of enteric organisms on dietary proteins and amino acids
2. liver – detoxified to urea
3. renal –  glutamine break down in proximal tubule (combines with H+ -> NH4+ and eliminated)

CAUSES OF HYPERAMMONAEMIA

Overproduction of ammonia

Protein/ amino acid load

• gastrointestinal hemorrhage
• gastric bypass
• multiple myeloma
• allogeneic stem cell transplantation
• parenteral nutrition
• glycine intoxication (TURP syndrome)

Increased catabolism

• starvation
• seizures
• vigorous exercise
• burns
• corticosteroids

Urinary

• urease producing infection (e.g. Proteus and Klebsiella spp.)
• congenital ureteric obstruction associated with infection

Reduced elimination of ammonia

Liver failure

• acute
• chronic
• porto-systemic shunt

Drugs and toxins

• valproate
• carbamazepine
• topiramate
• salicylates
• rifampicin
• hepatotoxic drugs (e.g. paracetamol, halothane, some chemotherapeutic agents) and toxins (e.g. mushrooms)

Metabolic errors

• urea cycle disorders (e.g. ornithine transcarbamylase deficiency, carbamoyl phosphate synthetase deficiency 1, and citrullinemia)
• organic acidemias (e.g. (propionic acidemia, methylmalonic acidemia, maple syrup urine disease, and dibasic aminoacidurias hyperammonemic-hyperornithinemia-homocitrullinuria)
• fatty acid oxidation disorders

Other

• Type 1 (distal) renal tubular acidosis

CLINICAL FEATURES

• tremor
• slurred speech
• blurred vision
• coma
• dehydration
• tachypnoea

INVESTIGATIONS

• plasma ammonia
• ABG – metabolic acidosis
• glucose
• lactate
• urinary and plasma ketones
• urinary and plasma amino acids
• CT: cerebral oedema

MANAGEMENT

• treat cause
• decreased intake: nutrition with low protein
• increased elimination
  • haemodialysis/ renal replacement therapy
  • drugs to lower ammonium level (e.g. sodium benzoate, sodium phenylacetate, sodium phenylbutyrate)
• liver transplantation if indicated

PROS AND CONS OF AMMONIA AS A TEST

Pros

• good availability and turn around times
• Used as an indicator of hepatic encephalopathy
• Very high levels may indicate cerebral herniation
• May be useful to indicate undiagnosed cirrhosis in patients presenting with altered mental status

Cons

• Normal values do not rule out encephalopathy – therefore of limited utility in patients with known chronic liver disease
• Not useful as a monitor during therapy
• Must be sent on ice

References and Links

Journal articles

• Clay AS, Hainline BE. Hyperammonemia in the ICU. Chest. 2007 Oct;132(4):1368-78. Review. PMID: 17934124. [article]
• Crosbie DC, et al. Late-onset ornithine transcarbamylase deficiency: a potentially fatal yet treatable cause of coma. Crit Care Resusc 2009; 11:222-227 PMID: 19737127.
• Gupta S, Fenves AZ, Hootkins R. The Role of RRT in Hyperammonemic Patients. Clin J Am Soc Nephrol. 2016;11(10): 1872-1878. PMID: 27197910