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

CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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