What Causes Hyperammonemia?

Patient Presentation
An 11-year-old male had a recent viral illness. He was improving but during the night he got up to use the restroom, collapsed and died. He was later diagnosed with Reye’s syndrome. His parents, along with other parents and researchers, worked trying to find a cause and advocated for changes in medical practice. Aspirin in the setting of viral illnesses was determined to be a major risk factor, and with continued advocacy, aspirin and aspirin products had warning labels placed on them in 1986. This happy, young boy is still remembered through educational scholarships for local high school students dedicated to his memory.

Reye’s syndrome (RS)is named for Dr. Douglas Reye who along with Drs. G. Morgan and J. Baral described encephalopathy and fatty accumulation and degeneration in children in a 1963 Lancet article. RS usually affects children but can occur at all ages. All organs can be affected but the liver and brain are primarily affected causing liver failure and encephalopathy as toxic metabolites (especially ammonia) accumulate, and intracranial hypertension and cerebral edema occurs. As the ammonia levels begin to rise (> 100 mg/dL) patients lose their appetite, have nausea and emesis and mental status changes which includes personality changes, agitation/combativeness, disorientation and insomnia. As the levels continue to rise (150-200 mg/dL) loss of consciousness and seizures can occur. At levels of 200-400 mg/dL coma and respiratory failure can occur.

RS occurs after a previous viral illness, especially varicella or influenza, usually during the recovery phase. Research in the 1970s and 80s determined that salicylates (aspirin) were a major risk factor for RS although the mechanism is still not understood. Warning labels were added to salicylate products in the US starting in 1986. Aspirin is therefore not recommended for use for most acute childhood illnesses and has been replaced by acetaminophen or ibuprofen. Similar products such as bismuth subsalicylate products also should be used with great care at any time particularly around the time of a viral illness. This change in medical practice has caused the number of RS cases to dramatically decrease.

The differential diagnosis of RS includes viral and bacterial meningoencephalitis, sepsis, diabetes, poisons or drug overdose, liver failure, non-accidental trauma, sudden infant death syndrome or psychiatric problems.

Learning Point
The differential diagnosis of hyperammonemia includes:

  • Increased production
    • Protein load
      • Gastrointestinal hemorrhage or bypass
      • Parenteral nutrition
      • Multiple myeloma
      • Stem cell transplant, allogenic
    • Increased catabolism
      • Corticosteroids
      • Exercise, strenuous
      • Starvation
      • Seizures
    • Genitourinary problems
      • Congenital ureteric obstruction with associated infection
      • Urease-producing organisms (e.g. Proteus, Klebsiella) causing infection
    • Infectious
      • Herpes simplex virus infection
      • Severe systemic neonatal illness
      • Neonatal sepsis
      • Reye syndrome
  • Decreased elimination
    • Liver and biliary tract problems
      • Liver failure, acute or chronic
      • Biliary atresia
      • Porto-systemic shunt (vascular bypass) of the liver
    • Inborn errors of metabolism
      • Urea cycle enzyme defects
        • Ornithine transcarbamoylase (OTC) deficiency
        • Arginase deficiency
        • Argininosuccinate synthase (ASS) deficiency – citrullinemia
        • Argininosuccinate lyase (ASL) deficiency – argininosuccinic aciduria
        • Carbamoylphosphate synthase 1 (CPS 1) deficiency
        • N-Acetylglutamate synthase (NAGS) deficiency
      • Transport defects of urea cycle intermediates
        • Aspartate-glutamate shuttle (citrin) deficiency
        • Lysinuric protein intolerance
        • Mitochondrial ornithine transporter (HHH syndrome)
        • Methylmalonic acidemia
        • Organic acidemias
        • Propionic acidemia
      • Fatty acid oxidation disorders
        • Medium-chain acyl-CoA dehydrogenase deficiency
        • Long-chain fatty acid oxidation defects
        • Systemic primary carnitine deficiency
      • Galactosemia
      • Hyperinsulinism-hyperammonemia syndrome
      • Ornithine aminotransferase deficiency
      • Mitochondrial respirator chain defects
      • Pyruvate carboxylase deficiency
      • Tyrosinemia type 1
    • Medications
      • 5-pentanoic acid
      • Acetaminophen
      • Asparaginase
      • Aspirin
      • Carbamazepine
      • Cyclophosphamide
      • Rifampicin
      • Valproic acid
  • Miscellaneous
    • Transient hyperammonemia of the newborn
    • Sampling error – inappropriate sample or sample not analyzed immediately

    Questions for Further Discussion
    1. How to various inborn errors of metabolism present? For a discussion of inborn error of metabolism presentations click here.
    2. How does liver failure present?

    Related Cases

    To Learn More
    To view pediatric review articles on this topic from the past year check PubMed.

    Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

    Information prescriptions for patients can be found at MedlinePlus for this topic: Reye Syndrome

    To view current news articles on this topic check Google News.

    To view images related to this topic check Google Images.

    To view videos related to this topic check YouTube Videos.

    Reye RD, Morgan G, Baral J (1963). “Encephalopathy and fatty degeneration of the viscera. A Disease entity in childhood”. Lancet. 2 (7311): 749-52.

    Greeley Daily Tribune. Parents Fighting the Puzzle of Reye’s Syndrome. May 26, 1977, Thu, Page 53. Available from the Internet at https://www.newspapers.com/clip/117982/parents_fighting_the_puzzle_of_reyes/(cited 12/16/16).

    New York Times. Aspirin Labels to Warn About Reye Syndrome. March 8, 1986. Available from the Internet at http://www.nytimes.com/1986/03/08/us/aspirin-labels-to-warn-about-reye-syndrome.html (cited 12/16/16).

    National Institute of Neurological Diseases and Stroke. NINDS Reye’s Syndrome Information Page. Available from the Internet at http://www.ninds.nih.gov/disorders/reyes_syndrome/reyes_syndrome.htm (rev. 9/25/2009, cited 12/16/16).

    Singh P, Goraya JS, Gupta K, Saggar K, Ahluwalia A. Magnetic resonance imaging findings in Reye syndrome: case report and review of the literature. J Child Neurol. 2011 Aug;26(8):1009-14.

    Paprocka J, Jamroz E. Hyperammonemia in children: on the crossroad of different disorders. Neurologist. 2012 Sep;18(5):261-5.

    Ahrens-Nicklas RC, Edmondson AC, Ficicioglu C. An 8-year-old girl with abdominal pain and mental status changes. Pediatr Emerg Care. 2015 Jun;31(6):459-62.

    El-Hattab AW. Inborn errors of metabolism. Clin Perinatol. 2015 Jun;42(2):413-39, x.

    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa Children’s Hospital