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Hyperammonemia Dangers of Hyperammonemia

Elevated ammonia levels, whether acute or chronic, may be toxic and may lead to significant neurological consequences.1

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  • May cause symptoms such as headaches, seizures, cognitive impairment, lethargy, and/or coma2
  • May affect the ability to learn and do well in school and/or at work1-4
  • May have severe effects on central nervous system3-6
  • May increase the risk of hyperammonemic crisis7

Potential Triggers of Hyperammonemic Crisis8

hyperammonemic-crisis-potential-triggers-pie-chart

The first hyperammonemic crisis may have severe neurological outcomes of disability or death when ammonia levels are particularly elevated. Neurocognitive function further declines with subsequent hyperammonemic events.

With acute or peak ammonia elevations, increases in blood ammonia concentration may result in cerebral edema, coma, and eventual death.5,9 These risks of mortality and neurological damage are influenced by the number, extent, and duration of acute episodes of hyperammonemic crisis.3,10-16

Similarly, chronic or moderate ammonia elevations over time may result in negative neurological and cognitive effects.1,9,17,18 The risk of irreversible brain damage is not predicted by the presence or absence of symptoms related to elevated ammonia levels.1,9,17,18 Even moderate increases in blood ammonia concentration may also lead to coma or death if left untreated.9

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  • References

    1. Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis. 2007;30(6):865-879. 2. Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: first revision. J Inherit Metab Dis. 2019;42(6):1192-1230. 3. Gropman AL, Prust M, Breeden A, Fricke S, VanMeter J. Urea cycle defects and hyperammonemia: effects on functional imaging. Metab Brain Dis. 2013;28(2):269-275. 4. Gyato K, Wray J, Huang ZJ, Yudkoff M, Batshaw ML. Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency. Ann Neurol. 2004;55(1):80-86. 5. Bosoi CR, Rose CF. Identifying the direct effects of ammonia on the brain. Metab Brain Dis. 2009;24(1):95-102. 6. Batshaw ML, Tuchman M, Summar M, Seminara J; Members of the Urea Cycle Disorders Consortium. A longitudinal study of urea cycle disorders. Mol Genet Metab. 2014;113(1-2):127-130. 7. Lee B, Diaz GA, Rhead W, et al. Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder [published correction appears in Genet Med. 2015 May;17(5):427. Genet Med. 2015;17(7):561-568. 8. Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. 2008;97(10):1420-1425. 9. Cohn RM, Roth KS. Hyperammonemia, bane of the brain. Clin Pediatr (Phila). 2004;43(8):683-689. 10. Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr. 2003;162(6):410-416. 11. Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med. 2007;356(22):2282-2292. 12. Kido J, Nakamura K, Mitsubuchi H, et al. Long-term outcome and intervention of urea cycle disorders in Japan. J Inherit Metab Dis. 2012;35(5):777-785. 13. Martín-Hernández E, Aldámiz-Echevarría L, Castejón-Ponce E, et al. Urea cycle disorders in Spain: an observational, cross-sectional and multicentric study of 104 cases. Orphanet J Rare Dis. 2014;9:187. Published 2014 Nov 30. 14. Uchino T, Endo F, Matsuda I. Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis. 1998;21(suppl 1):151-159. 15. Posset R, Garcia-Cazorla A, Valayannopoulos V, et al. Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders. J Inherit Metab Dis. 2016;39(5):661-672. 16. Nettesheim S, Kölker S, Karall D, et al. Incidence, disease onset and short-term outcome in urea cycle disorders-cross-border surveillance in Germany, Austria and Switzerland. Orphanet J Rare Dis. 2017;12(1):111. Jun 15. 17. Ah Mew N, Simpson KL, Gropman AL, et al. Urea cycle disorders overview. In: Adam MP, Mirzaa GM, Pagon RA, et al, eds. GeneReviews®. University of Washington, Seattle; 2017. Accessed March 13, 2023. http://www.ncbi.nlm.nih.gov/books/NBK1217/ 22. 18. Maestri NE, Lord C, Glynn M, Bale A, Brusilow SW. The phenotype of ostensibly healthy women who are carriers for ornithine transcarbamylase deficiency. Medicine (Baltimore). 1998;77(6):389-397.