Managing ammonia is vital in treating urea cycle disorders (UCDs)1,2

Any elevations in ammonia can endanger patients1

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Ammonia is a potent neurotoxin, even at elevated plasma levels that do not cause clinically recognizable symptoms.1,3-5 Hyperammonemia most commonly presents with neurologic signs and symptoms that may be acute or chronic, depending on the underlying abnormality.5 Hyperammonemia should be recognized early and treated immediately to prevent the development of life-threatening complications such as cerebral edema and brainstem herniation.5 During severe hyperammonemia, brain edema and death can result if ammonia levels are not reduced quickly.1 Hyperammonemic crises (HACs) are life-threatening events, but elevations in ammonia can cause neurocognitive damage in asymptomatic patients as well.1,6 The mechanisms of ammonia-induced brain damage are still not well understood, but studies have shown that ammonia alters several amino acid pathways and neurotransmitter systems, cerebral energy metabolism, nitric oxide synthesis, oxidative stress, and signal transduction pathways.7

Blood ammonia levels should be kept within a specified target range.1 If a UCD patient presents with any neurocognitive or other symptomatology, check their ammonia level.8

There is currently no US guidance on a specific ammonia target level for treatment. In a survey of 65 US genetic specialists and 1 pediatric neurologist, 82% of the physicians target ammonia levels of at least <50 µmol/L (<50 µmol/L, 54%; <35 µmol/L, 28%).1

The normal blood ammonia range is 11 to 32 µmol/L, but normal ranges may vary slightly among different laboratories.9

Neurotoxicity can occur with subclinical ammonia elevations, and cognitive deficits and fatalities have been reported even in patients who were previously not symptomatic and therefore not assessed for hyperammonemia1,2

Neurotoxicity can occur with subclinical ammonia elevations, and cognitive deficits and fatalities have been reported even in patients who were previously not symptomatic and therefore not assessed for hyperammonemia1,2

Current management strategies

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The cornerstones of UCD treatment are consistent dietary protein restriction and medications that facilitate ammonia clearance, including the nitrogen-scavengers sodium phenylbutyrate, glycerol phenylbutyrate, and sodium benzoate.10,11

  • Protein-restricted diets should minimize protein intake without compromising growth.8 Over-restriction of protein may compromise growth, development, and well-being and can cause metabolic instability. Optimal protein intake should be determined by individual titration in each patient. Physical activity levels, body weight, and other factors can affect the amount of protein needed.8 Nutritional supplementation with amino acids is also important12
  • Sodium phenylbutyrate is prescribed as tablets or as powder that patients mix with foods or liquids. Both are taken with meals13
  • Glycerol phenylbutyrate is an oral liquid that patients measure with a syringe. It is taken with or after meals14
  • Sodium benzoate is approved in the US only in a coformulation with sodium phenylacetate for central venous catheter administration during acute hyperammonemia15
  • Hemodialysis can be used to reduce ammonia levels in patients experiencing acute hyperammonemia16

Liver transplantation is the only curative option for UCDs, but it carries significant morbidity and mortality, does not correct all metabolic abnormalities, and is generally reserved only for patients who have recurrent hyperammonemia or are resistant to other treatments.12,17

The overall goal of UCD management is to help patients maintain normal development and neurocognitive function by minimizing ammonia buildup and preventing hyperammonemia.1,2

Dietary treatment is a cornerstone of UCD treatment.

Registered dietitians are key

Dietary treatment is a cornerstone of UCD therapy, and management plans should include the expertise of dietary specialists.2,8 Are you a registered dietitian? As an integral member of the care team for patients with UCDs, you are invited to sign up to get updates about UCDs and their treatment.

Dietary treatment is a cornerstone of UCD treatment.

Registered Dieticians are key

Dietary treatment is a cornerstone of UCD therapy, and management plans should include the expertise of dietary specialists.2,10 Are you a registered dietician? As an integral member of the care team for patients with UCDs, you are invited to sign up to get updates about UCDs and their treatment.

UCDs require a multidisciplinary approach1,8

Managing a patient with a UCD can require any or all of these healthcare professionals1,8:

  • Biochemical geneticists
  • Genetic counselors
  • Dietitians/nutritionists
  • Neuropsychologists
  • Nurses
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  • Laboratory technicians
  • Pharmacists
  • Intensivists
  • Nephrologists
  • Transplant surgeons

Medically treated UCD patients require lifelong monitoring by the entire multidisciplinary team.8

Nutritionists and registered dieticians are integral part of the care team for patients with urea cycle disorders.

Are you a physician or registered dietitian?

We know you’re an integral member of the care team for patients with UCDs, so we invite you to sign up to get updates about UCDs and their treatment.

Sign Up
Nutritionists and registered dieticians are integral part of the care team for patients with urea cycle disorders.

Are you a physician or registered dietitian?

We know you’re an integral member of the care team for patients with UCDs, so we invite you to sign up to get updates about UCDs and their treatment.

Sign Up

References

  1. Enns GM, Porter MH, Francis-Sedlak M, Burdett A, Vockley J. Perspectives on urea cycle disorder management: results of a clinician survey. Mol Genet Metab. 2019;128(1-2):102-108.
  2. Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32.
  3. Bosoi CR, Rose CF. Identifying the direct effects of ammonia on the brain. Metab Brain Dis. 2009;24(1):95-102.
  4. Sprouse C, King J, Helman G, et al. Investigating neurological deficits in carriers and affected patients with ornithine transcarbamylase deficiency. Mol Genet Metab. 2014;113(1-2):136-141.
  5. Ali R, Nagalli S. Hyperammonemia [updated November 25, 2021]. In: StatPearls [Internet]. StatPearls Publishing; 2022. Accessed March 20, 2022. https://www.ncbi.nlm.nih.gov/books/NBK557504/
  6. 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.
  7. Braissant O, McLin VA, Cudalbu C. Ammonia toxicity to the brain. J Inherit Metab Dis. 2013;36(4):595-612.
  8. 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.
  9. National Library of Medicine, National Institutes of Health and Human Services. Ammonia blood test. Accessed February 25, 2022. https://medlineplus.gov/ency/article/003506.htm#:~:text=The%20normal%20range%20is%2015,of%20your%20specific%20test%20results
  10. Soria LR, Ah Mew N, Brunetti-Pierri N. Progress and challenges in development of new therapies for urea cycle disorders. Hum Mol Genet. 2019;28(R1):R42-R48.
  11. Peña-Quintana L, Llarena M, Reyes-Suárez D, Aldámiz-Echevarria L. Profile of sodium phenylbutyrate granules for the treatment of urea-cycle disorders: patient perspectives. Patient Prefer Adherence. 2017;11:1489-1496.
  12. 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.
  13. BUPHENYL® (sodium phenylbutyrate). Prescribing information. Lake Forest, IL: Horizon Therapeutics.
  14. RAVICTI® (glycerol phenylbutyrate) oral liquid. Prescribing information. Deerfield, IL: Horizon Therapeutics.
  15. AMMUNOL® (sodium phenylacetate and sodium benzoate). Prescribing information. Scottsdale, AZ: Ucyclyd Pharma, Inc.
  16. Gupta S, Fenves AZ, Hootkins R. The role of RRT in hyperammonemic patients. Clin J Am Soc Nephrol. 2016;11(10):1872-1878.
  17. Machado MC, Pinheiro da Silva F. Hyperammonemia due to urea cycle disorders: a potentially fatal condition in the intensive care setting. J Intensive Care. 2014;2(1):22.