Understanding the causes of elevated ammonia

Episodes of hyperammonemia can result from several causes1,2

Numerous events can cause hyperammonemia, including1,2:

  • Viral infection
  • Surgery
  • Prolonged fasting

Infection, often respiratory, is the most common precipitant of acute hyperammonemia.1-3 Infections in UCDs are also associated with increased morbidity as indicated by increases in hospitalization rates, longer hospital stays, and use of intravenous ammonia scavengers.2

Dietary indiscretion can also trigger hyperammonemia.1,2 In addition to excess protein intake, insufficient protein or calorie intake can also cause hyperammonemia by enhancing whole-body protein catabolism.2

Certain medications can induce hyperammonemia by interfering with the urea cycle.4 These include4:

  • Valproic acid
  • Carbamazepine
  • Sulfadiazine
  • Ribavirin
  • Salicylates
  • Glycine

Treatment nonadherence hinders ammonia management1,5

Despite prescribed treatment, UCD patients remain at high risk of hyperammonemia that can cause cerebral edema and neurologic deficits and can also become life-threatening.1,5,6 Obstacles associated with current nitrogen-scavenger therapies and diet can lead to inadequate adherence, contributing to elevated ammonia levels.1,5

Physicians, patients, and caregivers all have indicated that UCD treatment adherence is inadequate and is impacted by attributes including1,5:

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Tolerability (eg, gastrointestinal discomfort, poor taste/odor)1,7-11
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Administration (eg, high pill burden, dosing frequency)1,12
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Cost and access (including navigating insurance)13

Children sometimes associate the bad taste of their medication with the food with which the medication is given.7 This can create problems adhering to the strict diet necessary in UCDs, compromising ammonia control and potentially leading to clinical decompensation.7

In UCDs, nonadherence to diet and medications can lead to elevated ammonia, neurocognitive damage, HACs, and potentially death.1,5

In UCDs, nonadherence to diet and medications can lead to elevated ammonia, neurocognitive damage, HACs, and potentially death.1,5

Barriers to adherence with current UCD treatments: survey results1

A survey of physicians (n=25), adult UCD patients (n=52), and caregivers of patients (n=114) identified some of the main problems with current treatment.1

The main problems identified by patients in the survey were1:

  • Side effects
  • Difficult to take due to taste and strong odor

Physician-reported reasons for their patients’ daily nonadherence with treatment included1:

  • Amount of medication taken each time
  • Difficulty swallowing the medication
  • Forgetting to take it
  • Dosing frequency
  • Side effects
  • Difficulty keeping the medication down

58% of physicians said they believed their UCD patients to be “compliant” (45%) or “very compliant” (13%) with their treatment.1

58% of physicians said they believed their UCD patients to be “compliant” (45%) or “very compliant” (13%) with their treatment.1

Cost and insurance coverage issues can
also impede appropriate treatment13

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Parents of patients with UCDs have cited both the cost of care and the burden of navigating insurance coverage as major challenges to treatment adherence.13

Financial implications of UCD treatment contribute to the overall burden of disease and can factor into treatment decisions.1,13

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References

  1. Shchelochkov OA, Dickinson K, Scharschmidt BF, Lee B, Marino M, Le Mons C. Barriers to drug adherence in the treatment of urea cycle disorders: assessment of patient, caregiver and provider perspectives. Mol Genet Metab Rep. 2016;8:43-47.
  2. McGuire PJ, Lee HS, members of the Urea Cycle Disorders Consortium, Summar ML. Infectious precipitants of acute hyperammonemia are associated with indicators of increased morbidity in patients with urea cycle disorders. J Pediatr. 2013;163(6):1705-1710.
  3. 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.
  4. Upadhyay R, Bleck TP, Busl KM. Hyperammonemia: what urea-lly need to know: case report of severe noncirrhotic hyperammonemic encephalopathy and review of the literature. Case Rep Med. 2016;2016:8512721.
  5. 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.
  6. Bosoi CR, Rose CF. Identifying the direct effects of ammonia on the brain. Metab Brain Dis. 2009;24(1):95-102.
  7. Guffon N, Kibleur Y, Copalu W, Tissen C, Breitkreutz J. Developing a new formulation of sodium phenylbutyrate. Arch Dis Child. 2012;97(12):1081-1085.
  8. Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr. 1996;43:127-170.
  9. Dover GJ, Brusilow S, Charache S. Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate. Blood. 1994;84(1):339-343.
  10. Collins AF, Pearson HA, Giardina P, McDonagh KT, Brusilow SW, Dover GJ. Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial. Blood. 1995;85(1):43-49.
  11. Feillet F, Leonard JV. Alternative pathway therapy for urea cycle disorders. J Inherit Metab Dis. 1998;21(suppl 1):101-111.
  12. 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.
  13. Gerstein MT, Markus AR, Gianattasio KZ, et al. Choosing between medical management and liver transplant in urea cycle disorders: a conceptual framework for parental treatment decision-making in rare disease. J Inherit Metab Dis. 2020;43(3):438-458.