Hyperammonemia

Hyperammonemia, or high ammonia levels, is a metabolic disturbance characterised by an excess of ammonia in the blood. Severe hyperammonemia is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.

Hyperammonemia
Other names	Hyperammonaemia; High ammonia levels
Ammonia
Specialty	Endocrinology
Causes	Due to accumulation of argininosuccinate, citrulline, and arginine in the liver when the urea cycle is deficient.

Ammonia is a substance that contains nitrogen. It is a product of the catabolism of protein. It is converted to the less toxic substance urea prior to excretion in urine by the kidneys. The metabolic pathways that synthesize urea involve reactions that start in the mitochondria and then move into the cytosol. The process is known as the urea cycle, which comprises several enzymes acting in sequence. It is greatly exacerbated by common zinc deficiency, which raises ammonia levels further.^[1]

Levels

Normal blood ammonia levels in adults range from 20 to 50 μmol/L or less than 26 to 30 μmol/L.^[2][3][4] There is at present no clear scientific consensus on the upper limits of ammonia levels for different age groups.^[4] In any case, hyperammonemia is generally defined as ammonia levels greater than 50 μmol/L in adults and greater than 100 μmol/L in newborns.^[2][4] These values should be considered as decision limits and the normal reference ranges of individual laboratories should be used for clinical interpretation.^[4]

Blood ammonia levels in different populations^[2][3][4]

Patient group	Ammonia levels (μmol/L)	Hyperammonemia (μmol/L)	Ref
Premature neonates	50–159	>159	[5][3]
Healthy term neonates	45–75	>75–100	[5][3]
Children and adolescents	24–48	>48–50	[6][3]
Adult females	11–48	>48	[7]
Adult males	15–55	>55	[7]

When ammonia levels rise greater than 200 μmol/L, serious symptoms, including seizures, encephalopathy, coma, and even death, can occur.^[3] Hyperammonemia with blood ammonia levels greater than 400 to 500 μmol/L is associated with 5- to 10-fold higher risk of irreversible brain damage.^[2]

Signs and symptoms

Complication

Hyperammonemia is one of the metabolic derangements that contribute to hepatic encephalopathy, which can cause swelling of astrocytes and stimulation of NMDA receptors in the brain.^{[citation needed]}

Cause

Diagnosis

Types

Primary vs. secondary

• Primary hyperammonemia is caused by several inborn errors of metabolism that are characterised by reduced activity of any of the enzymes in the urea cycle. The most common example is ornithine transcarbamylase deficiency, which is inherited in an X-linked fashion.^[8]
• Secondary hyperammonemia is caused by inborn errors of intermediary metabolism, which are characterised by reduced activity of enzymes that are not part of the urea cycle or dysfunction of cells that make major contributions to metabolism. Examples of the former are propionic acidemia and methylmalonic acidemia, and examples of the latter are acute liver failure and hepatic cirrhosis with liver failure.^[8]

Acquired vs. congenital

• Acquired hyperammonemia is usually caused by diseases that result in either acute liver failure, such as overwhelming hepatitis B or exposure to hepatotoxins, or cirrhosis of the liver with chronic liver failure. Chronic hepatitis B, chronic hepatitis C, and excessive alcohol consumption are common causes of cirrhosis. The physiologic consequences of cirrhosis include shunting of blood from the liver to the inferior vena cava, resulting in decreased filtration of blood and removal of nitrogen-containing toxins by the liver, and then hyperammonemia. This type of hyperammonemia can be treated with antibiotics to kill the bacteria that initially produce the ammonia, though this does not work as well as the removal of protein from the colon prior to its digestion to ammonia, achieved by lactulose administration for frequent (3-4 per day) bowel movements.^{[citation needed]}
• Medication-induced hyperammonemia can occur with valproic acid overdose, and is due to a deficiency in carnitine. Its treatment is carnitine replacement.^{[citation needed]}
• Urinary tract infection caused by urease-producing organisms (Proteus, Pseudomonas aeruginosa, Klebsiella, Morganella morganii, and Corynebacterium) can also lead to hyperammonemia.^[9] But there are case reports where hyperammonemia was caused by urease-negative organisms.^[10] Urease producers form ammonia and carbon dioxide from urea. Ammonia then enters the systemic circulation (most venous supply of the bladder bypasses portal circulation) and enters the blood–brain barrier causing encephalopathy.^[9]
• Severe dehydration and small intestinal bacterial overgrowth can also lead to acquired hyperammonemia.^{[citation needed]}
• Glycine toxicity causes hyperammonemia, which manifests as CNS symptoms and nausea. Transient blindness can also occur.^[11]
• Congenital hyperammonemia is usually due to genetic defects in one of the enzymes of the urea cycle, such as ornithine transcarbamylase deficiency, which leads to lower production of urea from ammonia.^{[citation needed]}

Specific types

The following list includes such examples:

• Online Mendelian Inheritance in Man (OMIM): 311250 - hyperammonemia due to ornithine transcarbamylase deficiency
• Online Mendelian Inheritance in Man (OMIM): 606762 - hyperinsulinism-hyperammonemia syndrome (glutamate dehydrogenase 1)
• Online Mendelian Inheritance in Man (OMIM): 238970 - hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
• Online Mendelian Inheritance in Man (OMIM): 237310 - hyperammonemia due to N-Acetylglutamate synthase deficiency
• Online Mendelian Inheritance in Man (OMIM): 237300 - hyperammonemia due to carbamoyl phosphate synthetase I deficiency (carbamoyl phosphate synthetase I)
• Online Mendelian Inheritance in Man (OMIM): 238750 - hyperlysinuria with hyperammonemia (genetics unknown)
• Methylmalonic acidemia
• Isovaleric acidemia
• Propionic acidemia
• Carnitine palmitoyltransferase II deficiency
• Transient hyperammonemia of the newborn, specifically in the preterm

Treatment

Treatment centres on limiting intake of ammonia and increasing its excretion. Dietary protein, a metabolic source of ammonium, is restricted, and caloric intake is provided by glucose and fat. Intravenous arginine (argininosuccinase deficiency), sodium phenylbutyrate and sodium benzoate (ornithine transcarbamylase deficiency) are pharmacologic agents commonly used as adjunctive therapy to treat hyperammonemia in patients with urea cycle enzyme deficiencies.^[12] Sodium phenylbutyrate and sodium benzoate can serve as alternatives to urea for the excretion of waste nitrogen. Phenylbutyrate, which is the product of phenylacetate, conjugates with glutamine to form phenylacetylglutamine, which is excreted by the kidneys. Similarly, sodium benzoate reduces ammonia content in the blood by conjugating with glycine to form hippuric acid, which is rapidly excreted by the kidneys.^[13] A preparation containing sodium phenylacetate and sodium benzoate is available under the trade name Ammonul. Acidification of the intestinal lumen using lactulose can decrease ammonia levels by protonating ammonia and trapping it in the stool. This is a treatment for hepatic encephalopathy.^[14]

Treatment of severe hyperammonemia (serum ammonia levels greater than 1000 μmol/L) should begin with hemodialysis if it is otherwise medically appropriate and tolerated.^[11]

Continuous renal replacement therapy (CRRT) is a remarkably effective mode of therapy in neonatal hyperammonemia, particularly in severe cases of Urea cycle defects like Ornithine transcarbamoylase (OTC) deficiency. Multidisciplinary team (MDT) collaboration is required to optimize this advanced treatment. Simulation training might be the best training and teaching strategy to ensure MDT successful therapy.^[15]

See also

• Arginase deficiency
• Citrullinemia
• N-acetylglutamate synthetase deficiency
• Ornithine translocase deficiency
• Carbamoyl phosphate synthetase I deficiency
• Orotic aciduria

References

1. Riggio, O.; Merli, M.; Capocaccia, L.; Caschera, M.; Zullo, A.; Pinto, G.; Gaudio, E.; Franchitto, A.; Spagnoli, R.; D'Aquilino, E. (September 1992). "Zinc supplementation reduces blood ammonia and increases liver ornithine transcarbamylase activity in experimental cirrhosis". Hepatology. 16 (3): 785–789. doi:10.1002/hep.1840160326. ISSN 0270-9139. PMID 1505922. S2CID 1141979.
2. Limón ID, Angulo-Cruz I, Sánchez-Abdon L, Patricio-Martínez A (2021). "Disturbance of the Glutamate-Glutamine Cycle, Secondary to Hepatic Damage, Compromises Memory Function". Front Neurosci. 15: 578922. doi:10.3389/fnins.2021.578922. PMC 7873464. PMID 33584185.
3. Ali, Rimsha; Nagalli, Shivaraj (7 April 2023). "Hyperammonemia". StatPearls Publishing. PMID 32491436. Retrieved 6 September 2024.
4. Alfadhel M, Mutairi FA, Makhseed N, Jasmi FA, Al-Thihli K, Al-Jishi E, AlSayed M, Al-Hassnan ZN, Al-Murshedi F, Häberle J, Ben-Omran T (2016). "Guidelines for acute management of hyperammonemia in the Middle East region". Ther Clin Risk Manag. 12: 479–487. doi:10.2147/TCRM.S93144. PMC 4820220. PMID 27099506.
5. Colombo JP, Peheim E, Kretschmer R, Dauwalder H, Sidiropoulos D (April 1984). "Plasma ammonia concentrations in newborns and children". Clin Chim Acta. 138 (3): 283–291. doi:10.1016/0009-8981(84)90135-9. PMID 6723064.
6. Donn, S. M.; Banagale, R. C. (1 January 1984). "Neonatal Hyperammonemia". Pediatrics in Review. 5 (7): 203–208. doi:10.1542/pir.5-7-203. ISSN 0191-9601.
7. Häberle J (January 2011). "Clinical practice: the management of hyperammonemia". Eur J Pediatr. 170 (1): 21–34. doi:10.1007/s00431-010-1369-2. PMID 21165747.
8. Häberle, Johannes; Chakrapani, Anupam; Ah Mew, Nicholas; Longo, Nicola (December 2018). "Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories". Orphanet Journal of Rare Diseases. 6 (13): 219. doi:10.1186/s13023-018-0963-7. PMC 6282273. PMID 30522498.
9. Nepal SP, Unoki T, Inoue T, Nakasato T, Naoe M, Ogawa Y, Omizu M, Kato R, Sugishita H, Oshinomi K, Morita J, Maeda Y, Shichijo T. A case of hyperammonemia in a patient with urinary tract infection and urinary retention. Urol Sci [serial online] 2020 [cited 2021 Apr 3];31:82-4. Available from: https://www.e-urol-sci.com/text.asp?2020/31/2/82/283250
10. Kenzaka T, Kato K, Kitao A, et al. Hyperammonemia in Urinary Tract Infections. PLoS One. 2015;10(8):e0136220. Published 2015 Aug 20. doi:10.1371/journal.pone.0136220
11. Chapter 298 – Inborn Errors of Metabolism and Continuous Renal Replacement Therapy Archived 2013-07-01 at the Wayback Machine in: John J. Ratey MD; Claudio Ronco MD (2008). Critical Care Nephrology: Expert Consult - Online and Print. Philadelphia: Saunders. ISBN 978-1-4160-4252-5. ISBN 9781416042525
12. Chawla, Jasvinder (12 September 2022). "Hyperammonemia". Medscape. Retrieved 18 March 2024.
13. "Ammonul (Sodium Phenylacetate and Sodium Benzoate Injection) clinical pharmacology - prescription drugs and medications at RxList". Archived from the original on 2008-06-16. Retrieved 2008-06-26.
14. Bloom, Patricia; Tapper, Elliot (November 2023). "Lactulose in cirrhosis: Current understanding of efficacy, mechanism, and practical considerations". Hepatology Communications. 7 (11): e0295. doi:10.1097/HC9.0000000000000295. PMC 10578757. PMID 37820287.
15. Elbaba, Mostafa. "IPE Simulation Enhances the Quality of Care in Neonatal Hyperammonemia". Cureus Journal of Medical Science.

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