Hyperammonemia 

  • Author: Elena Crisan, MD; Chief Editor: Tarakad S Ramachandran, MBBS, FRCP(C), FACP   more...
 
Updated: Jun 22, 2010
 

Background

Ammonia is a normal constituent of all body fluids. At physiologic pH, it exists mainly as ammonium ion. Reference serum levels are less than 35 µmol/L. Excess ammonia is excreted as urea, which is synthesized in the liver through the urea cycle. Sources of ammonia include bacterial hydrolysis of urea and other nitrogenous compounds in the intestine, the purine-nucleotide cycle and amino acid transamination in skeletal muscle, and other metabolic processes in the kidneys and liver.

Increased entry of ammonia to the brain is a primary cause of neurological disorders associated with hyperammonemia, such as congenital deficiencies of urea cycle enzymes, hepatic encephalopathies, Reye syndrome, several other metabolic disorders, and some toxic encephalopathies.

Next

Pathophysiology

Ammonia is a product of the metabolism of proteins and other compounds, and it is required for the synthesis of essential cellular compounds. However, a 5- to 10-fold increase in ammonia in the blood induces toxic effects in most animal species, with alterations in the function of the central nervous system.

Both acute and chronic hyperammonemia result in alterations of the neurotransmitter system.

Based on animal study findings, the mechanism of ammonia neurotoxicity at the molecular level has been proposed. Acute ammonia intoxication in an animal model leads to increased extracellular concentration of glutamate in the brain and results in activation of the N -methyl D-aspartate (NMDA) receptor. Activation of this receptor mediates ATP depletion and ammonia toxicity; sustained blocking of the NMDA receptor by continuous administration of antagonists dizocilpine (MK-801) or memantine prevents both phenomena, leading to significantly increased survival time in rats.[1] The ATP depletion is due to activation of Na+/K+ -ATPase, which, in turn, is a consequence of decreased phosphorylation by protein kinase C. Activation of the NMDA receptor is probably the cause of seizures in acute hyperammonemia.

Neuropathologic evaluation demonstrates alteration in the astrocyte morphology. Recent studies demonstrated a significant downregulation of the gap–junction channel connexin 43, the water channel aquaporin 4 genes, and the astrocytic inward-rectifying potassium channel genes, colocalized to astrocytic end-feet at the brain vasculature, where they regulate potassium and water transport. A downregulation of these channels in hyperammonemic mice suggests an alteration in astrocyte-mediated water and potassium homeostasis in the brain as a potential key factor in the development of brain edema.[2]

Also, studies on cultured astrocytes examined the potential role of p53, a tumor suppressor protein and a transcriptional factor, in ammonia-induced neurotoxicity. Activation of p53 contributes to astrocyte swelling and glutamate uptake inhibition, leading to brain edema. Both processes are blocked by p53 inhibition.[3]

High levels of ammonia induce other metabolic changes that are not mediated by activation of the NMDA receptor and thus are not involved directly in ammonia-induced ATP depletion or neurotoxicity. These include increases in brain levels of lactate, pyruvate, glutamine, and free glucose, and decreases in brain levels of glycogen, ketone bodies, and glutamate.

Chronic hyperammonemia is associated with an increase in inhibitory neurotransmission as a consequence of 2 factors. The first is downregulation of glutamate receptors secondary to excessive extrasynaptic accumulation of glutamate. In addition, changes in the glutamate-nitric oxide-cGMP pathway result in impairment of signal transduction associated with NMDA receptors, leading to alteration in cognition and learning.[4] The second is an increased GABAergic tone resulting from benzodiazepine receptor overstimulation by endogenous benzodiazepines and neurosteroids. These changes probably contribute to deterioration of intellectual function, decreased consciousness, and coma. Treatment of chronic hyperammonemic rats with inhibitors of phosphodiesterase 5 restores the function of glutamate-nitric oxide-cGMP pathway and cGMP levels in rats’ brain, with restored ability to learn a conditional task.[5]

RNA oxidation offers an explanation for multiple disturbances of neurotransmitter system, gene expression, and secondary cognitive deficiencies noticed in hepatic encephalopathy. In chronic hepatic encephalopathies, a small-grade astrocyte swelling was observed without overt brain edema. Astrocyte edema produces reactive oxygen and nitrogen oxide species, resulting in RNA oxidation and increased of free intracellular zinc. RNA oxidation may impair synthesis of postsynaptic proteins involved in learning and memory consolidation.[6]

Ammonia also increases the transport of aromatic amino acids (eg, tryptophan) across the blood-brain barrier. This leads to an increase in the level of serotonin, which is the basis for anorexia in hyperammonemia.

Previous
Next

Epidemiology

Frequency

United States

Collecting accurate data on the frequency of metabolic disorders is difficult, because the information collected is representative of the particular area or the population group; however, the prevalence of urea cycle disorders is estimated at 1 case per 30,000 live births.

International

In a recently published study, the incidence of urea cycle disorders in British Columbia was shown to be 1 case per 53,717 persons, which is approximately 1.9 cases per 100,000 live births.

Mortality/Morbidity

Coma and cerebral edema are the major causes of death; the survivors of coma have a high incidence of intellectual impairment.

Race

These disorders have been observed in all races.

Sex

All the urea cycle disorders are inherited in an autosomal recessive pattern, except ornithine transcarbamoylase (OTC) deficiency, which is inherited as an X-linked trait; however, female carriers of the OTC gene can become symptomatic.

Age

Early-onset hyperammonemia presents in the neonatal period. Urea cycle disorders can present later in life (see History).

Previous
Proceed to Clinical Presentation
 
 
Contributor Information and Disclosures
Author

Elena Crisan, MD  Neurology Staff, Department of Neurology, Edwards Hines Veterans Affairs Hospital; Assistant Professor of Neurology, Loyola University Medical Center

Elena Crisan, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Coauthor(s)

Jasvinder Chawla, MD, MBA  Chief of Neurology, Hines Veterans Affairs Hospital; Associate Professor and Director, Neurology Residency Training Program, Loyola University Medical Center

Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, and American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

J Stephen Huff, MD  Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Richard J Caselli, MD  Professor, Department of Neurology, Mayo Medical School, Rochester, MN; Chair, Department of Neurology, Mayo Clinic of Scottsdale

Richard J Caselli, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, American Neurological Association, and Sigma Xi

Disclosure: Nothing to disclose.

Chief Editor

Tarakad S Ramachandran, MBBS, FRCP(C), FACP  Professor of Neurology, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Chair, Department of Neurology, Crouse Irving Memorial Hospital

Tarakad S Ramachandran, MBBS, FRCP(C), FACP is a member of the following medical societies: American Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners, American College of International Physicians, American College of Managed Care Medicine, American College of Physicians, American Heart Association, American Stroke Association, Royal College of Physicians, Royal College of Physicians and Surgeons of Canada, Royal College of Surgeons of England, and Royal Society of Medicine

Disclosure: Abbott Labs None None; Teva Marion None None; Boeringer-Ingelheim Honoraria Speaking and teaching

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Kazi Imran Majeed, MD to the development and writing of this article.

References

  1. Rodrigo R, Cauli O, Boix J, ElMlili N, Agusti A, Felipo V. Role of NMDA receptors in acute liver failure and ammonia toxicity: therapeutical implications. Neurochem Int. Jul-Aug 2009;55(1-3):113-8. [Medline].

  2. Lichter-Konecki U, Mangin JM, Gordish-Dressman H, Hoffman EP, Gallo V. Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo. Glia. Mar 2008;56(4):365-77. [Medline].

  3. Panickar KS, Jayakumar AR, Rao KV, Norenberg MD. Ammonia-induced activation of p53 in cultured astrocytes: role in cell swelling and glutamate uptake. Neurochem Int. Jul-Aug 2009;55(1-3):98-105. [Medline].

  4. Llansola M, Rodrigo R, Monfort P, Montoliu C, Kosenko E, Cauli O, et al. NMDA receptors in hyperammonemia and hepatic encephalopathy. Metab Brain Dis. Dec 2007;22(3-4):321-35. [Medline].

  5. Monfort P, Cauli O, Montoliu C, Rodrigo R, Llansola M, Piedrafita B, et al. Mechanisms of cognitive alterations in hyperammonemia and hepatic encephalopathy: therapeutical implications. Neurochem Int. Jul-Aug 2009;55(1-3):106-12. [Medline].

  6. Schliess F, Görg B, Häussinger D. RNA oxidation and zinc in hepatic encephalopathy and hyperammonemia. Metab Brain Dis. Mar 2009;24(1):119-34. [Medline].

  7. Ichikawa K, Gakumazawa M, Inaba A, Shiga K, Takeshita S, Mori M, et al. Acute encephalopathy of Bacillus cereus mimicking Reye syndrome. Brain Dev. Sep 29 2009;[Medline].

  8. Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). Feb 2009;47(2):101-11. [Medline].

  9. DeWolfe JL, Knowlton RC, Beasley MT, Cofield S, Faught E, Limdi NA. Hyperammonemia following intravenous valproate loading. Epilepsy Res. Jul 2009;85(1):65-71. [Medline].

  10. Cheung E, Wong V, Fung CW. Topiramate-valproate-induced hyperammonemic encephalopathy syndrome: case report. J Child Neurol. Feb 2005;20(2):157-60. [Medline].

  11. Deutsch SI, Burket JA, Rosse RB. Valproate-induced hyperammonemic encephalopathy and normal liver functions: possible synergism with topiramate. Clin Neuropharmacol. Nov-Dec 2009;32(6):350-2. [Medline].

  12. Adams EN, Marks A, Lizer MH. Carbamazepine-induced hyperammonemia. Am J Health Syst Pharm. Aug 15 2009;66(16):1468-70. [Medline].

  13. Adatia S, Poladia B, Joshi SR, Panikar V, Chauhan V, Hastak SM. Hyperammonemic coma presenting as Hashimoto's encephalopathy. J Assoc Physicians India. Dec 2008;56:989-91. [Medline].

  14. Rimar D, Kruzel-Davila E, Dori G, Baron E, Bitterman H. Hyperammonemic coma--barking up the wrong tree. J Gen Intern Med. Apr 2007;22(4):549-52. [Medline].

  15. Lora-Tamayo J, Palom X, Sarrá J, Gasch O, Isern V, Fernández de Sevilla A, et al. Multiple myeloma and hyperammonemic encephalopathy: review of 27 cases. Clin Lymphoma Myeloma. Dec 2008;8(6):363-9. [Medline].

  16. Rovira A, Alonso J, Córdoba J. MR imaging findings in hepatic encephalopathy. AJNR Am J Neuroradiol. Oct 2008;29(9):1612-21. [Medline].

  17. Zwingmann C. Nuclear magnetic resonance studies of energy metabolism and glutamine shunt in hepatic encephalopathy and hyperammonemia. J Neurosci Res. Nov 15 2007;85(15):3429-42. [Medline].

  18. Al-Hassnan ZN, Rashed MS, Al-Dirbashi OY, Patay Z, Rahbeeni Z, Abu-Amero KK. Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with stroke-like imaging presentation: clinical, biochemical and molecular analysis. J Neurol Sci. Jan 15 2008;264(1-2):187-94. [Medline].

  19. Oldham MS, VanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL. Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts. Pediatr Neurol. Jan 2010;42(1):49-52. [Medline].

  20. Arbeiter AK, Kranz B, Wingen AM, Bonzel KE, Dohna-Schwake C, Hanssler L, et al. Continuous venovenous haemodialysis (CVVHD) and continuous peritoneal dialysis (CPD) in the acute management of 21 children with inborn errors of metabolism. Nephrol Dial Transplant. Nov 23 2009;[Medline].

  21. Cardenas JF, Bodensteiner JB. Osmotic Demyelination Syndrome as a Consequence of Treating Hyperammonemia in a Patient With Ornithine Transcarbamylase Deficiency. J Child Neurol. Feb 18 2009;[Medline].

  22. Meyburg J, Das AM, Hoerster F, Lindner M, Kriegbaum H, Engelmann G, et al. One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. Transplantation. Mar 15 2009;87(5):636-41. [Medline].

  23. Meyburg J, Schmidt J, Hoffmann GF. Liver cell transplantation in children. Clin Transplant. Dec 2009;23 Suppl 21:75-82. [Medline].

  24. Davies NA, Wright G, Ytrebø LM, Stadlbauer V, Fuskevåg OM, Zwingmann C, et al. L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats. Hepatology. Feb 9 2009;[Medline].

  25. Albrecht J. Roles of neuroactive amino acids in ammonia neurotoxicity. J Neurosci Res. Jan 15 1998;51(2):133-8. [Medline].

  26. Albrecht J, Jones EA. Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome. J Neurol Sci. Nov 30 1999;170(2):138-46. [Medline].

  27. Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. Jan 2000;105(1):e10. [Medline].

  28. Batshaw ML. Hyperammonemia. Curr Probl Pediatr. Nov 1984;14(11):1-69. [Medline].

  29. Batshaw ML. Inborn errors of urea synthesis. Ann Neurol. Feb 1994;35(2):133-41. [Medline].

  30. Becker L, Prior T, Yates A. Metabolic diseases. Textbook of Neuropathology, Baltimore: Williams & Wilkins. 1997;487.

  31. Berlot G, Battaglia K, Ukmar M. [Hyperammoniemia and central pontine myelinolysis in a patient with Sjögren syndrome and chronic valproate use]. Recenti Prog Med. Oct 2008;99(10):502-4. [Medline].

  32. Bhoyar A, Short A. Congenital hypopituitarism associated with hyperammonemia. Indian J Pediatr. Mar 2009;76(3):327-8. [Medline].

  33. Bosoi CR, Rose CF. Identifying the direct effects of ammonia on the brain. Metab Brain Dis. Mar 2009;24(1):95-102. [Medline].

  34. Breningstall GN. Neurologic syndromes in hyperammonemic disorders. Pediatr Neurol. Sep-Oct 1986;2(5):253-62. [Medline].

  35. Brusilow SW, Horwich AL. Urea cycle disorders. The Metabolic and Molecular Bases of Inherited Disease, New York: McGraw-Hill. 1995;1:1187-1232.

  36. Chung MY, Chen CC, Huang LT, et al. Transient hyperammonemia in a neonate. Acta Paediatr Taiwan. Mar-Apr 2005;46(2):94-6. [Medline].

  37. Cohn RM, Roth KS. Hyperammonemia, bane of the brain. Clin Pediatr (Phila). Oct 2004;43(8):683-9. [Medline].

  38. Collins FS, Summer GK, Schwartz RP, Parke JC Jr. Neonatal argininosuccinic aciduria-survival after early diagnosis and dietary management. J Pediatr. Mar 1980;96(3 Pt 1):429-31. [Medline].

  39. del Rosario M, Werlin SL, Lauer SJ. Hyperammonemic encephalopathy after chemotherapy. Survival after treatment with sodium benzoate and sodium phenylacetate. J Clin Gastroenterol. Dec 1997;25(4):682-4. [Medline].

  40. Deodato F, Boenzi S, Rizzo C, et al. Inborn errors of metabolism: an update on epidemiology and on neonatal-onset hyperammonemia. Acta Paediatr Suppl. May 2004;93(445):18-21. [Medline].

  41. Feillet F, Leonard JV. Alternative pathway therapy for urea cycle disorders. J Inherit Metab Dis. 1998;21 Suppl 1:101-11. [Medline].

  42. Felipo V, Kosenko E, Minana MD, et al. Molecular mechanism of acute ammonia toxicity and of its prevention by L-carnitine. Adv Exp Med Biol. 1994;368:65-77. [Medline].

  43. Hamed SA, Abdella MM. The risk of asymptomatic hyperammonemia in children with idiopathic epilepsy treated with valproate: Relationship to blood carnitine status. Epilepsy Res. May 13 2009;[Medline].

  44. Hauser ER, Finkelstein JE, Valle D, Brusilow SW. Allopurinol-induced orotidinuria. A test for mutations at the ornithine carbamoyltransferase locus in women. N Engl J Med. Jun 7 1990;322(23):1641-5. [Medline].

  45. Jalan R, Lee WM. Treatment of Hyperammonemia in Liver Failure: A Tale of Two Enzymes. Gastroenterology. Apr 28 2009;[Medline].

  46. Kuntze JR, Weinberg AC, Ahlering TE. Hyperammonemic coma due to Proteus infection. J Urol. Nov 1985;134(5):972-3. [Medline].

  47. Logan W. Neonatal hyperammonemic encephalopathy. Topics in Neonatal Neurology, Orlando: Grune & Stratton. 1984;137-157.

  48. Maestri NE, McGowan KD, Brusilow SW. Plasma glutamine concentration: a guide in the management of urea cycle disorders. J Pediatr. Aug 1992;121(2):259-61. [Medline].

  49. McCall M, Bourgeois JA. Valproic acid-induced hyperammonemia: a case report. J Clin Psychopharmacol. Oct 2004;24(5):521-6. [Medline].

  50. Msall M, Batshaw ML, Suss R, et al. Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med. Jun 7 1984;310(23):1500-5. [Medline].

  51. Prasad AN, Breen JC, Ampola MG, Rosman NP. Argininemia: a treatable genetic cause of progressive spastic diplegia simulating cerebral palsy: case reports and literature review. J Child Neurol. Aug 1997;12(5):301-9. [Medline].

  52. Rajpoot DK, Gargus JJ. Acute hemodialysis for hyperammonemia in small neonates. Pediatr Nephrol. Apr 2004;19(4):390-5. [Medline].

  53. Ratnaike RN, Schapel GJ, Purdie G, et al. Hyperammonaemia and hepatotoxicity during chronic valproate therapy: enhancement by combination with other antiepileptic drugs. Br J Clin Pharmacol. Jul 1986;22(1):100-3. [Medline].

  54. Schaefer F, Straube E, Oh J, et al. Dialysis in neonates with inborn errors of metabolism. Nephrol Dial Transplant. Apr 1999;14(4):910-8. [Medline].

  55. Schutze GE, Edwards MS, Adham BI, Belmont JW. Hyperammonemia and neonatal herpes simplex pneumonitis. Pediatr Infect Dis J. Oct 1990;9(10):749-50. [Medline].

  56. Smith W, Kishnani PS, Lee B, et al. Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin. Oct 2005;21(4 Suppl):S9-17. [Medline].

  57. Summar ML, Barr F, Dawling S, et al. Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin. Oct 2005;21(4 Suppl):S1-8. [Medline].

  58. 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 1:151-9. [Medline].

  59. Weng TI, Shih FF, Chen WJ. Unusual causes of hyperammonemia in the ED. Am J Emerg Med. Mar 2004;22(2):105-7. [Medline].

  60. Whitington PF, Alonso EM, Boyle JT, et al. Liver transplantation for the treatment of urea cycle disorders. J Inherit Metab Dis. 1998;21 Suppl 1:112-8. [Medline].

  61. Williams CA, Tiefenbach S, McReynolds JW. Valproic acid-induced hyperammonemia in mentally retarded adults. Neurology. Apr 1984;34(4):550-3. [Medline].

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.