eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Hyperammonemia
Updated: Jun 3, 2009
Introduction
Background
Hyperammonemia is not a true disease; it is a sign that specific abnormalities that cause blood ammonia levels to become elevated may be present. Elevated blood ammonia levels cause a constellation of signs and symptoms that may appear to be a single disease.1
Normal blood ammonia levels range from 10-40 µmol/L, compared with a BUN level of 6-20 mg/dL. The total soluble ammonia level in a healthy adult with 5 L of circulating blood is only 150 mcg, in contrast to approximately 1000 mg of urea nitrogen present. Because urea is the end product of ammonia metabolism, the disparity in blood quantities of the substrate and product illustrates the following 2 principles:
- The CNS is protected from the toxic effects of free ammonia.
- The metabolic conversion system that leads to production of urea is highly efficient.
An individual is unlikely to become hyperammonemic unless the conversion system is impaired in some way. In newborns, this impairment is often the result of genetic defects, whereas, in older individuals, the impairment is more often the consequence of a diseased liver. However, a growing number of reports address adult-onset genetic disorders of the urea cycle in previously healthy individuals.
Pathophysiology
The true mechanism of neurotoxicity in hyperammonemia is not yet fully determined. Irrespective of the underlying cause, the clinical picture is relatively constant. This implies that the pathophysiologic mechanism, focusing on the CNS, is common to all individuals with hyperammonemia.
The normal process of removing the amino group present on all amino acids produces ammonia. The a -amino group is a catabolic key that protects amino acids from oxidative breakdown. Removing the a -amino group is essential for producing energy from any amino acid.
Under normal circumstances, both the liver and the brain generate ammonia in this removal process, substantially contributing to total body ammonia production. The urea cycle is completed in the liver, where urea is generated from free ammonia.
The hepatic urea cycle (see Media file 1) is the major route for disposal of waste nitrogen chiefly generated from protein and amino acid metabolism.
Urea cycle. Compounds that comprise the urea cycle are numbered sequentially, beginning with carbamyl phosphate. At the first step (1), the first waste nitrogen is incorporated into the cycle; also at this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamyl phosphate synthetase (CPS). Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (4); the reaction is mediated by argininosuccinate (ASA) synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.
In the same context, low-level synthesis of certain cycle intermediates in extrahepatic tissues also makes a small contribution to waste nitrogen disposal. Two moles of waste nitrogen are eliminated with each mole of urea excreted. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction may impair urea production and result in hyperammonemia. Overall, activity of the cycle is regulated by the rate of synthesis of N -acetylglutamate (NAG), the enzyme activator that initiates incorporation of ammonia into the cycle.
The brain must expend energy to detoxify and to export the ammonia it produces. This is accomplished in the process of producing adenosine diphosphate (ADP) from ATP by the enzyme glutamine synthetase, which is responsible for mediating the formation of glutamine from an amino group. Synthesis of glutamine also reduces the total free ammonia level circulating in the blood; therefore, a significant increase in blood glutamine concentration can signal hyperammonemia.
The biologic requirement for tight regulation is satisfied because the capacity of the hepatic urea cycle exceeds the normal rates of ammonia generation in the periphery and transfer into the blood. Hyperammonemia never results from endogenous production in a state of health.
An elevated blood ammonia level, although it may be secondary, must never be ignored. Moreover, since the normal ureagenic capacity of the liver is so great in relation to physiologic load, such a finding points directly to an impairment of the urea cycle in the liver.
The CNS is most sensitive to the toxic effects of ammonia. Many metabolic derangements occur as a consequence of high ammonia levels, including alteration of the metabolism of important compounds, such as pyruvate, lactate, glycogen, and glucose. High ammonia levels also induce changes in N -methyl D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) receptors and causes downregulation in astroglial glutamate transporter molecules.
As ammonia exceeds normal concentration, an increased disturbance of neurotransmission and synthesis of both GABA and glutamine occurs in the CNS. A correlation between arterial ammonia concentration and brain glutamine content in humans has been described. Moreover, brain content of glutamine is correlated with intracranial pressure. In vitro data also suggest that direct glutamine application to astrocytes in culture causes free radical production and induces the membrane permeability transition phenomenon, which leads to ionic gradient dissipation and consequent mitochondrial dysfunction. However, the true mechanism for neurotoxicity of ammonia is not yet completely defined. The pathophysiology of hyperammonemia is that of a CNS toxin that causes irritability, somnolence, vomiting, cerebral edema, and coma that leads to death.
Frequency
United States
The frequency of each genetic cause of hyperammonemia is undetermined because of the absence of an organized newborn screening program. The combined incidence of urea cycle disorders has been estimated at approximately 1 per 20,000-25,000 live births. Providing incidence figures for secondary causes of hyperammonemia is not possible. Any severe impairment of liver function, whether temporary or permanent, can initiate the onset of hepatic encephalopathy.
Mortality/Morbidity
Progressive hyperammonemia, whether treated or not, eventually causes cerebral edema, coma, and death. A rapid diagnostic evaluation and alleviation of the cause must be accompanied by treatment.
Although the vast majority of morbidity associated with hyperammonemia derives from the primary cause, such as chronic liver disease, repeated hyperammonemic episodes can also cause morbidity. The result, given the direct toxicity of ammonia on the CNS, is a progressive decrease in intellectual function. Animal studies suggest actual cell death as the cause.
Sex
In the genetic forms of hyperammonemia, men and women are affected equally because almost all types are autosomal recessive traits. The only exception to equal sex distribution is X-linked ornithine transcarbamylase (OTC) deficiency, the most common of the urea cycle disorders. OTC deficiency predominantly affects males, although female carriers have been clinically affected.
Acquired causes are distributed randomly between the sexes. However, some acquired causes, such as alcoholic cirrhosis, show a population distribution skewed by societal phenomena.
Age
Genetic causes of hyperammonemia manifest as a wide variety of conditions. The different presentations are categorized as catastrophic newborn, late-infantile, and adult. Each inherited disorder is reported in various clinical presentations. In some patients with adult-onset disease, no precedent sign of intellectual dysfunction was present, leading to the assumption that the disorder was truly latent until the first acute presentation.
Age of onset depends on the age and rate of progression of the underlying disease process. Impairments that must be considered range from hepatic necrosis with hepatocellular damage to inborn genetic disorders of the urea cycle. Although history and age of the patient are helpful to diagnosis, genetic causes must never be disregarded, irrespective of the stage of life.
Clinical
History
- The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, vary in presentation, diagnostic features, and treatment. For these reasons, the members of the family of urea cycle defects are individually considered in this article. However, the common denominator, hyperammonemia, can be clinically manifested by some or all of the following: anorexia, irritability, heavy or rapid breathing, lethargy, vomiting, disorientation, somnolence, asterixis (rarely), combativeness, obtundation, coma, cerebral edema, and death, if treatment is not forthcoming or effective. As a consequence, the most striking clinical findings of each individual urea cycle disorder relate to this constellation and roughly temporal sequence of events.
- The most helpful diagnostic information of history in a patient with suspected hyperammonemia is intercurrent illnesses with exaggerated lethargy and vomiting.
Physical
- General
- Poor growth may be evident.
- Hypothermia is occasionally seen.
- Head, ears, eyes, nose, and throat (HEENT): Papilledema may be present if cerebral edema and increased intracranial pressure have ensued.
- Pulmonary
- Tachypnea or hyperpnea may be present.
- Apnea and respiratory failure may occur in latter stages.
- Abdominal: Hepatomegaly is usually mild, if present.
- Neurologic
- Poor coordination
- Dysdiadochokinesia
- Hypotonia or hypertonia
- Ataxia
- Tremor
- Seizures
- Lethargy that progresses to combativeness to obtundation to coma
- Decorticate or decerebrate posturing
Causes
- Urea cycle defects with resulting hyperammonemia are due to deficiencies of the enzymes involved in the metabolism of waste nitrogen. The enzyme deficiencies lead to disorders with nearly identical clinical presentations. The exception is arginase, the last enzyme of the cycle. Arginase deficiency causes a somewhat different set of signs and symptoms.
- Genetic defects of the urea cycle include the following:
- N-acetylglutamate (NAG) synthetase deficiency
- Carbamyl phosphate synthetase (CPS) deficiency
- Ornithine transcarbamylase (OTC) deficiency
- Citrullinemia (argininosuccinic acid synthase deficiency, citrullinuria)
- Argininosuccinate (ASA) lyase deficiency (argininosuccinic aciduria, argininosuccinase deficiency)
- Arginase deficiency (hyperargininemia, familial argininemia, argininemia)
More on Hyperammonemia |
 Overview: Hyperammonemia |
| Differential Diagnoses & Workup: Hyperammonemia |
| Treatment & Medication: Hyperammonemia |
| Follow-up: Hyperammonemia |
| Multimedia: Hyperammonemia |
| References |
| Next Page » |
References
Bosoi CR, Rose CF. Identifying the direct effects of ammonia on the brain. Metab Brain Dis. Mar 2009;24(1):95-102. [Medline].
[Guideline] Moeschler JB, Shevell M. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics. Jun 2006;117(6):2304-16. [Medline]. [Full Text].
Meyburg J, Das AM, Hoerster F, 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].
Albrecht J. Roles of neuroactive amino acids in ammonia neurotoxicity. J Neurosci Res. Jan 15 1998;51(2):133-8. [Medline].
Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr. Jun 2003;162(6):410-6. [Medline].
Bachmann C, Braissant O, Villard AM, Boulat O, Henry H. Ammonia toxicity to the brain and creatine. Mol Genet Metab. Apr 2004;81 Suppl 1:S52-7. [Medline].
Belanger-Quintana A, Martinez-Pardo M, Garcia MJ, et al. Hyperammonaemia as a cause of psychosis in an adolescent. Eur J Pediatr. Nov 2003;162(11):773-5. [Medline].
Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr. Jan 2001;138(1 Suppl):S56-60; discussion S60-1. [Medline].
Cohn RM, Roth KS. Hyperammonemia, bane of the brain. Clin Pediatr (Phila). Oct 2004;43(8):683-9. [Medline].
Felipo V, Hermenegildo C, Montoliu C, Llansola M, Minana MD. Neurotoxicity of ammonia and glutamate: molecular mechanisms and prevention. Neurotoxicology. Aug-Oct 1998;19(4-5):675-81. [Medline].
Felipo V, Kosenko E, Minana MD, Marcaida G, Grisolia S. Molecular mechanism of acute ammonia toxicity and of its prevention by L-carnitine. Adv Exp Med Biol. 1994;368:65-77. [Medline].
Guffon N, Schiff M, Cheillan D, et al. Neonatal hyperammonemia: the N-carbamoyl-L-glutamic acid test. J Pediatr. Aug 2005;147(2):260-2. [Medline].
Jackson MJ, Beaudet AL, O'Brien WE. Mammalian urea cycle enzymes. Annu Rev Genet. 1986;20:431-64. [Medline].
Kosenko E, Kaminski Y, Lopata O, Muravyov N, Felipo V. Blocking NMDA receptors prevents the oxidative stress induced by acute ammonia intoxication. Free Radic Biol Med. Jun 1999;26(11-12):1369-74. [Medline].
Marcaida G, Felipo V, Hermenegildo C, Minana MD, Grisolia S. Acute ammonia toxicity is mediated by the NMDA type of glutamate receptors. FEBS Lett. Jan 13 1992;296(1):67-8. [Medline].
McBride KL, Miller G, Carter S, et al. Developmental outcomes with early orthotopic liver transplantation for infants with neonatal-onset urea cycle defects and a female patient with late-onset ornithine transcarbamylase deficiency. Pediatrics. Oct 2004;114(4):e523-6. [Medline].
Miga DE, Roth KS. Hyperammonemia: the silent killer. South Med J. Jul 1993;86(7):742-7. [Medline].
Norenberg MD. Astroglial dysfunction in hepatic encephalopathy. Metab Brain Dis. Dec 1998;13(4):319-35. [Medline].
Norenberg MD, Rama Rao KV, Jayakumar AR. Ammonia neurotoxicity and the mitochondrial permeability transition. J Bioenerg Biomembr. Aug 2004;36(4):303-7. [Medline].
Ott P, Clemmesen O, Larsen FS. Cerebral metabolic disturbances in the brain during acute liver failure: from hyperammonemia to energy failure and proteolysis. Neurochem Int. Jul 2005;47(1-2):13-8. [Medline].
Rama Rao KV, Jayakumar AR, Norenberg DM. Ammonia neurotoxicity: role of the mitochondrial permeability transition. Metab Brain Dis. Jun 2003;18(2):113-27. [Medline].
Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med. Aug 14 1997;337(7):473-9. [Medline].
Snyder MJ, Bradford WD, Kishnani PS, Hale LP. Idiopathic hyperammonemia following an unrelated cord blood transplant for mucopolysaccharidosis I. Pediatr Dev Pathol. Jan-Feb 2003;6(1):78-83. [Medline].
Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr. Jan 2001;138(1 Pt 2):S21-S29. [Medline].
Tofteng F, Hauerberg J, Hansen BA, et al. Persistent arterial hyperammonemia increases the concentration of glutamine and alanine in the brain and correlates with intracranial pressure in patients with fulminant hepatic failure. J Cereb Blood Flow Metab. Jan 2006;26(1):21-7. [Medline].
Further Reading
Keywords
hyperammonemia, elevated serum ammonia level, ammoniemia, elevated ammonia levels, urea, adult-onset genetic disorders of the urea cycle, alpha-amino group, a-amino group, hepatic urea cycle, waste nitrogen, extrahepatic tissues, mitochondrial dysfunction, N -acetylglutamate, NAG, adenosine diphosphate, ADP, adenosine triphosphate, ATP, total free ammonia, glutamine, N -methyl D-aspartate, NMDA, gamma-aminobutyric acid, GABA, astroglial glutamate transporter molecules, astrocytes, membrane permeability transition phenomenon, hepatic encephalopathy, ornithine transcarbamylase deficiency, OTC, hepatic necrosis, N -acetylglutamate synthetase, arginase deficiency, carbamyl phosphate synthetase, CPS, citrullinemia, argininosuccinic acid synthase deficiency, citrullinuria, argininosuccinate lyase deficiency, ASA, argininosuccinic aciduria, argininosuccinase deficiency, hyperargininemia, familial argininemia
