eMedicine Specialties > Neurology > Neurotoxicology

Hyperammonemia

Author: Elena Crisan, MD, Consulting Staff, Department of Neurology, Edwards Hines Veterans Affairs Hospital
Coauthor(s): Jasvinder Chawla, MBBS, MD, MBA, Chief of Neurology, Hines Veterans Affairs Hospital; Associate Professor and Director, Neurology Residency Training Program, Loyola University Medical Center
Contributor Information and Disclosures

Updated: Aug 20, 2009

Introduction

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.

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 also 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.

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).

Clinical

History

  • Family history may reveal unexplained neonatal deaths or undiagnosed chronic illness. A history of males being affected is suggestive of OTC deficiency, which is inherited as an X-linked trait. Consanguinity results in an increased risk of inheriting a metabolic disorder.
  • Early-onset hyperammonemia presents in the neonatal period. The baby is usually well for the first day or two. As the ammonia level rises, the baby becomes symptomatic. The family gives a history of lethargy, irritability, poor feeding, and vomiting. These symptoms correlate with an ammonia level of 100-150 µmol/L, which is 2-3 times the reference range. This may be followed by hyperventilation and grunting respiration; seizures also may develop.
  • Late-onset hyperammonemia typically is due to urea cycle disorders, which can present later in life. The frequently altered clinical presentation of urea cycle disorders later in life develops from intrinsic differences in physiology based on age, as well as molecular aspects of the underlying biochemistry. Older children have greater energy reserves than neonates, allowing them to compensate for periods of stress. They also have a greater capacity and more opportunity to regulate their own environment. Adults with partial enzyme deficiency can become symptomatic when hyperammonemia is triggered by a stressful medical condition such as postpartum stress, heart-lung transplant, short bowel and kidney disease, parenteral nutrition with high nitrogen intake, and gastrointestinal bleeding.
    • Intermittent ataxia: Patients have an unstable gait and dysmetria. The intermittent nature of the symptoms is due to a periodic exacerbation of ammonia level.
    • Intellectual impairment: Episodic minor hyperammonemia may produce subtle intellectual deficits even in clinically asymptomatic individuals.
    • Failure to thrive: Children with an underlying metabolic disorder have suboptimal growth secondary to poor feeding and frequent vomiting.
    • Gait abnormality: In arginase deficiency, patients present with spastic diplegia, which manifests as toe walking.
    • Behavior disturbances: These include sleep disturbances, irritability, hyperactivity, manic episodes, and psychosis.
    • Epilepsy: Intractable seizures in a few patients have been secondary to an underlying urea cycle defect.
    • Recurrent Reye syndrome: A recurrent Reye syndromelike picture strongly suggests the possibility of a metabolic disorder.
    • Episodic headaches and cyclic vomiting may, rarely, be found to be caused by urea cycle defects.
    • Protein avoidance: Females with OTC deficiency may give a history of protein avoidance.

Physical

  • No specific physical findings are associated with hyperammonemia. Affected infants usually present with the following:
    • Dehydration secondary to vomiting
    • Lethargy
    • Tachypnea due to stimulation of the medullary center of respiration by the ammonium ion
    • Hypotonia as a nonspecific response to acute stress
    • Bulging fontanelle as a sign of raised intracranial pressure
  • Sometimes examination reveals a peculiar finding, such as odor of "sweaty feet" in isovaleric acidemia or abnormally fragile hair in argininosuccinic aciduria. Infants with argininosuccinic lyase deficiency may present with hepatomegaly.

Causes

  • Enzyme defects in urea cycle
    • N -acetylglutamate synthetase (NAGS) deficiency: Deficiency of this enzyme results in a lack of N -acetylglutamate, which is an activator of carbamoyl phosphate synthetase. Mode of inheritance is autosomal recessive. N -acetylglutamate also could become deficient if acetyl-CoA is not available.
    • Carbamoyl phosphate synthetase I (CPS I) deficiency: This defect is inherited in an autosomal recessive pattern. In the presence of N -acetylglutamate, ammonium ions combine with bicarbonate to form carbamoyl phosphate. The reaction takes place in hepatic mitochondria. Hyperammonemia develops as early as the first day of life. A majority of affected infants die in the neonatal period. This enzyme has been mapped to the short arm of chromosome 2.
    • Ornithine transcarbamoylase (OTC) deficiency: OTC also is found inside the mitochondria. In its presence, ornithine combines with carbamoyl phosphate to form citrulline, which is then transported out of the mitochondria. In the absence of the enzyme, accumulated carbamoyl phosphate enters the cytosol and participates in pyrimidine synthesis in the presence of CPS II. This is the most common urea cycle defect, with an estimated incidence of 1 case in 14,000 persons. It is transmitted as an X-linked trait. Neonatal onset is seen in males who have null mutations and thus no residual enzyme activity. Males who have significant residual enzyme activity and females who are heterozygous for OTC deficiency present later with quite variable clinical pictures. Thus, as many as 60% of OTC deficiency diagnoses are made in non-neonates. The oldest reported patient was aged 61 years.
    • Argininosuccinic acid synthetase (AS) deficiency: Citrulline combines with aspartate to form argininosuccinic acid. The AS deficiency results in citrullinemia. Onset is usually between hours 24 and 72 of life, but late-onset forms have been described in the literature. The mode of inheritance is autosomal recessive. The gene for this defect has been localized to chromosome 9.
    • Argininosuccinic lyase (AL) deficiency: This enzyme cleaves argininosuccinic acid to yield fumarate and arginine. The lack of this enzyme leads to argininosuccinic aciduria. It is the second most common urea cycle disorder. Symptoms may appear in the neonatal period or later in life. It also is inherited in an autosomal recessive pattern. Abnormally fragile hair (trichorrhexis nodosa) has been observed in these infants as early as age 2 weeks. The gene has been localized to chromosome 7.
    • Arginase deficiency: This enzyme is involved in the final step of the urea cycle when arginine is cleaved to form urea and ornithine. Its deficiency results in argininemia, which is the least frequent of the urea cycle disorders. Hyperammonemia is not severe and the probable cause of neurotoxicity is arginine. The gene for this defect has been localized to chromosome band 6q23. Neonatal course is usually uneventful. These patients present with progressive spastic diplegia or quadriplegia, intellectual impairment, recurrent vomiting, delayed growth, and seizures.
  • Organic acidemias
    • Usually these disorders are associated with ketosis and acidosis in addition to hyperammonemia; however, sometimes hyperammonemia dominates the picture, raising the possibility of a urea cycle disorder. The proposed mechanism for hyperammonemia is the accumulation of CoA derivatives of organic acids, which inhibit the formation of N -acetylglutamate, the activator of carbamoyl phosphate synthetase in liver.
    • Disorders in this group include the following:
      • Isovaleric acidemia
      • Propionic acidemia
      • Methylmalonic acidemia
      • Glutaric acidemia type II
      • Multiple carboxylase deficiency
      • beta-ketothiolase deficiency
  • Congenital lactic acidosis
    • These disorders are characterized by increased lactate (10-20 mmol/L), increased lactate/pyruvate ratio, metabolic acidosis, and ketosis. Hyperammonemia and citrullinemia have been observed in some cases.
    • This group includes the following:
      • Pyruvate dehydrogenase deficiency
      • Pyruvate carboxylase deficiency
      • Mitochondrial disorders
  • Fatty acid oxidation defects
    • Acyl CoA dehydrogenase deficiency: Deficiency of medium- or long-chain acyl CoA dehydrogenase leads to defective beta-oxidation of fats. Patients present with severe hypoglycemia. Some patients have modest hyperammonemia secondary to hepatic dysfunction.
    • Systemic carnitine deficiency: Carnitine is required for transport of long-chain fatty acids into mitochondria. Its deficiency causes nonketotic hypoglycemia, increase in liver transaminases, and modest elevation of ammonium level. Patients may have muscle weakness, cardiomyopathy, hepatomegaly, and/or growth retardation.
  • Dibasic amino acid transport defects
    • Lysinuric protein intolerance (LPI): This disorder is characterized by a defect in membrane transport of cationic amino acids lysine, arginine, and ornithine. The mechanism for hyperammonemia is the deficiency of ornithine and arginine. Citrulline, when given orally, abolishes the hyperammonemia as it is transported by a different mechanism in the intestine. Affected individuals have normal neurologic development when adequately treated.
    • Hyperammonemia-hyperornithinemia-homocitrullinuria (HHH): These infants present in the first few weeks of life with seizures, feeding difficulty, and altered level of consciousness. A defect in transport of ornithine from cytosol into mitochondria causes hyperornithinemia, and disruption of the urea cycle causes hyperammonemia. In the absence of ornithine, mitochondrial carbamoyl phosphate reacts with lysine to form homocitrulline.
  • Transient hyperammonemia of the newborn
    • This disorder is seen in premature infants. Onset of symptoms is on the first or second day of life before introduction of any protein.
    • These infants have seizures, decreased consciousness, fixed pupils, and loss of oculocephalic reflex. Because of these clinical findings, conditions like severe hypoxic-ischemic encephalopathy and intracranial hemorrhage are considered first.
    • Hyperammonemia is marked and is treated with hemodialysis.
    • Twenty to thirty percent of these infants die, and about 35-45% have abnormal neurologic development.
    • Possible mechanism is slow maturation of the urea cycle function.
  • Asphyxia
    • Hyperammonemia has been observed in newborns with severe perinatal asphyxia. High levels of ammonia are found within the first 24 hours of life.
    • Increased ammonia is usually accompanied by elevated serum glutamic oxaloacetic transaminase (SGOT).
  • Reye syndrome
    • This is an acquired disorder usually occurring after a viral infection (particularly influenza A or B or varicella). Statistically, it has some association with aspirin ingestion.
    • Patients present with symptoms and signs of cerebral and hepatic dysfunction—vomiting, altered level of consciousness, seizures, cerebral edema, and hepatomegaly without jaundice.
    • Laboratory studies reveal marked increases in liver transaminases, hyperammonemia, and lactic acidosis.
  • Drugs
    • Valproate: Therapy with valproate is associated with hyperammonemia, usually less than 2-3 times the upper limit of the reference range. It is frequent in patients on combination therapy for epilepsy. The mechanism is decreased production of mitochondrial acetyl CoA, which causes decrease in N -acetylglutamate, an activator of carbamoyl phosphate synthetase. Thus, patients with partial enzyme deficiencies may be at increased risk of developing symptomatic hyperammonemia during treatment with valproate.

      Valproate can also cause a carnitine deficiency, which leads to B-oxidation impairment followed by urea cycle inhibition. Administration of carnitine has been shown to speed the decrease of ammonia in patients with valproic acid – induced encephalopathy, but further studies are needed to clarify the therapeutic and prophylactic role of carnitine and optimal regimen of administration.7 Asymptomatic hyperammonemia has been reported as a frequent, but transient finding following intravenous loading dose of valproic acid.8
    • Chemotherapy: Acute hyperammonemia has been reported after high-dose chemotherapy such as 5-fluorouracil, resulting in a high mortality rate.
    • Salicylate: Intoxication with aspirin can present findings similar to Reye syndrome with an initial respiratory alkalosis and hyperammonemia.
  • Liver disease
    • This is a common cause of hyperammonemia in adults. It may be due to an acute process, for example, viral hepatitis, ischemia, or hepatotoxins.
    • Chronic liver diseases that can cause hyperammonemia include the following:
      • Biliary atresia
      • Alpha1-antitrypsin deficiency
      • Wilson disease
      • Cystic fibrosis
      • Galactosemia
      • Tyrosinemia
  • Renal
    • Urinary tract infection with a urease-producing organism, such as Proteus mirabilis, Corynebacterium species, or Staphylococcus species, can produce a hyperammonemic state.
    • This usually happens in association with high urinary residuals and an alkaline pH.
  • Other causes
    • Herpes infection: Hyperammonemia, in association with neonatal herpes simplex pneumonitis, has been reported. The increase in ammonia level resulted from protein catabolism caused by prolonged hypoxia.
    • Parenteral hyperalimentation: Increased nitrogen load in patients receiving parenteral alimentation can cause hyperammonemia.
    • Hyperammonemia has been reported in patients with thyroid disease and Hashimoto encephalopathy.9,10
    • Hyperammonemia is a rare but severe complication of multiple myeloma and is associated with high mortality.11

Other diagnostic considerations

  • The clinical presentation of hyperammonemia in the neonatal period is nonspecific and merely indicates that the infant is in distress; therefore, disorders such as sepsis, intracranial hemorrhage, cardiac disease, and gastrointestinal obstruction should be ruled out with appropriate laboratory and imaging studies. Plasma ammonium level should be determined in all such scenarios. Once it is found to be elevated (ie, >200 µmol/L), then a specific diagnosis can be made with the help of the following laboratory studies:
    • Plasma and urinary amino acids
    • Urinary organic acids
    • Serum glucose
    • Arterial blood gases
    • Bicarbonate
    • Lactate
    • Citrulline
    • Urinary ketones
    • Urinary orotate
  • Hyperammonemia, along with acidosis, ketosis, and a low bicarbonate level, is suggestive of an organic acidemia. In addition, hyperglycinemia and hypoglycemia also are seen in some organic acidemias. Hyperammonemia, in addition to acidosis, ketosis, and increased lactate and citrulline, indicates pyruvate carboxylase deficiency.
  • Hyperammonemia with respiratory alkalosis is caused by a urea cycle defect or transient hyperammonemia of the newborn. Plasma citrulline level can help to localize the defect within the urea cycle. In AS deficiency (ie, citrullinemia), plasma citrulline level is very high (>1000 µmol/L). In AL deficiency (ie, argininosuccinic aciduria), citrulline level is increased moderately (100-300 µmol/L). Trace levels of citrulline or complete absence suggests deficiency of CPS or OTC. Determination of urinary orotate, which is elevated in OTC deficiency, differentiates the two. Thus, CPS deficiency is a diagnosis of exclusion and can be confirmed by enzyme assay on a tissue specimen. NAGS deficiency resembles CPS deficiency and also requires a liver biopsy for a definitive diagnosis.
  • The presence of hyperammonemia within the first 24 hours in a premature infant with normal to mildly elevated citrulline levels represents transient hyperammonemia of the newborn.
  • Differential diagnosis of late-onset hyperammonemia
    • In a child presenting with hyperammonemia, the differential diagnosis includes all the disorders already mentioned, as well as some other conditions. The additional laboratory studies for these disorders include liver function tests, plasma carnitine, and arginine.
    • Hyperammonemia with metabolic acidosis, ketosis, markedly elevated hepatic transaminases, and hyperbilirubinemia suggests liver disease and hepatotoxicity.
    • A similar laboratory profile without hyperbilirubinemia is seen in Reye syndrome or systemic carnitine deficiency.
    • In the absence of acidosis or ketosis, the possibilities are a urea cycle defect or an amino acid transport defect. Determination of citrulline and urinary orotate would help to diagnose the specific enzyme deficiency, except for argininemia, in which citrulline level is within the reference range but plasma arginine level is raised markedly (>500 µmol/L).
    • If serum levels of citrulline and arginine are within reference ranges, amino acid transport defects should be considered. Increased urinary excretion of lysine is seen in LPI, whereas in HHH syndrome, plasma ornithine level is elevated along with increased urinary homocitrulline.

More on Hyperammonemia

Overview: Hyperammonemia
Differential Diagnoses & Workup: Hyperammonemia
Treatment & Medication: Hyperammonemia
Follow-up: Hyperammonemia
References
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References

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Further Reading

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Keywords

hyperammonemia, urea cycle disorders, urea cycle enzyme deficiencies, hepatic encephalopathies, Reye syndrome, toxic encephalopathies, metabolic disorders, ornithine transcarbamoylase deficiency, OTC deficiency, N -acetylglutamate synthetase deficiency, NAGS deficiency, carbamoyl phosphate synthetase I deficiency, carbamyl phosphate synthetase I deficiency, CPS I deficiency, argininosuccinic acid synthetase deficiency, AS deficiency, argininosuccinic lyase deficiency, AL deficiency, arginase deficiency, isovaleric acidemia, propionic acidemia, methylmalonic acidemia, glutaric acidemia type II, multiple carboxylase deficiency, beta-ketothiolase deficiency, congenital lactic acidosis, pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, mitochondrial disorders, acyl CoA dehydrogenase deficiency, systemic carnitine deficiency, hyperammonemia-hyperornithinemia-homocitrullinuria, HHH

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Contributor Information and Disclosures

Author

Elena Crisan, MD, Consulting Staff, Department of Neurology, Edwards Hines Veterans Affairs Hospital
Elena Crisan, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Coauthor(s)

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

Medical Editor

J Stephen Huff, MD, Associate Professor, Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia Health Sciences Center
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.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

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.

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

 
 
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