AUTHOR INFORMATION

Section 1 of 12

Authored by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research

Edited by Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Head of Division of Metabolism, Department of Pediatrics, Oregon Health & Science University; Director, Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, Inc; Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Karl S Roth, MD
Editor's Email:	Robert D Steiner, MD

eMedicine Journal, January 3 2006, VOLUME 7, Number 1

INTRODUCTION

Section 2 of 12

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.

Normal blood ammonia levels range from 10-40 mmol/L, compared to a blood urea nitrogen (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 central nervous system (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, contributing substantially 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 Image 1) is the major route for disposal of waste nitrogen generated chiefly from protein and amino acid metabolism. 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 adenosine triphosphate (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:

• In the US: 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 adult-onset patients, 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

Section 3 of 12

History:

• The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, are somewhat variable in presentation, diagnostic features, and treatment. For these reasons, the family of urea cycle defects is considered individually in this publication. 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


• • 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)

  
  
  

DIFFERENTIALS

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Arginase Deficiency
Argininosuccinate Lyase Deficiency
Carbamoyl Phosphate Synthetase Deficiency
Citrullinemia
Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome
Hyperinsulinemia
Methylmalonic Acidemia
N-Acetylglutamate Synthetase Deficiency
Ornithine Transcarbamylase Deficiency
Propionic Acidemia (Propionyl CoA Carboxylase Deficiency)

Other Problems to be Considered:

Organic acid disorders (eg, isovaleric acidemia)
Lysinuric protein intolerance
Transient hyperammonemia of the newborn
Hepatic insufficiency/dysfunction
Mitochondrial diseases and pyruvate carboxylase deficiency
Valproate ingestion
L-asparaginase ingestion
Reye syndrome

WORKUP

Section 5 of 12

Lab Studies:

• Plasma ammonia level


• • Obtain this test when clinical signs and symptoms are suggestive of hyperammonemia.
  
  
  
  • No other laboratory test can substitute for this measurement, nor does any other test indicate need for it.
  
  
  
  • Only clinical suspicion indicates need.
  
  
  
• Liver function studies (ie, serum transaminases, prothrombin time [PT]/activated partial thromboplastin time [aPTT]), alkaline phosphatase levels, bilirubin levels): Severe liver disease can cause hyperammonemia; therefore, evaluating the function of the liver is always appropriate as a first approximation to etiology.



• Plasma amino acid level quantitation


• • Certain primary genetic causes can be suspected based on specific increases in amino acid levels, such as increased citrulline or argininosuccinic acid levels.
  
  
  
  • By contrast, severe liver disease tends to cause a generalized increase in plasma amino acid levels.
  
  
  
• Urinary organic acid profile


• • Disorders that involve metabolic intermediates of amino acid catabolism can cause mild-to-moderate inhibition of the urea cycle, resulting in hyperammonemia as a secondary phenomenon.
  
  
  
  • This test can help to identify level increases in such intermediates as propionic acid, methylmalonic acid, isovaleric acid, or other organic acids and aid in diagnosis.
  
  
  
• Urine amino acids: These are helpful in confirming argininosuccinic aciduria; lysinuric protein intolerance; or hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome.



• Blood lactate: This is useful in ruling out mitochondrial diseases.



• Blood gases


• • Patients with urea cycle disorders may be alkalotic due to stimulation of the respiratory drive by ammonia.
  
  
  
  • Patients with urea cycle disorders are rarely acidotic. Severe refractory acidosis suggests organic acid disorder or mitochondrial disorder.
  
  
  
• BUN level: This is often very low ( <3 mg of urea/100 mL) in persons with urea cycle disorders.



• N-carbamoyl-L-glutamic acid: In infants with confirmed hyperammonemia, oral loading with N-carbamoyl-L-glutamic acid has been advocated as both diagnostic and therapeutic for patients with N-acetylglutamate (NAG) synthetase deficiency.

Imaging Studies:

• Some authors advocate baseline MRI studies in patients with confirmed genetic causes of hyperammonemia; this is because some suggestive data indicate an elevated risk for stroke in these patients.

TREATMENT

Section 6 of 12

Medical Care:

• Hyperammonemia is a medical emergency because of the neurotoxicity, which is a direct effect of ammonia on the CNS.



• Initial management should consist of protein intake cessation with the provision of as many nonprotein calories as is practical via intravenous routes, oral routes, or both (if possible). More specific therapy depends on the etiology of the hyperammonemia. Hemodialysis, intravenous sodium phenylacetate/benzoate (an investigational new drug), or both may be needed.

Consultations:

• Geneticist


• • The role of the biochemical geneticist is to assist in interpretation of available laboratory tests toward a diagnosis of a specific genetic entity. Treatment must be guided by a professional experienced in the treatment of urea cycle disorders. This professional may be a biochemical geneticist, clinical geneticist, endocrinologist, or pediatrician, depending on the expertise available at a specific institution.

  • If such a diagnosis is confirmed, the patient requires long-term follow-up with a geneticist.
  
  
  
• Neurologist


• • The role of the neurologist is to provide a basic status evaluation for later reference during follow-up care.
  
  
  
  • This evaluation is especially useful in the primary genetic entities, in which recurrence is a virtual certainty and the risk of additional nervous system compromise exists.
  
  
  
• Gastroenterologist: A gastroenterologist may be of assistance in evaluation of liver disease or when hepatic transplant is considered as therapy for a urea cycle defect.

Diet:

• Dietary therapy greatly depends on the etiologic diagnosis.



• Protein restriction is helpful in most cases, and restriction of specific amino acids may be imperative in treatment of particular entities.



• Dietary treatment of urea cycle disorders is highly specialized and usually requires consultation with a registered dietitian who works in a metabolic disease clinic.

MEDICATION

Section 7 of 12

Treatment of hyperammonemia is somewhat dependent on cause. Emergency treatment of life-threatening severe hyperammonemia is hemodialysis. Recommendations for treatment of urea cycle disorders may be found in the specific articles (ie, Ornithine Transcarbamylase Deficiency). (See Differentials and Other Problems to be Considered.)

FOLLOW-UP

Section 8 of 12

Transfer:

• During initial stabilization, transfer to an academic medical center for further investigation and long-term treatment is mandatory. Transfer is especially necessary for newborns, who may require highly specialized equipment and personnel for hemodialysis, for example.

Complications:

• Hyperammonemia can cause irreversible neurotoxicity and cell death in the CNS.



• Acutely, the effects can conspire to cause cerebral edema, increased intracranial pressure, and death.

Prognosis:

• Regardless of the etiology, prognosis depends on both the severity and duration of the ammonia level elevation. The sites of damage are not predictable and require careful neurologic evaluation for documentation.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Failure to recognize symptoms and signs associated with hyperammonemia may cause prolongation of the episode and increased severity of CNS damage.

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which of the following is most useful in the diagnosis of hyperammonemia?

A: Plasma total bicarbonate level
B: Serum calcium level
C: Serum creatinine level
D: Serum total protein level
E: None of the above

The correct answer is E: Obtain plasma ammonia level any time clinical signs and symptoms are suggestive of hyperammonemia. No other laboratory test can substitute for this measurement, nor does any other test indicate need for this measurement. Only clinical suspicion indicates need.

CME Question 2: Which of the following is the most helpful diagnostic information of history in a patient with suspected hyperammonemia?

A: Age
B: Sex
C: Family pedigree
D: Intercurrent illnesses with exaggerated lethargy and vomiting
E: Diet

The correct answer is D: Intercurrent illnesses with exaggerated lethargy and vomiting is the most helpful diagnostic information of the history in a patient with suspected hyperammonemia.

Pearl Question 1 (T/F): Of the urea cycle defects, carbamyl phosphate synthetase deficiency is the only sex-linked cause of hyperammonemia.

The correct answer is False: Ornithine transcarbamylase (OTC) deficiency is a sex-linked cause of hyperammonemia.

Pearl Question 2 (T/F): For each mole of urea excreted, one mole of waste nitrogen is eliminated.

The correct answer is False: Two moles of waste nitrogen are eliminated with each mole of urea excreted.

Pearl Question 3 (T/F): The urea cycle is completed in the liver, where urea is generated from free ammonia.

The correct answer is True: The liver is where the urea cycle is complete.

Pearl Question 4 (T/F): Hyperammonemia does not affect the central nervous system (CNS).

The correct answer is False: The CNS is affected by hyperammonemia. As ammonia exceeds a normal concentration, an increased disturbance of neurotransmission and synthesis of both gamma-aminobutyric acid (GABA) and glutamine occurs in the CNS. 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.

PICTURES

Section 11 of 12

Caption: Picture 1. 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.
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BIBLIOGRAPHY

Section 12 of 12

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• Riordan SM, Williams R: Treatment of hepatic encephalopathy. N Engl J Med 1997 Aug 14; 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 2003 Jan-Feb; 6(1): 78-83[Medline].
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• 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 2005 Jun 15;[Medline].

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