Genetics of Hyperammonemia 

Updated: Sep 20, 2018
Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD 

Overview

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 α -amino group is a catabolic key that protects amino acids from oxidative breakdown. Removing the α -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 the image below) 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 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, whether genetically or pharmacologically induced, 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.

Studies in mice suggest that increased ammonia concentration in brain causes upregulation of aquaporin-4, a water channel which has been associated with increased water permeability in other neurodisorders.[2, 3] 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.

Epidemiology

Frequency

United States

The frequency of each genetic cause of hyperammonemia is undetermined because of the technical difficulties in accurately detecting each through an organized newborn screening program. The reported incidence of argininosuccinic acid synthase and argininosuccinic acid lyase deficiencies from a database of more than 6 million live births across the United States is 1 per 35,000 live births per year.[4] The combined incidence of urea cycle disorders has been estimated at approximately 1 per 20,000-25,000 live births. Providing incidence figures for clinically significant partial defects or secondary causes of hyperammonemia is not possible. Any severe impairment of liver function, whether temporary or permanent, can initiate the onset of hepatic encephalopathy.

International

A report from a single screening site in Germany, analyzing samples from almost 1.1 million newborns over a decade, detected a combined total of 11 cases of citrullinemia and argininosuccinic aciduria.[5] A second report indicates that the European incidence of all urea cycle disorders is in the range of 1:8000, a figure difficult to confirm through mass screening because of the aforementioned technical problems.[6]

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.[7]

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. Data from a very large cohort of patients (260) with inherited urea cycle disorders showed a surprisingly high rate of initial onset beyond the neonatal period (66%).[8] Indeed, in a subgroup of 69 males with OTC deficiency, 35% presented when older than 2 years in this series.

Prognosis

In general, it is difficult to determine the prognosis for an individual with hyperammonemia. The extent of lasting damage done by a single episode of hyperammonemia may be trivial if the episode is mild and short-lived, whereas such situations, if repetitive, can cause extensive and permanent dysfunction. Likewise, a single occasion of severe hyperammonemia may cause irreversible damage and/or death. Age at onset is also an important factor in determination of likely recovery.

 

Presentation

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 not 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 genetic 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

Neurologic history may include the following:

  • 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)

 

DDx

 

Workup

Laboratory Studies

Plasma ammonia level

Obtain this measurement when clinical signs and symptoms are suggestive of hyperammonemia. Especially in the newborn, symptoms and signs suggestive of sepsis must always be accompanied by a plasma ammonia measurement, since the distinction between the two entities cannot be made by any clinical means and the presence of one does not preclude the other, in any case.

No other laboratory test can substitute for this measurement, nor does any other test indicate the 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 increases in levels of such intermediates as propionic acid, methylmalonic acid, isovaleric acid, or other organic acids and aid in diagnosis.

Urine amino acid levels

These are helpful in confirming argininosuccinic aciduria; lysinuric protein intolerance; or hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome.

Blood lactate levels

This is useful in ruling out mitochondrial diseases, in some of which an elevated blood ammonia level may be found.

Blood gas levels

Patients with urea cycle disorders may have alkalosis 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

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 (Ammonul), or both may be needed.

Surgical Care

Liver transplantation has been effective in the long-term treatment of the genetic disorders of ammonia metabolism. Inasmuch as each is a monogenic disorder, a successful surgical outcome is effectively curative. However, many factors must be considered prior to undertaking such a procedure. The long-term outcome data are generally fairly encouraging, with one study reporting a survival rate exceeding 75% at 15 years postoperatively.[9]

There is some conflict in the data concerning survival based on age at transplantation (< 2 years vs >2 years), with some studies reporting an inverse success rate with age, while others suggest the opposite.[10] Some data also suggest adverse cerebral effects of the disorder, independent of the age/severity at surgery, although it remains unclear as to what other factors might be implicated. In selected cases of acquired hepatic disease, a portocaval shunt may be appropriate.

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.

Guidelines for clinical genetic evaluation of children with mental retardation or developmental delays have been established.[11]

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. A study of four children with neonatal urea cycle defects concluded that, given the poor prognosis of urea cycle defects with conservative therapy, liver cell transplantation had considerable beneficial effects.[12]

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

Medication Summary

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.)

Metabolic agents

Class Summary

The use of benzoate and phenylacetate is based on the need to provide alternate routes for disposition of waste nitrogen. Benzoate is transaminated to form hippuric acid, which is rapidly cleared by the kidney. Phenylacetate is converted to phenylacetyl CoA and then conjugated with glutamine to form phenylacetylglutamine. Each of these 2 pathways results in disposition of 1 and 2 molecules of ammonia, respectively. Phenylbutyrate is more acceptable as a form of oral therapy because of a diminished odor but is not available for intravenous use.

Sodium phenylacetate and sodium benzoate (Ammonul)

Benzoate combines with glycine to form hippurate, which is excreted in urine. One mole of benzoate removes 1 mole of nitrogen. Phenylacetate conjugates (via acetylation) glutamine in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. The nitrogen content of phenylacetylglutamine per mole is identical to that of urea (2 mol of nitrogen). Ammonul must be administered with arginine for CPS, OTC, ASA synthetase, or ASA lyase deficiencies. Indicated as adjunctive treatment of acute hyperammonemia associated with encephalopathy caused by urea cycle enzyme deficiencies. Serves as an alternative to urea to reduce waste nitrogen levels.

 

Follow-up

Transfer

During initial stabilization of patients with hyperammonemia, 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.