Hyperammonemia 

Updated: Nov 09, 2018
Author: Jasvinder Chawla, MD, MBA; Chief Editor: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS 

Overview

Practice Essentials

Hyperammonemia is a metabolic condition characterized by elevated levels of ammonia in the blood. Increased entry of ammonia to the brain is a primary cause of neurologic disorders, such as congenital deficiencies of urea cycle enzymes, hepatic encephalopathies, Reye syndrome, several other metabolic disorders, and some toxic encephalopathies.[69]

Signs and symptoms

Signs and symptoms of early-onset hyperammonemia (neonates) may include the following:

  • Lethargy

  • Irritability

  • Poor feeding

  • Vomiting

  • Hyperventilation, grunting respiration

  • Seizures

Signs and symptoms of late-onset hyperammonemia (later in life) may include the following:

  • Intermittent ataxia

  • Intellectual impairment

  • Failure to thrive

  • Gait abnormality

  • Behavior disturbances

  • Epilepsy

  • Recurrent Reye syndrome

  • Protein avoidance

  • Rarely, episodic headaches and cyclic vomiting

See Clinical Presentation for more detail.

Diagnosis

No specific physical findings are associated with hyperammonemia. Affected infants usually present with the following:

  • Dehydration

  • Lethargy

  • Tachypnea

  • Hypotonia

  • Bulging fontanelle

Examination occasionally 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.

Lab tests

Perform the following tests in patients with suspected hyperammonemia:

  • Arterial blood gas analysis

  • Serum amino acid levels

  • Urinary orotic acid levels

  • Urinary ketone tests

  • Plasma and urinary organic acid levels

  • Enzyme assays

  • DNA mutation analysis: Method of choice to confirm the diagnosis of urea cycle disorders[1]

  • Heterozygote identification in ornithine transcarbamoylase deficient pedigrees

Imaging studies

The following imaging studies may be used in evaluating patients with hyperammonemia:

  • Neuroimaging: CT or MRI of the brain

  • MR spectroscopy

See Workup for more detail.

Management

The therapeutic aims in patients with hyperammonemia are to correct the biochemical abnormalities and ensure adequate nutritional intake. Treatment involves compounds that increase the removal of nitrogen waste.

Pharmacotherapy

Medications used in the treatment of hyperammonemia include the following:

  • Urea cycle disorder treatment agents (eg, sodium phenylbutyrate, carglumic acid, sodium phenylacetate, and sodium benzoate)

  • Antiemetic agents (eg, ondansetron, granisetron, palonosetron, dolasetron)

Other treatments

Other management approaches for hyperammonemia include the following:

  • Cessation of protein and/or nitrogen intake

  • Hemodialysis

  • Supportive care with parenteral intake of calories

Surgery

Surgical intervention for patients with hyperammonemia include liver transplantation for correction of the metabolic error and/or liver cell transplantation as an alternative or bridge to liver transplantation.[2, 3]

See Treatment and Medication for more detail.

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.[4] 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. 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.[5]

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.[6]

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.[7] 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.[8]

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.[9]

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.

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; the incidence of urea cycle disorders in the United States is estimated at 1 in 25,000 live births.[10]

International

The prevalence of urea cycle disorders is currently estimated at 1:8,000-1:44,000 births internationally. The prevalence may be underestimated due to underdiagnosis of fatal cases and unreliable newborn screening.[1]

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).

 

Presentation

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

See the list below:

  • 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

See the list below:

  • 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

See the list below:

  • 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

Reye syndrome 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. In one case, Reye-like syndrome was reported due to food poisoning caused by Bacillus cereus.[11]

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

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.[12] Asymptomatic hyperammonemia has been reported as a frequent, but transient finding following intravenous loading dose of valproic acid.[13]

A topiramate/valproate-induced hyperammonemic encephalopathy was reported in patients on dual therapy, which is reversible with cessation of either medication. The hypothesized mechanism of the encephalopathy is a synergy between valproate and topiramate.[14, 15, 16, 17]

Carbamazepine-induced hyperammonemia is rarely encountered.[18]

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.

In a large study of 2944 pediatric patients with epilepsy, investigators identified young age and concomitant use of carbonic anhydrase inhibitors—with or without valproic acid—as a risk factor for hyperammonemia.[19] In addition, of children who received valproic acid, concomitant administration of phenytoin and/or phenobarbital also increased the risk for hyperammonemia.[19] Other significant risk factors included female sex, symptomatic generalized epilepsy, and concomitant use of acetazolamide, topiramate, or zonisamide.

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

See the list below:

  • 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.[20, 21]

  • Hyperammonemia is a rare but severe complication of multiple myeloma and is associated with high mortality.[22]

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.

 

DDx

 

Workup

Laboratory Studies

The following tests should be performed after a patient is found to be hyperammonemic:

  • Arterial blood gas analysis: This study determines acid-base status; respiratory alkalosis strongly suggests a urea cycle defect; it is the result of hyperventilation due to stimulation of the central respiratory drive.

  • Serum amino acid tests

    • Glutamine and alanine levels are increased in all urea cycle defects except for arginase deficiency.

    • Citrulline level is decreased mildly in CPS/NAGS and OTC deficiencies but increased markedly in AS deficiency and moderately in AL deficiency.

    • Arginine level is increased markedly in arginase deficiency but decreased mildly in all the other enzyme deficiencies of the urea cycle.

    • Argininosuccinic acid level is increased markedly in AL deficiency.

  • Urinary orotic acid tests: The level is increased markedly in OTC deficiency and mildly in other enzyme deficiencies except for CPS/NAGS deficiency, in which it is decreased mildly.

  • Urinary ketone tests: Presence of ketosis indicates an organic acidemia.

  • Plasma and urinary organic acid tests: These levels screen for the presence of an organic acidemia that may be causing the hyperammonemia.

  • Enzyme assays: Assays performed on tissue specimens obtained by percutaneous liver biopsy can determine diagnosis in cases of CPS, NAGS, and OTC deficiency. Enzyme assays are also performed on red blood cells (for arginase deficiency), fibroblast from skin biopsy (ASS, ASL, and HHH), and intestinal mucosa (CPS, OTC). Enzyme analysis has largely been replaced by genetic analysis. It is still indicated in selected cases with negative genetic testing or if genetic testing is not available.[1]

  • DNA mutation analysis is the method of choice in confirming the diagnosis of UCD as it is clinically available for all genes of the urea cycle.[1]

  • Heterozygote identification in OTC-deficient pedigrees

    • Allopurinol loading test: This test establishes the carrier status of women at risk for OTC deficiency. After a loading dose of allopurinol, urinary orotidine excretion is measured; it is increased greatly in carriers.

    • DNA analysis: Several techniques are available to determine the presence of a mutation at the OTC locus.

  • Antenatal diagnosis: All urea cycle defects can be diagnosed antenatally by different techniques including, DNA analysis on chorionic villus or amniotic fluid cells, measurements of amniotic fluid metabolites or enzyme activities in the amniotic cells, chorionic villi, fetal liver, and fetal erythrocytes.[1]

Imaging Studies

See the list below:

  • Neuroimaging: CT or MRI of the brain may show cerebral edema in acute hyperammonemia. The classic MR finding in patients with chronic liver disorders is hyperintense signal in the globus pallidum on T1 weighted images due to increased tissue concentration of manganese.

  • MR spectroscopy: This shows an elevated glutamine/glutamate peak coupled with decreased myoinositol and choline signals.[23, 24]

  • Multiple strokelike lesions have been recently reported as MRI finding in a patient with hyperornithinemia-hyperammonemia-homocitrullinuria.[25]

  • Newer imaging technique involving diffusion tensor imaging reveals damage to corticospinal tracts in patients with arginase deficiency.[26]

Histologic Findings

The most consistent neuropathologic change in encephalopathies with hyperammonemia is prominent Alzheimer type II astrogliosis.

 

Treatment

Medical Care

The aims are to correct biochemical abnormalities and ensure adequate nutritional intake. Treatment involves compounds that increase the removal of nitrogen waste. These compounds convert nitrogen into products other than urea, which are then excreted; hence, the load on the urea cycle is reduced. The first compounds to be used were sodium benzoate and arginine. Later, phenylacetate was used, which has now been replaced by phenylbutyrate.

  • Treatment of neonatal hyperammonemic coma

    • Protein intake should be stopped.

    • Calories should be supplied by giving hypertonic 10% glucose.

    • Hemodialysis should be started promptly in all comatose neonates with plasma ammonium levels greater than 10 times reference range. Plasma ammonium levels are reduced quickly and the total dialysis time is shorter with hemodialysis than with peritoneal dialysis. Continuous arteriovenous or venovenous hemofiltration may be used as an alternative method.[27]

    • Intravenous sodium benzoate and phenylacetate should be started once the plasma ammonium level falls to 3-4 times the upper limit of the reference range.

    • Intravenous arginine should be provided.

    • Corticosteroids are not indicated for the management of increased intracranial pressure in hyperammonemia because they induce negative nitrogen balance. Mannitol is not effective in treating cerebral edema induced by hyperammonemia.

    • Valproic acid should not be used to treat seizures as it decreases urea cycle function and increases serum ammonia levels.

  • Treatment of intercurrent hyperammonemia

    • Patients with urea cycle defects may present with episodes of hyperammonemia secondary to increased protein intake, increased catabolism, or noncompliance with therapy. This should be recognized early and treated as an emergency.

    • Treatment should be started if the plasma ammonium level is 3 times the reference level.

    • All nitrogen intake should be stopped.

    • High parenteral intake of calories from 10-15% glucose and intralipids should be provided.

    • Intravenous infusion of sodium benzoate and phenylacetate should be started.

    • Plasma ammonium levels should be checked at the end of the infusion and every 8 hours.

    • Once the ammonia level is near normal, oral medication should be started.

    • If the level does not decrease in 8 hours, hemodialysis should be started.

    • Osmotic demyelination syndrome has been reported as a potential serious complication of standard therapy for hyperammonemia in patients with ornithine transcarbamylase deficiency.[28]

Surgical Care

See the list below:

  • Liver transplantation: The main goal of liver transplantation is to correct the metabolic error. In one recent study of liver transplantation in patients with defects causing hyperammonemia, metabolic errors were corrected in all patients, and requirements for medication and dietary restriction were eliminated. Neurologic outcomes correlated closely with status prior to transplantation. Thus, liver transplantation is a good option for patients with urea cycle defects who have not suffered major brain injury.

  • Liver cell transplantation, administered as multiple intraportal infusions of cryopreserved hepatocytes, has been reported as a potentially less invasive alternative or bridging to liver transplantation.[2, 3]

Consultations

See the list below:

  • Nephrologist for hemodialysis

  • Dietitian to help with the dietary management and education of the family

  • Geneticist for possible testing of family members and to provide genetic counseling

Diet

Dietary management consists of the following:

  • Low protein intake: Current recommendation is 0.7 g/kg/day of protein and 0.7 g/kg/day of essential amino acid mixture. During the first 6 months, an infant may tolerate 1.5-2 g/kg/day of protein.

  • Arginine supplementation: Arginine is an essential amino acid in patients with urea cycle defects. In neonates and in OTC and CPSI deficiencies, citrulline can be given as a source of arginine as it gives one less nitrogen atom; in late-onset cases, however, arginine is acceptable because of increased nitrogen tolerance. Citrulline levels are elevated in ASS and ASL deficiencies and citrulline should not be administered in patients with unknown enzyme deficiency.

  • Providing enough calories to meet energy requirements

  • A tube feeding may be needed to provide a stable feeding route. A gastrostomy tube is the most reliable way to administer medications and fluids during illness and helps provide adequate nutritional support to prevent catabolism.[1]

Activity

Restricting physical activity of these children is not necessary; however, caloric intake should be sufficient to avoid protein breakdown.

 

Medication

Medication Summary

The medical management of urea cycle disorders used to be limited to dietary modifications, which were not sufficient in many patients. Introduction of compounds that promote alternate pathways for nitrogen excretion was a big breakthrough. As nitrogen is converted to compounds other than urea, the load on the urea cycle is reduced.

Urea Cycle Disorder Treatment Agents

Class Summary

This group consists of sodium benzoate, sodium phenylacetate, and sodium phenylbutyrate. These drugs lower blood ammonia concentrations by conjugation reactions involving acylation of amino acids. Sodium phenylbutyrate is a prodrug and is metabolized to phenylacetate. Phenylacetate then conjugates with glutamine to form phenylacetylglutamine, which is then excreted by the kidneys. On a molar basis, 1 mole of phenylacetate removes 2 moles of nitrogen.

Sodium phenylbutyrate (Buphenyl)

Phenylacetate was introduced after benzoate but now has been replaced by phenylbutyrate because former has bad odor. Adverse effects include menstrual disturbances (23% of patients), anorexia, pH disturbance, hypoalbuminemia, disturbance in phosphate metabolism, Fanconi syndrome, bad taste, and offensive body odor. Available in powder and tablet forms.

Carglumic acid (Carbaglu)

Also called N -carbamoyl-L-glutamate, carbamylglutamic acid, or carglutamic acid. Structural analogue of N -acetylglutamate, which enters cells and enables activation of CPS I (first enzyme of urea cycle) in vivo. Decreases hyperammonemia by converting ammonia into urea. More resistant to enzymatic degradation by hydrolysis compared with N -acetylglutamate.

Carglumic acid was recently approved by the FDA as adjunctive therapy for acute hyperammonemia and maintenance therapy for chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS), a rare genetic disorder resulting in hyperammonemia.[27]

Available as a 200-mg dispersible tab. Tab is scored and can be split to provide accurate dose.

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 moles of nitrogen). Ammonul must be administered with arginine for carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or argininosuccinate lyase (ASL) 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.

Glycerol phenylbutyrate (Ravicti)

Glycerol phenylbutyrate is a nitrogen-binding agent for chronic management of adult and pediatric patients (including newborns) with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. It is a pre-prodrug that is metabolized by ester hydrolysis and pancreatic lipases to phenylbutyrate and then by beta oxidation to phenylacetate. Glutamine is conjugated with phenylacetate to form phenylacetylglutamine, a nitrogen waste product that is excreted in the urine. It is not indicated for treatment of hyperammonemia.

Antiemetic

Class Summary

These agents control nausea and vomiting associated with IV administration of sodium benzoate and phenylacetate.

Ondansetron hydrochloride (Zofran)

Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with sodium benzoate and phenylacetate and carglumic acid.

Granisetron (Granisol, Sancuso)

Used for prevention of chemotherapy-induced nausea and vomiting. At chemoreceptor trigger zone, blocks serotonin peripherally on vagal nerve terminals and centrally. Prevents nausea and vomiting associated with sodium benzoate and phenylacetate and carglumic acid.

Palonosetron (Aloxi)

Selective 5-HT3 receptor antagonist with long half-life (40 h). Blocks 5-HT3 receptors peripherally and centrally in chemoreceptor trigger zone. Prevents nausea and vomiting associated with sodium benzoate and phenylacetate and carglumic acid.

Dolasetron (Anzemet)

Prevents nausea and vomiting by binding to 5-HT3-receptors located on chemoreceptor trigger zone and vagal neurons in GI tract. Prevents nausea and vomiting associated with sodium benzoate and phenylacetate and carglumic acid.

 

Follow-up

Further Outpatient Care

Outpatient care involves monitoring growth and development of the child that would indicate the adequacy of treatment. Additionally, periodic fasting levels of the following should be determined:

  • Plasma ammonium

  • Plasma glutamine (should be maintained at < 1000 µmol/L)

  • Arginine

  • Total protein

Further Inpatient Care

Patients usually can go back to their dietary regimen and oral medications in 3-4 days. They should be admitted to an intensive care unit initially, and their neurologic status should be monitored carefully.

Inpatient & Outpatient Medications

See the list below:

  • Sodium phenylbutyrate: Patients with CPS, OTC, or AS deficiency should receive sodium phenylbutyrate at a dose of 450-600 mg/kg/day.

  • Citrulline: Patients with CPS or OTC deficiency should receive citrulline (150-200 mg/kg/day for < 20 kg and 3-4 g/m2/day if >20 kg) as a source of arginine; because citrulline is elevated in ASS and ASL deficiencies, it should not be given to patients with an unknown diagnosis. After stabilization, citrulline 170 mg/kg/day is given to patients with OTC and CPS deficiency.

  • Arginine: It is administered IV together with sodium phenylacetate and sodium benzoate solution as part of the initial hyperammonemia treatment. In patients ≤20 kg, CPS and OTC deficiency or if a specific defect in the urea cycle has not been identified, administer arginine hydrochloride bolus 200 mg/kg in patients who weigh less than 20 kg and 4 g/m2 for patients over 20 kg, infused over 90 min; this is followed by a maintenance dose of 200 mg/kg/day in patients under 20 kg and 4 g/m2/day for patients over 20 kg. In ASS and ASL deficiency, the maintenance dose recommended is 600 mg/kg/day if less than 20 kg and 12 g/m2/day if over 20 kg. After stabilization, an arginine base (500 mg/kg/day PO) is recommended for AS and AL deficiency.

Transfer

Patients should be transferred to a facility having a neonatal or pediatric intensive care unit.

Deterrence/Prevention

Parents should be educated to take the symptoms of hyperammonemia (ie, lethargy, vomiting, changes in behavior) very seriously. They should contact their physician immediately at the onset of these symptoms. Following dietary recommendations and compliance with medications decreases the frequency of hyperammonemic episodes.

Antenatal diagnosis of urea cycle disorders can be made using several laboratory techniques. Families should be informed about the availability of these tests if they have had an affected infant or if the mother is a carrier of OTC mutation.

Complications

See the list below:

  • Cerebral edema

  • Cortical blindness

Prognosis

See the list below:

  • In a previous study of patients with urea cycle defects in Japan, the 5-year survival rate was 22% for the neonatal-onset group and 41% for the late-onset group. Among the survivors of the neonatal-onset group, 90% had moderately severe to severe neurologic deficits, whereas 28% of the survivors of the late-onset group had similar problems.

  • In another study including 260 patients in the United States, the 11-year survival rate was 35% for the neonatal-onset group compared with 87% for the group with onset in late infancy.[10]

  • In previous study, a group of 21 patients with neonatal hyperammonemia was monitored over the long term. Duration of coma was the only reliable sign influencing the short-term outcome. Among the 13 survivors, only 3 had a normal/borderline outcome as far as neurocognitive development was concerned.

  • Suggested guidelines indicate that the most important factor for the neurodevelopmental prognosis is the total duration of coma and peak ammonia levels.[1]

Patient Education

See Deterrence/Prevention.

 

Questions & Answers

Overview

What is hyperammonemia?

What are the signs and symptoms of early-onset hyperammonemia (neonates)?

What are the signs and symptoms of late-onset hyperammonemia (late in life)?

What is the clinical presentation of infants with hyperammonemia?

How are physical exam findings characterized in patients with hyperammonemia?

Which lab tests are indicated in suspected hyperammonemia?

Which imaging studies are used in the workup of hyperammonemia?

What are the treatment goals in hyperammonemia?

Which medications are used in the treatment of hyperammonemia?

What are the management approaches to hyperammonemia aside from medication?

What is the role of transplantation in the treatment of hyperammonemia?

What is the physiology of ammonia and how does hyperammonemia cause neurological disorders?

What is the pathophysiology of hyperammonemia?

What is the mechanism of ammonia neurotoxicity that results in hyperammonemia?

What is the role of astrocyte morphology in hyperammonemia?

What are the manifestations of high levels of ammonia that may result in hyperammonemia?

How are the neurochemical disturbances in chronic hyperammonemia characterized?

What is the role of RNA oxidation in hyperammonemia?

What is the relationship between hyperammonemia and anorexia?

What is the incidence of hyperammonemia in the US?

What is the prevalence of hyperammonemia internationally?

What are the morbidities associated with hyperammonemia?

What are the race-related demographics of hyperammonemia?

What are the sex-related demographics of hyperammonemia?

What are the age-related demographics of hyperammonemia?

Presentation

What is the importance of family history in hyperammonemia?

What is the presentation of early-onset hyperammonemia?

What is the presentation of late-onset hyperammonemia?

How does hyperammonemia present in infants?

What unusual physical exam findings are associated with hyperammonemia in infants?

How is Reye syndrome associated with hyperammonemia characterized?

Which enzyme defects in the urea cycle are associated with hyperammonemia?

What is the role of organic acidemias in hyperammonemia?

Which organic acidemias are associated with hyperammonemia?

How is congenital lactic acidosis characterized in relation to hyperammonemia?

Which lactic acidosis disorders are associated with hyperammonemia?

Which fatty acid oxidation defects are associated with hyperammonemia?

Which dibasic amino acid transport defects are associated with hyperammonemia?

How is transient hyperammonemia of the newborn characterized?

What is the relationship between asphyxia and hyperammonemia in newborns?

How does valproate cause hyperammonemia?

What is the role of topiramate/valproate in the development of hyperammonemia?

Does carbamazepine cause hyperammonemia?

Does chemotherapy cause hyperammonemia?

Does aspirin cause hyperammonemia?

Why are children with epilepsy at increased risk for hyperammonemia?

What is the role of liver disease in hyperammonemia?

Which chronic liver diseases cause hyperammonemia?

How do renal conditions cause hyperammonemia?

What are other causes of hyperammonemia?

Which lab studies are used in the workup of neonates with suspected hyperammonemia?

Which acidemias are associated with hyperammonemia?

What causes hyperammonemia with respiratory alkalosis?

How is transient hyperammonemia of the newborn characterized?

Which conditions should be considered in the differential diagnosis of late-onset hyperammonemia?

DDX

What are the differential diagnoses for Hyperammonemia?

Workup

Which lab tests are used in the workup of hyperammonemia?

Which imaging studies are used in the workup of hyperammonemia?

Which histologic findings are associated with hyperammonemia?

Treatment

What are the treatment goals in hyperammonemia?

How is neonatal hyperammonemic coma treated?

How is intercurrent hyperammonemia treated?

What are the surgical options for treatment of hyperammonemia?

Which specialist consultations are indicated in the treatment of hyperammonemia?

What is the dietary management strategy in hyperammonemia?

Should activity be restricted in patients with hyperammonemia?

Medications

What are the medication recommendations for patients with hyperammonemia?

Which medications in the drug class Antiemetic are used in the treatment of Hyperammonemia?

Which medications in the drug class Urea Cycle Disorder Treatment Agents are used in the treatment of Hyperammonemia?

Follow-up

How are children with hyperammonemia monitored on an outpatient basis?

What is the approach to inpatient care of hyperammonemia?

Which medications are used in the treatment of hyperammonemia?

When is transfer indicated for hyperammonemia?

What information on signs and symptoms of hyperammonemia should be provided to parents?

What are the complications of hyperammonemia?

What is the prognosis of hyperammonemia?