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Neurology > Neurotoxicology
Hyperammonemia
Article Last Updated: Jan 10, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: Kazi Imran Majeed, MD, Private Practice, Dallas Pediatric Neurology Associates
Kazi Imran Majeed is a member of the following medical societies: American Academy of Neurology and American Academy of Pediatrics
Editors: J Stephen Huff, MD, Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia Health Sciences Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Richard J Caselli, MD, Professor, Department of Neurology, Mayo Medical School, Rochester, MN; Chair, Department of Neurology, Mayo Clinic of Scottsdale; Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Author and Editor Disclosure
Synonyms and related keywords:
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
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.
On the basis of 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; blocking the NMDA receptor with dizocilpine (MK-801) prevents both phenomena. 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.
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 two factors. The first is down-regulation of glutamate receptors secondary to excessive extrasynaptic accumulation of glutamate. 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.
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).
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. Another mechanism is that valproate can cause a carnitine deficiency, which leads to B-oxidation impairment, followed by urea cycle inhibition.
- 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.
- 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.
Ataxia with Identified Genetic and Biochemical Defects
Diseases of Tetrapyrrole Metabolism: Refsum Disease and the Hepatic Porphyrias
Disorders of Carbohydrate Metabolism
EEG in Dementia and Encephalopathy
Inherited Metabolic Disorders
Metabolic Disease & Stroke: Homocystinuria/Homocysteinemia
Metabolic Disease & Stroke: Methylmalonic Acidemia
Syncope and Related Paroxysmal Spells
Lab 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.
- 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.
Imaging Studies
- Neuroimaging: CT or MRI of the brain may show cerebral edema in acute hyperammonemia.
Histologic Findings
The most consistent neuropathologic change in encephalopathies with hyperammonemia is prominent Alzheimer type II astrogliosis.
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 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.
- Intravenous 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.
- 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.
Surgical Care
- 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.
Consultations
- 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, 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.
- Providing enough calories to meet energy requirements
Activity
Restricting physical activity of these children is not necessary; however, caloric intake should be sufficient to avoid protein breakdown.
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.
Drug Category: Urea cycle disorder treatment agents
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.
| Drug Name | Sodium benzoate and sodium phenylacetate (Ucephan) |
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| Description | Benzoate combines with glycine to form hippurate, which is excreted in urine. One mole of benzoate removes 1 mole of nitrogen. |
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| Adult Dose | 250 mg/kg/d PO in 3-6 equally divided doses; not to exceed 10 g/d each of sodium benzoate and sodium phenylacetate
Alternatively, 250 mg/kg/dose IV given over 90 min in 25-35 mL/kg of 10% glucose solution; continue IV administration at 250 mg/kg/d; to be infused over 24 h |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Penicillin may decrease effects; probenecid may inhibit renal excretion of products; valproate may antagonize efficacy |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
|
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| Precautions | Caution when administering to patients with neonatal hyperbilirubinemia (competes for bilirubin binding sites on albumin); due to sodium content, caution when giving to patients with congestive heart failure, severe renal dysfunction, or sodium retention with edema; common adverse effects include nausea, vomiting, tinnitus, and visual disturbance |
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| Drug Name | Sodium phenylbutyrate (Buphenyl) |
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| Description | 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. |
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| Adult Dose | 450-600 mg/kg/d PO or 9.9-13 g/m2/d given in divided doses 4-6 times/d with meals; not to exceed 20 g/d |
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| Pediatric Dose | <20 kg: 250-600 mg/kg/d PO
>20 kg: 9.9-13 g/m2/d PO in divided doses 4-6 times/d with meals; not to exceed 20 g |
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| Contraindications | Documented hypersensitivity; acute hyperammonemic episodes |
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| Interactions | Corticosteroids may decrease effectiveness by inducing catabolic state; valproate and haloperidol may increase ammonia levels, thus administer these combinations with caution |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
|
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| Precautions | Due to sodium content, avoid in congestive heart failure, severe renal dysfunction, or sodium retention with edema |
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Drug Category: Antiemetic
These agents control nausea and vomiting associated with IV administration of sodium benzoate and phenylacetate.
| Drug Name | Ondansetron hydrochloride (Zofran) |
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| Description | Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and complete body radiotherapy as well as sodium benzoate and phenylacetate. |
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| Adult Dose | 32 mg IV infused over 15 min beginning 30 min before start of IV sodium benzoate and phenylacetate infusion |
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| Pediatric Dose | 0.15 mg/kg IV |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Although potential for cytochrome P-450 inducers (barbiturates, rifampin, carbamazepine, and phenytoin) to change half-life and clearance, dosage adjustment not usually required |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
|
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| Precautions | Commonly observed adverse effects in children include local reactions, anxiety, agitation, headache, drowsiness; medication to be administered for prevention of nausea and vomiting, not for rescue of nausea and vomiting |
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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.
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
In/Out Patient Meds
- Sodium phenylbutyrate: Patients with CPS, OTC, or AS deficiency should receive sodium phenylbutyrate at a dose of 450-600 mg/kg/day.
- Citrulline: Neonates with CPS or OTC deficiency should receive 0.17 g/kg/day of citrulline as a source of arginine.
- Arginine: Patients with AS or AL deficiency should receive 400-700 mg/kg/day of arginine.
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
- Cerebral edema
- Cortical blindness
Prognosis
- In a recent 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, a group of 21 patients with neonatal hyperammonemia was monitored over 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.
Patient Education
Medical/Legal Pitfalls
- Plasma ammonium must be checked in a neonate who is in distress or develops seizures.
- Symptoms of lethargy, vomiting, or altered behavior in a patient with a hyperammonemic disorder should be presumed to be secondary to the underlying disorder until proven otherwise.
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- Albrecht J. Roles of neuroactive amino acids in ammonia neurotoxicity. J Neurosci Res. Jan 15 1998;51(2):133-8. [Medline].
- Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. Jan 2000;105(1):e10. [Medline].
- Batshaw ML. Inborn errors of urea synthesis. Ann Neurol. Feb 1994;35(2):133-41. [Medline].
- Batshaw ML. Hyperammonemia. Curr Probl Pediatr. Nov 1984;14(11):1-69. [Medline].
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Hyperammonemia excerpt Article Last Updated: Jan 10, 2007
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