Hyperammonemia Clinical Presentation

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.

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.

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. ^[12]

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. ^[13] Asymptomatic hyperammonemia has been reported as a frequent, but transient finding following intravenous loading dose of valproic acid. ^[14]

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. ^{[15, 16, 17, 18]}

Carbamazepine-induced hyperammonemia is rarely encountered. ^[19]

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. ^[20] In addition, of children who received valproic acid, concomitant administration of phenytoin and/or phenobarbital also increased the risk for hyperammonemia. ^[20] 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. ^{[21, 22]}

• Hyperammonemia is a rare but severe complication of multiple myeloma and is associated with high mortality. ^[23]  

• Ureaplasma species: The most common manifestations of ureaplasma infection in many individuals are neurological deficits due to hyperammonemia. Patients with this infection have a greater likelihood of developing hyperammonemia syndrome as compared to un-infected patients.[ref70}

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.

Complications of hyperammonemia may include cerebral edema and cortical blindness.