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. [1]
Signs and symptoms
Signs and symptoms of early-onset hyperammonemia (neonates) may include the following:
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Lethargy
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Irritability
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Poor feeding
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Vomiting
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Hyperventilation, grunting respiration
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Seizures
Signs and symptoms of late-onset hyperammonemia (later in life) may include the following:
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Intermittent ataxia
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Intellectual impairment
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Failure to thrive
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Gait abnormality
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Behavior disturbances
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Epilepsy
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Recurrent Reye syndrome
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Protein avoidance
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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:
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Dehydration
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Lethargy
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Tachypnea
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Hypotonia
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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:
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Arterial blood gas analysis
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Serum amino acid levels
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Urinary orotic acid levels
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Urinary ketone tests
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Plasma and urinary organic acid levels
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Enzyme assays
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DNA mutation analysis: Method of choice to confirm the diagnosis of urea cycle disorders [2]
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Heterozygote identification in ornithine transcarbamoylase deficient pedigrees
Imaging studies
The following imaging studies may be used in evaluating patients with hyperammonemia:
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Neuroimaging: CT or MRI of the brain
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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:
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Urea cycle disorder treatment agents (eg, sodium phenylbutyrate, carglumic acid, sodium phenylacetate, and sodium benzoate)
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Antiemetic agents (eg, ondansetron, granisetron, palonosetron, dolasetron)
Other treatments
Other management approaches for hyperammonemia include the following:
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Cessation of protein and/or nitrogen intake
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Hemodialysis
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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. [3, 4]
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. [5] 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. [6]
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. [7]
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. [8] 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. [9]
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. [10]
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. [11]
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. [2]
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).
Prognosis
In a 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. [11]
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. [2]
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CT scan of cerebral edema caused by hyperammonemia. Republished with permission of American Society of Neuroradiology from U-King-Im JM, Yu E, Bartlett E, Soobrah R, Kucharczyk W. Acute hyperammonemic encephalopathy in adults: imaging findings. AJNR Am J Neuroradiol. 2011 Feb;32(2):413-8; permission conveyed through Copyright Clearance Center, Inc.
