Introduction
Hyperammonemia is a medical condition characterized by abnormally high serum ammonia levels. Elevated serum ammonia levels can cause neurotoxicity. The sudden onset of significant hyperammonemia is associated with severe encephalopathy and brain damage. It can result in cerebral edema, vomiting, seizures, hypotonia, and even fatality.
How Is Ammonia Produced in the Body?
The breakdown of proteins and amino acids in the human body results in the production of ammonia, which is a metabolite. In addition to this, ammonia contributes to the production of amino acids and helps to regulate the acid–base balance. However, exposure to ammonia in high concentrations can result in severe poisoning.
What Is Hyperammonemia?
A condition known as hyperammonemia occurs when there is an abnormally high quantity of serum ammonia in the body. If the levels are high enough in the serum, it could cause neurotoxicity. Extreme hyperammonemia that comes on suddenly can lead to severe encephalopathy, which in turn can harm the brain. In addition, there is a possibility of cerebral edema, emesis, convulsions, hypotonia, and even death. However, a chronic rise in ammonia levels that is only slightly beyond the normal range might produce neuropsychiatric issues such as delirium and changes in behavior. Those who survive severe cases of newborn hyperammonemia typically have structural brain damage.
Adult patients who are suffering from a complex form of liver illness often have hyperammonemia. Inadequacies in the enzymes involved in the urea cycle, citrin, and pyruvate carboxylase are some metabolic conditions that can lead to hyperammonemia. The majority of patients with hyperammonemia arrive with an abrupt spike in ammonia in critical care units. This requires rapid intervention to prevent brain damage and death as a result of the condition—ornithine carbamoyltransferase deficiency (the most common urea cycle disease. X-linked genetic disease hinders ammonia breakdown and excretion. Ammonia builds up and poisons the central nervous system, and hematologic malignancy and the adverse effects of Valproic acid and 5-Fluorouracil (5-FU) are some additional factors that can lead to hyperammonemia.
What Causes the Serum Amino Acids Levels to Increase?
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All urea cycle disorders except arginase deficiency increase glutamine and alanine.
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Citrulline decreases marginally in CPS/NAGS and OTC deficiencies but increases significantly in AS and moderately in AL deficiencies.
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Arginine levels increase significantly in arginase deficit but fall modestly in all other urea cycle enzyme abnormalities.
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AL deficiency significantly raises argininosuccinic acid.
Which Is the Diagnostic Method?
Hyperammonemic patients should have the following tests:
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Arterial Blood Gas Analysis: It measures acid-base status; respiratory alkalosis strongly supports a urea cycle malfunction caused by central respiratory drive activation and hyperventilation.
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Urinary Orotic Acid Tests: OTC deficiency increases the amount significantly, while other enzyme defects increase it modestly, except for CPS/NAGS, which decreases it. Urinary ketones indicate organic acidemia.
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Plasma and Urine Organic Acid Tests: These levels detect organic acidemia that may cause hyperammonemia.
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Enzyme Testing: Percutaneous liver biopsy specimens can diagnose CPS, NAGS, and OTC deficiency. Red blood cells (arginase deficiency), skin biopsy fibroblast, and intestinal mucosa undergo enzyme testing. Genetic analysis has surpassed enzyme analysis. In circumstances where genetic testing is negative or unavailable, it is nonetheless recommended.
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DNA Mutation Analysis can prove UCD for all urea cycle genes. Several methods can detect OTC locus mutations.
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Allopurinol Loading Test: Determines OTC deficient carrier status in women. Carriers have much higher urine orotidine excretion after a loading dose of Allopurinol.
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Antenatal Diagnosis: DNA analysis on chorionic villus or amniotic fluid cells, amniotic fluid metabolites, or enzyme activities in amniotic cells, chorionic villi, fetal liver, and fetal erythrocytes can detect all urea cycle defects.
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Image Studies: CT or MRI brain imaging may reveal cerebral edema in acute hyperammonemia. The classic MR finding in patients with chronic liver disorders is a hyperintense signal in the globus pallidus on T1-weighted images caused by an elevated manganese tissue concentration. MR spectroscopy reveals a high glutamine/glutamate peak accompanied by diminished Myo-inositol and choline signals.
The MRI of a patient with hyperornithinemia-hyperammonemia-homocitrullinuria revealed multiple lesions resembling strokes. In patients with arginase deficiency, injury to corticospinal tracts is detected by a more recent imaging technique involving diffusion tensor imaging.
What Is the Treatment Method?
The treatment goals for hyperammonemia are to ensure appropriate nutrition is consumed and to repair metabolic abnormalities. Compounds used in treatment help remove nitrogen waste more effectively. The load on the urea cycle is decreased because these molecules transform nitrogen into products other than urea that are eliminated. The first substances utilized were arginine and sodium benzoate. Phenylbutyrate has now taken the position of phenylacetate, which was formerly employed.
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Neonatal hyperammonemia for coma treatment.
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Protein consumption needs to end.
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A hypertonic ten percent glucose should be administered to provide calories.
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All comatose newborns with plasma ammonium levels greater than ten times the standard range should begin hemodialysis right once. Hemodialysis reduces plasma ammonium levels more quickly and takes less time than peritoneal dialysis. An alternate technique is continuous arteriovenous or venovenous hemofiltration.
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Once the plasma ammonium level drops to three to four times the upper limit of the standard range, intravenous Sodium benzoate and phenylacetate should be commenced.
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There should be intravenous arginine available. They generate a negative nitrogen balance; corticosteroids are not advised for managing elevated intracranial pressure in hyperammonemia. Hyperammonemia-induced cerebral edema cannot be treated with Mannitol. As Valproic acid impairs urea cycle performance and raises serum ammonia levels, it should not be used to treat seizures.
Surgical Method
- Liver Transplant: Hyperammonemia liver transplantation aims to rectify metabolic errors. In one liver transplantation study for hyperammonemia, metabolic mistakes were addressed in all patients, and medication and dietary restrictions were discontinued. Neurologic outcomes were closely related to pre-transplant status. Thus, non-brain-injured urea cycle malfunction individuals can benefit from liver transplantation. Multiple intraportal infusions of cryopreserved hepatocytes may be a less invasive alternative to liver transplantation.
- Diet: Hyperammonemia is treated with diet.
1. Low Protein Intake, 0.7 g/kg/day of protein and necessary amino acids is recommended. In the first six months, infants can handle 1.5 to 2 g/kg/day of protein.2. Urea cycle dysfunction patients need arginine supplementation. Late-onset cases of arginine deficiency can be treated with citrulline, which has one less nitrogen atom than arginine. In patients with unknown enzyme deficits, citrulline should not be given due to high citrulline levels in ASS and ASL deficiencies.3. Supplying enough calories to meet energy needs.4. A tube may be needed for stable feeding. A gastrostomy tube is the best technique to give drugs and fluids and prevent catabolism.
What Is the Preventive Method?
The indications of hyperammonemia should be taken very seriously by parents. At the beginning of these symptoms, they should consult their physician immediately. The incidence of hyperammonemia episodes is reduced by following suggested diets and taking medications as prescribed.
Several laboratory techniques allow for the early identification of urea cycle disorders. If a family has had an affected infant or suspects that the mother is an OTC mutation carrier, they should be made aware of the availability of these tests.
Conclusion
Hyperammonemia needs to be considered as an alternative diagnosis for encephalopathy along with seizures, particularly in the presence of bilateral symmetric involvement of the insular and cingulate cortices as detected by MRI. In the absence of hepatocellular dysfunction, hyperammonemia may result from increased ammonia production or decreased ammonia excretion. Intensive management with ammonia-reducing measures, cerebral edema, and elevated intracranial pressure is required.
