OVERVIEW
Hyperammonemia is a clinical syndrome characterized by abnormally elevated blood ammonia levels and central nervous system dysfunction. Due to the low incidence of the disease and the lack of specificity of the clinical manifestations, it is easy to cause misdiagnosis and omission of diagnosis, and some patients cannot be correctly diagnosed until they die.
Causes
The protein ingested by the human body every day is digested and decomposed in the intestines to produce a certain amount of ammonia. Ammonia is a toxic substance that is synthesized into urea by hepatic urea synthase to relieve toxicity. The enzyme urea synthase required for this process contains biotin. If there is insufficient biotin in the body, the enzyme activity decreases and ammonia cannot be metabolized smoothly, which can cause hyperammonemia.
Symptoms
The main manifestation is the neurotoxicity of hyperammonemia. The severity of the clinical symptoms of hereditary hyperammonemia parallels the degree of enzyme activity defects, i.e., the more severe the enzyme defects, the earlier the onset of the disease and the more severe the symptoms. In the neonatal period, signs and symptoms are closely related to brain dysfunction. Usually, affected infants are normal at birth and develop symptoms a few days later after feeding a protein-containing diet, such as breast milk, which manifests itself as refusal to eat, vomiting, shortness of breath, lethargy, and quickly entering a deep coma, often with convulsive seizures. Physical examination reveals that in addition to deep coma, there may be a large liver and increased or low muscle tone. Childhood onset of symptoms are mild, intermittent episodes, acute hyperammonemia manifested as vomiting, neuropsychiatric symptoms such as ataxia, confusion, anxiety, irritability and aggressive behavior, etc., may be lethargy or even coma, but also may be manifested as anorexia and headache. Chronic hyperammonemia is characterized by progressive cerebral degeneration and may be characterized by physical and mental retardation.
Examination
1. Increased blood ammonia
Blood ammonia often ranges from 234.8 to 587 μmol/L (400 to 1000 μg/dl), and the normal reference range is 27 to 82 μmol/L (46 to 139 μg/dl). In hyperammonemic coma, blood ammonia can be as high as 352.2～1526.2μmol/L (600～2600μg/dl).
2. Quantitative amino acid analysis
Check the amino acids in blood and urine to determine whether there is a specific increase. Special attention should be paid to the quantitative analysis of glutamate, glutamine, alanine, citrulline, arginine and argininosuccinic acid urine to distinguish enzyme defects in the urea cycle.
3. Protein loading test
In urea cycle disorders with intolerance to protein foods, a protein loading test can be performed for clinical diagnosis and heterozygote detection. Eat naturally at breakfast, give protein, observe the change of blood ammonia, blood and urine amino acid and whey acid, measure once every 2 hours, total 3 times.
4. Measure blood glucose, blood gas analysis, organic acid in urine.
Respiratory alkalosis is often present in urea cycle disorders. Organic aciduria is also often accompanied by hyperammonemia, but it is different from urea cycle disorders because of the decrease in blood glucose, metabolic acidosis, and urinary excretion of specific organic acids.
5. Enzyme activity measurement
Hyperammonemia caused by deficiency of carbamoylphosphate synthetase (CPS) activity requires percutaneous liver biopsy to determine CPS activity. The diagnosis of ornithine carbamoyltransferase (OTC) deficiency also requires measurement of hepatocyte OTC activity. Argininosuccinate synthetase (AS) activity should be measured for the diagnosis of citrullinemia. In argininosuccinic aciduria, the activity of argininosuccinic acid lyase (AL) is measured in hepatocytes, peripheral erythrocytes, and skin fibroblasts. When argininemia is suspected, liver, erythrocyte, and leukocyte arginase activity should be measured.
6. Genetic analysis
OTC deficiency and CPS deficiency are available for DNA diagnosis by molecular genetic methods.
7. Heterozygote detection
It can be based on family line analysis, protein loading test, genetic analysis or enzyme activity test.
8. Imaging
Electroencephalography (EEG) with abnormal brain waves, brain CT when available, and other routine examinations such as ultrasound and X-ray.
Diagnosis
Diagnosis is made on the basis of history, clinical manifestations and examination.
Differential Diagnosis
Hyperammonemia needs to be differentiated from the following symptoms.
1. Transient hyperammonemia in newborns
It is mainly seen in preterm infants. The extremely high ammonia level is associated with severe neurologic depression and respiratory distress. If early hemodialysis, the symptoms can be relieved within 5 days and the prognosis is good. Asymptomatic hyperammonemia can also be seen in low birth weight infants.
2. Organic aciduria
Organic aciduria is often accompanied by hyperammonemia. It is characterized by normal blood amino acid quantification, low urinary lactic acid, increased specific organic acids in urine, low blood glucose, increased blood glycine, and metabolic acidosis.
3. Lysine urinary protein intolerance
Accompanied by hyperammonemia. Due to the defective transport of arginine, lysine and ornithine by renal tubules and intestinal epithelium, there is an increase in the blood of each of the above amino acids, which affects the metabolic function of the urea cycle.
4. Hyperammonemia – Hyperornithinemia – Homocitrullinemia
HHH syndrome is a disorder of ornithine transport into the mitochondria.
Treatment
1. Excretion of blood ammonia to provide amino acid
Blood ammonia should be excreted from the body as soon as possible, and enough calories and essential amino acids should be given to reduce the breakdown of proteins in the body.
2. Enhance renal excretion of ammonia
Give enough fluids and electrolytes, add glucose and insulin to replenish calories, and feed fat intravenously at 1g/kg per day.
3. Intravenous sodium benzoate and sodium phenylacetate.
Sodium benzoate can be combined with endogenous glycine to form horse uric acid, which has a high rate of renal clearance, while sodium phenylacetate can be combined with glutamic acid to form glutamic acid phenylacetate, which can be easily excreted from the urine. In emergency, sodium benzoate and sodium phenylacetate can be added to dextrose and fed intravenously within 2 hours, and then sodium benzoate and sodium phenylacetate can be given daily.
4. Arginine hydrochloride
Arginine can be used to treat all cases of hyperammonemia except those due to arginase deficiency. Arginine promotes the elimination of ammonia while replenishing the body with essential amino acids. Arginine may be given as an emergency in newborns with a first episode of hyperammonemia of undetermined etiology. In hyperammonemia secondary to organic acidemia, arginine has no therapeutic effect. Benzoic acid, phenylacetic acid, and arginine can be used together for optimal efficacy, and should be continued after the first dose until the acute crisis is resolved.
5. Hemodialysis or peritoneal dialysis.
Peritoneal dialysis can significantly reduce the level of blood ammonia after a few hours, and most of them can return to normal after 48 hours of dialysis.
6. Neomycin and lactulose
In order to reduce the production of ammonia by intestinal bacteria, neomycin or lactulose should be given nasally or by enema at the earliest possible time. The child’s neurological symptoms can be relieved by first aid measures, but it may take a few days for the child to regain full consciousness.
7. Dietary treatment
Limit protein intake, supply 1~2g/kg of protein per day.
8. Carnitine supplementation
Carnitine should be supplemented in the above treatment, because benzoic acid and phenylacetic acid can cause carnitine deficiency in the body.
9. Convulsions prohibited valproic acid
Because the drug can induce hyperammonemia.