Hyperammonemia, or high ammonia levels, is a metabolic disturbance characterised by an excess of ammonia in the blood. Severe hyperammonemia is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.

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Hyperammonemia
Other namesHyperammonaemia; High ammonia levels
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Ammonia
SpecialtyEndocrinology 
CausesDue to accumulation of argininosuccinate, citrulline, and arginine in the liver when the urea cycle is deficient.
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Ammonia is a substance that contains nitrogen. It is a product of the catabolism of protein. It is converted to the less toxic substance urea prior to excretion in urine by the kidneys. The metabolic pathways that synthesize urea involve reactions that start in the mitochondria and then move into the cytosol. The process is known as the urea cycle, which comprises several enzymes acting in sequence. It is greatly exacerbated by common zinc deficiency, which raises ammonia levels further.[1]

Levels

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Perspective

Normal blood ammonia levels in adults range from 20 to 50 μmol/L or less than 26 to 30 μmol/L.[2][3][4] There is at present no clear scientific consensus on the upper limits of ammonia levels for different age groups.[4] In any case, hyperammonemia is generally defined as ammonia levels greater than 50 μmol/L in adults and greater than 100 μmol/L in newborns.[2][4] These values should be considered as decision limits and the normal reference ranges of individual laboratories should be used for clinical interpretation.[4]

More information Patient group, Ammonia levels (μmol/L) ...
Blood ammonia levels in different populations[2][3][4]
Patient groupAmmonia levels (μmol/L)Hyperammonemia (μmol/L)Ref
Premature neonates50–159>159[5][3]
Healthy term neonates45–75>75–100[5][3]
Children and adolescents24–48>48–50[6][3]
Adult females11–48>48[7]
Adult males15–55>55[7]
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When ammonia levels rise greater than 200 μmol/L, serious symptoms, including seizures, encephalopathy, coma, and even death, can occur.[3] Hyperammonemia with blood ammonia levels greater than 400 to 500 μmol/L is associated with 5- to 10-fold higher risk of irreversible brain damage.[2]

Signs and symptoms

Complication

Hyperammonemia is one of the metabolic derangements that contribute to hepatic encephalopathy, which can cause swelling of astrocytes and stimulation of NMDA receptors in the brain.[8]

Diagnosis

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Perspective

Types

Primary vs. secondary

Acquired vs. congenital

Specific types

The following list includes such examples:

Treatment

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Perspective

Treatment centres on limiting intake of ammonia and increasing its excretion. Dietary protein, a metabolic source of ammonium, is restricted, and caloric intake is provided by glucose and fat. Intravenous arginine (argininosuccinase deficiency), sodium phenylbutyrate and sodium benzoate (ornithine transcarbamylase deficiency) are pharmacologic agents commonly used as adjunctive therapy to treat hyperammonemia in patients with urea cycle enzyme deficiencies.[13] Sodium phenylbutyrate and sodium benzoate can serve as alternatives to urea for the excretion of waste nitrogen. Phenylbutyrate, which is the product of phenylacetate, conjugates with glutamine to form phenylacetylglutamine, which is excreted by the kidneys. Similarly, sodium benzoate reduces ammonia content in the blood by conjugating with glycine to form hippuric acid, which is rapidly excreted by the kidneys.[14] A preparation containing sodium phenylacetate and sodium benzoate is available under the trade name Ammonul. Acidification of the intestinal lumen using lactulose can decrease ammonia levels by protonating ammonia and trapping it in the stool. This is a treatment for hepatic encephalopathy.[15]

Treatment of severe hyperammonemia (serum ammonia levels greater than 1000 μmol/L) should begin with hemodialysis if it is otherwise medically appropriate and tolerated.[12]

Continuous renal replacement therapy (CRRT) is a remarkably effective mode of therapy in neonatal hyperammonemia, particularly in severe cases of Urea cycle defects like Ornithine transcarbamoylase (OTC) deficiency. Multidisciplinary team (MDT) collaboration is required to optimize this advanced treatment. Simulation training might be the best training and teaching strategy to ensure MDT successful therapy.[16]

See also

References

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