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.
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.
Levels
Normal blood ammonia levels in adults range from 20 to 50μmol/L or less than 26 to 30μmol/L. There is at present no clear scientific consensus on the upper limits of ammonia levels for different age groups.
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| Adult males || 15–55 || >55 ||
Diagnosis
Types
Primary vs. secondary
- Primary hyperammonemia is caused by several inborn errors of metabolism that are characterised by reduced activity of any of the enzymes in the urea cycle. The most common example is ornithine transcarbamylase deficiency, which is inherited in an X-linked fashion.
- Secondary hyperammonemia is caused by inborn errors of intermediary metabolism, which are characterised by reduced activity of enzymes that are not part of the urea cycle or dysfunction of cells that make major contributions to metabolism. Examples of the former are propionic acidemia and methylmalonic acidemia, and examples of the latter are acute liver failure and hepatic cirrhosis with liver failure. But there are case reports where hyperammonemia was caused by urease-negative organisms. Urease producers form ammonia and carbon dioxide from urea. Ammonia then enters the systemic circulation (most venous supply of the bladder bypasses portal circulation) and enters the blood–brain barrier causing encephalopathy. 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. 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.
Treatment of severe hyperammonemia (serum ammonia levels greater than 1000 μmol/L) should begin with hemodialysis if it is otherwise medically appropriate and tolerated.
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.
See also
- Arginase deficiency
- Citrullinemia
- N-acetylglutamate synthetase deficiency
- Ornithine translocase deficiency
- Carbamoyl phosphate synthetase I deficiency
- Orotic aciduria