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]
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.[2]
Acquired vs. congenital
Acquired hyperammonemia is usually caused by diseases that result in either acute liver failure, such as overwhelming
hepatitis B or exposure to
hepatotoxins, or cirrhosis of the liver with chronic liver failure. Chronic hepatitis B, chronic
hepatitis C, and
excessive alcohol consumption are common causes of cirrhosis. The physiologic consequences of cirrhosis include shunting of blood from the liver to the
inferior vena cava, resulting in decreased filtration of blood and removal of nitrogen-containing toxins by the liver, and then hyperammonemia. This type of hyperammonemia can be treated with antibiotics to kill the bacteria that initially produce the ammonia, though this does not work as well as the removal of protein from the colon prior to its digestion to ammonia, achieved by
lactulose administration for frequent (3-4 per day) bowel movements.
Medication-induced hyperammonemia can occur with
valproic acid overdose, and is due to a deficiency in
carnitine. Its treatment is carnitine replacement.
Glycine toxicity causes hyperammonemia, which manifests as CNS symptoms and nausea. Transient blindness can also occur.[5]
Congenital hyperammonemia is usually due to
genetic defects in one of the enzymes of the urea cycle, such as ornithine transcarbamylase deficiency, which leads to lower production of urea from ammonia.
Treatment centers 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.[6] 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.[7] 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.[8]
Treatment of severe hyperammonemia (serum ammonia levels greater than 1000
μmol/L) should begin with
hemodialysis if it is otherwise medically appropriate and tolerated.[5]
Continuous renal replacement therapy (CRRT) is remarkably effective mode of therapy in neonatal
hyperammonemia, particularly in severe cases of
Urea cycle defect 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.[9]
^
abNepal SP, Unoki T, Inoue T, Nakasato T, Naoe M, Ogawa Y, Omizu M, Kato R, Sugishita H, Oshinomi K, Morita J, Maeda Y, Shichijo T. A case of hyperammonemia in a patient with urinary tract infection and urinary retention. Urol Sci [serial online] 2020 [cited 2021 Apr 3];31:82-4. Available from:
https://www.e-urol-sci.com/text.asp?2020/31/2/82/283250
^Kenzaka T, Kato K, Kitao A, et al. Hyperammonemia in Urinary Tract Infections. PLoS One. 2015;10(8):e0136220. Published 2015 Aug 20. doi:10.1371/journal.pone.0136220