Hyperammonemia

Hyperammonemia
Specialty	Endocrinology

Hyperammonemia (or hyperammonaemia) is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to encephalopathy 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.

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 X-linked.
• 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.

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 hepatoxins, 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 doesn't work as well as removal of protein from the colon prior to its digestion to ammonia; achieved by lactulose administration for frequent (6-10 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.
• 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.

Specific types

The following list includes such examples:

• Online Mendelian Inheritance in Man (OMIM): 311250 - hyperammonemia due to ornithine transcarbamylase deficiency
• Online Mendelian Inheritance in Man (OMIM): 606762 - hyperinsulinism-hyperammonemia syndrome (glutamate dehydrogenase 1)
• Online Mendelian Inheritance in Man (OMIM): 238970 - hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (ornithine translocase)
• Online Mendelian Inheritance in Man (OMIM): 237310 - hyperammonemia due to N-acetylglutamate synthetase deficiency
• Online Mendelian Inheritance in Man (OMIM): 237300 - hyperammonemia due to carbamoyl phosphate synthetase I deficiency (carbamoyl phosphate synthetase I)
• Online Mendelian Inheritance in Man (OMIM): 238750 - hyperlysinuria with hyperammonemia (genetics unknown)
• Methylmalonic acidemia
• Isovaleric acidemia
• Propionic acidemia
• Carnitine palmitoyltransferase II deficiency
• Transient hyperammonemia of the newborn, specifically in the preterm

Treatment

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 transcarbamoylase deficiency) are pharmacologic agents commonly used as adjunctive therapy to treat hyperammonemia in patients with urea cycle enzyme deficiencies. 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.

Sequelae

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. Overstimulation of NMDA-receptors induces excitotoxicity.

See also

• Arginase deficiency
• Citrullinemia
• N-acetylglutamate synthetase deficiency
• Ornithine translocase deficiency
• Carbamoyl phosphate synthetase I deficiency
• Orotic aciduria

External links

• Organic Acidemia Association
• Article on causes of hyperammonemia in the newborn.