Hyperammonemia
Encyclopedia
Hyperammonemia 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 kidney
s. The metabolic pathways that synthesize urea are located first in the mitochondria and then into the cytosol. The process is known as the urea cycle
, which comprises several enzymes acting in sequence.
- hyperammonemia due to ornithine transcarbamylase deficiency
- hyperinsulinism-hyperammonemia syndrome (glutamate dehydrogenase 1
) - hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (ornithine translocase
) - hyperammonemia due to N-acetylglutamate synthetase deficiency
- hyperammonemia due to carbamoyl phosphate synthetase I deficiency
(carbamoyl phosphate synthetase I
) - hyperlysinuria with hyperammonemia (genetics unknown)
are pharmacologic agents commonly used as adjunctive therapy to treat hyperammonemia in patients with urea cycle enzyme deficiencies. Sodium phenylacetate and sodium benzoate can serve as alternatives to urea for the excretion of waste nitrogen. 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.
.
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
in the blood. It is a dangerous condition that may lead to encephalopathy
Encephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...
and death. It may be primary or secondary.
Ammonia is a substance that contains nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
. It is a product of the catabolism
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
. It is converted to the less toxic substance urea
Urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
prior to excretion
Excretion
Excretion is the process by which waste products of metabolism and other non-useful materials are eliminated from an organism. This is primarily carried out by the lungs, kidneys and skin. This is in contrast with secretion, where the substance may have specific tasks after leaving the cell...
in urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
by the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s. The metabolic pathways that synthesize urea are located first in the mitochondria and then into the cytosol. The process is known as the urea cycle
Urea cycle
The urea cycle is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia . This cycle was the first metabolic cycle discovered , five years before the discovery of the TCA cycle...
, which comprises several enzymes acting in sequence.
Primary vs. secondary
- Primary hyperammonemia is caused by several inborn errors of metabolism that are characterised by reduced activity of any of the enzymeEnzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s in the urea cycleUrea cycleThe urea cycle is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia . This cycle was the first metabolic cycle discovered , five years before the discovery of the TCA cycle...
. - Secondary hyperammonemia is caused by inborn errors of intermediary metabolismMetabolismMetabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
characterised by reduced activity in enzymes that are not part of the urea cycle (e.g. .Propionic acidemiaPropionic acidemiaPropionic acidemia, also known as propionic aciduria, propionyl-CoA carboxylase deficiency and ketotic glycinemia, is an autosomal recessive metabolic disorder, classified as a branched-chain organic acidemia....
, Methylmalonic acidemiaMethylmalonic acidemiaMethylmalonic acidemia , also called methylmalonic aciduria, is an autosomal recessive metabolic disorder. It is a classical type of organic acidemia....
) or dysfunction of cells that make major contributions to metabolism (e.g. hepatic failure).
Specific types
The following list includes such examples:- hyperammonemia due to ornithine transcarbamylase deficiency
Ornithine transcarbamylase deficiency
Ornithine transcarbamylase deficiency , the most common of the urea cycle disorders, is a rare metabolic disorder, occurring in one out of every 80,000 births...
- hyperinsulinism-hyperammonemia syndrome (glutamate dehydrogenase 1
Glutamate Dehydrogenase 1
GLUD1 is a mitochondrial matrix enzyme, with a key role in the nitrogen and glutamate metabolism and the energy homeostasis. GLUD1 is expressed at high levels in liver, brain, pancreas and kidney, but not in muscle. In the pancreatic cells, GLUD1 is thought to be involved in insulin secretion...
) - hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (ornithine translocase
Ornithine translocase
Ornithine translocase is responsible for transporting ornithine from the cytosol into the mitochondria in the urea cycle.-Pathology:A disorder is associated with ornithine translocase deficiency, and a form of hyperammonemia....
) - hyperammonemia due to N-acetylglutamate synthetase deficiency
N-Acetylglutamate synthetase deficiency
N-Acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder.-Mechanism:Carbamoyl phosphate synthase I is an enzyme found in mitochondrial matrix and it catalyzes the very first reaction of the Urea cycle, in which carbamoyl phosphate is produced.Carbamoyl Phosphate Synthase...
- hyperammonemia due to carbamoyl phosphate synthetase I deficiency
Carbamoyl phosphate synthetase I deficiency
Carbamoyl phosphate synthetase I deficiency is an autosomal recessive metabolic disorder that causes ammonia to accumulate in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high...
(carbamoyl phosphate synthetase I
Carbamoyl phosphate synthetase I
Carbamoyl Phosphate Synthetase I is a ligase enzyme located in the mitochondria involved in the production of urea. Carbamoyl Phosphate Synthetase I transfers an ammonia from glutamine to a molecule of bicarbonate that has been phosphorylated by a molecule of ATP. The resulting carbamate is...
) - hyperlysinuria with hyperammonemia (genetics unknown)
- Methylmalonic acidemia
- Isovalemic acidemia
- Propionic acidemia
- Carnitine palmitoyltransferase II deficiencyCarnitine palmitoyltransferase II deficiencyCarnitine palmitoyltransferase II deficiency is a metabolic disorder characterized by an enzymatic defect that prevents long-chain fatty acids from being transported into the mitochondria for utilization as an energy source....
Treatment
Treatment centers on limiting intake of ammonia and increasing its excretion. Dietary protein (a source of ammonium) is restricted and caloric intake is provided by glucose and fat. Intravenous sodium phenylacetate and sodium benzoateSodium benzoate
Sodium benzoate has the chemical formula NaC6H5CO2; it is a widely used food preservative, with E number E211. It is the sodium salt of benzoic acid and exists in this form when dissolved in water. It can be produced by reacting sodium hydroxide with benzoic acid.-Uses:Sodium benzoate is a...
are pharmacologic agents commonly used as adjunctive therapy to treat hyperammonemia in patients with urea cycle enzyme deficiencies. Sodium phenylacetate and sodium benzoate can serve as alternatives to urea for the excretion of waste nitrogen. Phenylacetate conjugates with glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
to form phenylacetylglutamine, which is excreted by the kidneys. Similarly, sodium benzoate reduces ammonia content in the blood by conjugating with glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
to form hippuric acid
Hippuric acid
Hippuric acid is a carboxylic acid found in the urine of horses and other herbivores. Hippuric acid crystallizes in rhombic prisms which are readily soluble in hot water, melt at 187 °C and decompose at about 240 °C...
, 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.
Sequelae
Hyperammonemia is one of the metabolic derangements that contribute to hepatic encephalopathyHepatic encephalopathy
Hepatic encephalopathy is the occurrence of confusion, altered level of consciousness and coma as a result of liver failure. In the advanced stages it is called hepatic coma or coma hepaticum...
.
See also
- CitrullinemiaCitrullinemiaCitrullinemia, also called citrullinuria, is an autosomal recessive urea cycle disorder that causes ammonia and other toxic substances to accumulate in the blood....
- N-acetylglutamate synthetase deficiencyN-Acetylglutamate synthetase deficiencyN-Acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder.-Mechanism:Carbamoyl phosphate synthase I is an enzyme found in mitochondrial matrix and it catalyzes the very first reaction of the Urea cycle, in which carbamoyl phosphate is produced.Carbamoyl Phosphate Synthase...
- Ornithine translocase deficiencyOrnithine translocase deficiencyOrnithine translocase deficiency, also called Hyperornithinemia-Hyperammonemia-Homocitrullinuria syndrome, is a rare autosomal recessive urea cycle disorder affecting the enzyme ornithine translocase, which causes ammonia to accumulate in the blood, a condition called hyperammonemia.Ammonia, which...
- Arginase deficiency