Hyperammonemia is a metabolic disturbance characterised by an excess of

ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous was ...

in the

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...

. It is a dangerous condition that may lead to

brain injury An injury is any physiological damage to living tissue caused by immediate physical stress. An injury can occur intentionally or unintentionally and may be caused by blunt trauma, penetrating trauma, burning, toxic exposure, asphyxiation, or o ...

and

death Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...

. It may be primary or secondary. Ammonia is a substance that contains

nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...

. It is a product of the

catabolism Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids, ...

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

. It is converted to the less toxic substance

urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important r ...

prior to

excretion Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates 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 lea ...

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra. Cel ...

by the

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...

s. The metabolic pathways that synthesize urea involve reactions that start in the

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

and then move into the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

. The process is known as the

urea cycle The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic. The urea cycle converts highl ...

, which comprises several

enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

acting in sequence. It is greatly exacerbated by common

zinc deficiency Zinc deficiency is defined either as insufficient zinc to meet the needs of the body, or as a serum zinc level below the normal range. However, since a decrease in the serum concentration is only detectable after long-term or severe depletion, s ...

, which raises ammonia levels further.

Signs and symptoms

Complication

Hyperammonemia is one of the metabolic derangements that contribute to

hepatic encephalopathy Hepatic encephalopathy (HE) is an altered level of consciousness as a result of liver failure. Its onset may be gradual or sudden. Other symptoms may include movement problems, changes in mood, or changes in personality. In the advanced stages ...

, which can cause swelling of

astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...

s and stimulation of

NMDA receptors The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and ...

in the brain. Overstimulation of NMDA receptors induces

excitotoxicity In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate re ...

Diagnosis

Types

Primary vs. secondary

* Primary hyperammonemia is caused by several

inborn errors of metabolism Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances ( substra ...

that are characterised by reduced activity of any of the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

s in the

. The most common example is

ornithine transcarbamylase deficiency Ornithine transcarbamylase deficiency also known as OTC deficiency is the most common urea cycle disorder in humans. Ornithine transcarbamylase, the defective enzyme in this disorder is the final enzyme in the proximal portion of the urea cycle, re ...

, which is inherited in an

X-linked Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, ...

fashion. * Secondary hyperammonemia is caused by inborn errors of intermediary

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

, 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 Propionic acidemia, also known as propionic aciduria or propionyl-CoA carboxylase deficiency (PCC deficiency), is a rare autosomal recessive metabolic disorder, classified as a branched-chain organic acidemia. The disorder presents in the ear ...

and

methylmalonic acidemia Methylmalonic acidemia, also called methylmalonic aciduria, is an autosomal recessive metabolic disorder that disrupts normal amino acid metabolism. It is a classical type of organic acidemia. The result of this condition is the inability to prope ...

, and examples of the latter are acute liver failure and

hepatic cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...

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 Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. Fo ...

or exposure to

hepatotoxins Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fro ...

, or cirrhosis of the liver with chronic liver failure. Chronic hepatitis B, chronic

hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, a ...

, 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 The inferior vena cava is a large vein that carries the deoxygenated blood from the lower and middle body into the right atrium of the heart. It is formed by the joining of the right and the left common iliac veins, usually at the level of the ...

, 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 the removal of protein from the colon prior to its digestion to ammonia, achieved by

lactulose Lactulose is a non-absorbable sugar used in the treatment of constipation and hepatic encephalopathy. It is used by mouth for constipation and either by mouth or in the rectum for hepatic encephalopathy. It generally begins working after 8–12 ...

administration for frequent (3-4 per day) bowel movements. * Medication-induced hyperammonemia can occur with

valproic acid Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those ...

overdose, and is due to a deficiency in

carnitine Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids into mitochondria to be oxidized for energy production, an ...

. Its treatment is carnitine replacement. *

Urinary tract infection A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidney ...

caused by

urease Ureases (), functionally, belong to the superfamily of amidohydrolases and phosphotriesterases. Ureases are found in numerous bacteria, fungi, algae, plants, and some invertebrates, as well as in soils, as a soil enzyme. They are nickel-contai ...

-producing organisms ( ''Proteus'', ''

Pseudomonas aeruginosa ''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aerugi ...

'', ''

Klebsiella ''Klebsiella'' is a genus of Gram-negative, oxidase-negative, rod-shaped bacteria with a prominent polysaccharide-based capsule. ''Klebsiella'' species are found everywhere in nature. This is thought to be due to distinct sublineages developi ...

'', '' Morganella morganii'', and '' Corynebacterium'') can also lead to hyperammonemia.Nepal 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 erial online2020 ited 2021 Apr 331:82-4. Available from: https://www.e-urol-sci.com/text.asp?2020/31/2/82/283250 But there are case reports where hyperammonemia was caused by urease negative organisms. Urease producers form ammonia and

carbon dioxide Carbon dioxide (chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is transpar ...

from urea. Ammonia then enters the systemic circulation (most venous supply of the bladder bypasses

portal circulation In the circulatory system of animals, a portal venous system occurs when a capillary bed pools into another capillary bed through veins, without first going through the heart. Both capillary beds and the blood vessels that connect them are con ...

) and enters the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...

causing

encephalopathy Encephalopathy (; from grc, ἐνκέφαλος "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but r ...

. * Severe

dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...

and

small intestinal bacterial overgrowth Small intestinal bacterial overgrowth (SIBO), also termed bacterial overgrowth, or small bowel bacterial overgrowth syndrome (SBBOS), is a disorder of excessive bacterial growth in the small intestine. Unlike the colon (or large bowel), which is r ...

can also lead to acquired hyperammonemia. *

Glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...

toxicity causes hyperammonemia, which manifests as CNS symptoms and nausea. Transient blindness can also occur. *

Congenital A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...

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: * - hyperammonemia due to

* -

hyperinsulinism-hyperammonemia syndrome Hyperinsulinism-hyperammonemia syndrome (HI/HA) is an autosomal dominant disorder that results in the excess production of insulin and ammonia in mammals. HI/HA is caused by increased Glutamate dehydrogenase 1 (GDH) activity due to the presence ...

(

glutamate dehydrogenase 1 GLUD1 (glutamate dehydrogenase 1) is a mitochondrial matrix enzyme, one of the family of glutamate dehydrogenases that are ubiquitous in life, with a key role in nitrogen and glutamate (Glu) metabolism and energy homeostasis. This dehydrogenase is ...

) * - hyperornithinemia-hyperammonemia-homocitrullinuria syndrome * - hyperammonemia due to

N-Acetylglutamate synthase deficiency ''N''-Acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder. Signs and symptoms The symptoms are visible within the first week of life and if not detected and diagnosed correctly immediately consequences are fatal. ...

* - hyperammonemia due to

carbamoyl phosphate synthetase I deficiency Carbamoyl phosphate synthetase I deficiency (CPS I deficiency) is an autosomal recessive metabolic disorder that causes ammonia to accumulate in the blood due to a lack of the enzyme carbamoyl phosphate synthetase I. Ammonia, which is formed when ...

(

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 (CPS1 or CPSI) transfers an ammonia molecule to a molecule of bicarbonate that has been phospho ...

) * -

hyperlysinuria Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated − ...

with hyperammonemia (genetics unknown) *

Methylmalonic acidemia Methylmalonic acidemia, also called methylmalonic aciduria, is an autosomal recessive metabolic disorder that disrupts normal amino acid metabolism. It is a classical type of organic acidemia. The result of this condition is the inability to prope ...

Isovaleric acidemia Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia. Symptoms and signs A characteristic feature ...

Propionic acidemia Propionic acidemia, also known as propionic aciduria or propionyl-CoA carboxylase deficiency (PCC deficiency), is a rare autosomal recessive metabolic disorder, classified as a branched-chain organic acidemia. The disorder presents in the ear ...

Carnitine palmitoyltransferase II deficiency Carnitine palmitoyltransferase II deficiency is an autosomal recessively inherited genetic metabolic disorder characterized by an enzymatic defect that prevents long-chain fatty acids from being transported into the mitochondria for utilization ...

Transient hyperammonemia of the newborn Transient hyperammonemia of the newborn (THAN) is an idiopathic disorder occasionally present in preterm newborns but not always symptomatic. Continuous dialysis or hemofiltration have proven to be the most effective treatment. Nutritional support ...

, specifically in the preterm

Treatment

Treatment centers on limiting intake of ammonia and increasing its excretion.

Dietary protein Proteins are essential nutrients for the human body. They are one of the building blocks of body tissue and can also serve as a fuel source. As a fuel, proteins provide as much energy density as carbohydrates: 4 Calories, kcal (17 Joule, kJ) p ...

, a metabolic source of ammonium, is restricted, and caloric intake is provided by glucose and fat. Intravenous

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...

( argininosuccinase deficiency),

sodium phenylbutyrate Sodium phenylbutyrate, sold under the brand name Buphenyl among others, is a salt of an aromatic fatty acid, 4-phenylbutyrate (4-PBA) or 4-phenylbutyric acid. The compound is used to treat urea cycle disorders, because its metabolites offer an ...

and

sodium benzoate Sodium benzoate is the sodium salt of benzoic acid, widely used as a food preservative (with an E number of E211) and a pickling agent. It appears as a white crystalline chemical with the formula C6H5COONa. Production Sodium benzoate is commo ...

(ornithine transcarbamylase deficiency) are pharmacologic agents commonly used as

adjunctive therapy Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...

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 Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral, ...

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 Hippuric acid ( Gr. ''hippos'', horse, ''ouron'', urine) is a carboxylic acid and organic compound. It is found in urine and is formed from the combination of benzoic acid and glycine. Levels of hippuric acid rise with the consumption of phenoli ...

, 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 The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans ...

using lactulose can decrease ammonia levels by

protonating In chemistry, protonation (or hydronation) is the adding of a proton#Hydrogen ion, proton (or hydron (chemistry), hydron, or hydrogen cation), (H+) to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is ...

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 Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...

if it is otherwise medically appropriate and tolerated.Chapter 298 – Inborn Errors of Metabolism and Continuous Renal Replacement Therapy
in:

References

External links

{{Amino acid metabolic pathology Amino acid metabolism disorders Ammonia