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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.
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.^[1] Sodium phenylbutyrate and sodium benzoate can serve as alternatives to urea for the excretion of waste nitrogen. Phenylbutyrate, which is the prodrug 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.^[2] 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.^[3]

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.

References

^ eMedicine - Hyperammonemia: Article by Kazi Imran Majeed
^ Ammonul (Sodium Phenylacetate and Sodium Benzoate Injection) clinical pharmacology - prescription drugs and medications at RxList
^ Chapter 298 – Inborn Errors of Metabolism and Continuous Renal Replacement Therapy in: John J. Ratey MD; Claudio Ronco MD (2008). Critical Care Nephrology: Expert Consult - Online and Print. Philadelphia: Saunders. ISBN 1-4160-4252-0. ISBN 9781416042525

External links

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

UpToDate Contents

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1. 尿素サイクル障害：臨床的特徴および診断 urea cycle disorders clinical features and diagnosis
2. 成人における肝性脳症：治療 hepatic encephalopathy in adults treatment
3. 成人における肝性脳症：臨床症状および診断 hepatic encephalopathy in adults clinical manifestations and diagnosis
4. バルプロ酸中毒 valproic acid poisoning
5. 先天性代謝異常：代謝性救急疾患 inborn errors of metabolism metabolic emergencies

English Journal

Efficacy of clonidine in hyperammonemia induced hyperexcitability syndrome.

Calligaris L, Vidoni A, Bruno I, Vidoni M, Barbi E.SourceDepartment of Pediatric Emergency, Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo', Trieste, Italy. lorenzo.calligaris@inwind.it.
Paediatric anaesthesia.Paediatr Anaesth.2013 Feb;23(2):202-4. doi: 10.1111/pan.12088.
PMID 23289776

Prognostic values of blood ammonia and partial pressure of ammonia on hospital arrival in out-of-hospital cardiac arrests.

Lin CH, Chi CH, Wu SY, Hsu HC, Chang YH, Huang YY, Chang CJ, Hong MY, Chan TY, Shih HI.SourceDepartment of Emergency Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan. Electronic address: emergency.lin@gmail.com.
The American journal of emergency medicine.Am J Emerg Med.2013 Jan;31(1):8-15. doi: 10.1016/j.ajem.2012.04.037. Epub 2012 Jul 12.
PURPOSES: Outcome prediction for out-of-hospital cardiac arrest (OHCA) is of medical, ethical, and socioeconomic importance. We hypothesized that blood ammonia may reflect tissue hypoxia in OHCA patients and conducted this study to evaluate the prognostic value of ammonia for the return of spontaneo
PMID 22795429

Japanese Journal

特殊な表現型に着目した薬理遺伝学

佐野輝
日本神経精神薬理学雑誌 = Japanese journal of psychopharmacology 31(4), 163-165, 2011-08-25
NAID 10029565067

FOLFOX療法施行中に高アンモニア血症を呈した1例

正村裕紀,中野詩朗,稲垣光裕,柳田尚之,工藤岳秋,折茂達也,及川太,米谷理沙
日本大腸肛門病学会雑誌 64(7), 467-470, 2011-07-01
FOLFOX療法は切除不能進行再発大腸癌における標準化学療法の一つであり，近年急速に普及してきた．高アンモニア血症はFOLFOX療法における稀な有害事象である．今回我々はFOLFOX療法中に意識障害をともなう高アンモニア血症を来たした症例を経験したので若干の文献的考察を加え報告する．症例は30歳代女性．虫垂癌（H1P3）にてFOLFOX療法を開始．5クール施行中意識混濁が出現し，血液検査で高アン …
NAID 10029578765

Related Pictures

★リンクテーブル★

リンク元	「高アンモニア血症」「カルバモイルリン酸シンターゼ欠損症」
拡張検索	「hyperammonemia type I」

「高アンモニア血症」

Hyperammonemia
	Ammonia
Classification and external resources
Specialty	endocrinology
ICD-10	E72.2
ICD-9-CM	270.6
DiseasesDB	20468
eMedicine	neuro/162 ped/1057
MeSH	D022124