Editing Hyperammonemia

{{Infobox medical condition (new)
| name            = Hyperammonemia
| synonyms        = Hyperammonaemia; High ammonia levels
| image           = Ammonia lone electron pair.svg
| caption         = [[Ammonia]]
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| causes          = Due to accumulation of argininosuccinate, citrulline, and arginine in the liver when the urea cycle is deficient.
| risks           =
| diagnosis       =
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'''Hyperammonemia''', or '''high ammonia levels''', is a [[metabolic disturbance]] characterised by an excess of [[ammonia]] in the [[blood]]. Severe hyperammonemia is a dangerous condition that may lead to [[brain injury]] 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 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.<ref>{{cite journal |last1=Riggio |first1=O. |last2=Merli |first2=M. |last3=Capocaccia |first3=L. |last4=Caschera |first4=M. |last5=Zullo |first5=A. |last6=Pinto |first6=G. |last7=Gaudio |first7=E. |last8=Franchitto |first8=A. |last9=Spagnoli |first9=R. |last10=D'Aquilino |first10=E. |title=Zinc supplementation reduces blood ammonia and increases liver ornithine transcarbamylase activity in experimental cirrhosis |journal=Hepatology |date=September 1992 |volume=16 |issue=3 |pages=785–789 |doi=10.1002/hep.1840160326 |pmid=1505922 |s2cid=1141979 |issn=0270-9139|doi-access=free }}</ref>

==Levels==
Normal blood ammonia levels in adults range from 20 to 50{{nbsp}}μmol/L or less than 26 to 30{{nbsp}}μmol/L.<ref name="LimónAngulo-CruzSánchez-Abdon2021">{{cite journal | vauthors = Limón ID, Angulo-Cruz I, Sánchez-Abdon L, Patricio-Martínez A | title = Disturbance of the Glutamate-Glutamine Cycle, Secondary to Hepatic Damage, Compromises Memory Function | journal = Front Neurosci | volume = 15 | issue = | pages = 578922 | date = 2021 | pmid = 33584185 | pmc = 7873464 | doi = 10.3389/fnins.2021.578922 | doi-access = free | url = }}</ref><ref name="AliNagalli2023" /><ref name="AlfadhelMutairiMakhseed2016">{{cite journal | vauthors = Alfadhel M, Mutairi FA, Makhseed N, Jasmi FA, Al-Thihli K, Al-Jishi E, AlSayed M, Al-Hassnan ZN, Al-Murshedi F, Häberle J, Ben-Omran T | title = Guidelines for acute management of hyperammonemia in the Middle East region | journal = Ther Clin Risk Manag | volume = 12 | issue = | pages = 479–487 | date = 2016 | pmid = 27099506 | pmc = 4820220 | doi = 10.2147/TCRM.S93144 | doi-access = free | url = }}</ref> There is at present no clear scientific consensus on the upper limits of ammonia levels for different age groups.<ref name="AlfadhelMutairiMakhseed2016" /> In any case, hyperammonemia is generally defined as ammonia levels greater than 50{{nbsp}}μmol/L in adults and greater than 100{{nbsp}}μmol/L in newborns.<ref name="LimónAngulo-CruzSánchez-Abdon2021" /><ref name="AlfadhelMutairiMakhseed2016" /> These values should be considered as decision limits and the normal [[reference range]]s of individual laboratories should be used for clinical interpretation.<ref name="AlfadhelMutairiMakhseed2016" />

{| class="wikitable"
|+ Blood ammonia levels in different populations<ref name="LimónAngulo-CruzSánchez-Abdon2021" /><ref name="AliNagalli2023">{{cite web | last1=Ali | first1=Rimsha | last2=Nagalli | first2=Shivaraj | title=Hyperammonemia | publisher=StatPearls Publishing | date=7 April 2023 | pmid=32491436 | url=https://www.ncbi.nlm.nih.gov/books/NBK557504/ | access-date=6 September 2024}}</ref><ref name="AlfadhelMutairiMakhseed2016" />
|-
! Patient group !! Ammonia levels (μmol/L) !! Hyperammonemia (μmol/L) !! Ref
|-
| Premature neonates || 50–159 || >159 || <ref name="ColomboPeheimKretschmer1984">{{cite journal | vauthors = Colombo JP, Peheim E, Kretschmer R, Dauwalder H, Sidiropoulos D | title = Plasma ammonia concentrations in newborns and children | journal = Clin Chim Acta | volume = 138 | issue = 3 | pages = 283–291 | date = April 1984 | pmid = 6723064 | doi = 10.1016/0009-8981(84)90135-9 | url = }}</ref><ref name="AliNagalli2023" />
|-
| Healthy term neonates || 45–75 || >75–100 || <ref name="ColomboPeheimKretschmer1984" /><ref name="AliNagalli2023" />
|-
| Children and adolescents || 24–48 || >48–50 || <ref name="DonnBanagale1984">{{cite journal | last1=Donn | first1=S. M. | last2=Banagale | first2=R. C. | title=Neonatal Hyperammonemia | journal=Pediatrics in Review | volume=5 | issue=7 | date=1 January 1984 | issn=0191-9601 | doi=10.1542/pir.5-7-203 | pages=203–208}}</ref><ref name="AliNagalli2023" />
|-
| Adult females || 11–48 || >48 || <ref name="Häberle2011">{{cite journal | vauthors = Häberle J | title = Clinical practice: the management of hyperammonemia | journal = Eur J Pediatr | volume = 170 | issue = 1 | pages = 21–34 | date = January 2011 | pmid = 21165747 | doi = 10.1007/s00431-010-1369-2 | url = }}</ref>
|-
| Adult males || 15–55 || >55 || <ref name="Häberle2011" />
|}

When ammonia levels rise greater than 200{{nbsp}}μmol/L, serious symptoms, including [[seizure]]s, [[encephalopathy]], [[coma]], and even death, can occur.<ref name="AliNagalli2023" /> Hyperammonemia with blood ammonia levels greater than 400 to 500{{nbsp}}μmol/L is associated with 5- to 10-fold higher risk of irreversible [[brain damage]].<ref name="LimónAngulo-CruzSánchez-Abdon2021" />

==Signs and symptoms==
===Complication===
Hyperammonemia is one of the metabolic derangements that contribute to [[hepatic encephalopathy]], which can cause swelling of [[astrocyte]]s and stimulation of [[NMDA receptor]]s in the brain.<ref>{{Cite journal |last=Mukherjee |first=Arghya |last2=Singh |first2=Santosh |date=2024-11-17 |title=Andrographolide prevents acute hyperammonemia-induced motor dysfunction in rats. Evidences for its mechanism of action |url=https://linkinghub.elsevier.com/retrieve/pii/S2667031324001532 |journal=Phytomedicine Plus |pages=100679 |doi=10.1016/j.phyplu.2024.100679 |issn=2667-0313|doi-access=free }}</ref>

==Diagnosis==
===Types===
====Primary vs. secondary====
* Primary hyperammonemia is caused by several [[inborn errors of metabolism]] that are characterised by reduced activity of any of the [[enzyme]]s in the [[urea cycle]]. The most common example is [[ornithine transcarbamylase deficiency]], which is inherited in an [[X-linked]] fashion.<ref name="Haberle">{{cite journal |last1=Häberle |first1=Johannes |last2=Chakrapani |first2=Anupam |last3=Ah Mew |first3=Nicholas |last4=Longo |first4=Nicola |title=Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories |journal=Orphanet Journal of Rare Diseases |date=December 2018 |volume=6 |issue=13 |page=219 |doi=10.1186/s13023-018-0963-7 |doi-access=free |pmid=30522498 |pmc=6282273 }}</ref>
* 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.<ref name="Haberle"/>

====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 [[hepatotoxin]]s, or cirrhosis of the liver with chronic liver failure. Chronic hepatitis B, chronic [[hepatitis C]], and [[Alcohol dependence|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.{{cn|date=November 2024}}
* Medication-induced hyperammonemia can occur with [[valproic acid]] overdose, and is due to a deficiency in [[carnitine]].  Its treatment is carnitine replacement.{{cn|date=November 2024}}
* [[Urinary tract infection]] caused by [[urease]]-producing organisms ([[Proteus (bacterium)|''Proteus'']], ''[[Pseudomonas aeruginosa]]'', ''[[Klebsiella]]'', ''[[Morganella morganii]]'', and ''[[Corynebacterium]]'') can also lead to hyperammonemia.<ref name="auto">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 [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</ref> But there are case reports where hyperammonemia was caused by urease-negative organisms.<ref>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</ref> Urease producers form ammonia and [[carbon dioxide]] from urea. Ammonia then enters the systemic circulation (most venous supply of the bladder bypasses [[Portal venous system|portal circulation]]) and enters the [[blood–brain barrier]] causing [[encephalopathy]].<ref name="auto"/>
* Severe [[dehydration]] and [[small intestinal bacterial overgrowth]] can also lead to acquired hyperammonemia.{{Citation needed |date=April 2021}}
* [[Glycine]] toxicity causes hyperammonemia, which manifests as CNS symptoms and nausea. Transient blindness can also occur.<ref name=":0" />
* [[Birth defect|Congenital]] hyperammonemia is usually due to [[genetics|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.{{cn|date=November 2024}}

====Specific types====
The following list includes such examples:
* {{OMIM|311250}} - hyperammonemia due to [[ornithine transcarbamylase deficiency]]
* {{OMIM|606762}} - [[hyperinsulinism-hyperammonemia syndrome]] ([[glutamate dehydrogenase 1]])
* {{OMIM|238970}} - [[Hyperornithinemia-hyperammonemia-homocitrullinuria|hyperornithinemia-hyperammonemia-homocitrullinuria syndrome]]
* {{OMIM|237310}} - hyperammonemia due to [[N-Acetylglutamate synthase deficiency]]
* {{OMIM|237300}} - hyperammonemia due to [[carbamoyl phosphate synthetase I deficiency]] ([[carbamoyl phosphate synthetase I]])
* {{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 centres on limiting intake of ammonia and increasing its excretion. [[Protein (nutrient)|Dietary protein]], a metabolic source of ammonium, is restricted, and caloric intake is provided by glucose and fat. Intravenous [[arginine]] ([[Argininosuccinic aciduria|argininosuccinase deficiency]]), [[sodium phenylbutyrate]] and [[sodium benzoate]] (ornithine transcarbamylase deficiency) are [[Medication|pharmacologic agents]] commonly used as [[Combination therapy|adjunctive therapy]] to treat hyperammonemia in patients with urea cycle enzyme deficiencies.<ref>{{cite journal |last1=Chawla |first1=Jasvinder |title=Hyperammonemia |url=https://emedicine.medscape.com/article/1174503-overview |website=Medscape |date=12 September 2022 |access-date=18 March 2024}}</ref> 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.<ref>{{Cite web |url=http://www.rxlist.com/cgi/generic/ammonul_cp.htm |title=Ammonul (Sodium Phenylacetate and Sodium Benzoate Injection) clinical pharmacology - prescription drugs and medications at RxList<!-- Bot generated title --> |access-date=2008-06-26 |archive-url=https://web.archive.org/web/20080616130649/http://www.rxlist.com/cgi/generic/ammonul_cp.htm |archive-date=2008-06-16 |url-status=dead }}</ref> A preparation containing [[Phenylacetic acid|sodium phenylacetate]] and sodium benzoate is available under the trade name [[Sodium phenylacetate/sodium benzoate|Ammonul]].
Acidification of the [[Gastrointestinal tract|intestinal lumen]] using lactulose can decrease ammonia levels by [[Protonation|protonating]] ammonia and trapping it in the stool.  This is a treatment for hepatic encephalopathy.<ref name="Bloom">{{cite journal |last1=Bloom |first1=Patricia |last2=Tapper |first2=Elliot |title=Lactulose in cirrhosis: Current understanding of efficacy, mechanism, and practical considerations |journal=Hepatology Communications |date=November 2023 |volume=7 |issue=11 |page=e0295 |doi=10.1097/HC9.0000000000000295 |pmid=37820287 |pmc=10578757 }}</ref>

Treatment of severe hyperammonemia (serum ammonia levels greater than 1000 [[μmol/L]]) should begin with [[hemodialysis]] if it is otherwise medically appropriate and tolerated.<ref name=":0">[http://www.expertconsultbook.com/expertconsult/ob/book.do?method=display&type=bookPage&decorator=none&eid=4-u1.0-B978-1-4160-4252-5..50307-5--cebib1&isbn=978-1-4160-4252-5 Chapter 298 – Inborn Errors of Metabolism and Continuous Renal Replacement Therapy] {{Webarchive|url=https://web.archive.org/web/20130701165018/http://www.expertconsultbook.com/expertconsult/ob/book.do?method=display&type=bookPage&decorator=none&eid=4-u1.0-B978-1-4160-4252-5..50307-5--cebib1&isbn=978-1-4160-4252-5 |date=2013-07-01 }} in: {{cite book |author1=John J. Ratey MD |author2=Claudio Ronco MD |title=Critical Care Nephrology: Expert Consult - Online and Print |publisher=Saunders |location=Philadelphia |year=2008 |isbn=978-1-4160-4252-5 }} {{ISBN|9781416042525}}</ref>

[[Continuous renal replacement therapy]] (CRRT) is a remarkably effective mode of therapy in neonatal hyperammonemia, particularly in severe cases of [[Urea cycle enzymopathies|Urea cycle]] defects like [[Ornithine transcarbamylase deficiency|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.<ref>{{Cite journal |last=Elbaba |first=Mostafa |title=IPE Simulation Enhances the Quality of Care in Neonatal Hyperammonemia |url=https://www.cureus.com/posters/1142-ipe-simulation-enhances-the-quality-of-care-in-neonatal-hyperammonemia |journal=Cureus Journal of Medical Science}}</ref>

==See also==
* [[Arginase deficiency]]
* [[Citrullinemia]]
* [[N-acetylglutamate synthetase deficiency]]
* [[Ornithine translocase deficiency]]
* [[Carbamoyl phosphate synthetase I deficiency]]
* [[Orotic aciduria]]

==References==
{{reflist}}

== External links ==
{{Medical resources
|   DiseasesDB     = 20468
|   ICD10          = {{ICD10|E|72|2|e|70}}
|   ICD9           = {{ICD9|270.6}}
|   ICDO           =
|   OMIM           =
|   MedlinePlus    =
|   eMedicineSubj  = neuro
|   eMedicineTopic = 162
|   eMedicine_mult = {{eMedicine2|ped|1057}}
|   MeshID         = D022124
}}

{{Amino acid metabolic pathology}}

[[Category:Amino acid metabolism disorders]]
[[Category:Ammonia]]