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{{Short description|Disease characterized by rapid swelling}}
{{Infobox_Disease
{{Infobox medical condition (new)
| Name = {{PAGENAME}}
| Image =
| name = Angioedema
| synonyms = Angiooedema, Quincke's edema, angioneurotic edema
| Caption =
| DiseasesDB = 13606
| image = Angioedema2010.JPG
| caption = Allergic angioedema: this child is unable to open his eyes due to the swelling.
| ICD10 = {{ICD10|D|84|1|d|80}} , {{ICD10|T|78|3|t|66}}
| ICD9 = {{ICD9|277.6}}, {{ICD9|995.1}}
| field = [[Allergy and immunology]], [[emergency medicine]]
| ICDO =
| symptoms = Area of swelling<ref name=Bern2017/>
| OMIM = 606860
| complications =
| onset = Minutes to hours<ref name=Bern2017/>
| OMIM_mult = {{OMIM2|106100}} {{OMIM2|610618}}
| MedlinePlus = 000846
| duration =
| types = [[Histamine]] mediated, [[bradykinin]] mediated<ref name=Bern2017/>
| eMedicineSubj = emerg
| causes =
| eMedicineTopic = 32
| risks = Family history<ref name=IAP2003/>
| eMedicine_mult = {{eMedicine2|med|135}} {{eMedicine2|ped|101}}
| diagnosis = Based on symptoms<ref name=IAP2003>{{cite book|last1=Caterino|first1=Jeffrey M.|last2=Kahan|first2=Scott|title=In a Page: Emergency medicine|date=2003|publisher=Lippincott Williams & Wilkins|isbn=9781405103572|page=133|url=https://books.google.com/books?id=O0LwFPZDKbsC&pg=PA133|language=en|url-status=live|archive-url=https://web.archive.org/web/20170910152025/https://books.google.ca/books?id=O0LwFPZDKbsC&pg=PA133|archive-date=2017-09-10}}</ref>
| MeshID = D000799
| differential = [[Anaphylaxis]], [[abscess]], [[contact dermatitis]]<ref name=IAP2003/>
| prevention =
| treatment = [[Intubation]], [[cricothyroidotomy]]<ref name=Bern2017/>
| medication = '''Histamine''': [[antihistamine]]s, [[corticosteroid]]s, [[epinephrine]]<ref name=Bern2017/><br />'''Bradykinin''': [[C1 esterase inhibitor]], [[ecallantide]], [[icatibant]], [[fresh frozen plasma]]<ref name=Bern2017/>
| prognosis =
| frequency = ~100,000 per year (US)<ref name=Bern2017/>
| deaths =
}}
}}
<!-- Definition and symptoms -->
'''Angioedema''' is an area of swelling ([[edema]]) of the [[dermis|lower layer of skin]] and [[subcutaneous tissue|tissue just under the skin]] or [[mucous membrane]]s.<ref name=Bern2017/><ref name=Hab2009>{{cite book|last1=Habif|first1=Thomas P.|title=Clinical Dermatology E-Book|date=2009|publisher=Elsevier Health Sciences|isbn=978-0323080378|page=182|edition=5|url=https://books.google.com/books?id=kDWlWR5UbqQC&pg=PA182|language=en|url-status=live|archive-url=https://web.archive.org/web/20170910152025/https://books.google.ca/books?id=kDWlWR5UbqQC&pg=PA182|archive-date=2017-09-10}}</ref> The swelling may occur in the face, tongue, [[larynx]], abdomen, or arms and legs.<ref name=Bern2017/> Often it is associated with [[hives]], which are swelling within the upper [[skin]].<ref name=Bern2017/><ref name=Hab2009/> Onset is typically over minutes to hours.<ref name=Bern2017/>


<!-- Cause and diagnosis -->
'''Angioedema''' ([[British English|BE]]: '''angiooedema'''), also known by its [[eponym]] '''Quincke's edema''', is the rapid swelling ([[edema]]) of the [[skin]], [[mucosa]] and submucosal tissues. Apart from the common form, mediated by [[allergy]], it has been reported as a side effect of some [[medication]]s, specifically [[ACE inhibitor]]s.
The underlying mechanism typically involves [[histamine]] or [[bradykinin]].<ref name=Bern2017/> The version related to histamine is due to an [[allergic reaction]] to agents such as insect bites, foods, or [[medications]].<ref name=Bern2017/> The version related to bradykinin may occur due to an [[heredity|inherited]] problem known as [[C1 esterase inhibitor deficiency]], medications known as [[angiotensin-converting enzyme inhibitors]], or a [[lymphoproliferative disorder]].<ref name=Bern2017>{{cite journal|last1=Bernstein|first1=JA|last2=Cremonesi|first2=P|last3=Hoffmann|first3=TK|last4=Hollingsworth|first4=J|title=Angioedema in the emergency department: a practical guide to differential diagnosis and management.|journal=International Journal of Emergency Medicine|date=December 2017|volume=10|issue=1|pages=15|pmid=28405953|doi=10.1186/s12245-017-0141-z|pmc=5389952 |doi-access=free }}</ref>


<!-- Prevention and treatment -->
Additionally, there are three autosomal dominant inherited forms known, due to mutations in the genes that control the [[clotting cascade]], including the ''SERPING1'' gene, which results in deficiency of the blood protein [[C1-inhibitor]] (Type I HAE) and the ''F12'' gene, which controls [[Factor XII]], also known as [[Hageman Factor]] (Type III HAE). There is an additional type in which C1 levels are normal but C1 function is decreased. All three forms are called '''hereditary angioedema''' ('''HAE''') or occasionally by the outdated term "hereditary angioneurotic edema" (HANE). In all forms of '''HAE''', swelling may also occur in the [[digestive tract]] and other organs. It is life-threateneing when it involves the [[larynx]] due to the potential for [[asphyxiation]].
Treatment to protect the [[airway]] may include [[intubation]] or [[cricothyroidotomy]].<ref name=Bern2017/> Histamine-related angioedema can be treated with [[antihistamine]]s, [[corticosteroid]]s, and [[epinephrine]].<ref name=Bern2017/> In those with bradykinin-related disease a [[C1 esterase inhibitor]], [[ecallantide]], or [[icatibant]] may be used.<ref name=Bern2017/> [[Fresh frozen plasma]] may be used instead.<ref name=Bern2017/> In the United States the disease affects about 100,000 people a year.<ref name=Bern2017/>


==Signs and symptoms==
Cases where angioedema progresses rapidly should be treated as a [[medical emergency]] as [[airway]] obstruction and [[suffocation]] can occur. [[Epinephrine]] may be lifesaving when the cause of angioedema is allergic. In the case of hereditary angioedema, treatment with [[epinephrine]] has not been shown to prevent morbidity or delay the time necessary to treat.
{{unreferenced section|date=November 2023}}
[[File:Angioedema2013.JPG|thumb|upright=1.2|Angioedema of half of the tongue]]
[[File:Angioedema of the face.jpg|thumb|upright=1.2|Angioedema of the face, most strikingly in the upper lip.]]


The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the [[tongue]], swell over the period of minutes to hours. The swelling can also occur elsewhere, typically in the hands. The swelling can be [[itch]]y or painful. There may also be slightly decreased sensation in the affected areas due to compression of the nerves. [[Urticaria]] (hives) may develop simultaneously.
In the past, angioedema was referred to by the term '''angioneurotic edema''', which wrongly implied that the phenomenon was due to [[neurosis]].


In severe cases, [[stridor]] of the airway occurs, with gasping or wheezy inspiratory breath sounds and decreasing [[oxygen]] levels. [[Tracheal intubation]] is required in these situations to prevent [[respiratory arrest]] and risk of death.
==Signs and symptoms==
The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the [[tongue]], swell up over the period of minutes to several hours. The swelling can also occur elsewhere, typically in the hands. The swelling can be [[itch]]y. There may also be slightly decreased sensation in the affected areas due to compression of the nerves. [[Urticaria]] (hives) may develop simultaneously.


Sometimes, the cause is recent exposure to an [[allergen]] (e.g. [[peanut]]s), but more often it is either [[idiopathic]] (unknown) or only weakly correlated to allergen exposure.
In severe cases, [[stridor]] of the airway occurs, with gasping or wheezy inspiratory breath sounds and decreasing [[oxygen]] levels. [[Intubation]] is required in these situations to prevent [[respiratory arrest]] and risk of death.


In hereditary angioedema (HAE), often no direct cause is identifiable, although mild [[Physical trauma|trauma]], including dental work and other stimuli, can cause attacks.<ref>{{cite journal|author1=Bork K |author2=Barnstedt Se |title=Laryngeal edema and death from asphyxiation after tooth extraction in four patients with hereditary angioedema |journal=J Am Dent Assoc |volume=134 |issue=8 |pages=1088–94 |date=August 2003 |pmid=12956349 |doi=10.14219/jada.archive.2003.0323}}</ref> There is usually no associated itch or urticaria, as it is not an allergic response. Patients with HAE can also have recurrent episodes (often called "attacks") of [[abdominal pain]], usually accompanied by intense vomiting, weakness, and in some cases, watery diarrhea, and an unraised, nonitchy splotchy/swirly rash. These stomach attacks can last one to five days on average and can require hospitalization for aggressive pain management and hydration. Abdominal attacks have also been known to cause a significant increase in the patient's white blood cell count, usually in the vicinity of 13,000 to 30,000. As the symptoms begin to diminish, the white count slowly begins to decrease, returning to normal when the attack subsides. As the symptoms and diagnostic tests are almost indistinguishable from an [[acute abdomen]] (e.g. perforated [[appendicitis]]) it is possible for undiagnosed HAE patients to undergo [[laparotomy]] (operations on the abdomen) or [[laparoscopy]] (keyhole surgery) that turns out to have been unnecessary.
Sometimes, there has been recent exposure to an [[allergen]] (e.g. [[peanut]]s), but more often the cause is either [[idiopathic]] (unknown) or only weakly correlated to allergen exposure.


HAE may also cause swelling in a variety of other locations, most commonly the limbs, genitals, neck, throat and face. The pain associated with these swellings varies from mildly uncomfortable to agonizing pain, depending on its location and severity. Predicting where and when the next episode of edema will occur is impossible. Most patients have an average of one episode per month, but there are also patients who have weekly episodes or only one or two episodes per year. The triggers can vary and include infections, minor injuries, mechanical irritation, operations or stress. In most cases, edema develops over a period of 12–36 hours and then subsides within 2–5 days.
In hereditary angioedema, there is often no direct identifiable cause, although mild [[Physical trauma|trauma]], including dental work and other stimuli, can cause attacks. There is usually no associated itch or urticaria, as it's not an allergic response. Patients with HAE can also have recurrent episodes (often called "attacks") of [[abdominal pain]], usually accompanied by intense vomiting, weakness, and in some cases, watery diarrhea, and an unraised, non-itchy splotchy/swirly rash. These stomach attacks can last anywhere from 1-5 days on average, and can require hospitalization for aggressive pain management and hydration. Abdominal attacks have also been known to cause a significant increase in the patient's white blood cell count, usually in the vicinity of 13-30,000. As the symptoms begin to diminish, the white count slowly begins to decrease, returning to normal when the attack subsides. As the symptoms and diagnostic tests are almost indistinguishable from an [[acute abdomen]] (e.g. perforated [[appendicitis]]) it is possible for undiagnosed HAE patients to undergo [[laparotomy]] (operations on the abdomen) or [[laparoscopy]] (keyhole surgery) that turns out to have been unnecessary.


==Pathophysiology==
HAE Type III is understood to be associated with levels of estrogen. Originally, it was thought that this type was exclusive to women, but this theory has been disproved. <ref>Dewald, G.; Bork, K. ''Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor.'' Biochem. Biophys. Res. Commun. 343: 1286-1289, 2006.</ref>


[[Bradykinin]] plays a critical role in all forms of hereditary angioedema.<ref>{{cite journal |vauthors=Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G |title=Nonallergic angioedema: role of bradykinin |journal=Allergy |volume=62 |issue=8 |pages=842–56 |year=2007 |pmid=17620062 |doi=10.1111/j.1398-9995.2007.01427.x|s2cid=22772933 |doi-access=free }}</ref> This [[peptide]] is a potent [[vasodilator]] and increases vascular permeability, leading to rapid accumulation of fluid in the interstitium. This is most obvious in the face, where the skin has relatively little supporting [[connective tissue]], and edema develops easily. Bradykinin is released by various cell types in response to numerous different stimuli; it is also a [[pain]] mediator. Dampening or inhibiting bradykinin has been shown to relieve HAE symptoms.
HAE may also cause swelling in a variety of other locations, most commonly the limbs, genitals, neck, throat, and face. The pain associated with these swellings varies from mildly uncomfortable to agonizing pain, depending on its location and severity.


Various mechanisms that interfere with bradykinin production or degradation can lead to angioedema. ACE inhibitors block [[Angiotensin-converting enzyme|ACE]], the enzyme that among other actions, degrades bradykinin. In [[hereditary angioedema]], bradykinin formation is caused by continuous activation of the [[complement system]] due to a deficiency in one of its prime inhibitors, C1-esterase (aka: C1-inhibitor or C1INH), and continuous production of [[kallikrein]], another process inhibited by C1INH. This [[serine protease inhibitor]] (serpin) normally inhibits the association of C1r and C1s with C1q to prevent the formation of the C1-complex, which - in turn - activates other proteins of the complement system. Additionally, it inhibits various proteins of the [[coagulation]] cascade, although effects of its deficiency on the development of [[hemorrhage]] and [[thrombosis]] appear to be limited.
Predicting where and when the next episode of edema will occur is impossible. Most patients have an average of one episode per month, but there are also patients who have weekly episodes or only one or two episodes per year. The triggers can vary and include infections, minor injuries, mechanical irritation, operations or stress. In most cases, oedema develops over a period of 12-36 hours and then subsides within 2-5 days.


The three types of hereditary angioedema are:
==Diagnosis==
* Type I - decreased levels of C1INH (85%);
The diagnosis is made on the clinical picture. Routine blood tests ([[complete blood count]], [[electrolyte]]s, [[renal function]], [[liver enzyme]]s) are typically performed. [[Tryptase|Mast cell tryptase]] levels may be elevated if the attack was due to an acute allergic (anaphylactic) reaction. When the patient has been stabilized, particular investigations may clarify the exact cause; [[complement system|complement]] levels, especially depletion of complement factors 2 and 4, may indicate deficiency of ''[[C1-inhibitor]]'' or ''[[C4-inhibitor]]''. HAE Type III is a diagnosis of exclusion consisting of observed angioedema along with normal C1 and C4 function.
* Type II - normal levels, but decreased function of C1INH (15%);
* Type III - no detectable abnormality in C1INH, occurs in an [[X-linked]] dominant fashion and therefore mainly affects women; it can be exacerbated by [[pregnancy]] and use of [[hormonal contraception]] (exact frequency uncertain).<ref>{{cite journal |vauthors=Bork K, Barnstedt SE, Koch P, Traupe H |title=Hereditary angioedema with normal C1-inhibitor activity in women |journal=Lancet |volume=356 |issue=9225 |pages=213–7 |year=2000 |pmid=10963200 |doi=10.1016/S0140-6736(00)02483-1|s2cid=30105665 }}</ref> It has been linked with mutations in the [[factor XII]] gene.<ref>{{cite journal |vauthors=Cichon S, Martin L, Hennies HC |title=Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III |journal=Am. J. Hum. Genet. |volume=79 |issue=6 |pages=1098–104 |year=2006 |pmid=17186468 |doi=10.1086/509899 |pmc=1698720|display-authors=etal}}</ref>


Angioedema can be due to [[antibody]] formation against C1INH; this is an [[autoimmune disorder]]. This acquired angioedema is associated with the development of [[lymphoma]].
The hereditary form (HAE) often goes undetected for a long time, as its symptoms resemble those of more common disorders, such as allergy or intestinal colic. An important clue is the failure of angioedema to respond to [[antihistamines]] or [[glucocorticoid|steroids]], a characteristic that distinguishes it from allergic reactions. It is particularly difficult to diagnose HAE in patients whose episodes are confined to the gastrointestinal tract. Besides a family history of the disease, only a laboratory analysis can provide final confirmation. In this analysis, it is usually a reduced complement factor C4, rather than the C1-INH deficiency itself, that is detected. The former is used during the reaction cascade in the complement system of immune defense, which is permanently overactive due to the lack of regulation by C1-INH.


Consumption of foods that are themselves vasodilators, such as [[alcoholic beverage]]s or [[cinnamon]], can increase the probability of an angioedema episode in susceptible patients. If the episode occurs at all after the consumption of these foods, its onset may be delayed overnight or by some hours, making the correlation with their consumption somewhat difficult. In contrast, consumption of [[bromelain]] in combination with [[turmeric]] may be beneficial in reducing symptoms.<ref>University of Maryland Medical Center. ''Angioedema.'' {{cite web |url=http://www.umm.edu/altmed/articles/angioedema-000011.htm |title=Page is No Longer Available |access-date=2008-01-08 |url-status=live |archive-url=https://web.archive.org/web/20071012092019/http://www.umm.edu/altmed/articles/angioedema-000011.htm |archive-date=2007-10-12 }}</ref>
==Pathophysiology==
The final common pathway for the development of angioedema seems to be the activation of the [[bradykinin]] pathway. This [[peptide]] is a potent [[vasodilator]], leading to rapid accumulation of fluid in the interstitium. This is most obvious in the face, where the skin has relatively little supporting [[connective tissue]], and edema develops easily. Bradykinin is released by various cell types in response to numerous different stimuli; it is also a [[Pain and nociception|pain]] mediator.


The use of [[ibuprofen]] or [[aspirin]] may increase the probability of an episode in some patients. The use of [[acetaminophen]] typically has a smaller, but still present, increase in the probability of an episode.
Various mechanisms that interfere with bradykinin production or degradation can lead to angioedema. ACE inhibitors block ACE, the enzyme that among other actions, degrades bradykinin. In ''hereditary angioedema'', bradykinin formation is caused by continuous activation of the [[complement system]] due to a deficiency in one of its prime inhibitors, C1-esterase inhibitor (C1INH), and continuous production of [[kallikrein]], another process inhibited by C1INH. This [[serine protease inhibitor]] (serpin) normally inhibits the conversion of C1 to C1r and C1s, which - in turn - activate other proteins of the complement system. Additionally, it inhibits various proteins of the [[coagulation]] cascade, although effects of its deficiency on the development of [[hemorrhage]] and [[thrombosis]] appear to be limited.


==Diagnosis==
There are three types of hereditary angioedema:
The diagnosis is made on the clinical picture. Routine blood tests ([[complete blood count]], [[electrolyte]]s, [[kidney function]], [[liver enzyme]]s) are typically performed. [[Tryptase|Mast cell tryptase]] levels may be elevated if the attack was due to an acute allergic (anaphylactic) reaction. When the patient has been stabilized, particular investigations may clarify the exact cause; [[complement system|complement]] levels, especially depletion of complement factors 2 and 4, may indicate deficiency of ''[[C1-inhibitor]]''. HAE type III is a diagnosis of exclusion consisting of observed angioedema along with normal C1 levels and function.{{citation needed|date=November 2023}}
* Type I - decreased levels of C1INH (85%);
* Type II - normal levels but decreased function of C1INH (15%);
* Type III - no detectable abnormality in C1INH, occurs in an [[X-linked]] dominant fashion and therefore mainly affects women; it can be exacerbated by [[pregnancy]] and use of [[hormonal contraception]] (originally described by Bork ''et al'' in 2000, exact frequency uncertain).<ref>Bork K, Barnstedt SE, Koch P, Traupe H. ''Hereditary angioedema with normal C1-inhibitor activity in women.'' [[The Lancet|Lancet]] 2000;356:213-7. PMID 10963200.</ref> It has been linked with mutations in the [[factor XII]] gene.<ref>{{cite journal |author=Cichon S, Martin L, Hennies HC, ''et al'' |title=Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III |journal=Am. J. Hum. Genet. |volume=79 |issue=6 |pages=1098–104 |year=2006 |pmid=17186468 |doi=10.1086/509899}}</ref>


The hereditary form (HAE) often goes undetected for a long time, as its symptoms resemble those of more common disorders, such as allergy or intestinal colic. An important clue is the failure of hereditary angioedema to respond to [[antihistamines]] or [[glucocorticoid|steroids]], a characteristic that distinguishes it from allergic reactions. It is particularly difficult to diagnose HAE in patients whose episodes are confined to the gastrointestinal tract. Besides a family history of the disease, only a laboratory analysis can provide final confirmation. In this analysis, it is usually a reduced complement factor C4, rather than the C1-INH deficiency itself, that is detected. The former is used during the reaction cascade in the complement system of immune defense, which is permanently overactive due to the lack of regulation by C1-INH.
Angioedema can be due to [[antibody]] formation against C1INH; this is an [[autoimmune disorder]]. This ''acquired angioedema'' is associated with the development of [[lymphoma]].


Angioedema is classified as either hereditary or acquired.
Consumption of foods which are themselves vasodilators such as [[alcoholic beverage|alcohol]] or [[cinnamon]] can increase the probability of an angioedema episode in susceptible patients. If the episode occurs at all after the consumption of these foods, its onset may be delayed overnight or by some hours, making the correlation with their consumption somewhat difficult.


===Acquired angioedema===
The use of [[ibuprofen]] or [[aspirin]] may increase the probability of an episode in some patients. The use of [[acetaminophen]] typically has a smaller, but still present, increase in the probability of an episode.
Acquired angioedema (AAE) can be immunologic, nonimmunologic, or idiopathic.<ref name=Axelrod2011>{{cite journal|last=Axelrod|first=S|author2=Davis-Lorton, M|title=Urticaria and angioedema|journal=The Mount Sinai Journal of Medicine, New York|year=2011|volume=78|issue=5|pages=784–802|pmid=21913206|doi=10.1002/msj.20288}}</ref> It is usually caused by [[allergy]] and occurs together with other allergic symptoms and [[urticaria]]. It can also occur as a side effect to certain medications, particularly [[ACE inhibitor]]s. It is characterized by repetitive episodes of swelling, frequently of the face, lips, tongue, limbs, and genitals. Edema of the gastrointestinal mucosa typically leads to severe abdominal pain; in the upper respiratory tract, it can be life-threatening.<ref>{{cite web|last1=Moon |first1=Amanda T.|last2=Heymann |first2=Warren R.|title=Acquired Angioedema|url=http://emedicine.medscape.com/article/1048887-overview|website=MedScape|access-date=1 October 2015|url-status=live|archive-url=https://web.archive.org/web/20150905111954/http://emedicine.medscape.com/article/1048887-overview|archive-date=5 September 2015}}</ref>


===Hereditary angioedema===
==Therapy==
[[Hereditary angioedema]] (HAE) exists in three forms, all of which are caused by a genetic mutation inherited in an [[Dominance (genetics)|autosomal dominant]] form. They are distinguished by the underlying genetic abnormality. Types I and II are caused by mutations in the ''SERPING1'' gene, which result in either diminished levels of the [[C1-inhibitor]] protein (type I HAE) or dysfunctional forms of the same protein (type II HAE). Type III HAE has been linked with mutations in the ''F12'' gene, which encodes the coagulation protein [[factor XII]]. All forms of HAE lead to abnormal activation of the [[complement system]], and all forms can cause swelling elsewhere in the body, such as the [[digestive tract]]. If HAE involves the [[larynx]], it can cause life-threatening [[asphyxiation]].<ref>{{cite journal |author=Zuraw B.L. |title=Clinical practice. Hereditary angioedema |journal=N. Engl. J. Med. |volume=359 |issue=10 |pages=1027–36 |date=September 2008 |pmid=18768946 |doi=10.1056/NEJMcp0803977}}</ref> The pathogenesis of this disorder is suspected to be related to unopposed activation of the contact pathway by the initial generation of kallikrein and/or clotting factor XII by damaged endothelial cells. The end product of this cascade, bradykinin, is produced in large amounts and is believed to be the predominant mediator leading to increased vascular permeability and vasodilation that induces typical angioedema "attacks".<ref>{{cite web|last=Loew|first=Burr|title=A 68-Year-Old Woman With Recurrent Abdominal Pain, Nausea, and Vomiting|url=http://www.medscape.org/viewarticle/743937_2|publisher=MedScape|access-date=19 October 2012|url-status=live|archive-url=https://web.archive.org/web/20121022004946/http://www.medscape.org/viewarticle/743937_2|archive-date=22 October 2012}}</ref>
=== Allergic angioedema ===
In allergic angioedema, avoidance of the allergen and use of antihistamines may prevent future attacks. [[Cetirizine]], marketed as Zyrtec, is a commonly prescribed antihistamine for angioedema. Some patients have reported success with the combination of a nightly low dose of cetirizine to moderate the frequency and severity of attacks, followed by a much higher dose when an attack does appear. Severe angioedema cases may require desensitization to the putative allergen, as mortality can occur. Chronic cases require [[glucocorticoid|steroid]] therapy, which generally leads to a good response.


==Management==
=== Bradykinin mediated angioedema ===
==== Drug induced angioedema ====
In ACE inhibitor use, the medication needs to be discontinued, and all similar drugs need to be avoided. There is a certain degree of controversy whether [[angiotensin II receptor antagonist]]s are safe in patients with a previous attack of angioedema.
==== Hereditary angioedema ====


=== Allergic ===
In hereditary angioedema, specific stimuli that have previously luxated attacks may need to be avoided in the future.
In allergic angioedema, avoidance of the allergen and use of antihistamines may prevent future attacks. [[Cetirizine]] is a commonly prescribed antihistamine for angioedema. Some patients have reported success with the combination of a nightly low dose of cetirizine to moderate the frequency and severity of attacks, followed by a much higher dose when an attack does appear. Severe angioedema cases may require desensitization to the putative allergen, as mortality can occur. Chronic cases require [[glucocorticoid|steroid]] therapy, which generally leads to a good response. In cases where allergic attack is progressing towards airway obstruction, [[epinephrine]] may be life-saving.{{citation needed|date=March 2023}}


===== Acute treatment =====
=== Drug induction ===
[[ACE inhibitors]] can induce angioedema.<ref name = sabroe /><ref name = israili /><ref>{{cite journal| title = Incidence and characteristics of angioedema associated with enalapril|vauthors=Kostis JB, Kim HJ, Rusnak J, Casale T, Kaplan A, Corren J, Levy E | journal = [[Archives of Internal Medicine]]| date = July 25, 2005 | volume = 165| pages = 1637–42| pmid = 16043683| issue = 14| doi = 10.1001/archinte.165.14.1637| doi-access = free}}</ref> ACE inhibitors block the enzyme [[angiotensin-converting enzyme|ACE]] so it can no longer degrade bradykinin; thus, bradykinin accumulates and can cause angioedema.<ref name = sabroe>{{cite journal | title = Angiotensin-converting enzyme (ACE) inhibitors and angio-oedema|vauthors=Sabroe RA, Black AK | journal = British Journal of Dermatology|date=February 1997| volume = 136| pages = 153–8| pmid = 9068723| issue = 2 | doi = 10.1111/j.1365-2133.1997.tb14887.x}}</ref><ref name = israili>{{cite journal| title = Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology|vauthors=Israili ZH, Hall WD | journal = [[Annals of Internal Medicine]]| date = August 1, 1992 | volume = 117| pages = 234–42| pmid = 1616218| issue = 3| doi = 10.7326/0003-4819-117-3-234|s2cid=41952350 }}</ref> This complication appears more common in [[African-American]]s.<ref>{{cite journal | title = Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema|vauthors=Brown NJ, Ray WA, Snowden M, Griffin MR | journal = Clinical Pharmacologic Therapy|date=July 1996| volume = 60| pages = 8–13| pmid = 8689816| issue = 1 | doi = 10.1016/S0009-9236(96)90161-7|s2cid=12030323 }}</ref> In people with ACE inhibitor angioedema, the drug needs to be discontinued and an alternative treatment needs to be found, such as an [[angiotensin II receptor antagonist|angiotensin II receptor blocker]] (ARB),<ref>{{cite journal| title = Cough and angioedema from angiotensin-converting enzyme inhibitors: new insights into mechanisms and management| last = Dykewicz| first = MS| journal = Current Opinion in Allergy and Clinical Immunology|date=August 2004| volume = 4| pages = 267–70| pmid = 15238791| issue = 4| doi = 10.1097/01.all.0000136759.43571.7f| s2cid = 13313000}}</ref> which has a similar mechanism but does not affect bradykinin. However, this is controversial, as small studies have shown some patients with ACE inhibitor angioedema can develop it with ARBs, as well.<ref>{{cite journal| title = Investigation of angioedema associated with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers|vauthors=Malde B, Regalado J, Greenberger PA | journal = Annals of Allergy, Asthma & Immunology|date=January 2007| volume = 98| pages = 57–63| pmid = 17225721| issue = 1| doi = 10.1016/S1081-1206(10)60860-5}}</ref><ref>{{cite journal| title = Angioedema associated with angiotensin-converting enzyme inhibitor use: outcome after switching to a different treatment|vauthors=Cicardi M, Zingale LC, Bergamaschini L, Agostoni A | journal = [[Archives of Internal Medicine]]| date = April 26, 2004 | volume = 164| pages = 910–3| pmid = 15111379| issue = 8| doi = 10.1001/archinte.164.8.910| doi-access = free}}</ref>
The aim of acute treatment is to halt progression of the oedema as quickly as possible, which can be life-saving, particularly if the swelling is in the larynx. In Germany, most acute treatment consists of C1-INH concentrate from donor blood, which must be administered intravenously. In an emergency, fresh frozen blood plasma, which also contains C1-INH, can also be used. However, in most European countries, C1-INH concentrate is only available to patients who are participating in special programmes. Fresh Frozen Plasma (FFP) can be used as an alternative to C1-INH concentrate.


===== Long-term prophylaxis =====
=== Hereditary ===
In [[hereditary angioedema]] (HAE), specific stimuli that have previously led to attacks may need to be avoided in the future. It does not respond to antihistamines, corticosteroids, or epinephrine. Acute treatment consists of C1-INH (C1-esterase inhibitor) concentrate from donor blood, which must be administered intravenously. In an emergency, fresh frozen blood plasma, which also contains C1-INH, can also be used. However, in most European countries, C1-INH concentrate is only available to patients who are participating in special programmes.{{citation needed | date=May 2017}} The medications [[ecallantide]] and [[icatibant]] may be used to treat attacks.<ref name=Bern2017/> In 2017 these medications cost between 5,700 and 14,000 {{USD}} per dose in the United States, prices that tripled in two years.<ref>{{cite press release |title=Study: Drug Costs for Rare Hereditary Angioedema Disorder Tripled in Two Years|url=http://www.prnewswire.com/news-releases/study-drug-costs-for-rare-hereditary-angioedema-disorder-tripled-in-two-years-300061264.html|website=PR Newswire |language=en|url-status=live|archive-url=https://web.archive.org/web/20151025113056/http://www.prnewswire.com/news-releases/study-drug-costs-for-rare-hereditary-angioedema-disorder-tripled-in-two-years-300061264.html|archive-date=2015-10-25}}</ref>{{Medical citation needed|date=May 2017}} In those given icatibant, specialists monitor is recommended.<ref>{{cite web | title=Angioedema | website=Australasian Society of Clinical Immunology and Allergy (ASCIA) | url=https://www.allergy.org.au/patients/skin-allergy/angioedema | access-date=2020-03-24}}</ref>
Patients in whom episodes occur at least once a month or who are at high risk of developing laryngeal oedema require long-term prophylaxis. This often involves male sex hormones ([[androgen]]s), which increase production of C1-INH in the liver through an as yet unknown mechanism. The dose should be kept as low as possible because of its frequent adverse effects. The use of androgens is particularly problematic in children and they must not be taken during pregnancy. Several cases in which patients developed benign liver tumours during treatment with the androgen danazol resulted in the substance being taken off the market in Germany at the beginning of 2005.


=== Acquired ===
As an alternative, drugs known as fibrinolysis inhibitors, such as [[tranexamic acid]], are used, although their effect is comparatively weak and their potential for side effects is questionable.
In acquired angioedema, HAE types I and II, and nonhistaminergic angioedema, antifibrinolytics such as [[tranexamic acid]] or ε-aminocaproic acid may be effective. [[Cinnarizine]] may also be useful because it blocks the activation of C4 and can be used in patients with liver disease, whereas androgens cannot.<ref>{{cite web|url=http://www.iaari.hbi.ir/journal/archive/articles/v4n3mor.pdf |title=Archived copy |access-date=2007-01-26 |url-status=dead |archive-url=https://web.archive.org/web/20070928044140/http://www.iaari.hbi.ir/journal/archive/articles/v4n3mor.pdf |archive-date=2007-09-28 }}</ref>


===== Short-term prophylaxis =====
=== Prophylaxis ===
Future attacks of HAE can be prevented by the use of androgens such as [[danazol]], [[oxandrolone]] or [[methyltestosterone]]. These agents increase the level of aminopeptidase P, an enzyme that inactivates [[kinins]];<ref>{{cite journal|title=Metallopeptidase activities in hereditary angioedema: effect of androgen prophylaxis on plasma aminopeptidase P|vauthors=Drouet C, Désormeaux A, Robillard J, Ponard D, Bouillet L, Martin L |pmid=18158172|journal=The Journal of Allergy and Clinical Immunology|volume=121|issue=2|year=2008|doi=10.1016/j.jaci.2007.10.048|pages=429–33|display-authors=etal|pmc=4126900}}</ref> kinins (especially bradykinin) are responsible for the manifestations of angioedema.
Short-term prophylaxis is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1-11/2 hours before the procedure. In countries where C1-inhibitor concentrate is not available or only available in an emergency (laryngeal oedema), high-dose androgen treatment is administered for 5-7 days.


In 2018, the U.S. [[Food and Drug Administration]] approved [[lanadelumab]], an injectable [[monoclonal antibody]], to prevent attacks of HAE types I and II in people over age 12. Lanadelumab inhibits the plasma enzyme [[kallikrein]], which liberates the [[kinin]]s bradykinin and [[kallidin]] from their [[kininogen]] precursors and is produced in excess in individuals with HAE types I and II.<ref>{{cite web|url=https://www.drugs.com/newdrugs/fda-approves-takhzyro-lanadelumab-flyo-hereditary-angioedema-4809.html|title=FDA Approves Takhzyro (lanadelumab-flyo) for Hereditary Angioedema|website=Drugs.com}}</ref><ref>{{cite web|url=http://www.medscape.com/viewarticle/901177|title=FDA OKs New Prophylactic Drug for Rare Hereditary Angioedema|website=Medscape}}</ref>
==== New treatment options for HAE ====
Clinical development of several new active substances, which intervene in the disease process in different ways, is currently ongoing.


==Epidemiology==
C1-INH concentrate is not available in the US, so sometimes [[fresh frozen plasma]] is used. C1inh concentrate is currently under late-stage development for both acute and prophylactic use [http://www.levpharma.com]and in [http://www.allabouthae.com/ClinicalStudies/ an acute study]. DX-88 is an inhibitor of kallikrein under development as an [[orphan drug]] for hereditary angioedema [http://www.corporate-ir.net/ireye/ir_site.zhtml?ticker=DYAX&script=410&layout=23&item_id=581050]. [[Icatibant]] is a selective bradykinin receptor antagonist that is due to be marketed as an orphan drug for hereditary angioedema by [[Jerini|Jerini AG]], a German pharmaceutical company. [http://www.pharming.com/index.php?act=prod&pg=1&more=true Pharming], a Dutch biotechnology company, is developing a recombinant C1 inhibitor for acute attacks of hereditary angioedema. Pharming's rhC1INH product and Jerini's Icatibant are currently in phase III development and have [[orphan drug]] status in the US and Europe.
In the U.S., there are as many as 80,000 to 112,000 [[emergency department]] (ED) visits for angioedema annually, and it ranks as the top [[allergic disorder]] resulting in [[hospitalization]].<ref>"Emergency Medicine, Allergy Physicians Partner to Create New Standards" (July 3, 2014). ''UC Academic Health Center''. University of Cincinnati. http://healthnews.uc.edu/news/?/24791/ {{webarchive|url=https://web.archive.org/web/20140714170810/http://healthnews.uc.edu/news/?%2F24791%2F |date=2014-07-14 }}</ref>


==History==
It's important to note that no studies have been done on these agents in relation to HAE Type III.
[[Heinrich Quincke]] first described the clinical picture of angioedema in 1882,<ref>{{cite journal|author=Quincke H|title=Über akutes umschriebenes Hautödem|journal=Monatsh Prakt Derm|year=1882|volume=1|pages=129–131}}</ref> though there had been some earlier descriptions of the condition.<ref>{{WhoNamedIt|synd|482}}</ref><ref>Marcello Donati. De medica historia mirabili. Mantuae, per Fr. Osanam, 1586</ref><ref>J. L. Milton. On giant urticaria. Edinburgh Medical Journal, 1876, 22: 513-526.</ref>


[[William Osler]] remarked in 1888 that some cases may have a hereditary basis; he coined the term "hereditary angio-neurotic edema".<ref>{{cite journal|author=Osler W|title=Hereditary angio-neurotic oedema|journal=Am J Med Sci|year=1888|volume=95|pages=362–67|doi=10.1097/00000441-188804000-00004|issue=2|s2cid=72808776}} Reprint: {{PMID|20145434}}</ref>
====Alternative treatment options for HAE ====
One possible alternative treatment for HAE is a substance called [[epigallocatechin-3-gallate]] (EGCG), which has been shown to inhibit [[kallikrein]]. [[EGCG]] is found naturally in [[green tea]]. Consumption of green tea may be of benefit to sufferes of HAE, however no studies specific to HAE have been conducted. <ref>Fengge Ren, Shaobo Zhang, Susan H Mitchell, Rachel Butler, and Charles YF Young. ''Tea polyphenols down-regulate the expression of the androgen receptor in LNCaP prostate cancer cells.'' Oncogene, 6 April 2000, Volume 19, Number 15, Pages 1924-1932</ref>


The link with C1 esterase inhibitor deficiency was proved in 1963.<ref>{{cite journal |vauthors=Donaldson VH, Evans RR |title=A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C' 1-esterase |journal=Am. J. Med. |volume=35 |pages=37–44 |date=July 1963 |pmid=14046003 |doi= 10.1016/0002-9343(63)90162-1}}</ref>
[[Aloe]] is also a potential treatment due to its inhibitory effects on [[bradykinin]]. <ref>Rocío Bautista-Pérez, David Segura-Cobos and Beatriz Vázquez-Cruz. ''In vitro antibradykinin activity of Aloe barbadensis gel.'' Journal of Ethnopharmacology, Volume 93, Issue 1, July 2004, Pages 89-92.</ref>


The underground rapper [[MF Doom|MF DOOM]] was diagnosed with angioedema in 2020 and later passed from the disease on October 31
==== Acquired angioedema ====
In acquired angioedema, HAE types I and II, and non-histaminergic angioedema, antifibrinolytics such as [[tranexamic acid]] or ε-aminocaproic acid may be effective. [[Cinnarizine]] may also be useful because it blocks the activation of C4 and can be used in patients with liver disease while androgens cannot[http://www.iaari.hbi.ir/journal/archive/articles/v4n3mor.pdf].


==History==
==See also==
* [[Drug-induced angioedema]]
Dr [[Heinrich Quincke]] first described the clinical picture of angioedema in [[1882]]. <ref>Quincke H. ''Concerning the acute localized oedema of the skin.'' Monatsh Prakt Derm 1882;1:129-131.</ref> Sir [[William Osler]] remarked in [[1888]] that some cases may have a hereditary basis; he coined the term ''hereditary angio-neurotic edema''.<ref>Osler W. ''Hereditary angio-neurotic oedema.'' Am J Med Sci 1888;95:362-67.</ref>
* [[Gleich's syndrome]] (unexplained angioedema with high eosinophil counts)
* [[Ruconest]] (C1-inhibitor)


==References==
==References==
{{Reflist}}
<references/>



==External links==
==External links==
* [http://www.haei.org International Patient Organization for C1 inhibitor Deficiencies]
* [https://www.haei.org/patientdiary/ Online Symptom Diary for Patients with Hereditary Angioedema]
* [http://www.hereditaryangioedema.com US Hereditary Angioedema Association]
* [http://www.allabouthae.com All About HAE]


{{Lymphoid and complement immunodeficiency}}
{{Immune disorders}}
{{Consequences of external causes}}
{{Consequences of external causes}}
{{Disorders of volume state}}
{{Medical resources
| DiseasesDB = 13606
| ICD10 = {{ICD10|D|84|1|d|80}}, {{ICD10|T|78|3|t|66}}
| ICD9 = {{ICD9|277.6}}, {{ICD9|995.1}}
| ICDO =
| OMIM = 606860
| OMIM_mult = {{OMIM|106100||none}} {{OMIM|610618||none}}
| MedlinePlus = 000846
| eMedicineSubj = emerg
| eMedicineTopic = 32
| eMedicine_mult = {{eMedicine2|med|135}} {{eMedicine2|ped|101}}
| MeshID = D000799
}}
{{Authority control}}


[[Category:Effects of external causes]]
[[Category:Medical emergencies]]
[[Category:Medical emergencies]]
[[Category:Autoimmune diseases]]
[[Category:Complement deficiency]]
[[Category:Dermatology]]
[[Category:Urticaria and angioedema| ]]
[[Category:Gastroenterology]]
[[Category:Drug eruptions]]
[[Category:Wikipedia medicine articles ready to translate]]

[[Category:Wikipedia emergency medicine articles ready to translate]]
[[bs:Angioedem]]
[[da:Quinckes ødem]]
[[de:Quincke-Ödem]]
[[es:Angioedema]]
[[fr:Œdème de Quincke]]
[[it:Angioedema]]
[[nl:Angio-oedeem]]
[[no:Hereditært angioødem]]
[[sr:Ангиоедем]]

Latest revision as of 03:42, 2 November 2024

Angioedema
Other namesAngiooedema, Quincke's edema, angioneurotic edema
Allergic angioedema: this child is unable to open his eyes due to the swelling.
SpecialtyAllergy and immunology, emergency medicine
SymptomsArea of swelling[1]
Usual onsetMinutes to hours[1]
TypesHistamine mediated, bradykinin mediated[1]
Risk factorsFamily history[2]
Diagnostic methodBased on symptoms[2]
Differential diagnosisAnaphylaxis, abscess, contact dermatitis[2]
TreatmentIntubation, cricothyroidotomy[1]
MedicationHistamine: antihistamines, corticosteroids, epinephrine[1]
Bradykinin: C1 esterase inhibitor, ecallantide, icatibant, fresh frozen plasma[1]
Frequency~100,000 per year (US)[1]

Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes.[1][3] The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs.[1] Often it is associated with hives, which are swelling within the upper skin.[1][3] Onset is typically over minutes to hours.[1]

The underlying mechanism typically involves histamine or bradykinin.[1] The version related to histamine is due to an allergic reaction to agents such as insect bites, foods, or medications.[1] The version related to bradykinin may occur due to an inherited problem known as C1 esterase inhibitor deficiency, medications known as angiotensin-converting enzyme inhibitors, or a lymphoproliferative disorder.[1]

Treatment to protect the airway may include intubation or cricothyroidotomy.[1] Histamine-related angioedema can be treated with antihistamines, corticosteroids, and epinephrine.[1] In those with bradykinin-related disease a C1 esterase inhibitor, ecallantide, or icatibant may be used.[1] Fresh frozen plasma may be used instead.[1] In the United States the disease affects about 100,000 people a year.[1]

Signs and symptoms

[edit]
Angioedema of half of the tongue
Angioedema of the face, most strikingly in the upper lip.

The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue, swell over the period of minutes to hours. The swelling can also occur elsewhere, typically in the hands. The swelling can be itchy or painful. There may also be slightly decreased sensation in the affected areas due to compression of the nerves. Urticaria (hives) may develop simultaneously.

In severe cases, stridor of the airway occurs, with gasping or wheezy inspiratory breath sounds and decreasing oxygen levels. Tracheal intubation is required in these situations to prevent respiratory arrest and risk of death.

Sometimes, the cause is recent exposure to an allergen (e.g. peanuts), but more often it is either idiopathic (unknown) or only weakly correlated to allergen exposure.

In hereditary angioedema (HAE), often no direct cause is identifiable, although mild trauma, including dental work and other stimuli, can cause attacks.[4] There is usually no associated itch or urticaria, as it is not an allergic response. Patients with HAE can also have recurrent episodes (often called "attacks") of abdominal pain, usually accompanied by intense vomiting, weakness, and in some cases, watery diarrhea, and an unraised, nonitchy splotchy/swirly rash. These stomach attacks can last one to five days on average and can require hospitalization for aggressive pain management and hydration. Abdominal attacks have also been known to cause a significant increase in the patient's white blood cell count, usually in the vicinity of 13,000 to 30,000. As the symptoms begin to diminish, the white count slowly begins to decrease, returning to normal when the attack subsides. As the symptoms and diagnostic tests are almost indistinguishable from an acute abdomen (e.g. perforated appendicitis) it is possible for undiagnosed HAE patients to undergo laparotomy (operations on the abdomen) or laparoscopy (keyhole surgery) that turns out to have been unnecessary.

HAE may also cause swelling in a variety of other locations, most commonly the limbs, genitals, neck, throat and face. The pain associated with these swellings varies from mildly uncomfortable to agonizing pain, depending on its location and severity. Predicting where and when the next episode of edema will occur is impossible. Most patients have an average of one episode per month, but there are also patients who have weekly episodes or only one or two episodes per year. The triggers can vary and include infections, minor injuries, mechanical irritation, operations or stress. In most cases, edema develops over a period of 12–36 hours and then subsides within 2–5 days.

Pathophysiology

[edit]

Bradykinin plays a critical role in all forms of hereditary angioedema.[5] This peptide is a potent vasodilator and increases vascular permeability, leading to rapid accumulation of fluid in the interstitium. This is most obvious in the face, where the skin has relatively little supporting connective tissue, and edema develops easily. Bradykinin is released by various cell types in response to numerous different stimuli; it is also a pain mediator. Dampening or inhibiting bradykinin has been shown to relieve HAE symptoms.

Various mechanisms that interfere with bradykinin production or degradation can lead to angioedema. ACE inhibitors block ACE, the enzyme that among other actions, degrades bradykinin. In hereditary angioedema, bradykinin formation is caused by continuous activation of the complement system due to a deficiency in one of its prime inhibitors, C1-esterase (aka: C1-inhibitor or C1INH), and continuous production of kallikrein, another process inhibited by C1INH. This serine protease inhibitor (serpin) normally inhibits the association of C1r and C1s with C1q to prevent the formation of the C1-complex, which - in turn - activates other proteins of the complement system. Additionally, it inhibits various proteins of the coagulation cascade, although effects of its deficiency on the development of hemorrhage and thrombosis appear to be limited.

The three types of hereditary angioedema are:

  • Type I - decreased levels of C1INH (85%);
  • Type II - normal levels, but decreased function of C1INH (15%);
  • Type III - no detectable abnormality in C1INH, occurs in an X-linked dominant fashion and therefore mainly affects women; it can be exacerbated by pregnancy and use of hormonal contraception (exact frequency uncertain).[6] It has been linked with mutations in the factor XII gene.[7]

Angioedema can be due to antibody formation against C1INH; this is an autoimmune disorder. This acquired angioedema is associated with the development of lymphoma.

Consumption of foods that are themselves vasodilators, such as alcoholic beverages or cinnamon, can increase the probability of an angioedema episode in susceptible patients. If the episode occurs at all after the consumption of these foods, its onset may be delayed overnight or by some hours, making the correlation with their consumption somewhat difficult. In contrast, consumption of bromelain in combination with turmeric may be beneficial in reducing symptoms.[8]

The use of ibuprofen or aspirin may increase the probability of an episode in some patients. The use of acetaminophen typically has a smaller, but still present, increase in the probability of an episode.

Diagnosis

[edit]

The diagnosis is made on the clinical picture. Routine blood tests (complete blood count, electrolytes, kidney function, liver enzymes) are typically performed. Mast cell tryptase levels may be elevated if the attack was due to an acute allergic (anaphylactic) reaction. When the patient has been stabilized, particular investigations may clarify the exact cause; complement levels, especially depletion of complement factors 2 and 4, may indicate deficiency of C1-inhibitor. HAE type III is a diagnosis of exclusion consisting of observed angioedema along with normal C1 levels and function.[citation needed]

The hereditary form (HAE) often goes undetected for a long time, as its symptoms resemble those of more common disorders, such as allergy or intestinal colic. An important clue is the failure of hereditary angioedema to respond to antihistamines or steroids, a characteristic that distinguishes it from allergic reactions. It is particularly difficult to diagnose HAE in patients whose episodes are confined to the gastrointestinal tract. Besides a family history of the disease, only a laboratory analysis can provide final confirmation. In this analysis, it is usually a reduced complement factor C4, rather than the C1-INH deficiency itself, that is detected. The former is used during the reaction cascade in the complement system of immune defense, which is permanently overactive due to the lack of regulation by C1-INH.

Angioedema is classified as either hereditary or acquired.

Acquired angioedema

[edit]

Acquired angioedema (AAE) can be immunologic, nonimmunologic, or idiopathic.[9] It is usually caused by allergy and occurs together with other allergic symptoms and urticaria. It can also occur as a side effect to certain medications, particularly ACE inhibitors. It is characterized by repetitive episodes of swelling, frequently of the face, lips, tongue, limbs, and genitals. Edema of the gastrointestinal mucosa typically leads to severe abdominal pain; in the upper respiratory tract, it can be life-threatening.[10]

Hereditary angioedema

[edit]

Hereditary angioedema (HAE) exists in three forms, all of which are caused by a genetic mutation inherited in an autosomal dominant form. They are distinguished by the underlying genetic abnormality. Types I and II are caused by mutations in the SERPING1 gene, which result in either diminished levels of the C1-inhibitor protein (type I HAE) or dysfunctional forms of the same protein (type II HAE). Type III HAE has been linked with mutations in the F12 gene, which encodes the coagulation protein factor XII. All forms of HAE lead to abnormal activation of the complement system, and all forms can cause swelling elsewhere in the body, such as the digestive tract. If HAE involves the larynx, it can cause life-threatening asphyxiation.[11] The pathogenesis of this disorder is suspected to be related to unopposed activation of the contact pathway by the initial generation of kallikrein and/or clotting factor XII by damaged endothelial cells. The end product of this cascade, bradykinin, is produced in large amounts and is believed to be the predominant mediator leading to increased vascular permeability and vasodilation that induces typical angioedema "attacks".[12]

Management

[edit]

Allergic

[edit]

In allergic angioedema, avoidance of the allergen and use of antihistamines may prevent future attacks. Cetirizine is a commonly prescribed antihistamine for angioedema. Some patients have reported success with the combination of a nightly low dose of cetirizine to moderate the frequency and severity of attacks, followed by a much higher dose when an attack does appear. Severe angioedema cases may require desensitization to the putative allergen, as mortality can occur. Chronic cases require steroid therapy, which generally leads to a good response. In cases where allergic attack is progressing towards airway obstruction, epinephrine may be life-saving.[citation needed]

Drug induction

[edit]

ACE inhibitors can induce angioedema.[13][14][15] ACE inhibitors block the enzyme ACE so it can no longer degrade bradykinin; thus, bradykinin accumulates and can cause angioedema.[13][14] This complication appears more common in African-Americans.[16] In people with ACE inhibitor angioedema, the drug needs to be discontinued and an alternative treatment needs to be found, such as an angiotensin II receptor blocker (ARB),[17] which has a similar mechanism but does not affect bradykinin. However, this is controversial, as small studies have shown some patients with ACE inhibitor angioedema can develop it with ARBs, as well.[18][19]

Hereditary

[edit]

In hereditary angioedema (HAE), specific stimuli that have previously led to attacks may need to be avoided in the future. It does not respond to antihistamines, corticosteroids, or epinephrine. Acute treatment consists of C1-INH (C1-esterase inhibitor) concentrate from donor blood, which must be administered intravenously. In an emergency, fresh frozen blood plasma, which also contains C1-INH, can also be used. However, in most European countries, C1-INH concentrate is only available to patients who are participating in special programmes.[citation needed] The medications ecallantide and icatibant may be used to treat attacks.[1] In 2017 these medications cost between 5,700 and 14,000 US$ per dose in the United States, prices that tripled in two years.[20][medical citation needed] In those given icatibant, specialists monitor is recommended.[21]

Acquired

[edit]

In acquired angioedema, HAE types I and II, and nonhistaminergic angioedema, antifibrinolytics such as tranexamic acid or ε-aminocaproic acid may be effective. Cinnarizine may also be useful because it blocks the activation of C4 and can be used in patients with liver disease, whereas androgens cannot.[22]

Prophylaxis

[edit]

Future attacks of HAE can be prevented by the use of androgens such as danazol, oxandrolone or methyltestosterone. These agents increase the level of aminopeptidase P, an enzyme that inactivates kinins;[23] kinins (especially bradykinin) are responsible for the manifestations of angioedema.

In 2018, the U.S. Food and Drug Administration approved lanadelumab, an injectable monoclonal antibody, to prevent attacks of HAE types I and II in people over age 12. Lanadelumab inhibits the plasma enzyme kallikrein, which liberates the kinins bradykinin and kallidin from their kininogen precursors and is produced in excess in individuals with HAE types I and II.[24][25]

Epidemiology

[edit]

In the U.S., there are as many as 80,000 to 112,000 emergency department (ED) visits for angioedema annually, and it ranks as the top allergic disorder resulting in hospitalization.[26]

History

[edit]

Heinrich Quincke first described the clinical picture of angioedema in 1882,[27] though there had been some earlier descriptions of the condition.[28][29][30]

William Osler remarked in 1888 that some cases may have a hereditary basis; he coined the term "hereditary angio-neurotic edema".[31]

The link with C1 esterase inhibitor deficiency was proved in 1963.[32]

The underground rapper MF DOOM was diagnosed with angioedema in 2020 and later passed from the disease on October 31

See also

[edit]

References

[edit]
  1. ^ a b c d e f g h i j k l m n o p q r s t Bernstein, JA; Cremonesi, P; Hoffmann, TK; Hollingsworth, J (December 2017). "Angioedema in the emergency department: a practical guide to differential diagnosis and management". International Journal of Emergency Medicine. 10 (1): 15. doi:10.1186/s12245-017-0141-z. PMC 5389952. PMID 28405953.
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